Pneumocystis jirovecii is an opportunistic fungus that causes PCP in immunocompromised individuals. PCP is a serious problem in immunocompromised who are not received prophylaxis.
Pneumocystitis organisms have been identified in most mammalian species. They include a broad family of organisms, with species specificity among their mammalian hosts.
Transmission
Human to human .. airborne infection
Or environmental, but environmental source is unknown
Non human are not the source, it is species specific.
Human hosts can be infected with more than one strain of PJ leading to latent infection
The clinical disease PCP may occur as a reactivation of a prior latent or as a recent acquisition of an airborne pathogen.
Drug treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines,atovaquone and macrolides.
First drug used successfully for treatment was pentamidine
Then the studies showed that combination of Trimethoprim-sulfamethoxazole is effective in treatment and prophylaxis of murine then human PCP and is as effective as IV pentamidine.
TMP-SMX is still the treatment of choice and the most effective chemo prophylaxis for PCP.
The widespread use of TMP-SMX and dapsone for therapy and prophylaxis among HIV patients has led to the concern that sulfa resistance could develop in P.jirovecii.
Sulfonamide resistance is caused by mutation in the primary sequence of the DHPS gene. The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at position 55 and 57.
DHPS mutations of codon 55 and 57 are implicated in the failure of low dose sulfaprophylaxis , but there is no firm evidence that DHPS mutations result in significant resistance to high dose sulfa therapy.
However, it is possible that if additional mutations arise,then high level sulfa resistance could emerge and lead to diminished efficacy of TMP-SMX. This would be loss of the most efficient and inexpensive therapy for PCP.
In other fungal infections, clinical resistance is classically defined as the persistence or progression despite the administration of appropriate antimicrobial treatment. However, persistence of Pneumocystis organisms may happen in spite of a successful treatment response and the host inflammatory response, rather than resistance to antimicrobial drug treatment, may cause an apparent absence of response to treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides
Sulfonamide Resistance is due to the widespread use of TMP–SMX and dapsone for therapy and prophylaxis of P. jirovecii, malaria and bacterial infection in Africa.
In San Francisco, the increasing use of PCP prophylaxis among HIV patients led to a marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and seven genera of Enterobacteriaceae. In pathogens such as Escherichia coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene .the available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. However, the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides. Despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR . although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical signifi cant resistance to DHFR inhibitors.
Post-transplantation, kidney transplant patients are prescribed TMP-SMX prophylaxis. The treatment by blocking dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
Treatment for PCP:
sulfadiazine + pyrimethamine
Sulfamethoxazole +trimethoprim
Penthamidine
Dapsone + pyrimethamine
Clindamycin +primaquine
Atovaquone
Resistance
Sulfonamide resistance
DHFR resistance
What is the level of evidence provided by this article?
Level 5
Introduction:
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodeficiencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen, but increased after AIDS discovery. Organism:
The Organism Pneumocystis were identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini. These investigators mistakenly considered the organisms as a new form of Trypanozoma cruzi. In 1912, Pneumocystis was recognized as a new species and named in honor of Carini . Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug.
Drug Treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides. Sulfonamide Resistance
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
In 1997, Lane and co-workers were the first to identify nonsynonymous (resulting in changes in the encoded amino acid) DHPS mutations in Pneumocystis jirovecii. The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).
Conclusion: In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis. Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
PCP is an opportunistic infection that carries a high mortality rate among immunosuppressed and HIV patients who are not on appropriate chemoprophylaxis.
-Antifolate drugs: inhibition of dihydropteroate reductase (DHPR)-TMP/SMT is the drug of choice
-Pentamidine It’s 2nd line after TMP/SMT- in patients with sulfa sensitivity.
-Clindamycin–primaquine DHFR Resistance
-Trimetrexate
-Atovaquone
-Pentamidine and Clindamycin–Primaquine
It is now known that P. jirovecii mutations related to sulfa and atovaquone medication resistance have arisen as a result of selective pressure from the widespread use of PCP prophylaxis, notwithstanding the difficulty to culture the organisms. The clinical impact of the disclosed mutations currently appears to be minimal.The failure of low-dose sulfaprophylaxis is linked to DHPS mutations at codons 55 and 57, however there is no conclusive proof that DHPS mutations cause significant resistance to high-dose sulfa treatment. However, it’s probable that if more mutations occur, high-level sulfa resistance could appear and reduce TMP-SMX’s efficacy. This would result in the loss of the most effective and affordable treatment for PCP.
The danger of high-level resistance developing could be significantly increased by the growing HIV epidemic and the use of TMP-SMX in developing nations.As a result, research into medication resistance mechanisms and the identification of new molecular targets is ongoing.The completion of the Pneumocystis Genome Project, which was started in 1997, is a promising development. For the genomes of P. carinii , complete physical maps and gene sequences are being determined. The identification of new polymorphic areas and therapeutic targets, as well as the potential construction of a culture system, will all be made possible by these data, which are essential for advancing our understanding of the illness.
Its narrative review (level 5) was published in January 2009 In the book Antimicrobial Drug Resistance discussing PCP and pathogen-related mutation in the DHPD gene which results in only a reduction in sulfa drug sensitivity. Introduction – PCP is a serious opportunistic infection that carries a high mortality rate among immunosuppressed and HIV patients who are not on appropriate chemoprophylaxis. PCP was re-classified as fungi that have only one copy of the nuclear ribosomal RNA locus surrounded by a fragile cell wall.
– There is no cross-species infection and the organism infecting humans was renamed Pneumocystis jirovecii. Transmission and Infection –Most likely it’s an airborne pathogen but reactivation of latent organisms is still suspected in immunocompromised hosts. Drug Treatment -The major drug classes used for the treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides. 1. Antifolate drugs: these blocks the de novo synthesis of folates through the inhibition of dihydropteroate reductase (DHPR), which catalyzes (PABA) to produce dihydropteroate. Sulfa drugs are structural analogs of PABA and inhibit DHPS.TMP/SMT is the drug of choice 2. Pentamidine is an IV drug that needs to be administrated on a monthly basis associated with hypoglycemia and nephrotoxicity, pancreatitis, and IDDM. Hypotension with short infusion time, pancytopenia, and Q-T prolongation. It’s 2nd line after TMP/SMT, especially in patients with sulfa sensitivity. 3. Dapsone: it should not be used alone for treatment. Usually used as Dapsone–trimethoprim combination. There are cross-reacts with sulfa in 50% of allergic patients which is why it’s not offering any advantages over TMP–SMX. 4. Clindamycin–primaquine in moderate- to-severe PCP has an equivalent effect with TMP–SMX. 5. Atovaquone; This is a good alternative to TMP–SMX for patients with mild disease only who cannot tolerate TMP–SMX. Sulfonamide Resistance Double DHPS mutations (Thr55Ala and Pro57Ser) result in a reduction in sulfa drug sensitivity that’s why the only clinical significance of DHPS mutations will be in prophylaxis regimens. Therapy using a sulfa-based regimen has been controversial. . there is a clear association between previous exposure to sulfa drugs and DHPS mutations have been shown in all studies. DHFR Resistance 1. Trimetrexate is much more potent against PCP than trimethoprim in vitro so a combination of trimetrexate and sulfamethoxazole may be a good option but there is no clinical data to support this. 2. Atovaquone: Competitively binds to the cytochrome bc1 complex. It can be used for DHPS mutations but mutation in cytochrome bc complex may confer resistance to atovaquone. Pentamidine and Clindamycin–Primaquine: Resistance mechanisms not yet
Introduction:
Pneumocystis jirovecii, previously known as Pneumocystis carinii, is a fungal pathogen that causes pneumonia in immunocompromised patients. Despite a reduction in its incidence due to prophylaxis and antiretroviral therapy, Pneumocystis pneumonia (PCP) remains a serious opportunistic infection among heavily immunosuppressed individuals. This article discusses various aspects of Pneumocystis jirovecii, including its discovery, transmission, clinical manifestations, and treatment.
Pneumocystis jirovecii was first discovered in guinea pigs and rat lungs in the early 20th century. Its identification as a human pathogen occurred in 1942, and in 2002, it was officially named Pneumocystis jirovecii. The organism is believed to have a tropism for the lungs and is predominantly found in the alveoli.
Transmission and Infection:
Primary infection with Pneumocystis jirovecii is thought to occur during early childhood, and the organism is considered ubiquitous. The exact source of infection is unknown, but it is hypothesized to be an environmental source. Infection may correlate with respiratory symptoms or sudden infant death syndrome. It is possible for individuals to be infected with multiple strains of Pneumocystis jirovecii, leading to latency with different organisms.
Prophylaxis and Treatment:
Pneumocystis jirovecii has limited susceptibility to traditional antifungal agents, and initial drug testing focused on drugs with activity against protozoan infections. Trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly used and effective therapy for both treatment and prophylaxis of PCP. Other drug classes used include antifolate drugs, diamines, atovaquone, and macrolides.
Prophylaxis against PCP is crucial, particularly in high-risk populations such as organ transplant recipients and individuals receiving high-dose steroid treatment or chemotherapy. TMP-SMX is the preferred prophylactic regimen, while alternative regimens include dapsone, pentamidine, and atovaquone. Untreated PCP is almost always fatal, and the first-line treatment is trimethoprim-sulfamethoxazole. Alternative treatment options include dapsone plus trimethoprim, clindamycin plus primaquine, pentamidine, and atovaquone.
There are concerns about the development of sulfa resistance in Pneumocystis jirovecii due to the widespread use of sulfonamide drugs for PCP treatment and prophylaxis. Resistance to sulfonamides can limit their efficacy. Additionally, resistance to DHFR inhibitors, such as trimethoprim, has emerged in various bacterial and parasitic species. However, the occurrence of resistance in Pneumocystis jirovecii is relatively low.
Limitations of the Study:
Studying drug resistance in Pneumocystis jirovecii is challenging due to the absence of a culture system for susceptibility testing. The lack of a consistent definition for clinical failure and the difficulty in assessing non-adherence to prophylaxis pose additional challenges. Treatment of PCP can also be associated with side effects, making it challenging to differentiate between treatment-related effects and persistent infection.
Level of Evidence:
This article provides Level V evidence.
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).DHPS catalyzes the condensation of p-aminobenzoic acid (PABA) and hydroxymethyl dihydropterin–pryophospate to produce dihydropteroate, which is later converted to dihydrofolate by dihydrofolate synthase. Subsequently, dihydrofolate is reduced by dihydrofolate reductase (DHFR) into tetrahydrofolate. Sulfa drugs are structural analogs of PABA and inhibit DHPS.
Sulfonamide Resistance-
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.. A clear association between previous exposure to sulfa drugs (primarily for prophylaxis rather than therapy) and DHPS mutations has been shown in all studies.. Large geographical variation in the prevalence of DHPS mutations has been reported, ranging from 7 to 69% of isolates. The clinical significance of DHPS mutations, specifically with regard to response to prophylaxis and therapy using a sulfabased regimen (primarily trimethoprim– sulfamethoxazole or dapsone), has been controversial. Several studies have reported a significant association of DHPS mutations with failure of low-dose sulfa prophylaxis However, the extent to which this association refl ects actual drug resistance or failure to comply with prescribed prophylaxis is unknown.Hence, in spite of the emergence of mutant DHPS strains, current clinical experience supports the efficacy of trimethoprim– sulfamethoxazole prophylaxis when taken regularly. Available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. However, the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
While initial case reports suggested that patients with mutant DHPS strains had increased risk of failing sulfa therapy or prophylaxis , subsequent studies have not supported such a conclusion.Moreover, even in studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprim– sulfamethoxazole or dapsone–trimethoprim. These observations suggest that the currently identifi ed DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
The diaminopyrimidines, trimethoprim and pyrimethamine,are competitive inhibitors of dihydrofolate reductase (DHFR).In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical signifi cant resistance to DHFR inhibitors.
Atovaquone
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia sp. Development of atovaquone resistance can occur after selective pressure is exerted.. Survival from PCP did not differ between patients with or without mutations.
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
What is the level of evidence provided by this article?
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodefi ciencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen. However, with the AIDS pandemic PCP emerged as the most common AIDS-defi ning diagnosis in industrialized countries. The peak incidence of PCP was observed in the late 1980s and early 1990s. Subsequently, there has been a decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens. However, PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis. Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no fi rm evidence that DHPS mutations result in signifi cant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished effi – cacy of TMP–SMX. This would lead to the loss of the most effi cient and inexpensive therapy for PCP. The increasing HIV epidemic and use of TMP–SMX in the third world may signifi cantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identifi cation of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Complete physical maps and gene sequences are being determined for the genomes of P. carinii (111). These data will be crucial for further understanding of the infection and will enable identifi cation of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
Summary :
Pneumocystis jirovecii is ubiquitous fungus which causes opportunistic infection (Pneumocystis pneumonia – PCP), in the immunocompromised. Pneumocystis jirovecii infection when acquired, can remain latent for long time. The clinical presentation may appear due to reactivation of previous latent infection, or due to new acquisition of an airborne pathogen. Drug treatment:
First line – Trimethoprim-sulfamethoxazole.
Alternative protocol: Dapsone + Trimethoprim. Clindamycin + Primaquine, Pentamidine, Atovaquone.
Resistance to sulphonamide:
– use of sulfa drugs for malaria and bacterial infections in Africa led to high incidence of resistance in P. falciparum and several bacterial species
– Mutations related to resistance are located in a highly conserved active site of the DHPS protein.
Resistance of DHFR :
The diaminopyrimidines; trimethoprim & pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) that is related to catalysis of reduction of inactive 7,8-dihyfrofolate to the active form 5,6,7,8- tetrahydrofolate with presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used combined with sulfonamides.
It is not clear whether high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors.
Atovaquone:
Atovaquone is used for prevention and treatment of disease caused by P. jirovecii, Plasmodium spp, Toxoplasma gondii and Bebesia spp .Structurally ,it is similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex. Studies involving Plasmodium and Toxoplasma showed that these mutations lead to resistance to atovaquone. Studies of cytochrome b gene of Pneumocystis, were in harmony with the development of atovaquone resistance
Pentamidine – Primaquine – Clindamycin:
No resistance mechanisms have yet to been reported. Conclusion
DHPS mutations at codon 55 and 57 are involved in the failure of low-dose sulfa prophylaxis, but no solid evidence that DHPS mutations cause significant resistance to high-dose sulfa therapy. However, it is probable that if more mutations occur, high-level sulfa resistance could develop and result in reduced efficacy of TMP–SMX. This could lead to not using the most efficient and inexpensive therapy for PCP.
The increasing HIV incidence and use of TMP–SMX in the third world may markedly lead to increase of the risk for the development of high-level resistance. So, studies of the mechanisms of drug resistance and detection of new molecular targets are needed. A potential advance will be the achievement of the Pneumocystis Genome Project.
-Level of evidence: V .
This article has a narrative theme, and is based on drug resistance in pneumocystis jirovecii. In the past, PCP was a rare infection, however, after the spread of HIV AIDs, this infection has become more prevalent, causing severe respiratory distress and eventually death. However, chemoprophylaxis has a good outcome when fighting against PCP.
Discussion
There are four different classes of drugs that can be used in treatment and prophylaxis of PCP. These include
antifolate drugsdiaminesatovaquonemacrolidesThe specific drugs under these classes that can be used along with their dosage includes :
Trimethoprim-sulfamethoxazole OD – single or double doseDapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorine 25 mg weeklyDapsone 200 mg weekly + pyrimethamine 75 mg weekly + leucovorin 25 mg weeklyatovaquone 1500 mg dailyOutbreaks of PCP can be controlled with sulfadoxine plus pyrimethamine.
Other than HIV, other factors such as organ transplant, high dose steroids and high dose chemotherapy can increase the risk of PCP.
The most effective and safe prophylactic regimen is daily TMP-SMX. However, it can be toxic in 25-50% of patients. Adverse effects include fever, rashes and leucopenia, with possibility of anaphylaxis in some patients. Hyperkalemia is also a concern which should be monitored for in these patients. Hepatotoxicity is seen in some patients, in which case we can see elevated transaminases. More serious possible complications include pancreatitis, Stevens Johnson syndrome, interstitial nephritis, and renal calculus formation.
Atovaquone is generally well tolerated in comparison with TMP SMX, but is only available orally. It can be used for patients with mild disease.
The common use of TMP SMX has led to sulfonamide resistance. Mutations in the DHPS gene, in nucleotide positions 165 and 171 leading to amino acid position changes at 55 and 57. These mutations are found in patients with previous exposure to sulfa drugs, which suggests person to person spread of mutant strains.
It is possible that DHPS mutations are due to low dose sulfa prophylaxis. DHPS mutations may be an independent predictor of decreased survival in PCP patients.
The other mutation possible leading to antibiotic resistance is DHFR gene mutation. However, this is not thought to be impacted heavily by use of trimethoprim or pyrimethamine.
Nonadherence to medication during the prophylactic phase can be a big reason for failure of prophylaxis. This can lead to bad outcome post transplant for both the graft and the patient. Monitoring may be essential in more rapid intervals for patients who are suspected of non adherence to medication.
Conclusion
PCP is a fatal disease if not treated adequately. Adherence to treatment regimen along with completion of treatment will allow better chances for success in infection resolution. In addition, kidney transplant patients may need lowering of immunosuppressive drug doses in order to allow PCP to resolve satisfactorily. The best method would be to prevent the infection from impacting the patient in the first place, through aggressive prophylaxis for 3 to 6 months post kidney transplant.
Level of evidence:
This is a narrative study, and this level of evidence is 5.
Introduction:
Pneumocystis jiorveci is serious infection cause pneumonia in immunocompromised patients. The peak incidence of infection appear in 1980-1990 but in recent years it is decline because introduction of prophylaxis of PCP and treatment of HIV-1 antiviral therapy. Microorganisms:
Pneumocystis jirovecii previously named as Pneumocystis carinii and classified as a protozoa. Currently, it is considered a fungus based on nucleic acid and biochemical analysis and named as P. jirovecii organism. Transmission and Infection:
It’s type of fungus, Environmental cause of pneumocystis still not identified and transmission from person to persons by air. Drug Treatment:
The main drug used in prophylaxis of pneumocystis jiorvecii is:
Antifolate drugs
Diamines
Atovaquone
Macrolides
In 1958, the first drug of choice was pentamidine isethionate.
In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystosis in Iran.
In 1966, sulfadiazine and pyrimethamine was used as trials.
Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP. TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
These drugs like sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine shows effective therapy against pneumocystis jiorvecii. Not all drugs are effective for therapy it’s also effective for chemoprophylaxis.
Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis. Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
There are some drugs have activity in vitro like azithromycin, doxycycline, and caspofungin. Prophylaxis:
Patients with HIV
Congenital immunodeficiency
Patients with long term corticosteroids
Patients on chemotherapy such as fludarabine, ATG.
Primary prophylaxis should be considered in patients with HIV-1 with candidiasis or CD4 count less than 200 cell/ul.
Secondary prophylaxis against PCP should be considered in all patients exposed to PCP.
In non-HIV infected individuals, conditions such as organ transplantation, high dose steroid treatment and/or high dose chemotherapy may has high risk of PCP. Prophylaxis should be stared.
The best one and cheaper is TMP–SMX.
Dose of TMP–SMX (septrin), 400/80 mg daily is effective and is associated with few side effects than 160/800mg daily.
Side effects of septrin is skin rash, fever, anemia , neutropenia Hyperkalemia Hepatitis Nephritis and Anaphylactoid reaction. Treatment of PCP:
PCP is serious condition may be fatal if not treated. Mortality rate reached to 30-40% of cases and to 70-80% in cases with respiratory failure. adjuvant steroid to patients with moderate to severe PCP with PaO2 of less than 70mmHg or patients with HIV with CD4 less than 200cell/ ul. The treatment of PCP should be stared as early as possible even symptoms non specific ( dry cough, low grade fever and dyspnea), with presence of risk factors in immunocompromised patients or chest X ray abnormal and the first drug of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase or dihydrofolate reductase.
Pentamidine is very toxic associated with nephritis and pancreatitis and hypoglycemia and it’s may prolongs the QT interval, and cause torsades de pointe in some reported cases.
Alternative to o septrin and pentamidine include dapsone pyrimethamine, clindamycin primaquine, and atovaquone.
Clindamycin associated with high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
Atovaquone is used alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Dapsone pyrimethamine is used in mild to moderate cases with PCP.
Many patients shows progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration is caused by the drug induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. This inflammation can be reduced by corticosteroids. Sulfonamide Resistance:
Resistance develop due to wide use of septrin as prophylaxis and treatment of PCP, Falciparum malaria and bacterial infection. There’s marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and Enterobacteriaceae. This resistance against bacterial infection occur due to mutations of primary sequence of the DHPS gene. Many clinical studies investigated the frequency and significance of DHPS mutation in P jiorvecii. There’s large geographical variations in resistance to sulfa associated with DHPS mutations and some studies shows significant association with the failure of pyrimethamine–sulfadoxine prophylaxis and the Pro57Ser mutation. Also the major cause of resistance is poor adherence to chemoprophylaxis and mutation of DHPS. DHFR Resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR); so mutations to DHFR in Pneumocystis DHFR lead to resistance septrin but still no definitive evidence. Atovaquone:
It’s used to treat and prevent P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. It’s structural near to mitochondrial protein and competitively binds to the cytochrome bc1. However mutations of cytochrome bc1 gene in Plasmodium spp., Toxoplasma gondii and Pneumocystis leading to unresponse to Atovaquone but Survival from PCP did not differ between patients with or without mutations. Pentamidine and Clindamycine–Primaquine:
Pentamidine and clindamycine primaquine are used for prevention and treatment of PCP, and resistance to these agents can be happen but still rare.
What is the level of evidence provided by this article?
Drug Resistance in Pneumocystis jirovecii Jannik Helweg-Larsen, Thomas Benfi eld, Joseph Kovacs, and Henry Masur Summary of the article: Introduction: Pneumocystis jirovecii (previously known as Pneumocystis carinii) is ubiquitous fungus that causes opportunistic pulmonary infection (Pneumocystis pneumonia – PCP), in immunocompromised patient. Pneumocystis jirovecii infection can be acquired on multiple occasions, remain latent for long time. The clinical disease may occur as reactivation of prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Drug used for PCP: 1st line – Trimethoprim-sulfamethoxazole. Alternative regimen: Dapsone + Trimethoprim. Clindamycin + Primaquine, Pentamidine, Atovaquone. Sulphonamide resistance: TMP-SMX for prophylaxis and treatment of PCP has raised the development of sulfa (sulfonamide or sulfone) resistance. – use of sulfa drugs for malaria and bacterial infections in Africa has resulted in high rates of resistance in P. falciparum and many bacterial species – the mutations that confer resistance are located within a highly conserved active site of the DHPS protein. DHFR resistance: The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) which catalyses the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides. Whether high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors, is not clear. Atovaquone: Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp, Toxoplasma gondii and Bebesia spp. It is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex. Studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone. Studies of cytochrome b gene of Pneumocystis, were consistent with the development of atovaquone resistance Pentamidine – Primaquine – Clindamycin: Possible resistance mechanisms have yet to be discovered and reported. Conclusion DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP. The increasing HIV epidemic and use of TMP–SMX in the third world may significantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Level of evidence: Level of evidence is 5 – (narrative study)
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. It was diagnosed among patients with congenital immunodeficiencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen, however, with the AIDS pandemic PCP emerged. Subsequently, there has been a decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens . But, PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
P. jirovecii organism cannot be cultured in vitro, knowledge about its biology has been diffi cult to obtain. Antibody and PCR fi ndings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extrapulmonary sites.
DRUGS AND TREATMENTS
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
– TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
– Dapsone has not been studied as a single drug and thus should not be used alone for treatment. Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX. However, since this combination does not come as a fixed dose combination, is only available orally, and cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP–SMX.
– Clindamycin–primaquine appears to work on a metabolic pathway different from that of TMP–SMX. Two comparative trials of clindamycin/primaquine with TMP–SMX in moderate to severe PCP demonstrated apparent equivalence for clindamycin–primaquine, but both trials were underpowered
– Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX.
PROPHLAXIS
Are patients at risk for developing PCP:
– Among HIV-infected patients, the occurrence of PCP is closely related to the CD4 count: With lower CD4 counts, the risk of PCP increases. While a count of 200 cells/mm3 is often used as an indicator or susceptibility.
– Patients with congenital immunodefi ciencies ( particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID)
– patients receiving long-term and high-dose corticosteroid therapy,
– patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation;
The most effi cient, cheap and widely used regimen is daily TMP–SMX. This prophylaxis is relatively well tolerated by most non-HIV patients; in contrast, HIV patients have a high frequency of adverse effects, in particular rash and myelosuppression. Fortunately, 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily.
RESISTENCE
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
Several clinical studies have investigated the frequency and signifi cance of DHPS mutations in P. jirovecii, reporting frequencies of mutations in sulfa-exposed and sulfa-unexposed patients. Mutations have rarely been found in clinical isolates obtained prior to the early 1990s, but seem to have increased in frequency recently, presumably as a consequence of increasing selective pressure caused by the widespread use of sulfa drugs for prophylaxis. These observations suggest that the currently identifi ed DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors, however, despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR.
What is the level of evidence provided by this article?
For most of the twentieth century, Pneumocystis was considered as a protozoan. However, in 1988, based on the work by Edman and colleagues, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.
In 1994, an interim trinomial name change was adopted with the name P. carinii f.sp. hominis for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats.
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides .
Most traditional antifungal agents have no activity against Pneumocystis. As Pneumocystis was originally believed to be a protozoon.
Pentamidine was the first used drug for successful treatment of PCP in 1958.
In the 1960s, sulfadoxine and pyrimethamine as combination was used for the prevention of epidemic infantile pneumocystosis in Iran .
In 1966, Rifkind treated two patients with sulfadiazine and pyrimethamine; both patients died, but two patients were successfully treated 4 years later.
Between 1974 and 1977, studies led by Hughes et al. established that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP.
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Also TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore used for prevention.
despite this some drugs can develop resistance like:
1- Sulfonamide Resistance.
2- DHFR Resistance
Introduction:
PCP is an oppurtunistic fungus that causes pneumonia… PCP in immunocompromised host can cause Pneumonia… It used to be on of AIDS defining illness… It is a serious oppurtunistic infection and the incidence is on the decreasing trend in the last few years due to institution of all prophylaxis agents …
Originally PCP was mistaken for Trypanazoma…. It was described in humans in 1942 and was then on known to be protozoan organism….Genetic analysis and antigenic analysis have shown that Pneumocystis includes a broad family of organisms with species specificity among the mammalian host….The Organism was renamed as Pneumocystitis Jiroveci in honor of Jirovec, who was first to describe the microbe in humas…
It is a difficult organism to isolate by cultures and invitro techniques….Biopsy specimens have to be stained with special stains like Geimsa stain, toulidiene blue and Calcoflour white for demonstration…antibody and PCR techniques indicate that infection happens in childhood … PCP has specific tropism for lungs and it lives in the alveoli….It is rare that it is found in other organs…The Major surface glycoprotein found on the organism attaches firmly to the alveoli… There are known asexual and sexual life cycle of the organism described….
Treatment:
Makor drug classes used for treatment and prophylaxsis of PCP are antifolate drugs, Diamines, Atovaquone and macrolides..
Pentamidine esthionate was the first drug used to treat PCP… Most of the drugs used for treatment of PCP are effective for prophylaxis also except intravenous pentamidine and clindamycin – primaquine are not used for prophylaxsis
Prophylaxsis:
Systemic chemoprohylaxis agaisnt PCP was introduced in 1950 and became a standard of care for HIV infected patients in 1989.. Secondary prophylaxsis should be offered after an episode of PCP to prevent re infection.. In kidney transplant patients all patients are offered prophylaxis against PCP in the form of Trimethoprim sulfamethoxazole SS daily or double strength tablet alternate day…
Alternative drugs for prophylaxis are Dapsone 50mg twice daily or 100 mg twice weekly….Dapsone 50mg daily with pyrimethamine 50mg plus leucovorin 25mg weekly, Dapsone 200 mg weekly with pyremethamine 75mg weekly plus leucovorin 25 mg weekly or aerosolized pentamidine 300mg via a nebulizer…
Treatment of PCP:
Untreated PCP is fatal, but the improved mortality rates have been achieved is used to better treatment facilities in the last 2 decades…
TMP-SMX is the first line of treatment of choice for PCP…. 2 DS tablets every 8th hourly is the most common dose used….the commenst side effect is due to sulfa allergy and skin rash…. Intravenous Trimethoprim 5mg/kg with sulfamethoxazole 20mg/kg is used in severe cases…
If the patient is allergic to TMP-SMX, Available options are Dapsone 100mg Plus trimethoprim 320mg every eight hourly both used per orally, clindamycin 300-450mg every 6th hourly plus primaquine intravenous 30mg daily has been used….Intravenous Pentamidine 4mg/kg day has been used but there is high incidence of adverse events like rash, hepatotoxicity and neutropenia..
Atovoquone 750mg twice daily is also well tolerated….
wide spread use of TMP-SMX and dapsone among HIV patients has led to sulfanomide resistance could develop in P.Jirovecii…. Non synonomous DHPS mutations in pneumocystis and Sacchormyces have been found to be in increasing frequency… Studies show that DHPS mutations contribute to low level sulfa resistance.. but poor adhrence to chemoprophylaxsis is one of the reasons for sulfonamide resistance…
DHFR resistance: Trimethoprim and pyrimethamine are competitive inhibitors of DHFR which catalyzes the reduction of dihydrofolate to tetrahydrofolate…DHFR resistance is widespread but few mutations are identified in pneumocystis DHFR….
Atovoquone binds to cytochrome BC1 complex and disrupts the electron transport chain…Resistance to clindamycin primaquine and Atovoquone have not yet been reported..
but the lack of in vitro culture system makes evaluation of drug resistance in PCP difficult….Non adherence to prophylaxsis is the most important reason for PCP failure rather than evolution of drug resistance…
Atovaquone binds to the cytochrome bc1 complex and disrupts electron transport, leading to depletion of ATP and killing of Pneumocystis
The level of evidence is 5 ..It is a narrative review
●Pneumocystis was recognized as a new species and named in honor of Carini
●It was first described in humans in 1942
●Pneumocystis was first established as a human pathogen when Jirovec in 1952
●in 1988, analysis of (rRNA) and observations of genome size placed P. carinii in the fungal kingdom.
● It has recently been placed in a group of fungi Archiascomycetes.
Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall
● in 2002,the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec,
●It cannot be cultured in vitro
● primary infection with P. jirovecii happens in early childhood
● clinical infection was a result of reactivation in immunocompromised hosts.
●primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome
●human hosts can be infected with more than one strain of Pneumocystis jirovecii,
●nonhuman animals are not the source
Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
●the organism attaches tightly to the surface of type I alveolar cells
● Adherence is primarily mediated by the (MSG)
●MSG shows high level of antigenic variation by switching the expression of multiple MSG genes, with a system that resembles the antigenic system used for antigenic variation in Trypanozoma cruzi
●It is likely that this antigenic variation in MSG serves for avoiding the host immune response.
Drug Treatment
The major drug classes used for treatment and prophylaxis of PCP include
1- antifolate drugs,
2- diamines,
3- atovaquone, and
4- macrolides
□ Pentamidine isethionate was the fi rst drug used to successfully treat PCP
□Between 1974 and 1977, studies led by Hughes et al. established that the combination of (TMP–SMX) is effective for both treatment and prophylaxis
□Other drugs have proven activity for therapy,
sulfadiazine plus pyrimethamine,
atovaquone,
clindamycin plus pyrimethamine,
trimetrexate,
dapsone and aerosolized pentamidine.
effective for prophylaxis
1- Dapsone,
2- dapsone trimethoprim,
3- atovaquone and aerosolized pentamidine
There are other drugs that have in vitro activity or anecdotal anti-PCP activity in humans
1- azithromycin,
2- doxycycline,
3- caspofungin.
Prophylaxis
With lower CD4 counts, the risk of PCP increases. a count of 200 cells/mm3 is often used as an indicator.
●In HIV patients receiving prophylaxis; prophylaxis can safely be interrupted if immune function is improved above a CD4 count of 200 cells/μL for at least 3 months following antiretroviral therapy.
● In non-HIV infected individuals, conditions such as organ transplantation, Prophylaxis should be offered . daily TMP–SMX.
80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
Treatment of PCP
●Corticosteroids to patients with moderate-to-severe PCP as defi ned by a PaO2 of less than70 mmHg,
●Both patients and health care professionals must recognize that mild symptoms such as dyspnea, cough, or low-grade fever can be the initial manifestation of PCP
1—– □The most potent drugs for PCP treatment are antifolate drugs,
2—- □The earliest clinical trials to treat PCP were performed with sulfadiazine plus pyrimethamine
□TMP–SMX and pentamidine appear to have roughly comparable effi cacy
Adverse effects
generally occur after 7 days of therapy
● most commonly include rash, fever and leukopenia.
● Hepatotoxicity [ elevated transaminases ]
●Trimethroprim can be associated with hyperkalemia
●Stevens–Johnson syndrome have occurred.
● rapid infusions of pentamidine were associated with hypotension and death, so this route of administration was abandoned.
● Pentamidine is nephrotoxic (glomerular and tubular damage) and it is toxic to the pancreas;
●Pentamidine prolongs the QT interval, and cases of torsades de pointe
3—- □dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone
4—- □Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
Primaquine can only be given orally.
Atovaquone is also only available orally,
Effi cacy of dapsone–pyrimethamine has only been demonstrated for mild-to-moderate PCP
atovaquone only for mild PCP
Sulfonamide Resistance
●Widespread use of sulfa drugs has produced high rates of resistance
●In Pneumocystis, the DHPS protein is part of a trifunctional protein that together are encoded by the multidomain FAS gene
●The most frequent DHPS mutations occur at nucleotide positions 165 and 171
● these variants appear to represent true mutations rather than allelic polymorphisms.
Either mutation can occur alone.
● Using this model, two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance
● a summary of the studies reporting frequencies of mutations in sulfa-exposed and sulfa-unexposed patients.
● a clear association between previous exposure to sulfa drug and DHPS mutations has been shown in all studies.
●The prevalence of DHPS mutations ranging from 7 to 69% of isolates.
In the US, the incidence of mutations was lower in Indianapolis and Denver compared to San Francisco 《80%》
Wide variations have also been observed in studies from Europe with a particularly low incidence in Italy (8% frequency)
● DHPS mutations have also been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
● The emergence of DHPS mutations appears to be specifi c for P. jirovecii
●Several studies have reported a signifi cant association of DHPS mutations with failure of low-dose sulfa prophylaxis
●Hence, in spite of the emergence of mutant DHPS strains, current clinical experience supports the effi cacy of TMP-SMX prophylaxis when taken regularly.
● Some observations suggest that the currently identifi ed DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
■ diaminopyrimidines, trimethoprim and pyrimethamine,
■They are used in combination with sulfonamides.
■Ma and Kovacs observed that the human Pneumocystis-derived DHFR had ~10-fold increase in sensitivity than rat
■ Trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively
■ there are currently no clinical data to support the combination of trimetrexate and sulfamethoxazole
■ In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
■only relatively few DHFR mutations have been identifi ed in Pneumocystis DHFR
■Ma et al. detected only a single synonymous DHFR mutation in specimens obtained from 32 patients, of whom 22 had previous exposure to TMP–SMX therapy or prophylaxis
■In studies, patients were successfully treated with TMP–SMZ.
In conclusion, although
♤Nahimana et al.
♤A South African study
,♤ Matos and coworkers
studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical signifi cant resistance to DHFR inhibitors.
Atovaquone
○It is used to prevent and treat disease.
○ It is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q),
○Introduction of mutations near the binding pocket led to decreased activity of atovaquone
○Introduction of seven mutations
Results from two clinical studies have been published.
■In the fi rst, Three of four patients receiving atovaquone as prophylaxis demonstrated such variations.
Notably, two of them had mutation .
.
■In the second study, a nested case- control study, signifi cantly more patients who previously had been exposed to atovaquone (5 of 15 patients) had mutations compared to unexposed patients
■ Five different mutations near the ubiquitol pocket were described bringing the total number to seven.
■Overall, these fi ndings are consistent with the development of atovaquone resistance after selective pressure is exerted.
Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine
are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Limitations
●there exists no in vitro culture system for propagation of Pneumocystis
● no consistent defi nition of clinical failure exists
●contribution of nonadherence in presumed failure of prophylaxis may be diffi cult to assess.
1. Please summarise this article. Pneumocystis jirovecii has remain a serious opportunistic infection and has been the main stay in loss of graft function in renal transplantation. Since 1980s and 1990 the PCP has higher incidence of infection, then it was seen decreasing trend with better use of prophylaxes. Transmission and infection; PCP is a ubiquitous organism, the primary infection occurs mostly in childhood, and spread by healthy humans. The primary infection can manifest in child hood with upper and lower respiratory infection and infant death syndrome, because it has specific tropism for lung parenchyma and alveoli. There is no such detailed life cycle of PCP, mode of transmission, but both sexual and asexual cycles have been proposed, and suggest sexual replication with in the lungs with environmental changes in the lung like immunosuppression. Drug treatment; In 1958, pentamidine was the first drug used successfully to treat PCP. The major classes of drugs used for treatment of the PCP included anti-folate, diamines, atovaquone, and microlides. In 1960s, the combination of sulfadoxine and pyriamide used in Iran. In 1974-1977, TMP-SMX used effectively, and since now the most effective drug being used. Other drugs being used are dapsone, aerosolized pentamidine, clindamycine plus pyeramethamine. The mortality has decreased in recent decade’s up-to 10 to 15% due to prophylaxes and treatment, otherwise, there was 70-90% mortality. Due to better diagnostic tools, early treatment and use of corticosteroids use. Prophylaxes; Opportunistic infection has been the main stay of mortality in immunocompromissed patients and loss of graft function in renal transplantation. Chemoprophylaxis was initially used by Dutz by 1950s in Iran. In high risk patients with HIV, and other immunosuppressive medication for SOT are at high risk for PCP. Conclusion; There is no firm evidence that DHPS mutation has result in significant resistance and failure, however, there is possible codon 55-57 mutation. Pneumocystis genome project started at 1997, its completion may enable for some new prophylaxes, understanding, and identification of new polymorphism. Level of evidence V
Introduction
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodefi ciencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen.
The Organism
Pneumocystis was fi rst described in humans in 1942 by two Dutch investigators, van der Meer and Brug, who described it in three cases: a 3-month-old infant with congenital heart disease and in 2 of 104 autopsy cases – a 4-month-old infant and a 21-year-old adult
Pneumocystis organisms have been identifi ed in most mammalian species in which it has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species specifi city among its mammalian hosts
Transmission and Infection
It was previously though that the infection was carried life-long and that clinical infection was a result of reactivation in immunocompromised hosts. PCR fi ndings have questioned this view and support a more complex picture of transmission and infection.
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms .The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Drug Treatment
In 1958, pentamidine isethionate was the fi rst drug used to successfully treat PCP
In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystosis in Iran
In 1966, Rifkind treated two patients with sulfadiazine and pyrimethamine; both patients died, but two patients were successfully treated 4 years later
(TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis. There are other drugs that have in vitro activity or anecdotal anti-PCP activity in humans and could have a role in managing human disease if all other alternatives were not feasible. These include azithromycin, doxycycline, and caspofungin.
Prophylaxis
Patients with congenital immunodefi ciencies, particularly
X-linked immunodefi ciency with hyper-immunoglobulin M and SCID, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP.
Systemic chemoprophylaxis against PCP was introduced by Dutz in Iran in the early 1950s. He showed that outbreaks of PCP could be aborted with the use of sulfadoxine plus pyrimethamine . Hughes et al. followed this observation with a classic study of children with acute lymphocytic leukemia (ALL); they showed that PCP could be virtually eliminated by TMP–SMX prophylaxis
In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP. Prophylaxis should be offered
Treatment of PCP
Untreated PCP is invariably fatal. In the beginning of the HIV epidemic, the mortality rate of PCP was reported to be 30–40% increasing to 70–90% among patients who progressed to respiratory failure
Over the past decade, mortality rates have dropped to 5–15%
The importance of educating patients to seek medical attention early, when symptoms are still mild, must be an emphasis of patient management programs. Both patients and health care professionals must recognize that mild symptoms such as dyspnea, cough, or low-grade fever can be the initial manifestation of PCP, especially in patients with CD4+ T lymphocyte counts below 200 cells/mm3
The choice of specifi c chemotherapy is also important. The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
The earliest clinical trials to treat PCP were performed with sulfadiazine plus pyrimethamine on the assumption that these drugs would have synergistic action against pneumocystis, as against plasmodia.
Pentamidine is associated with a high frequency of toxicities, some of which are treatment-limiting. Early experiences with rapid infusions of pentamidine were associated with hypotension and death, so this route of administration was abandoned. Intramusuclar injections were better tolerated in terms of blood pressure, but they caused a high frequency of sterile abscesses.
Alternatives for the therapy to TMP–SMX and pentamidine include dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone
Trimetrexate has activity, but is no longer commercially available. Dapsone has not been studied as a single drug and thus should not be used alone for treatment. Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX. However, since this combination does not come as a fi xed-dose combination, is only available orally, and cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP–SMX.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX
This is a good alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Many patients experience progressive oxygen desaturation during the fi rst 4–5 days of therapy. This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar infl ammation. This infl ammation can be reduced by corticosteroids. Four randomized, controlled trials demonstrated that corticosteroids could reduce mortality in patients with moderate or severe disease
On the basis of these results, adjunctive steroids are now recommended for all patients with severe disease (PaOs
< 70 mmgh).
Sulfonamide Resistance
In many pathogenic bacteria and parasites, resistance to sulfonamides has increased as a consequence of selective pressure, and has limited the effi cacy of sulfonamides
Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many bacterial species
In pathogens such as Escherichia coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene
In 1997, Lane and co-workers were the fi rst to identify nonsynonymous (resulting in changes in the encoded amino acid) DHPS mutations in Pneumocystis jirovecii
Large geographical variation in the prevalence of DHPS mutations has been reported, ranging from 7 to 69% of isolates. In the US, the incidence of mutations was lower in Indianapolis and Denver compared to San Francisco, where one study reported that more than 80% of patients were infected with mutant strains
Wide variations have also been observed in studies from Europe with a particularly low incidence in Italy; in one study, an 8% frequency of mutations was found among 107 HIV patients between 1994 and 2001
DHFR Resistance
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
Recently, Ma and Kovacs evaluated the activity of DHFR inhibitors by using a yeast assay expressing P. jirovecii DHFR and observed that the human Pneumocystis-derived DHFR had ~10-fold increase in sensitivity to trimetrexate and trimethoprim compared to rat Pneumocystis-derived DHFR. For the human Pneumocystisderived DHFR yeast strain, trimethoprim and pyrimethamine were both weak inhibitors, with IC50 s in the micromolar
range; trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively (Table 5). Given that trimetrexate is much more potent against PCP than trimethoprim in vitro, the combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.
South African study found nonsynonymous DHFR mutations in samples obtained between 2001 and 2003 in 3 of 27 patients. None had long-term exposure to TMP–SMX before developing PCP
Finally, Matos and coworkers from Portugal recently reported a 27% rate of DHFR Atovaquone (2-[trans-4-(4´-chlorphenyl)cyclohexyl]-3-hydroxy1,4-hydroxynaphthoquinone) is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.mutations in 128 PCP episodes, without association to failure of PCP prophylaxis
Atovaquone
Atovaquone is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q), and competitively binds to the cytochrome bc1
complex. The bc1 complex catalyzes electron transfer from ubiquinone
to cytochrome c and thereby proton translocation across the mitochondrial membrane resulting in the generation of ATP.
Results from two clinical studies have been published. In the fi rst, sequencing of the cytochrome b gene of Pneumocystis from ten patients showed sequence variations in four patients .Three of four patients receiving atovaquone as prophylaxis demonstrated such variations. Notably, two of them had nonsynonymous changes leading to amino acid substitutions within the ubiquitol pocket. Similar mutations in other microorganisms are associated with resistance to atovaquone. One patient, who had not received atovaquone prophylaxis, had a synonymous change that did not confer any change in amino acid sequence.
Conclusion
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no fi rm evidence that DHPS mutations result in signifi cant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished effi cacy of TMP–SMX. This would lead to the loss of the most effi cient and inexpensive therapy for PCP.
The increasing HIV epidemic and use of TMP–SMX in the third world may signifi cantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identifi cation of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997.
Summary :
Introduction:
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised patient.
P. jirovecii organisms are ubiquitous.Pneumocystis jirovecii infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms. The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Drug used for PCP :1st line :Trimethoprim-sulfamethoxazole. Alternative regimn:Dapsone plus trimethoprim.Clindamycin plus primaquine ,Pentamidine,Atovaquone.
Sulphonamide resistance:
TMP-SMX for prophylaxis and treatment of PCP has raised the development of sulfa (sulfonamide or sulfone) resistance.
– use of sulfa drugs for malaria and bacterial infections in Africa has resulted in high rates of resistance in P. falciparum and many bacterial species
– the mutations that confer resistance are located within a highly conserved active site of the DHPS protein.
DHFR resistance: The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and c ertain amino acids. They are used in combination with sulfonamides. There is no data that using high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors.
Atovaquone
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. Atovaquone is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex..Studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.Studies of cytochrome b gene of Pneumocystis, were consistent with the development of atovaquone resistance
Pentamididine-Primaquine -clindamycine:
Possible resistance mechanisms have yet to be discovered and reported.
Level of evidence :
This is a narrative study, and this level of evidence is 5
This article has a narrative theme, and is based on drug resistance in pneumocystis jirovecii. In the past, PCP was a rare infection, however, after the spread of HIV AIDs, this infection has become more prevalent, causing severe respiratory distress and eventually death. However, chemoprophylaxis has a good outcome when fighting against PCP.
Discussion
There are four different classes of drugs that can be used in treatment and prophylaxis of PCP. These include
antifolate drugsdiaminesatovaquonemacrolidesThe specific drugs under these classes that can be used along with their dosage includes :
Trimethoprim-sulfamethoxazole OD – single or double doseDapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorine 25 mg weeklyDapsone 200 mg weekly + pyrimethamine 75 mg weekly + leucovorin 25 mg weeklyatovaquone 1500 mg dailyOutbreaks of PCP can be controlled with sulfadoxine plus pyrimethamine.
Other than HIV, other factors such as organ transplant, high dose steroids and high dose chemotherapy can increase the risk of PCP.
The most effective and safe prophylactic regimen is daily TMP-SMX. However, it can be toxic in 25-50% of patients. Adverse effects include fever, rashes and leucopenia, with possibility of anaphylaxis in some patients. Hyperkalemia is also a concern which should be monitored for in these patients. Hepatotoxicity is seen in some patients, in which case we can see elevated transaminases. More serious possible complications include pancreatitis, Stevens Johnson syndrome, interstitial nephritis, and renal calculus formation.
Atovaquone is generally well tolerated in comparison with TMP SMX, but is only available orally. It can be used for patients with mild disease.
The common use of TMP SMX has led to sulfonamide resistance. Mutations in the DHPS gene, in nucleotide positions 165 and 171 leading to amino acid position changes at 55 and 57. These mutations are found in patients with previous exposure to sulfa drugs, which suggests person to person spread of mutant strains.
It is possible that DHPS mutations are due to low dose sulfa prophylaxis. DHPS mutations may be an independent predictor of decreased survival in PCP patients.
The other mutation possible leading to antibiotic resistance is DHFR gene mutation. However, this is not thought to be impacted heavily by use of trimethoprim or pyrimethamine.
Nonadherence to medication during the prophylactic phase can be a big reason for failure of prophylaxis. This can lead to bad outcome post transplant for both the graft and the patient. Monitoring may be essential in more rapid intervals for patients who are suspected of non adherence to medication.
Conclusion
PCP is a fatal disease if not treated adequately. Adherence to treatment regimen along with completion of treatment will allow better chances for success in infection resolution. In addition, kidney transplant patients may need lowering of immunosuppressive drug doses in order to allow PCP to resolve satisfactorily. The best method would be to prevent the infection from impacting the patient in the first place, through aggressive prophylaxis for 3 to 6 months post kidney transplant.
Level of evidence
This is a narrative study, and this level of evidence is 5.
DRUG RESISTANCE IN PJP
BACKGROUND
PCP can’t be cultured in lab
we have limited knowledge of metabolic pathways so drug development is empirical
NO clear definition of clinical failure , meaning PCP can persist in body samples even after successful treatment
Host inflammatory response, rather than resistance to antimicrobial drug treatment, can mimic like absence of response
Fever can be due to ongoing PCP or adverse reaction to drugs
prophylaxis
with TMP-SMX
1DS /SS daily
DS 3 PER WEEK
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone with pyrimethamine and leucoverin / prednisolone
Atovaquone 750 mf twice a day
Pyrimethamine and sulfadiazine
TREATMENT
MECHANISM- ANTIFOLATE
inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
DRUGS
TMP-SMX
DAPSONE IN COMBINATION
CLINDAMYCIN AND PRIMIQUINE
STERIOD IF PO2 less than 70 mm hg on room air
DRUG RESISTANCE
Mutation in DHPS gene is common at codon 55 and 57 ( associated with failure of low dose sulfonamide)
but its clinical relevance is poor as mutated PCP also respond to TMP-SMX
CD4 count is good indicator for susceptibility in HIV and not in organ transplants
DHFR mutation is known but clinically it is not significant when PCP is treated with antifolate drugs
ATOVAQUONE
similar to ubiquinone
survival in patient with mutation is similar , suggesting no clinical significance
CLINDAMYCIN AND PRIMIQUINE
resistance pathways are yet to be known
Drug Resistance in Pneumocystis jirovecii 1 Introduction
· The peak incidence of PCP was observed in the late 1980s and early 1990s then declined after introduction of PCP chemoprophylaxis and potent HIV-1 antiretroviral regimens
· PCP still a serious opportunistic infection in heavily immunosuppressed patients who were not given appropriate chemoprophylaxis. 2 The Organism
· Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug
· Pneumocystis was first established as a human pathogen by Jirovec in 1952
· Pneumocystis was considered as a protozoon until 1988, it was placed in the fungal kingdom
· In contrast to most other fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
· The organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, in 2002. 3 Transmission and Infection
· Primary infection with P. jirovecii happens in early childhood and P. jirovecii organisms are ubiquitous.
· Recent data suggests that human hosts can be infected with more than one strain of P. jirovecii.
· Pneumocystis has specific tropism for the lung, where it exists in the alveoli.
· After inhalation, the organism attaches tightly to the surface of type I alveolar cells
4 Drug Treatment
· Hughes et al. found that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP
· TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
· Other drugs have proven activity for therapy: sulfadiazine + pyrimethamine, atovaquone, clindamycin + pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
· Other alternative drugs: azithromycin, doxycycline, and caspofungin.
5 Prophylaxis
· HIV-1 infected patients with oral candidiasis or a CD4 count less than 200 cells/μL, should be offered primary prophylaxis.
· all patients following an episode of PCP should be given secondary prophylaxis
· In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP
· The most efficient, cheap and widely used regimen is daily TMP–SMX
· 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
6 Treatment of PCP
· The most potent drugs for PCP treatment are antifolate drugs
· TMP–SMX found to have better survival than pentamidine but comparable efficacy
· Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX
· Alternatives for the therapy to TMP–SMX and pentamidine include dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone
· Two comparative trials of clindamycin/primaquine with TMP–SMX in moderate-to-severe PCP demonstrated apparent equivalence for clindamycin–primaquine
· Atovaquone is well tolerated but less effective than TMP–SMX and an alternative to patients with mild disease who cannot tolerate TMP–SMX.
· HIV-negative patients should receive 2 weeks and HIV-positive patients three weeks of drug treatment.
· Oxygen desaturation due to alveolar inflammation can be reduced by corticosteroids.
· Adjunctive steroids should be given for all patients with severe disease (PaOs < 70 mmgh).
7 Sulfonamide Resistance
· The use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to resistance to sulfa
· In Africa the use of sulfa drugs for malaria and bacterial infection produced high rates of resistance in P. falciparum and many bacterial species
· In some pathogens, resistance to sulfa is caused by mutations in the primary sequence of the DHPS gene
· The mutations that confer resistance are localized within a highly conserved active site of the DHPS protein.
8 DHFR Resistance
· The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of DHFR
· In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
· Inspite of DHFR mutations, there is no evidence that the widespread use of trimethoprim or pyrimethamine have caused clinically significant resistance to DHFR inhibitors.
8.1 Atovaquone
· is used to prevent and treat diseases caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp
· Mutations of the cytochrome b gene have been identifi ed in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
· Studies found that atovaquone resistance has developed
9 Pentamidine and Clindamycine–Primaquine
· Are used for prevention and treatment of PCP, with possible resistance
10 Conclusion
· mutations involved in sulfa and atovaquone drug resistance have occured in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
· DHPS mutations at codon 55 and 57 are involved in in the failure of low-dose sulfaprophylaxis, but not high dose.
· The use of TMP–SMX in the third world for HIV epidemic may increase the risk for the development of high-level resistance.
· Pneumocystis Genome Project is promising
PCP is a fungus that mostly affects HIV +VE pts and those who are immunocompromised like post transplant pts esp those not not on prophylactic medications.
THE ORGANISM.
P .Carinni f.sp hominis affects humans while P Carinni f.sp carinni infects rats.PCP is pneumocystis jirovecii after Otto Jiroveci who was amongst its pioneer investigators.
TRANSMISSION AND INFECTION.
-Primary infection occurs in early childhood ,becomes latent and later manifests once immunity is compromised. The source of infection is not clear.
-PCP mostly infects and causes pulmonary manifestation with rare extrapulmonary manifestation. PCP lifecycle and replication mode not clear.
DRUG TX.
-Septrin is effective in tx and prophylaxis as parenteral pentamidine and is the treatment of choice.
-Other tx choices ; sulfadiazine + pyrimethamine, atovaquone, clindamycin +pyrimethamine, trimetrexate, dapsone and aerolized pentamidine.
-IV pentamidine and clindamycin – primaquine are not effective chemoprophylaxis.
PROPHYLAXIS.
-In HIV,CD4 <200 increases risk of PCP, other risk factors include ;congenital immunodeficiencies, SCID, long term steroids use and pts on certain chemotherapeutic meds(fludarabine ,ATG)
-In HIV ,prophylaxis is given until CD4 > 200 for at least 3/12.Post transplant it is given for a minimum of 6/12 post sx with possibility of increasing to at least 1 year depending on malignancy and level of immunosuppression.
-Septrin is the cheapest, most available and effective regimen.
-Other options for prophylaxis ; dapsone, dapsone + pyrimethamine+ leucovorine, aerolized pentamidine, atovaquone and pyrimethamine + sulfadiazine.
SULFONAMIDE RESISTANCE.
-This could be secondary to increased use of septrin and dapsone for tx and prophylaxis in PCP in pts with HIV.
-DHPS mutation and non adherence to treatment could lead to resistance and breakthrough PCP respectively.
-PCP infection in those with DHPS mutation have responded to higher doses of septrin or dapsone-trimethoprim signifying that this mutation confers low level sulfa resistance.
DHFR RESISTANCE.
-Despite the aforementioned being seen in studies, we are yet to have enough evidence that widespread use of trimethoprim or pyrimethamine has caused significant DHFR inhibitor resistance.
ATOVAQUONE.
-A number of mutations have been shown to confer resistance to atovaquone but this hasn’t been extensively studied in PCP and has not affected outcome in PCP tx in the few studies done.
● Pneumocystis jirovecii is An opportunistic fungus causes pneumonia in immunocompromised individuals with peak incidence in AIDS pandemic
● Primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome
● Following primary infection it becomes latent, and later manifesting clinically if the patient becomes immunosuppressed.
● Human can be infected with more than one strain of Pneumocystis jirovecii
● The clinical disease may be a reactivation or as acquisition infection
● It has specific tropism “alveoli in lung” although it may detected in other organs, it seldom causes disease at these sites.
● After inhalation it attaches to surface of alveolar cells and adherence by MSG resulting in antigenic variation in MSG that avoiding it the host immune response.
● The organism has a sexual replication cycle that responds to environmental changes in the lung
Drug Treatment
● The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides
● TMP–SMX is effective for both treatment and prophylaxis and is still the treatment of choice.
● Other drugs as sulfadiazine plus pyrimethamine, atovaquone, clindamycin
plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
● Not all drugs that are effective for therapy are also effective for prophylaxis.
● Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis.
● IV pentamidine and clindamycin–primaquine aren’t effective for prophylaxis.
Prophylaxis
● The risk of PCP increases with CD4 lower than 200 cells/mm3 in HIV-infected patients
● High risk patients for PCP :
☆ Congenital immunodeficiencies “hyper-immunoglobulin M and SCID ”
☆ Long-term and high-dose Steroid therapy
☆ Chemotherapeutic regimens for cancer and therapy or transplantation
☆ Some chemotherapeutic agents such as fludarabine or antithymocyte globulin
● In patients without HIV, CD4 counts are not a reliable marker of susceptibility
● Secondary prophylaxis should be offered to all patients following an episode of PCP.
● In HIV patients prophylaxis can safely be interrupted if CD4 count above 200 cells/μL for at least 3 months and should be restarted if antiretroviral therapy fails to increase CD4 above 200 cells/μL
● TMP–SMX is efficient, cheap , and well tolerated by non-HIV patients regimen in contrast, HIV patients have a high frequency of adverse effects
● 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
Treatment of PCP
● Mortality rate of PCP is 30–40% and 70–90% in patients with respiratory failure
● Treatment decreases mortality rates to 5–15%
● Educating patients is essential in management programs.
● TMP–SMX and pentamidine appear to have comparable efficacy
● AEs occur after 7 days of therapy and include rash, fever, Hepatotoxicity and leukopenia.
● SMX can induce interstitial nephritis, renal calculus , anaphylactoid reactions and pancreatitis
● TMP associated with hyperkalemia.
● Stevens–Johnson syndrome have occurred and it may be fatal
● Hypoglycemia can occur after starting therapy, or few days after stopping therapy
● Dapsone–trimethoprim is effective
● Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX it is available only orally
● Recommendations for optimal duration of therapy for PCP are :
☆ HIV-negative patients need 2 weeks
☆ HIV-positive patients need three weeks
● A djunctive steroids are recommended for patients with severe disease (PaOs < 70 mmgh)
● Causes of Sulfonamide Resistance :
☆ The widespread use of TMP–SMX for therapy and prophylaxis of PCP
☆ Mutations in the primary sequence of the DHPS gene
☆ Person-to-person spread of mutant strains
☆ Poor adherence
● Pneumocystis can not be cultured because functional enzymes are unavailable
● An association between previous exposure to sulfa drugs and DHPS mutations has been shown
● DHPS mutations implicated in failure of low-dose sulfa prophylaxis, but not high-dose sulfa therapy. But if additional mutations arise, then high-level sulfa resistance could emerge
● The majority of patients with mutant DHPS strains have been treated with trimethoprimsulfamethoxazole or dapsonetrimethoprim successfully .
● Combination of trimetrexate and sulfamethoxazole is a more potent than trimethoprim plus sulfamethoxazole.
Atovaquone
● It is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
● Pentamidine and Clindamycine–Primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have discovered
Limitations to the study of drug resistance in Pneumocystis
● Absence of a culture system impeded investigations into the mechanisms of drug resistance.
● Most drug development has been empiric as knowledge of the metabolic pathways is limited,
● Experimental mainly relied on immuno-suppressed animal
● There is no consistent definition of clinical failure exists.
● Clinical resistance definition is problematic when applied to PCP because
* Persistence of Pneumocystis organisms
may happen in spite of a successful treatment response.
* Host inflammatory response, rather than resistance to antimicrobial as a severe inflammatory response with respiratory distress, rather than drug resistance, may cause treatment failure.
* Treatment of PCP is associated with a high incidence of AEs
– PCP is a serious opportunistic infection among
immunocompromised patients not receiving chemoprophylaxis
The organism
– pneumocystis carinii belongs to the fungal kingdom and because of its genetic and functional distinctness, the organism infecting man was renamed pneumocystis jirovecii
Transmission and infection
– P. jirovecii is ubiquitous and primary infection occurs in early childhood
– human hosts can be infected by more than one strain of P. jirovecii
– this suggests that PCP can occur as a reactivation of a prior latent organism or as a result of a recently acquired airborne pathogen
– pneumocystis has specific tropism for the lung, it exists in the alveoli, it seldom causes extrapulmonary disease
– following inhalation, the organism attaches tightly to type I alveola cell surface mediated by the major surface glycoprotein (MSG)
– MSG has antigenic variation enabling the organism to escape the host immune response
– the life cycle and mode of replication remains unknown
Drug treatment
– the major classes of drugs used in the treatment and prophylaxis of PCP include antifolate drugs, atovaquone, diamines, macrolides
– trimethoprim-sulfamethoxazole (TMP-SMX) is effective for both prophylaxis and treatment of PCP
– TMP-SMX is as effective as pentamidine and is the most effective/ drug of choice for PCP chemoprophylaxis
– other drugs with activity for therapy against PCP include atovaquone, sulfadiazine plus pyrimethamine, clindamycin plus pyrimethamine, dapsone, aerosolized pentamidine, trimetrexate
– not all drugs used in therapy are effective in chemoprophylaxis
– dapsone, atovaquone, dapsone-primaquine, aerosolized pentamidine are also effective for chemoprophylaxis
– clindamycin-primaquine and IV pentamidine are not effective for chemoprophylaxis
– azithromycin, caspofungin, doxycycline can be considered if other alternatives are not feasible
Prophylaxis
– immunocompromised patients are at an increased risk of developing PCP
– use of ATG portends a higher risk of PCP than other induction regimens
– secondary prophylaxis should be offered following an episode of PCP
– TMP-SMX is the most efficient, cheap and widely used chemoprophylaxis regimen
Treatment of PCP
– if left untreated, PCP is invariably fatal
– prompt initiation of treatment, use of adjuvant corticosteroids in patients with moderate-to-severe PCP (i.e., PaO₂ <70mmHg), better diagnostic tools, therapeutic strategies and improved ICU care has improved the outcomes
– the most potent therapeutic agents for PCP treatment are antifolate drugs
– TMP-SMX is associated with a better survival than pentamidine but both are equally efficacious
– sulfamethoxazole can cause interstitial nephritis and renal calculi
– trimethoprim is associated with hyperkalemia
– pentamidine is nephrotoxic and causes predictable glomerular and tubular damage
– alternatives to TMP-SMX and pentamidine include: – atovaquone, dapsone-pyrimethamine, clindamycin-atovaquone
– trimetrexate is no longer commercially available
– dapsone should not be used as a single agent – no studies to support its use as a single drug
– dapsone-trimethoprim is effective and has similar potency as TMP-SMX; however, it is not available as a single pill and it cross-reacts with sulfa in 50% of allergic patients hence it does not offer many advantages over TMP-SMX
– clindamycin-primaquine is an alternative therapy which acts on a metabolic pathway different from that of TMP-SMX
– Atovaquone is well tolerated, but is not as potent as TMP-SMX, it acts on a metabolic pathway different from that of TMP-SMX, is available as an oral formulation, it is a good alternative for patients with mild PCP who cannot tolerate TMP-SMX
– dapsone-pyrimethamine is efficacious in mild-to-moderate PCP, is administered orally
– optimal duration of PCP treatment has never been well studied but the recommendations suggest 2 weeks for HIV negative patients and 3 weeks for HIV positive patients
– drug-induced death of the pneumocystis organisms causes exacerbation of alveolar inflammation resulting in progressive oxygen desaturation in the first 4-5 days of therapy
– this alveolar inflammation can be reduced by use of corticosteroids
– corticosteroids reduce mortality in patients with moderate or severe PCP therefore, corticosteroids are recommended for all patients with severe disease i.e., PaO₂ <70mmHg
Sulfonamide resistance
– use of TMP-SMX for prophylaxis and treatment of PCP has raised concerns about development of sulfa (sulfonamide or sulfone) resistance in P. jirovecii
– use of sulfa drugs for malaria and bacterial infections in Africa has resulted in high rates of resistance in P. falciparum and many bacterial species
– the mutations that confer resistance are located within a highly conserved active site of the DHPS protein
DHFR resistance
– trimethoprim and pyrimethamine are competitive inhibitors of DHFR (dihydrofolate reductase)
– only few DHFR mutations have been identified in pneumocystis
– there is no evidence that widespread use of trimethoprim or pyrimethamine cause emergence of clinically significant resistance to DHFR inhibitors
Atovaquone
– used for prophylaxis and treatment of P. jirovecii, Plasmodium spp, T. gondii and Bebesia spp
– mutations of the cytochrome b gene have been identified in pneumocystis, plasmodium spp and toxoplasma
– these mutations confer mutations to atovaquone
Pentamidine and clindamycin-primaquine
– are used for prophylaxis and treatment of PCP
– possible resistance mechanisms are yet to be discovered
Conclusion
– selective pressure following widespread use of PCP prophylaxis has led to mutations involved in sulfa and atovaquone drug resistance in P. jirovecii
– DHPS mutations have been implicated in the failure of low-dose sulfa prophylaxis but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy
– with additional mutations, high-level sulfa resistance can emerge leading to reduced efficacy of TMP-SMX – can result in the loss of the most efficient and cheap therapy for PCP
– increased use of TMP-SMX in the HIV population increases the risk of high-level resistance
– completion of the pneumocystis genome project will provide data that will enhance further understanding of the infection
Summary: · Pneumocystis jirovecii is an opportunistic fungus; causes pneumonia in immunocompromised individuals like AIDS, transplant recipients and congenitally immune deficients. · Source unknown, more than one genotype might infect human being in several times and could stay latent for long time. Reactivated when there is immunosuppression of the host. · Reservior is uncertain, it might be the infected humen being or trees and grass shedding the fungus. · Once it enters in to the body through respiratory tract, it dwells in type I alveolar cells attached to its surface, leading to pneumonia in immunocompromised. · Prophylaxis: TMP-SMX DS (TMP 160+ SMX 800) or SS(TMP 80+ SMX 400) daily · Treatment: sensitive to antifolate , atovagoune and Macrolides. It was found that Trimethoprim-Sulfamethoxazol is the most effective in prophylaxis and treatment , by inhibiting dihydrofolate reducatse enzymes DHFR and dihydrofolate synthase enzyme. · In conclusion it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
Organism
PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis. In 1988, based on the work by Edman and colleagues, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.In 2002, because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii.
Transmission and Infection
-Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood.
-The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
-Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs,
-After inhalation, the organism attaches tightly to the surface of type I alveolar cells.
-Adherence is primarily mediated by the major surface glycoprotein
Prophylaxis
-TMP–SMX is still the treatment of choice.
-Dapsone, dapsone– trimethoprim, atovaquone, leucovorine and aerosolized pentamidine are also effective for prophylaxis.
-Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
Special risk factor
-With lower CD4 counts, the risk of PCP increases. While a count of 200 cells/mm3 is often used as an indicator or susceptibility,
-Fludarabine or ant thymocyte globulin produce a much higher risk of PCP than other regimens.
Treatment of PCP First choice Trimethoprim– sulfamethoxazole TMP–SMX was associated with a better survival than pentamidine. Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Trimethroprim can be associated with hyperkalemia. Alternatives Dapsone plus trimethoprim Clindamycin plus primaquine Pentamidine Atovaquone Adjunctive therapy Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
Sulfonamide Resistance
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa resistance could develop in P. jirovecii.
In San Francisco, the increasing use of PCP prophylaxis among HIV patients led to a marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and seven genera of Enterobacteriaceae.
DHPS
Several clinical studies have investigated the frequency and significance of DHPS mutations in P. jirovecii. a clear association between previous exposure to sulfa drugs (primarily for prophylaxis rather than therapy) and DHPS mutations has been shown in all studies.
Studies suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinically significant resistance to DHFR inhibitors.
Atovaquone resistance
-Mutations of the cytochrome b gene have been identified in Pneumocystis.
-Introduction of mutations near the binding pocket led to decreased activity of atovaquone.
-Introduction of seven mutations observed in isolates of Pneumocystis from atovaquone-experienced patients into S. cervisiae cytochrome b increased the inhibitory concentration from 25 to >500 nM
-Pentamidine and Clindamycine resistantance–not reported.
Conclusion
-In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
-There is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
-These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
Limitation
No vitro culture system for propagation of Pneumocystis
Since the knowledge of the metabolic pathways is limited, most drug development has been empiric and the currently available treatment options for PCP have been unchanged during the last 15 years.
No consistent definition of clinical failure exists.
PJP prophylaxis has lead to markedly low incidence of this fatal disease however emergence of resistance remains alarming. This chapter has shed light on this important aspect.
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia.
Pneumocystis were identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini.Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug.Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extrapulmonary sites.
Transmission and Infection
Since P. jirovecii organism cannot be cultured in vitro. Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. Its environmental source is, however, unknown. Organisms may be coming from inanimate environmental sources, or may be spread by healthy humans.
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms .
This means that PJP May result as reactivation of previous latent infection or as a new airborne infection.
Drug Treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
Most traditional antifungal agents have no activity against Pneumocystis. The the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine. Not all drugs that are effective for therapy are also effective for chemoprophylaxis. Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis.
Prophylaxis.
Among HIV-infected patients, the occurrence of PCP is closely related to the CD4 count: With lower CD4 counts, the risk of PCP increases.
Systemic chemoprophylaxis against PCP was introduced by Dutz in Iran in the early 1950s. He showed that outbreaks of PCP could be aborted with the use of sulfadoxine plus pyrimethamine.Hughes later in his study showed that that PCP could be virtually eliminated by TMP–SMX prophylaxis.
. In non HIV patients like SOT 80/400mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800mg daily . Because of its efficacy, ease of administration and cost, every effort should be tried to maintain patients at risk of PCP on TMP–SMX.
Sulfonamide Resistance
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
In 1997, Lane and co-workers were the first to identify non- synonymous (resulting in changes in the encoded amino acid) DHPS mutations in Pneumocystis jirovecii.The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).
These observations suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. Given that Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance.
In conclusion, although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
There are findings consistent with the development of atovaquone resistance after selective pressure is exerted.
Conclusion
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in sig- nificant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished effi- cacy of TMP–SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
This is a book chapter which explains about drug resistance in Pneumocystis jirovecii (PJ)
INTRODUCTION
PJ is an opportunistic fungus that causes pneumonia. It was relatively rare before 1982 but emerged severely with onset of AIDS pandemic. But with the starting of PCP prophylaxis, its incidence significantly declined.
But still it is a serious opportunistic infection specially among immunocompromised patients.
ORGANISM
Pneumocystis were identifi ed early in the last century in guinea pigs by Chagas and in rat lungs by Carini . It was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug. However, Pneumocystis was first
established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell
pneumonia among premature or malnourished infants in orphanages. Initially it was considered as protozoan but based on the work by Edman and colleagues , phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.
TRANSMISSION
Antibody and PCR fi ndings indicate that primary infection with P. jirovecii happens in early childhood with a uniform
high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. Its environmental
source is, however, unknown. Organisms may be coming from inanimate environmental sources, or may be spread by
healthy humans. Studies have not conclusively demonstrated the environmental niche.
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions.
The organism is being shed into the environment regularly by healthy hosts, or whether the organism is introduced into the environment from an inanimate environmental source such as trees or grass is unknown. However, non human animals are not the source, because, as mentioned above, each animal species is infected with a different strain of Pneumocystis, and there is no cross species infection that has been identified.
DRUG TREATMENT
Main drug classes used for the treatment and prophylaxis are antifolates, diamines, atovaquone and macrolides. Usual anftifungals dont work against PJ. Various drugs have been studied and tried. But TMP–SMX is the most effective
chemoprophylaxis for PCP, and therefore the standard for prevention.
PROPHYLAXIS
For the first time systemic chemoprophylxis was proposed by Dutz in iran in 1950s. He showed that PCP could be virtually eliminated by TMP–SMX prophylaxis.
SULFONAMIDE RESISTANCE
Widespread use of sulfa group of drugs in various conditions have increased the risk of drug resistance.
CONCLUSION
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug
resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Complete physical maps and gene sequences are being determined for the genomes of P. carinii . These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals.
Transmission and Infection
Since P. jirovecii organism cannot be cultured in vitro, knowledge about its biology has been difficult to obtain.
Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
When the organism is obtained initially as a primary infection, it is not clear whether an immunocompetent host develops a transient disease. Various investigators have proposed that primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome (21–23). Following primary infection, the presumption, based on murine models, has been that the organism becomes latent, later manifesting clinically if the patient becomes profoundly immunosuppressed.
most infants acquire antibody against Pneumocystis during the first year of life, the organism must be ubiquitous.
Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extrapulmonary sites. After inhalation, the organism attaches tightly to the surface of type I alveolar cells .
Adherence is primarily mediated by the major surface glycoprotein (MSG).
This protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family.
Drug Treatment
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Dapsone, dapsonetrimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis. Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
Prophylaxis
In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP.
The most efficient, cheap and widely used regimen is daily TMP–SMX. TMP–SMX prophylaxis is relatively well tolerated by most non-HIV patients; in contrast, HIV patients have a high frequency of adverse effects, in particular rash and myelosuppression.
TMP–SMX 80/400 mg daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
Treatment of PCP
Untreated PCP is invariably fatal. In the beginning of the HIV epidemic, the mortality rate of PCP was reported to be 30–40% ,increasing to 70–90% among patients who
progressed to respiratory failure .Over the past decade, mortality rates have dropped to 5–15% .
This appears to be a consequence of earlier recognition of the infection, the introduction of adjuvant corticosteroids to patients with moderate-to-severe PCP as defined by a P PaO 2 of less than 70 mmHg, better diagnostic and therapeutic abilities related to concomitant processes, and improved ICU supportive measures.
The choice of specific chemotherapy is also important. The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
TMP–SMX was associated with a better survival than pentamidine. However, when all the trials are considered, TMP–SMX and pentamidine appear to have roughly comparable efficacy .
Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX.
Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Hepatotoxicity characterized by elevated transaminases also occurs. There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported. Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.
Pentamidine is associated with a high frequency of toxicities, some of which are treatment-limiting. Early experiences with rapid infusions of pentamidine were associated with hypotension and death, so this route of administration was abandoned. Intramusuclar injections were better tolerated in terms of blood pressure, but they caused a high frequency of sterile abscesses. Therapy was then administered by slow intravenous infusion, which is the best tolerated route. Inhaled pentamidine has been used for therapy, and is well tolerated, but efficacy is poor. Pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney. Pentamidine is toxic to the pancreas; its initial effects cause a surge of insulin release that often manifests as hypoglycemia. Hypoglycemia can occur days or weeks after starting therapy, and may occur many days after stopping therapy. Leukopenia can also occur. Pentamidine prolongs the QT interval, and cases of torsades de pointe have been reported.
Alternatives for the therapy to TMP–SMX and pentamidine include dapsone–pyrimethamine, clindamycinprimaquine, and atovaquone
Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX.
Clindamycin–primaquine appears to work on a metabolic pathway different from that of TMP–SMX. Two comparative trials of clindamycin/primaquine with TMP–SMX in moderate-to-severe PCP demonstrated apparent equivalence for clindamycin–primaquine, but both trials were underpowered .
Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX .
This is a good alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Efficacy of dapsone–pyrimethamine has only been demonstrated for mild-to-moderate PCP and for atovaquone only for mild PCP .Both must be administered orally.
Usual recommendations are that HIV-negative patients should receive 2 weeks and HIVpositive patients three weeks of drug treatment.
Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
adjunctive steroids are now recommended for all patients with severe disease (PaO s < 70 mmgh).
Sulfonamide Resistance
In San Francisco, the increasing use of PCP prophylaxis among HIV patients led to a marked increase in trimethoprimsulfamethoxazole resistance among isolates of Staphylococcus aureus and seven genera of Enterobacteriaceae .
In a retrospective study, trimethoprim–sulfamethoxazole resistance was more than twice as likely in blood culture isolates from HIV patients receiving trimethoprim–sulfamethoxazole compared to patients not receiving this prophylaxis.
Several clinical studies have investigated the frequency and significance of DHPS mutations in P. jirovecii.
On the basis of a genetic analysis of multiple loci, it appears that the mutations arose independently in multiple strains of Pneumocystis .
In a genotype study of 13 European HIV patients with recurrent episodes of PCP, a switch from wild-type to mutant DHPS occurred in five of seven patients who had a recurrence of the otherwise same molecular type of P. jirovecii .
All patients had received treatment or secondary prophylaxis with trimethoprimsulfamethoxazole or dapsone. These findings suggest that DHPS mutants may be selected in vivo (within a given patient) under the pressure of trimethoprim–sulfamethoxazole or dapsone. The emergence of DHPS mutations appears to be specific for P. jirovecii because only wild-type Pneumocystis DHPS has been found in other primate species .
a relatively high number of prophylaxis failures associated with DHPS mutations have been described in patients receiving dapsone prophylaxis. Thus, available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. However, the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
Moreover, even in studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprimsulfamethoxazole or dapsone–trimethoprim. These observations suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. Given that Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance.
DHFR Resistance
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8-tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
Given that trimetrexate is much more potent against PCP than trimethoprim in vitro, the combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.
In conclusion, although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Limitations to the study of drug resistance in Pneumocystis
The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
Another problem is that no consistent definition of clinical failure exists.
PCP is characterized by marked pulmonary inflammation that in severe cases results in alveolar damage and respiratory failure. Although an efficient immune response is required to control the infection, it has also been demonstrated that an excessive inflammatory response, rather than direct effects of Pneumocystis organisms, is crucial for the pulmonary injury
Third, treatment of PCP is associated with a high incidence of adverse effects including fever. In clinical practice, it may be difficult to know whether a slow treatment response with continuing fever is caused by the infection or by the treatment. Given the difficulties in defining clinical failure, reported failure rates for primary trimethoprim–sulfamethoxazole treatment in AIDS patients have varied considerably, ranging from 10 to 40% of cases
In addition, the contribution of nonadherence in presumed failure of prophylaxis may be difficult to assess. The most important reason for prophylaxis failure continues to be nonadherence to prescribed prophylaxis
In theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure.
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Conclusion
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis. Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
The increasing HIV epidemic and use of TMP–SMX in the third world may significantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Complete physical maps and gene sequences are being determined for the genomes of P. carinii (111). These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
PPlease summarise this article
pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals.in the past define as infection in AIDS defining diagnosis or post malignancy treaments.it is serious opportunistc infection but decline recently after prophylactic treatments. organism
The history of identifying the PCP is very old in last century mistake as trypanzoma .
In 1942 first describe in human,then considered as protozoa . Pneumocystis organisms have been identifi ed in most mammalian species in which it has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species specifi city among its mammalian host.
The organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was the first describe the microbe in humans. Transmission and Infection
The difficulties in isolated or obtaining the Pneumocytis jirovecii that is not live invetro and no way to be cultured.
Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas.the PCR solved many questions about transmissions and infections.
When the infection of PCP occure ,may be new or from latent ,as PCP can come from multiple strains. Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
It is rare that P Jirovicii detect in other organ.
The glycoprotein is first attached to alveoli when the pt inhaled the organism.
This glycoprotein is major surface glycoprotein (MSG).
It is not yet to know what is life cycle and mode of replication but asexual and sexual life cycle has been proposed.
The PCP suggesting that the organism has a sexual replication cycle that responds to environmental changes in the lung. Drug Treatment
Trimethoprim-slfamethoxazole (TMP–SMX )is the most effective chemoprophylaxis for PCP, and the best for prevention.
Befor discovering of TMP-SMX ,pentamidine firstly discovered to treat PCP.
There are many drugs using in treatment of PCP :
sulfadiazine plus pyrimethamine
atovaquone
clindamycin plus pyrimethamine
trimetrexate,
dapsone
aerosolized pentamidine. Prophylaxis
The risk of PCP infection:
HIV-infected patients with low CD4 count.
congenital immunodefi ciencies.
Patients who receiving long-term and high-dose corticosteroid therapy.
Patients who receiving certain chemotherapeutic regimens for cancer therapy or transplantation.
PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989.
The most effective regimen is daily TMP–SMX. TMP–SMX prophylaxis is relatively well tolerated by most non-HIV patients.
HIV patients TMP–SMX have a high frequency of adverse effects.
Other prophylactic drugs that use apart from TMP–SMX :
Dapsone 50 mg twice adaily.
Dapon with pyremethamine and leucovorin
Pentamidine aerosolized 300mg monthly.
Treatment of PCP
PCP if not treated is fatal.
The drug of choice is TMP-SMX .
There are some Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia,hepatotoxicity.drug toxicity also can occur.
Pentamidine is other choice ,other drugs:
dapsone–pyrimethamine
clindamycin– primaquine.
atovaquone. Sulfanomide resistance
The wide use of sulfanomide which in TMP-SMX and dapsone in treatment of PCP resistance can easily occur.
In many pathogenic bacteria and parasites, resistance to sulfonamides has increased as a consequence of selective pressure, and has limited the efficacy of sulfonamides.
Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many bacterial species.
The association with sulfa exposure is consistent with the concept that these mutations represent resistance that developed under drug pressure, documenting resistance is very difficult partly because Pneumocystis cannot be cultured, and partly because functional enzymes are unavailable.
In some bacteria. such as Escherichia coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
This gene discovered that all mutation gene that responsible of resistance are in this DHPS.
Several studies have reported a significant association of DHPS mutations with failure of low-dose sulfa prophylaxis.
majority of patients with mutant DHPS strains have been successfully treated with trimethoprim– sulfamethoxazole or dapsone–trimethoprims. DHFR Resistance.
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and c ertain amino acids. They are used in combination with sulfonamides.
There is no data that using high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors. Atovaquone.
is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
The resistance to atovaquone is related to mutation in cytochrome b detected in Plasmodium spp., Toxoplasma gondii and Pneumocystis. Pentamidine and clindamycine–primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported. Conclusion
mutations involved in sulfa and atovaquone drug
resistance have emerged in P. Jirovecii .
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis.
The increasing HIV epidemic and use of TMP–SMX in the third world may signifi cantly
increase the risk for the development of high-level resistance.
What is the level of evidence provided by this article? Level V.
Introduction
Pneumocystis organisms have been identified in most mammalian species which has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species-specific among its mammalian hosts.Since P. jirovecii organism cannot be cultured in vitro the advance of molecular and immunological techniques has acceptable large insight into this organism and how it interacts with its many animal hosts. It was previously thought that the infection was carried life-long and that clinical infection was a result of reactivation in immunocompromised hosts. PCR findings have questioned this view and support a more complex picture of transmission and infection. More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms (24).
The clinical disease PCP may happen as a reactivation of a past latent organism, or as a result of the new gaining of an airborne pathogen.
Pneumocystis has a specific tropism for the lung, where it exists in the alveoli. After inhalation, the organism attaches tightly to the surface of type I alveolar cells (25). Adherence is primarily mediated by the major surface glycoprotein (MSG) Treatment and prophylaxis of PCP
The major drug classes used for the treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides Most traditional antifungal agents have no activity against Pneumocystis. As Pneumocystis was originally believed to be a protozoon, the initial drug testing focused on drugs with activity against protozoan infection.In 1958, pentamidine isethionate was the first drug used to successfully treat PCP.In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystis in Iran.
In 1977, Hughes et al. established that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP (37–39). TMP–SMX is the most effective
chemoprophylaxis for PCP, and therefore the standard for prophylaxis and treatment pentamidine. However, when all the trials are considered, TMP–SMX and
pentamidine appears to have roughly comparable efficacy (59). Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX (63)
Pentamidine is associated with a high rate of toxicities, especially with IV or IM routes with some reports of IV rapid infusions of pentamidine associated with hypotension and death, IM route also can be associated with sterile abscesses but inhaled pentamidine is more tolerated with poor efficacy and more nephrotoxic including glomerular and tubular damage, also toxic to the pancreas and can results in profound hypoglycemia even after stopping the treatment lecupenia and can induced tordaes depoint due to prolong QT interval. its use is limited due to the wide range of side effects , alternative second-line therapy for PCP includes dapsone–pyrimethamine, clindamycin–primaquine, and atovaquone
What is the level of evidence provided by this article?
level 5 narrative review article
Introduction
Pneumocysitis jirovecii is an opportunistic fungus that causes Pneumocystis pneumonia (PCP) in immunocompromised individuals. The incidence of PCP has reduced due to the introduction of PCP chemoprophylaxis. PCP still causes significant mortality.
The organism
Pneumocystis was identified in the lungs of rats by Carini. It was first established as a human pathogen by Jirovecii in 1952, when it was identified as the organism causing interstitial plasma cell pneumonia among premature or malnourished infants. In 1988, Edman et al analyzed its ribosomal RNA and categorized it as a fungus. However, unlike other fungi, Pneumocystis only has one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
Transmission & infection P. jiroveciicannot be cultured in vitro. Antibody and PCR findings indicate that primary infection with P. jiroveciioccurs in early childhood. It has a uniform incidence in all geographical areas. Its environmental source is unknown. Following primary infection, the organism becomes latent and manifests clinically if the patient becomes immunosuppressed. Pneumocystis moves in the direction of the lung, where it exists in the alveoli. After inhalation, the organism attaches tightly to the surface of type I alveolar cells, mediated by the major surface glycoprotein (MSG). It is an abundant antigen on the surface of pneumocystis. It shows a high level of antigenic variation, which helps in avoiding the host immune response. Recent studies have shown that pneumocystis has a sexual replication cycle that responds to the environmental changes in the lung.
Drug treatment
Anti-folate drugs, diamines, atovaquone and macrolides are the major drug classes used for the treatment and prophylaxis of PCP. In 1977, the combination of trimethoprim-sulfamethoxazole (TMP-SMX) was shown to be effective for both the treatment and prophylaxis of PCP. It is as effective as intravenous pentamidine for therapy and is the most effective chemoprophylaxis for PCP, therefore the standard for prevention.
Other drugs that can be used for treatment include sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine. Drugs that are effective as prophylaxis include dapsone, dapsone-trimethoprim, atovaquone and aerosolized pentamidine.
Prophylaxis
Among patients infected with HIV, the lower the CD4 counts, the risk of PCP increases. Other patients at an increased risk of developing PCP include patients with congenital immune deficiencies (especially X-linked immunodeficiency with hyper-immunoglobulin M and SCID) and patients receiving long-term and high-dose corticosteroid therapy or transplantation. It has been observed that PCP can be eliminated by TMP-SMX prophylaxis. It is a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3since 1989. Prophylaxis should also be offered to the following patients at risk of PCP: patients with oropharyngeal candidiasis, organ transplant recipients, patients with leukemia and lymphoma. The most widely used, cheap and efficient regimen is daily TMP-SMX.
Treatment of PCP
Untreated PCP can be fatal. Better diagnostic and therapeutic abilities have significantly decreased mortality rates. It is important for both health care professionals and patients to recognize that mild symptoms such as dyspnea, cough or low-grade fever can be the initial manifestation of PCP. The most potent medications for PCP are anti-folate drugs. They work by blocking de novo synthesis of folate through inhibition of dihydroperoate synthase dihydrofolate reductase (DHFR). First choice for the treatment is TMP-SMX, alternatives include dapsone plus trimethoprim, clindamycin plus primaquin, pentamidine and atovaquone. It has been shown that TMP-SMX has been associated with better survival than pentamidine. Drug toxicity occurs in 24 to 57% of HIV-infected patients treated with TMP-SMX. The adverse effects usually occur after 7 days of treatment. The most common adverse effects include rash fever, leukopenia and hepatotoxicity. Some cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis have been reported.
Treatment-limiting toxicities with pentamidine treatment occur in 13 to 80% of patients. Intramuscular injections are better tolerated in terms of blood pressure, but they can cause sterile abscesses. The best tolerated route is slow intravenous infusion. It is nephrotoxic, toxic to the pancreas, can cause leukopenia and prolong the QT interval.
The optimal duration of PCP treatment has never been properly tested. Usual recommendations are 2 weeks for HIV-negative patients and three weeks for patients infected with HIV. Exacerbation of alveolar inflammation can occur initially after initiating treatment. The inflammation can be reduced by the use of corticosteroids.
Sulfonamide resistance
As TMP-SMX and dapsone has been used extensively for the treatment and prophylaxis of PCP, there are concerns regarding the development of sulfonamide resistance in P. jirovecii. The use of sulfa drugs for the treatment of malaria and bacterial infections has led to high rates of resistance in P. falciparum and many bacterial species. Several clinical studies have investigating the frequency and significance of variations in P. jirovecii. The mutations have also been found in patients not exposed sulfa drugs, suggesting person-to-person spread of mutant strains. It has been noted that the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis. A study showed that patients with the mutations, still responded to TMP-SMX treatment, indicating that the mutations may confer to a low-level of resistance to sulfonamides. Knowing that P. jirovecii has the ability to undergo variations, brings about the concern that further mutations may result in high-level resistance.
Dihydrofolate reductase (DHFR) resistance
Diaminopyrimidine, trimethoprim and pyrimethamine are competitive inhibitors of DHFR. In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors. However, despite the widespread use of TMP-SMX for the prevention and treatment of PCP, only a few DHFR mutations have been identified in P. jirovecii DHFR. The mutations elicited were not associated with prior TMP-SMX, and were successfully treated with the same.
Atovaquone
Atovaquone is similar in structure to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1complex. Binding of atovaquone to the ubiquinol oxidation pocket of the bc1complex and the Rieske iron-sulphur protein disrupts electron transport and leads to collapse of the mitochondrial membrane potential. Eventually, this results in the depletion of ATP within P. jirovecii and leads to the killing of the organism. Mutations of the cytochrome b gene have been identified in P. jirovecii. Survival of the patients with or without the mutations has not shown to be significantly different.
Pentamidine and clindamycin-primaquine
Possible resistance mechanisms of P. jiroveciiagainst pentamidine and clindamycin-primaquine have not been discovered or reported.
Conclusion
Despite the inability to culture the organisms, it has been noted that the mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii,due to the selective pressure by the widespread use of PCP prophylaxis. Currently, the effect of the mutations are modest, but high-level sulfa drug resistance may emerge, leading to a reduced efficacy of TMP-SMX. This may lead to the loss of the most efficient and inexpensive treatment for PCP. The increasing incidence of HIV and the use of TMP-SMX may lead to an increased risk for the development of high-level resistance.
# Introduction:
*Pneumocystis jirovecii earlier it is called Pneumocystis carinii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia in immunocompromised patients.
*The rate of PCP has been reduced due to initiation of PCP chemoprophylaxis and potent HIV-1 antiretroviral regimens, but it is still considered as a serious opportunistic infection between heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
# The Organism:
*It was discovered early in the last century in guinea pigs by Chagas and in rat lungs by Carini, and they considered it as a new form of Trypanozoma cruzi.
*It was described first in humans in 1942 in 3 cases by two Dutch investigators, van der Meer and Brug.
*Pneumocystis was first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in
Orphanages
*In 1994, an interim trinomial name change was adopted with the name P. carinii f.sp. hominis for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats, then in 2002 the organism infecting humans was renamed Pneumocystis jirovecii.
# Transmission and Infection
*The antibody and PCR findings indicate that primary infection happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. It’s may be environmental source, but unknown
* It is proposed that primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome.
*The human hosts can be infected with more than one strain of P. jirovecii, indicating that infection can occur on multiple occasions, leading to latency with a variety of organisms.
*The clinical disease of PCP may occur as a reactivation of a prior latent organism, or due to recent acquisition of an airborne pathogen.
*The organism has specific c tropism to the lung, where it exists in the alveoli, but n rare cases have been detected at extrapulmonary sites.
# Drug Treatment:
* The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
* Most traditional antifungal agents have no activity against Pneumocystis.
*It was originally believed to be a protozoon, initial drug testing focused on drugs with activity against protozoan infections.
*(TMP–SMX) is still effective therapy for both treatment and prophylaxis
# Regimens for prophylaxis against Pneumocystis pneumonia First choice
1DS of Trimethoprim(160mg)–sulfamethoxazole(800) or SS daily TMP 80 + SMX 400)
Alternatives
Trimethoprim–sulfamethoxazole 1 DS three times per week
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone 50 mg daily with Pyrimethamine 50 mg weekly plus Leucovorin 25 mg weekly
Dapsone 200 mg weekly with pyrimethamine 75 mg weekly plus Leucovorin 25 mg weekly
Pentamidine aerosolized 300 mg monthly via nebulizer system
Atovaquone 1,500 mg daily
Pyrimethamine 25–75 mg qd plus Sulfadiazine 0.5–2.0 g q6h
*In organ transplantation, high-dose steroid treatment and/or high-dose
chemotherapy may confer a high risk of PCP.
*The most efficient, cheap and widely used regimen is daily TMP–SMX, it well tolerated by most non-HIV patients.
# Drug regimens for the treatment of PCP
*Untreated PCP is invariably fatal.
First choice
Trimethoprim– sulfamethoxazole
Alternatives
*Dapsone plus trimethoprim
*Clindamycin plus primaquine
*Pentamidine
*Atovaquone
*Adjunctive therapy Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
# Sulfonamide Resistance
*The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa resistance could develop in P. jirovecii.
*In many pathogenic bacteria and parasites, resistance to sulfonamides has increased as a consequence of selective pressure, and has limited the efficacy of sulfonamides.
*Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many bacterial species
*In pathogens such as E. coli, N.meningitidis, M. leprae and P. falciparum, sulfonamide
resistance is caused by mutations in the primary sequence of the DHPS gene.
*Studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprim–sulfamethoxazole or dapsone–trimethoprim.
# DHFR Resistance
*In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
*Despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR
# The limitation of the study:
The study of drug resistance in P. jirovecii has been and continues to be difficult.
*The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
*No consistent definition of clinical failure exists
*The contribution of non adherence in presumed failure of prophylaxis may be difficult to assess.
*treatment of PCP is associated with S/E including fever, so it may be difficult to know whether a slow treatment response with continuing fever is caused by the infection or by the treatment.
What is the level of evidence provided by this article?
Please summarise this article. Introduction
-Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised
individuals. Transmission and Infection
– P. jirovecii organism cannot be cultured in vitro, so knowledge about its biology has been diffi cult to obtain.
-Primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome .
-Following primary infection, the organism becomes latent, later manifesting clinically if the patient becomes profoundly immunosuppressed.
– The clinical disease PCP may, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
-As noted above, the environmental source of Pneumocystis
has not been identified.
-Pneumocystis has specific tropism for the lung, where it
exists in the alveoli. After inhalation, the organism attaches
tightly to the surface of type I alveolar cells . Drug Treatment
-The major drug classes used for treatment and prophylaxis of
PCP include antifolate drugs, diamines, atovaquone, and
macrolides .
– TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
-Other drugs have proven activity for therapy, including
sulfadiazine plus pyrimethamine, atovaquone, clindamycin
plus pyrimethamine, trimetrexate, dapsone and aerosolized
pentamidine.
-Not all drugs that are effective for therapy are
also effective for chemoprophylaxis.
– Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis Prophylaxis
-Among HIV-infected patients, the occurrence of PCP is
closely related to the CD4 count: With lower CD4 counts,
the risk of PCP increases.
-Patients with congenital immunodefi ciencies, particularly X-linked immunodefi ciency with hyper-immunoglobulin M, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP.
– Secondary prophylaxis should be offered to all patients following an
episode of PCP.
-80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily . Treatment of PCP
-It is important educate patients to seek medical attention early, when symptoms are still mild, must be an emphasis of patient management programs.
-Both patients and health care professionals must recognize that mild symptoms such as dyspnea, cough, or low-grade fever can be the
initial manifestation of PCP, especially in patients with
CD4+ T lymphocyte counts below 200 cells/mm3.
– Once there is a high suspicion therapy should be instituted promptly if the diagnostic procedures will be delayed.
-The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR) .
– Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX .
-Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Hepatotoxicity characterized by elevated transaminases also occurs. There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported.
-Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.
-Pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney. Pentamidine is toxic to the pancreas; its initial effects cause a surge of insulin release that often manifests as hypoglycemia.Leukopenia can also occur. Pentamidine prolongs the QT
interval, and cases of torsades de pointe have been reported.
-Usual recommendations are that HIV-negative patients should receive 2 weeks and HIV positive patients three weeks of drug treatment.
-Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. This inflammation can be reduced by corticosteroids. Sulfonamide Resistance
-DHPS mutations have been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
– The emergence of DHPS mutations appears to be specific for P. jirovecii because only wild-type Pneumocystis DHPS has been found in other primate species .
-In spite of the emergence of mutant DHPS strains, current clinical experience supports the effi cacy of trimethoprim– sulfamethoxazole prophylaxis when taken regularly.
– There is evidence to suggest a contributory role for DHPS
mutations in breakthrough PCP in patients using alternative
sulfa prophylaxis.
-Available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. DHFR Resistance
-The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
-Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors. Atovaquone
-It is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention
and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported. What is the level of evidence provided by this article?
Level 5.
Introduction: Pneumocystis jirovecii (PCP) is an opportunistic fungus that causes pneumonia in immunocompromised individuals, with increased incidence in the late 1980’s. Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug, who described it in three cases, However, Pneumocystis was first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages. In the most of the 20th century, Pneumocystis was considered as a protozoon and single species based on its morphologic features, its resistance to classical antifungal drugs, in 1988, based on the work by Edman and colleagues, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom. Transmission of PCP: The primary infection approved by antibody testing and PCR, occurs in early childhood with demographic variations, indicates environmental source of infection. Airborne ? Inanimate environmental source such as trees or grass? Drug prophylaxis and treatment: Anti-folate drugs: trimethoprim sulfamethoxazole, dapsone Diamines: pentamidine isethionate, pyrimethamine. Atovaqoune. Macrolides.
Regimens for prophylaxis against Pneumocystis pneumonia: First choice is TMP/SMX double strength (800/160 mg) or single strength (400/80mg) daily for 6 months. Or: – Double strength every other day for 6 months. – Dapsone 50 mg twice daily or 100 mg twice weekly for 6 months. – Dapsone with 50 mg daily/ 200 mg weekly+ Pyrimethamine 50 mg weekly+ Leucovorin 25 mg weekly. – Pentamidine aerosolized 300 mg monthly via nebulizer. – Atovaquone 1,500 mg daily – Sulfadiazine 0.5–2.0 g q6h – Pyrimethamine plus 25–75 mg qd only used when concurrent toxoplasmosis. Drug regimens for the treatment of PCP: Drug of first choice is double strength TMP/SMX 2 tabs x3/day, or IV Trimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 hrs. Or: – Oral Dapsone 100 mg x1/day + oral trimpethoprim 360 mg q 8hrs. – Oral clindamycin 300-450 mg q 6 hrs + IV primaquine 30 mg daily. – IV pentamidine 4mg/kg/day. – Oral Atovaqoune 750 mg q 12 hrs. Adjunctive therapy with prednisolone 40 mg twice daily for 5 days then 40 mg daily till day 11 and 20 mg to day 21 (the completion of treatment course), is indicted when PaO2 < 70 mmHg/9.3kPa. Drug resistance:
Sulfonamide resistance TMP/SMX and Dapsone, increased due to its wide use in treatment and prophylaxis in many bacterial , parasitic infections, and malaria, and occur by mutations in the primary sequence of the Dihydroperoate synthase (DHPS) gene, with demographic variations, and these mutaions increased in those who were exposed to sulpha drugs, with person to person transmission.
Atovaqoune resistance is high when it is used as a prophlayxis due to higher tendency to sequence variation in cytochrome b (mutation).
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, no data yet on drug resistance.
Limitation to the study of drug resistance in PCP:
Absence of culture sensitivity in PCP.
Severe inflammatory response and lung injury, may indicate treatment failure rather than drug resistance.
The side effect of drugs including fever may be mistaken with resistance.
No adherence to prophylaxis may increase the chance of resistance mutations.
Conclusion: In spite of absence of organism culture, resistance to low dose TMP/SMX and Atovaqoune have been identified due to sequence mutations in (DHPS) gene, additional mutations could emerge leading to failure of response to TMP/SMX (the most efficient and inexpensive therapy for PCP). A promising Pneumocystis Genome Project, with Complete physical maps and gene sequences are being determined for the genomes of P. carinii, may lead to identification of new polymorphic regions, new drugs target for treatment and facilitate culture system development.
What is the level of evidence provided by this article? The level of evidence is V – erratic review.
Introduction Pneumocystis jirovecii is a fungal infection causing Pneumocystis pneumonia (PCP) in immunocompromised patients.
PCP chemoprophylaxis in immunocompromised host and potent HIV antiretroviral regimens have lowered its incidence significantly. Organism Notified first in human as a pathogen in 1952 by Jirovec in premature malnourished infants causing interstitial plasma cell pneumonia. The organism is categorized as a fungus (Archi ascomycetes) In 2002 the organism infecting humans was renamed Pneumocystis jirovecii. Primary infection with P. jirovecii happens in early childhood, the clinical infection results from reactivation in immunocompromised hosts. Transmission
The primary infection leads to respiratory tract infection or some time sudden infant death syndrome or it remains latent and is reactivated when the host is immunocompromised due to any reason. Multiple strains of P.jirovecii could infect an individual on different occasions.
It has specific tropism for the lung tissue by adherence to the surface of type I alveolar cells after inhalation. This process is mediated by the major surface glycoprotein (MSG) with multiple variable antigens as a defense mechanism. Drug treatment
The usual antifungal drugs are ineffective against Pneumocystis pneumonia. The drugs groups like Antifolate drugs, diamines, atovaquone, and macrolides are used for prophylaxis and treatment.
TMP–SMX is the treatment and prophylaxis of choice.
Alternative drugs may be sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine can be used for prophylaxis.
Prophylaxis
PCP risk increases with lower CD4 counts. 200 cells/mm is indicator of high risk for PCP in HIV infected cases meanwhile patients can develop PCP at higher CD4 counts.
Immunocompromised status like congenital immunodeficiency, long term steroids use, pts on chemotherapy are risk for PCP.
TMP–SMX prophylaxis can prevent PCP occurrence. therefore HIV-1 infected patients with CD4 count < 200 cells/μL, need primary prophylaxis. Cases treated for PCP infection also needs secondary prophylaxis. PCP treatment
Treatment of PCP reduces mortality up to 5–15% from 50–80%.
Corticosteroids addition to patients with moderate-to-severe PCP and PaO2< 70 mmHg improves outcome significantly. Early detection and immediate treatment without delay improves the prognosis.
TMP–SMX
Its intake was associated with better survival compared to pentamidine.
Adverse effects recorded rash, fever, leukopenia, hepatotoxicity, interstitial nephritis, renal calculus formation, anaphylactoid reactions and sometime Stevens–Johnson syndrome has been reported. Pentamidine
Intravenous infusion is the tolerated route for pentamidine administration. With main side effects of nephrotoxicity, pancreatic injury, leucopenia, torsade de pointe. Dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone are alternative. Dapsone–pyrimethamine was suitable for mild-to-moderate PCP and atovaquone for mild PCP. Recommendation of therapy for HIV-negative cases is 2 weeks and HIV positive patients for 3 weeks. Adjunctive steroids are recommended for all patients with severe disease (PaOs< 70 mmgh). Sulfonamide resistance Double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, leading to resistance with altered substrate binding. Previous exposure to sulfa drugs for prophylaxis had been associated with DHPS mutations. In spite of presence of mutant DHPS strains, the efficacy of trimethoprim–sulfamethoxazole prophylaxis is still noticed. A study detected failure of pyrimethamine–sulfadoxine prophylaxis association with the Pro57Ser mutation. DHPS mutations was associated with dapsone prophylaxis. The effect of DHPS mutations on response to therapeutic, high-dose trimethoprim was controversial. DHFR resistance The combination of trimetrexate and sulfamethoxazole are more efficient in vitro than the combination of trimethoprim plus sulfamethoxazole. There is no evidence that extensive trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors. Atovaquone Used for Prophylaxis and treatment of P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. Resistance to atovaquone is due to Mutations of the cytochrome b gene detected in Plasmodium spp., Toxoplasma gondii and Pneumocystis. Pentamidine and Clindamycine–Primaquine They are used for prophylaxis and treatment of PCP. Conclusion Sulfa and atovaquone drug resistance mutations occurred in P. jirovecii. No evidence that DHPS mutations is accompanied with significant resistance to high dose of sulfa treatment.
Pneumocystis Genome Project completion and physical maps and gene sequences are studied for the genomes of P. carinii which will be crucial for detection of new polymorphic regions and drug targets. Level of evidence is V
Pneumocystis jirovecii is an opportunistic pathogen that causes serious lung infections in immunocompromised individuals. The incidence of P. jirovecii pneumonia (PCP) ranges from 0.6 to 14% in renal transplant recipients who do not receive prophylaxis despite active antibiotic treatment. Mortality from it reaches 50%. PCP remains a serious opportunistic infection among severely immunosuppressed patients who do not receive adequate chemoprophylaxis.
The Organism:
Pneumocystis was first identified early in the last century in guinea pigs by Chagas and rat lungs by Carini. It was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug. Jirovec in 1952 identified it as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
For most of the twentieth century, it was considered as a protozoon and single species based on its morphologic features, resistance to classical antifungal agents, and effectiveness of certain drugs used to treat protozoan infections. However, in 1988, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed it in the fungal kingdom.
Pneumocystis jirovecii was renamed in honor of Otto Jirovec, the first to describe the microbe in humans.
Transmission and Infection:
–The Pneumocystis jirovecii organism cannot be cultured in vitro, but the development of molecular and immunological techniques has provided insight into its biology and how it interacts with its various animal hosts. -Antibody and PCR findings suggest that primary infection with the organism occurs in early childhood, and its environmental source is unknown. PCP may occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen. PCP has a specific tropism for the lung, where it attaches tightly to the surface of type I alveolar cells. Adherence is mediated by the major surface glycoprotein (MSG) which is highly polymorphic, repeated and distributed among all the chromosomes. Several genes have been demonstrated to be involved in mating, pheromone responsiveness, and responses to environmental changes in the lung.
Drug treatment :
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides, with pentamidine isethionate being the first to successfully treat PCP. Drugs that are effective for therapy are also effective for prophylaxis, but intravenous pentamidine and clindamycin-primaquine are not.
Prophylaxis :
Systemic chemoprophylaxis against PCP was introduced in the 1950s and became a standard of care for HIV-infected patients in 1989. Secondary prophylaxis should be offered to all patients following an episode, with daily TMP–SMX one double strength(DS) or single strength (SS) daily being the most effective. Tolerability may improve with lower doses or intermittent regimens.
Alternatives drugs :
-Trimethoprim–sulfamethoxazole 1 DS three times per week -Dapsone 50 mg twice daily or 100 mg twice weekly -Dapsone 50 mg daily with pyrimethamine 50 mg weekly plus leucovorin 25 mg weekly -Dapsone 200 mg weekly with pyrimethamine 75 mg weekly plus leucovorin 25 mg weekly -Pentamidine aerosolized 300 mg monthly via nebulizer
Treatment of PCP: Untreated PCP is fatal, but over the past decade, mortality rates have decreased due to earlier recognition and the introduction of adjuvant corticosteroids. The importance of educating patients to seek medical attention early, when symptoms are still mild, and choosing antifolate drugs for PCP treatment is important . Treatment options for PCP include :
Trimethoprim–sulfamethoxazole Is the first choice 2 DS tabs PO every 8 h common side effect is skin rash. Intravenous Trimethoprim 5 mg/kg with sulfamethox-azole 20 mg/kg every 8 h (in severe cases ) .
Alternatives:
-Dapsone 100 mg plus trimethoprim 320 mg every 8 h both used PO on a daily basis . – Clindamycin PO 300–450 mg every 6 h plus primaquine intravenous 30 mg daily. – Pentamidine Intravenous 4 mg/kg day (High incidence of adverse effects,) – Atovaquone By mouth 750 mg twice daily( well tolerated but expensive )
Adjunctive therapy:
Prednisone in patients with room air pAO< 70 mmhg (9.3 kPa) – used orally 40 mg twice daily for 5 days ,40 mg daily, from day (6 to 11) ,20 mg daily, from day (12 to 21 ) while on anti-PCP therapy. IV pulse methylprednisolone also can be used in severe cases .
Sulphonamide resistant :
The widespread use of TMP–SMX and dapsone among HIV patients has led to concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii. Lane and co-workers were the first to identify nonsynonymous DHPS mutations in Pneumocystis and Saccharomyces cerevisiae, which have increased in frequency recently. DHPS mutations may contribute to low-level sulfa resistance, but the major reason for PCP breakthrough is poor adherence to chemoprophylaxis. Clinical evidence supports trimethoprim-sulfamethoxazole or dapsone.
DHFR Resistance:
Trimethoprim and pyrimethamine are competitive inhibitors of DHFR, which catalyzes the reduction of 7,8-dihyfrofolate to 5,6,7,8- tetrahydrofolate. DHFR resistance to trimetrexate and sulfamethoxazole is widespread, but only few DHFR mutations have been identified in Pneumocystis DHFR. Several studies have reported DHFR mutations, but there is no evidence that the widespread use of trimethoprim or pyrimethamine has caused clinical significant resistance to DHFR inhibitors. Atovaquone binds to the cytochrome bc1 complex and disrupts electron transport, leading to depletion of ATP and killing of Pneumocystis
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Limitation to the study :
Lack of in vitro culture system
No consistent definition of clinical failure.
Nonadherence to prescribed prophylaxis is the most important reason for PCP failure, and clinical resistance may be markers of poor adherence rather than the direct cause.
Conclusion :
Mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii, but the clinical effect is modest. Investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. Complete physical maps and gene sequences are being determined for the genomes of P. carinii.
What is the level of evidence provided by this article?
Pneumocystis jirovecii is an opportunistic fungus that
causes Pneumocystis pneumonia (PCP), in immunocompromised individuals.
Was mainly diagnosed patients with congenital immuno-deficiencies, and
patients receiving immunosuppression as antineoplastic
treatment and patients with AIDS.
*The organism
Pneumocystis was frst described in humans in 1942
It was considered as a protozoon and based on its morphologic features, and
the effectiveness of drugs used to treat protozoan infections.
In 1988, analysis of ribosomal RNA (rRNA) sequences and observations of
genome size placed P. Carinii in the fungus
There is great level of genetic divergence between Pneumocystis organisms
infecting different mammals
The organism infecting humans was renamed Pneumocystis jirovecii, in honor
of Otto Jirovec.
*Transmission and Infection
Primary infection with P. Jirovecii occurs in early childhood.
Its environmental source is still unknown.
It may come from inanimate environmental sources, or may be spread by
healthy humans. Studies didn’t demonstrate the environmental niche.
investigators proposed that early childhood infection may cause upper or
lower respiratory manifestations, or sudden infant death syndrome.
After initial infection the organism becomes latent, to be reactivated in
immunosuppressed host .
recent data, suggests that more than
one strain may infect the human and the infection can be acquired on multiple
occasions, leading to latency with a variety of distinct organisms.
The clinical disease PCP may, occur
as a reactivation, or as a result of recent airborne pathogen.
Pneumocystis has specific tropism for the lung, where it exists in the
alveoli.
Organism attaches to the surface of type I alveolar cells through a major
surface glycoprotein (MSG).
This protein is the most abundant
antigen on the surface of Pneumocystis and is encoded by a multicopy gene
family.
MSG shows high level of antigenic variation allowing resistance to host
immune response.
*Drug Treatment
-The major drug classes used for treatment and prophylaxis of PCP include
antifolate drugs, diamines, atovaquone, and macrolides with no effect for
antifungal agents .
-trimethoprim–sulfamethoxazole (TMP–SMX) is as effective as intravenous
pentamidine for therapy, and is still the treatment of choice.
-TMP–SMX is the most effective
chemoprophylaxis for PCP, and therefore the standard for prevention.
-Other effective drugs for therapy includes:
sulfadiazine plus pyrimethamine,
atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and
aerosolized pentamidine.
-Effective drugs for prophylaxis includes:
Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine .
-azithromycin, doxycycline, and
caspofungin were used if other alternatives were not feasible.
*Prophylaxis
Immunocompromised patients as Transplant
recipients are at the risk of
developing PCP and induction with ATG was associated with higher risks.
In contrast to HIV patients CD4 counts are not a reliable marker of susceptibility in this group of
patients.
TMP–SMX is effective
in prophylaxis used for primary prophylaxis in HIV-1 infected patients
with oral candidiasis or a CD4 count less than 200 cells/μL.
And
for Secondary prophylaxis for all patients following an episode of PCP and In
immunocompromised patients (organ transplantation, high-dose steroid treatment
and/or high-dose chemotherapy ).
Several prophylactic regimens are available.
The most efficient, cheap, well tolerated and widely used regimen is daily
TMP–SMX.
* Treatment of PCP
Mortality rates due to PCP had markedly declined due to Early
recognition of the infection, the introduction of adjuvant corticosteroids to
patients with moderate-to-severe PCP as defined by a PaO2 of less than 70 mmHg,
better diagnostic and therapeutic abilities, and improved ICU supportive
measures.
In high risk patients and patients with
with CD4+ counts below 200
cells/mm3 mild symptoms as dyspnea, cough, or
low-grade fever can be the initial manifestation of PCP.
Clinicians should start Treatment
early when suspecting infection and not wait for all the features of PCP to be
present, or for the chest radiograph to be abnormal.
-TMP–SMX is effective Treatment ,the trials showed TMP–SMX and pentamidine appear to have
roughly comparable efficacy.
Adverse effects occur after 7 days of therapy and commonly include rash,
fever and leukopenia, hepatotoxicity.
There are cases of sulfamethoxazole-induced
interstitial nephritis, renal calculus formation, anaphylactoid reactions and
pancreatitis reported, hyperkalemia, and rare cases of Stevens–Johnson syndrome
have occurred.
-Pentamidine is associated with a high level of side effects which may be Treatment
limiting.
Other Treatment options includes dapsone–pyrimethamine, clindamycin–
primaquine, and atovaquone .
-Dapsone–trimethoprim is effective,
and it has potency that is comparable to TMP–SMX and it cross-reacts with sulfa
in 50% of allergic patients, so it does not offer many advantages over TMP–SMX.
-Atovaquone is well tolerated
It is available orally only , and does not appear to be as potent as
TMP–SMX and it is mainly for mild cases .
-Dapsone–pyrimethamine has only been demonstrated for mild-to-moderate PCP.
-Recommended duration for ttt are that for HIV-negative patients should
receive 2 weeks and HIV-positive patients 3 weeks of drug treatment.
-Corticosteroids could reduce mortality in patients with moderate or severe
disease with exacerbation of alveolar inflammation and desaturation in the
first days after ttt.
On the basis of these results,
adjunctive steroids are now recommended for all patients with severe disease
(PaOs < 70 mmgh).
*Sulfonamide Resistance
Widespread use of sulfa drugs for treatment and prophylaxis of PCP resulted
in resistance due to DHPS mutations.
DHPS mutations have also been found in patients without any previous
exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
In spite of the emergence of mutant DHPS strains, Current clinical
experience supports the efficacy of trimethoprim– sulfamethoxazole prophylaxis
when taken regularly.
data suggests that DHPS mutations
contribute to low-level sulfa resistance, and may be the most important in
failure of second-line sulfa prophylaxis.
And the major reason for PCP breakthrough continues to be the poor
adherence to chemoprophylaxis.
*DHFR Resistance
Despite the widespread use of trimethoprim in combination with
sulfamethoxazole for the prevention and treatment of PCP, only relatively few
DHFR mutations have been identified in Pneumocystis DHFR.
*Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but
possible resistance mechanisms have yet to be discovered and reported.
*Conclusion
-it is now clear that mutations involved in sulfa and atovaquone drug
resistance have emerged in P. Jirovecii .
– the clinical effect of the described mutations seems modest.
-no evidence that DHPS mutations result in significant resistance to
high-dose sulfa therapy.
– it is possible that if additional mutations arise, then high-level sulfa
resistance could emerge.
What is the level of evidence provided by this article?
Drug Resistance in Pneumocystis jirovecii. Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia,Pneumocystis pneumonia (PCP), which is usually associated with immunocompromised patients such as AIDs or patient receiving potent immunosuppressive therapy, but it is incidence now decreased due to prophylactic treatment. Pneumocystis jirovecii leads to primary infection that might be correlate with the development of upper or lower respiratory manifestations which becomes latent and later manifesting clinically if the patient becomes profoundly immunosuppressed, till now the environmental source of Pneumocystis has not been identified. Drug Treatment. Most traditional antifungal agents have no activity against Pneumocystis and the major drug classes used for treatment and prophylaxis of PCP include ant folate drugs, diamines, Atovaquone, and macrolides. Studies, shown that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP, other proven active therapy including sulfadiazine plus pyrimethamine, Atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine. Prophylaxis of PCP. PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989, many prophylactic regimens are available but the most efficient, cheap and widely used regimen is daily TMP–SMX. TMP–SMX prophylaxis. Treatment of PCP. 1-TMP–SMX and Pentamidine appear to have roughly comparable efficacy and drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX such as rash, fever and leukopenia. Hepatotoxicity and others, and Pentamidine also is nephrotoxic and causes predictable glomerular and tubular damage to the kidney, has toxic effect to the pancreas lead to hypoglycemia and leukopenia can also occur. 2-Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX, but this combination does not come as a fixed-dose combination. 3-Clindamycin–primaquine, some studies compare this combination with TMP–SMX in moderate-to-severe PCP and demonstrated apparent equivalence for clindamycin–primaquine. 4-Atovaquone is well tolerated but does not appear to be as potent as TMP–SMX, but used as alternative with mild disease who cannot tolerate TMP–SMX. Usually the treatment duration should be for 2 weeks and in HIV positive patients three weeks of drug treatment, oxygen desaturation during the first 4–5 days of therapy which caused due to drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. Finally many studies proven that corticosteroids could reduce mortality in patients with moderate or severe disease. Sulfonamide Resistance. Two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding, there is a clear association between previous exposure to sulfa drugs (primarily for prophylaxis rather than therapy) and DHPS mutations has been shown in all studies. DHFR Resistance. In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors and there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors. Atovaquone. Survival from PCP did not differ between patients with or without mutations. Overall, these findings are consistent with the development of Atovaquone resistance after selective pressure is exerted. Pentamidine and Clindamycin–Primaquine. Possible resistance mechanisms have yet to be discovered and reported. Conclusion. The widespread use of PCP prophylaxis such as sulfa and Atovaquone is considered the clear cause of that mutations and involved in the occurrence of resistance, DHPS mutations not result in significant resistance to high-dose sulfa therapy, hence, investigations into the mechanisms of drug resistance and identification of new molecular targets are required. What is the level of evidence provided by this article? Narrative review=Level V.
Summary of the article Drug Resistance in Pneumocystis jirovecii Pneumocystis jirovecii 1. Pneumocystis was first established as a human pathogen by Jirovec in 1952 and was renamed Pneumocystis jirovecii, in honor of Otto Jirovec. 2. Pneumocystis species represent an early divergent line in the fungal kingdom, has recently been placed in a group of fungi entitled the Archiascomycetes. 3. Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
Transmission and Infection of PCP
1. P. jirovecii organism cannot be cultured in vitro and It’s environmental source is, however, unknown.
2. Non-human animals are not the source and there is no cross- species infection that has been identified.
3. Since most infants acquire antibody against Pneumocystis during the first year of life, the organism must be ubiquitous.
4. The clinical disease PCP may occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
5. Pneumocystis has specific tropism for the lung, where it exists in the alveoli. It seldom causes disease at extrapulmonary sites. Risk factors for developing PCP
1. Patients with congenital immunodeficiencies, particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID.
2. HIV infected patients.
3. Patients on immunosuppression for SOT.
4. Long-term and high-dose corticosteroid therapy.
5. Patients receiving certain chemotherapeutic regimens for cancer therapy (fludarabine or antithymocyte globulin produce a much higher risk of PCP than other regimens). Drug Treatmentfor PCP
1. Most traditional antifungal agents have no activity against Pneumocystis.
2. The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
a) Pentamidine isethionate was the first drug used to successfully treat PCP.
b) TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
c) Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
d) other drugs that have anti-PCP activity in humans and could have a role in managing human disease include azithromycin, doxycycline, and caspofungin.
3. Drug treatment options for PCP:
a) The first choice: trimethoprim-sulfam ethoxazoleat a dose of 2tablets DS every 8h or IVTrimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h.
b) Alternatives:
I. Dapsone( 100 mg daily) plus trimethoprim(320 mg every 8 h).
II. Clindamycin(PO 300–450 mg every 6 h) plus primaquine (IV 30 mg daily).
III. Pentamidine IV at 4mg/kg/day.
IV. Atovaquone PO 750 mg BID.
c) Adjunctive therapy: Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
· 40 mg twice daily for 5 days.
· 40 mg daily; days 6 through 11.
· 20 mg daily, days 12 through 21 while on anti-PCP therapy.
d) Dapsone has not been studied as a single drug and thus should not be used alone for treatment. Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX.
4. The optimal duration of therapy for PCP has never been properly tested. Usual recommendations are that:
· HIV-negative patients should receive 2 weeks of drug treatment.
· HIV- positive patients should receive 3 weeks of drug treatment. Prophylaxis for PCP
Several prophylactic regimens are available:
1. The most efficient, cheap and widely used regimen is daily TMP–SMX.
2. The combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis.
3. Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis.
4. Not all drugs that are effective for therapy are also effective for chemoprophylaxis.
5. Regimen for prophylaxis:
A. First choice Trimethoprim-sulfamethoxazole 1 DS or SS daily.
B. Alternatives Trimethoprim-sulfamethoxazole(1 DS three times per week) Dapsone (50 mg twice daily or 100 mg twice weekly).
C. Dapsone(50 mg daily) with Pyrimethamine(50 mg weekly) plus Leucovorin(25 mg weekly).
D. Dapsone(200 mg weekly) with pyrimethamine(75 mg weekly) plus Leucovorin(25 mg weekly)Pentamidine aerosolized (300 mg monthly via nebulizer system).
E. Atovaquone(1500 mg daily) Pyrimethamine(25-75 mg qd) plus Sulfadiazine(0.5-2.0 g q6h):This regimen only for use in case of concurrent toxoplasmosis. Drug resistance in PCP A. Sulfonamide Resistance
a. Due towidespread use of sulfa drugs for malaria and bacterial infection.
b. Causes of resistance:
c. Mutations in the primary sequence of the DHPS gene as in E.coli and and other pathogen.
d. Non- synonymous (resulting in changes in the encoded amino acid) DHPS mutations as in Pneumocystis jirovecii. B. DHFR resistance
a. Few DHFR mutations have been identified in Pneumocystis despite of widespread use of trimethoprim or pyrimethamine.
b. For the human Pneumocystis- derived DHFR yeast strain, trimethoprim and pyrimethamine were both weak inhibitors.
c. Trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively. C. Atovaquone resistance
a. Overall, findings are consistent with the development of atovaquone resistance after selective pressure is exerted. D. Pentamidine and Clindamycine-Primaquine
a) Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported. Stud’s limitations 1. The absence of a culture system precludes standard susceptibility testing. 2. No in vitro culture system for propagation of Pneumocystis. 3. No consistent definition of clinical failure exists.
The level of evidence provided by this article: This is a narrative review article with level of evidence grade 5.
Pneumocystis Jirovecii PJ :
Is the most common opportunistic infection encountered in immune-compromized patients such as HIV ,transplant recipients and congenitally immune deficient.
Its associated with Pneumocystis Jirovecii pneumonia PJP as the cardinal presentation of this fungal infection. PJ:
its difficult to culture this fungi. its extremely ubiquitous that most of the infants are tested antibodies positive towards the end of first year. The source of infection is not clearly identified, as the it was discovered that more than one genotype might infect human being several times and could stay latent for long time before being reactivated by immune suppression of the host.
Reservior is uncertain, it might be the infected humen being or trees and grass shedding the fungus.Animal sourse is not proved as different species are causing infection in varied animals. Rout of infection:
Its either a current infection or reactivation of latent infection. Tropisim:
once it enters the body through respiratory pathway, it dwells in type I alveolar cells attached to its surface.Without treatment its fatal when causing pneumonia.
In HIV patients its commonly encountered when CD4 T-lymphocytes below 200.
This factor is not applicable in other conditions such as kidney transplant on immune suppressants. Treatment:
Its sensitive to antifolate , atovagoune and Macrolides. It was found that Trimethoprim-Sulfamethoxazol is the most effective in prophylaxis and treatment , by inhibiting dihydrofolate reducatse enzymes DHFR and dihydrofolate synthase enz. DHFS.
PJ was reported to show resistance to Sulfa and Atovagoune resultant fron selective pressure. owing to extended usage of the same particularly with lower doses of 80/400 per day ,mutation of DHFS was reported to cause resistance as well.
Better understanding of genomic system and development of culture system is promising for better understanding of this micro-organism.
It is a narrative study with level of evidence 5.
Introduction Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia. There is decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of HIV-1 antiretroviral regimens
The organism Initially considered as a new form of Trypanozoma cruzi Pneumocystis was first established as a human pathogen by Jirovec in 1952 As compared to fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
Transmission and Infection P. jirovecii organism cannot be cultured in vitro Human hosts can be infected with more than one strain of Pneumocystis jiroveci Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli. It attaches tightly to the surface of type I alveolar cells Adherence is primarily mediated by the major surface glycoprotein (MSG) The antigenic variation in MSG serves for avoiding the host immune response
Drug Treatment The main agents include antifolate drugs, diamines, atovaquone, and macrolides Pentamidine isethionate was the fi rst drug used to successfully treat PCP in 1958. Combination of sulfadoxine and pyrimethamine was used in 1960 Trimethoprim–sulfamethoxazole (TMP–SMX) for both treatment and prophylaxis of murine and then human PCP in 1977 Other drugs include – sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine
Prophylaxis Primary in patients with HIV and oral candidiasis. Secondary in all those who had who had first episode. Trimethoprim and sulphamethoxazole stanadard of care for treatment and prevention.
Treatment Trimethoprim and sulphamethoxazole Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX Side effects-rash, fever and leukopenia, Hepatotoxicity , interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis. Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred
Pentamidine Given by slow IV. It has renal hepatic, pancreatic and haematological toxicity.
Dapsone- Trimethoprim Quite effective Can have allergic reactions
Clindamycim- Primaquine Can have side effects like rash , diarrhoea and liver toxicity.
Atovaquone Can be used in mild disease
Sulphonamide resistance Exposure to sulpha drugs DHPS mutations occur at nucleotide positions 165 and 171 leading to amino acid change Currently identified DHPS mutations may confer only low-level sulfa resistance
DHFR Resistance There is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors
Atovaqupone It depletes ATP leading to death of organism Drug resistance can develop
Pentamidine and Clindamycine–Primaquine These are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered
Limitations The absence of a culture system precludes standard susceptibility testing No consistent definition of clinical failure Nonadherence in presumed failure of prophylaxis can be difficult to assess It may difficult to know that slow treatment response with continuing fever is caused by the infection or by the treatment
What is the level of evidence provided by this article? Narrative review Level V
Introduction : Pneumocystis jirovecii is an opportunistic pathogen that causes serious lung infections in immunocompromised individuals. The incidence of P. jirovecii pneumonia (PCP) ranges from 0.6 to 14% in renal transplant recipients who do not receive prophylaxis despite active antibiotic treatment. Mortality from it reaches 50%. PCP remains a serious opportunistic infection among severely immunosuppressed patients who do not receive adequate chemoprophylaxis. The Organism: Pneumocystis was considered as a protozoon and single species based on its morphologic features, its resistance to classical antifungal agents and the effectiveness of certain drugs used to treat protozoan infections. The organism has recently been placed in a group of fungi entitled the Archiascomycetes Pneumocystis organisms have been identified in most mammalian species in which it has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species specificity among its mammalian hosts Transmission and Infection: More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen. Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli In rare cases organism have been detected in other organs, After inhalation, the organism attaches tightly to the surface of type I alveolar cells Adherence is primarily mediated by the major surface glycoprotein (MSG) . This protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family. MSG is a family of highly polymorphic proteins that are repetitive and distributed throughout the Pneumocystis chromosome. Therapy: The main drugs used to treat and prevent PCP include antifolates, diamines, atobaquone, and macrolides. Between 1974 and 1977 Hughes et al. We found that the combination trimethoprim-sulfamethoxazole (TMP-SMX) is effective for both treatment and prevention of murine and late-stage human PCP (37-39). TMP-SMX is as effective for treatment as intravenous pentamidine and is still used for treatment. select. In addition, TMP-SMX is the standard for prevention as it is the most effective chemical prophylaxis against Pneumocystis pneumonia. Prophylaxis: HIV-infected patients develop PCP at CD4 counts higher than 200 cells/mm3 Patients with congenital immune deficiencies, particularly X-linked immunodefi ciency with hyper-immunoglobulin M and SCID, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989 Secondary prophylaxis should be offered to all patients following an episode of PCP. In HIV patients receiving prophylaxis; prophylaxis can safely be interrupted if immune function is improved above a CD4 count of 200 cells/ìL for at least 3 months following antiretroviral therapy In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP. Prophylaxis should be offered TMP–SMX prophylaxis is relatively well tolerated Treatment of PCP: The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR) The earliest clinical trials to treat PCP were performed with sulfadiazine plus pyrimethamine on the assumption that these drugs would have synergistic action against pneumocystis, as against plasmodia Sulfonamide Resistance The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii. Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many types of bacteria Recently, Saccharomyces cerevisiae was used as a model to study P. jirovecii resistance to DHPS. Limitations of Pneumocystis parasitic drug resistance studies Standard culture systems are lacking. There is no clear definition of clinical failure. Contribution of non-compliance due to prophylaxis failure . Conclusion : Mutations of resistance to sulfanilamide drugs and atovaquone in P. jirovecii as a result of the selective pressure resulting from the widespread use of PCP prophylaxis. The clinical effects of currently described mutations are You look humble. DHPS mutations in codons 55 and 57 are associated with failure of low-dose sulfa prophylaxis, but there is no conclusive evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
This article is level v
I like your analysis of the level of evidence, and summary. Would have any personal experience of sulfa resistance of PCP? Please use bold or underline for headings or sub-headings to make it easier to read
Pneumocystis jirovecii, formerly known as Pneumocystis carinii, is a fungus that causes PCP in immunocompromised patients. Its prevalence increased throughout the era of HIV diagnosis. The advent of PCP chemoprophylaxis and the emergence of HIV antiretroviral treatment have led to a remarkable decline in the disease’s occurrence.
Organism
Chagas discovered it in Guinea pigs and Carini in rat lungs early in the 20th century. The organisms were a new Trypanozoma cruzi strain. In 1942, Dutch researchers van der Meer and Brug recorded three occurrences of pneumocystis in humans. In 1952, Jirovec discovered that pneumocystis caused interstitial plasma cell pneumonia in premature or malnourished orphans.
Based on its morphology, Pneumocystis was regarded a protozoon and single species in the 20th century, although it resists standard antifungals and several protozoan infection medicines. rRNA sequences and genome size placed P. carinii in the fungal kingdom in 1988. Pneumocystis species are an early divergent fungal line, according to phylogenetic evidence. The Archiascomycetes fungi now include the organism. Pneumocystis has a weak cell wall, one nuclear ribosomal RNA locus, and little or no ergosterol, unlike most fungi.
Pneumocystis jirovecii, named after Otto Jirovec, who first described the microorganism in humans, was renamed in 2002 due to its genetic and functional uniqueness.
Transmission & infection
Early childhood infection with P. jirovecii occurs with a high incidence in all geographic regions, suggesting that P. jirovecii organisms are widespread. The organism becomes dormant and is only awakened in immunocompromised people; antibodies against it are typically generated in the first year of life; and it can cause rapid newborn death. The organism has a specific tropism towards the lung, where it is located, but it can also be discovered in other organs. When an organism is inhaled, it adheres to type 1 alveolar cells. This adhesion is encoded by a large surface protein that is abundant on the organism’s surface and is polymorphic, so evading immune reaction.
Treatment/Drugs history
Pentamidine isethionate was the first PCP treatment in 1958. Sulfadoxine-pyrimethamine was utilized in the 1960s. Sulfadiazine and pyrimethamine were used 1966. Trimethoprim–sulfamethoxazole (TMP–SMX) was effective for treatment and prevention of mouse and human PCP between 1974 and 1977. TMP–SMX is as effective as intravenous pentamidine for treatment. TMP–SMX prevents PCP best. Sulfadiazine, atovaquone, clindamycin, trimetrexate, dapsone, and aerosolized pentamidine are other effective treatments.
Prophylaxis
PCP can occur in HIV patients with a CD4 count below 200, but it can also develop with a count above 200, making it an inconsistent predictor for PCP susceptibility.
Chemoprophylaxis is used as main prophylaxis for HIV patients with CD4 less than 200 and can be stopped when CD4 rises above 200 for 3 months after anti-retroviral treatment.
All PCP patients can receive secondary prophylaxis.
HIV individuals get more TMP-SMX adverse effects include rash and myelosuppression.
TMP-SMX is well-tolerated, inexpensive, and available for preventative treatment of cancer, SOT, and high-dose steroid patients.
Treatment of PCP
Untreated PCP causes respiratory failure and mortality, thus early detection and treatment are crucial to save lives. Immunocompromised patients with low-grade fever, dry cough, shortness of breath, and hypoxia should be tested for PCP.
Antifolate medications block de novo folate synthesis by inhibiting dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR). TMP–SMX use may cause rashes, fever, and leukopenia which usually appear after 7 days of treatment. Transaminase-raising hepatotoxicity occurs. Sulfamethoxazole has caused interstitial nephritis, renal calculus, anaphylactoid responses, and pancreatitis. Trimethroprim can cause hyperkalemia. These toxins rarely kill, although Stevens–Johnson syndrome can.
Pentamidine is nephrotoxic, pancreatic, and has a high rate of toxicities such hypotension and mortality. It should be given as an intravenous infusion.
HIV treatment lasts 3 weeks, non-HIV 2 weeks.
HIV, cancer, SOT, and high-dose steroid users enhance the requirement for PCP prophylaxis, which increases sulpha resistance and the probability of alternative medications being introduced.
· PCP is one of the most common opportunistic infection, fungal in nature, that occurs among immunocompromised individuals as HIV with WBC< 200 cells/mm3, cancer patients with chemotherapy and transplant recipients with immunosuppressive medications.
· It was previously considered from the protozoa, however it is now classified as fungal infection.
· It is unique from fungi that has RNA and lack strong dell wall with excess ergosterol.
· Pneumocystis carinii found only in rates, while in human it is called Jirovecii.
· Mode of transmission are air borne, may be nosocomial or reactivation of old infection.
· It has lung tropism and attacks type I alveolar cells.
· Pentamidine can be given either IV or aerolized, while SMX-TMP can be given either oral or intravenous.
· ⭐Not all drugs that can be used for PCP treatment are effective for chemoprophylaxis.
o Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine can be used for both prophylaxis and treatment.
o ⭐ IV pentamidine and clindamycin–primaquine are not effective for chemoprophylaxis.
· 👉 Standard prophylaxis is indicated for 3-6 months after kidney transplantation.
· 👉 SMX-TMP is the most effective and cheap chemoprophylaxis agent, with relatively few side effects as neutropenia, hepatitis and interstitial nephritis. Single strength is better than double strengthformulation (same efficacy with fewer adverse effects).
· 👉 Alternatives to SMX-TMP in treatmentof PCP:
o Oral dapsone + trimethoprim.
o Oral clindamycin +primaquine.
o IV pentamidine.
· 👉Adjuvant steroid therapy(either oral or IV) is indicated in moderate-severe cases if hypoxemia and PaO2 is <70 mmHg.
· Wide spread use of SMX-TMP has increased its resistance through certain mutations involved in sulfa and atovaquone drug resistance.
· 👉 Definition of resistance is difficult, as clearance of the organism is not evident in all cases after ttt (persistent detection of PCP in BAL). .. 👉Sulfonamide. Resistance
It is caused by mutations in the primary sequence of the DHPS gene, mostly at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).
This association was demonstrated clearly in several clinical studies.
The available data suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis.
The major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
Several mutations can produce high-level resistance.
👉 several resistance mechanisms have been identified in penatmidine and primaquine.
I like your analysis of the level of evidence, and summary.
Would have any personal experience of sulfa resistance of PCP? Typing whole sentence in bold or capitals equals to shouting !
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia (PCP), in immunocompromised patients.
PCP is a serious opportunistic infection among heavily immunosuppressed patients if not receiving appropriate chemoprophylaxis.
The Organism
P. carinii is now regarded as a fungus.
In contrast to most other fungi, it has only one copy of the nuclear ribosomal RNA locus and has a fragile cell wall.
Pneumocystis organisms have been identified in most mammalian species and there is phylogenetic difference between the host species.
The organism infecting humans was renamed Pneumocystis jiroveci.
Transmission and Infection
P. jirovecii organisms are ubiquitous and primary infection happens in early childhood.
Following primary infection, the organism becomes latent, later manifesting clinically if the patient becomes heavily immunosuppressed.
The clinical disease PCP may occur with more than one strain.
Pneumocystis has specific tropism for the lung, where it exists in the alveoli.
Adherence is primarily mediated by the major surface glycoprotein (MSG).
MSG shows high level of antigenic variation which serves for avoiding the host immune response.
Drug Treatment
Trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of PCP.
Other drugs, include include dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone.
Other alternatives include azithromycin, doxycycline, and caspofungin.
Prophylaxis
Recommended in HIV and non-HIV infected individuals, such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy.
The most efficient, cheap and widely regimen is daily TMP–SMX (80/400 mg).
There are other alternatives include, dapsone, Dapsone with Pyrimethamine plus Leucovorin, aerosolized Pentamidine and Atovaquon.
Treatment of PCP
PCP is invariably fatal if left untreated.
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
DHPS catalyzes the condensation of p-aminobenzoic acid (PABA).
Sulfa drugs are structural analogs of PABA and inhibit DHPS.
Once there is a high suspicion therapy should be instituted promptly if the diagnostic procedures will be delayed.
TMP–SMX and pentamidine (slow intravenous infusion) appear to have roughly comparable efficacy.
Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy, caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
This inflammation can be reduced by corticosteroids. Corticosteroids could reduce mortality in patients with moderate or severe disease.
Adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh).
Sulfonamide Resistance
The wide use of TMP–SMX and dapsone for therapy and prophylaxis of PCP may lead to sulfa resistance in in P. jirovecii.
Sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).
Documenting resistance is difficult in Pneumocystis because it cannot be cultured.
The DHPS enzyme of Saccharomyces cerevisiae has high functional and genetic similarity to the DHPS of P. jirovecii, Why used to study P. jirovecii DHPS resistance.
Using this model, two recent studies reported that the double DHPS mutations, Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding.
A clear association between previous exposure to sulfa drugs and DHPS mutations has been shown in several clinical studies.
Importantly, DHPS mutations have also been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
The clinical significance of DHPS mutations, specifically when using a sulfa based regimen, has been controversial.
The available data suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis.
The major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
Additional mutations may develop that produce high-level resistance.
DHFR Resistance
Trimethoprim and pyrimethamine, (which are used in combination with sulfonamides) are competitive inhibitors of dihydrofolate reductase (DHFR).
They are used in combination with sulfonamide.
Several studies have reported DHFR mutations.
But no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Atovaquone
Is used to prevent and treat P. jirovecii, Plasmodium spp, Toxoplasma gondii and Bebesia spp.
Atovaquone is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex.
Studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.
Studies of cytochrome b gene of Pneumocystis, were consistent with the development of atovaquone resistance.
Pentamidine ,Clindamycine–Primaquine
Possible resistance mechanisms have yet to be discovered and reported.
Conclusion
The widespread use of PCP prophylaxis, has led to mutations involved in sulfa and atovaquone drug resistance in P. jirovecii.
If additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX.
Complete physical maps and gene sequences of P. jirovecii, will enable identification of new polymorphic regions and lead to the development of a culture system, which will help in mechanisms of drug resistance
SUMMARY Introduction
PCP is a serious opportunistic infection in healthy immunosuppressed individuals not on prophylaxis.
Primary infection occurs in childhood with equal geographic distribution and can lead to upper or lower respiratory tract manifestations.
The organism can remain latent, later manifesting with disease when the host is immunosuppressed.
Recent studies also show that humans can be infected with more than one strain. Therefore the clinical disease can be due to reactivation of the latent organism or infection with a new strain.
Transmission and infection
Its environmental source is not known though transmission is thought to be airborne and there is no cross-infection with animal host.
The fungi has tropism for the lungs and it rarely causes extra-pulmonary disease.
Drug treatment
Drugs used to treat and prophylaxis include antifolate drugs, diamines, atovaquone, and macrolides.
Anti-fungal have no activity against it.
TMP-SMX is as effective as iv pentamidine and is the drug of choice for treatment and chemoprophylaxis.
Not all drugs used for treatment are effective chemoprophylaxis.
Dapsone, dapsone– trimethoprim, atovaquone and aerosolised pentamidine are effective for prophylaxis, however, iv pentamidine and clindamycin–primaquine are not.
Prophylaxis
Low CD4 counts <200cells/ml is associated with increased risk of PCP in HIV patients and they should be offered primary prophylaxis. Once the CD4 counts >200cells/ml for at least 3 months then the prophylaxis can be stopped. Secondary prophylaxis should be offered after treatment for PCP.
Other patients at risk of PCP are patients on longterm steroids, patients on chemotherapy, transplant recipients on immunosuppressive agents and patients with acquired and congenital immunodeficiencies.
HIV patients have a high frequency of adverse effects eg myelosuppression and rash with TMP-SMX.
TMP/SMX 80/400mg daily is as effective as 160/800mg daily.
Treatment
The beginning of HIV pandemic the mortality of PCP was 30-40% rising to 70-90% in respiratory failure, this has decreased to 5-15% due to early recognition, better diagnostic and treatment.
Antifolate drugs are the most potent drugs for treatment of PCP, they block denovo synthesis of folate via inhibition of DHPS or DHFR.
HIV infected patients have drug toxicity with TMP-SMX ranging between 24-57% and usually occurs within 7 days after initiation. Some adverse effects are less life threatening like rash and leucopenia, though it can cause SJS which is life threatening. TMP-SMX in the kidneys can cause interstitial nephritis, renal calculus formation and hyperkalemia
Pentamidine on the other hand has been associated with treatment limiting toxicities in the ranges of 13-80%. The rapid IV infusion is associated with hypotension, while IM injections was associated with sterile abscesses, the inhaled pentamidine is associated with poor efficacy thus its given as slow infusion.
Pentamidine is also toxic to several organs, in the kidneys it causes glomerular and tubular damage, in the pancreas it causes an insulin surge leading to hypoglycaemia, and in the heart can prolong the QT leading to torsades de pointe.
Other treatment alternatives are dapsone-pyrimethamine, clindamycin-primaquine and atovaquone.
Dapsone has not been studied as a single drug thus should not be used alone.
Dapsone-pyrimethamine is potent as TMP-SMX, however its efficacy is only demonstrated in mild -moderate PCP. It also cross reacts in 50% sulphur allergic patients thus doesn’t offer much advantage over TMP-SMX.
Clindamycin-primaquine works in a different metabolic pathway, however clindamycin leads to a high incidence of hepatitis, rash and diarrhoea.
Atovaquone though it also works in a different metabolic pathway it is not as potent as TMP-SMX and its efficacy has only been demonstrated in mild PCP.
Duration of treatment has not been tested however it is recommended that HIV patients should be treated for 2 weeks and non-HIV for three weeks.
Sulfonamide resistance
Resistance to sulphonamides has increased in both bacteria and parasites this has limited its efficacy.
Resistance is caused in mutations in the DHPS gene.
However documenting this resistance is difficult because P.Jivorecii can’t be cultured.
A clear association between prior sulpha exposure and presence of DHPS mutations has been shown in several studies.
Interestingly some studies have documented the presence of DHPS mutation and no prior sulpha exposure, this could be due to transmission of a mutant strain.
The significance of the mutant strain in terms of drug resistance and failure to comply to treatment is unknown.
This is further supported by the fact that patients with mutant strains have been successfully treated with TMP-SMX.
This DHPS mutations could thus only confer low level strain resistance that allows the organism to survive in low prophylactic dose. This can be overcome by use of high dose TMP-SMX.
DHFR resistance
Diaminopyrimidines, trimethoprim and pyrimethamine are competitive inhibitors of DHFR.
Some bacteria and parasitic species like plasmodium falciparum have developed resistance to DHFR.
However despite widespread use of TMP-SMX use there are few DHFR mutations in P.jivorecii.
Currently there is no evidence that widespread use of TMP-SMX has lead to DHFR resistance with clinical significance.
Atovaquone
It’s used to treat and prevent diseases caused by P. jirovecii, Plasmodium, Toxoplasma gondii and Bebesia.
Mutations in plasmodium and toxoplasma have been identified in vitro and this confers resistance to atovaquone.
Since P.jivorecii can’t be cultured resistance testing have not be done.
Presence of PCP mutation to atovaquone have been found not to affect survival of the patients.
Pentamidine and Clindamycine–Primaquine
Possible resistance mechanism are yet to be discovered and reported.
Conclusion
Mutations to sulpha and atovaquone have developed in P.Jivorecii via selective pressure by widespread use of prophylaxis.
DHPS mutation is implicated in low dose sulpha prophylaxis but this can be overcome by high dose sulpha.
Use of PCP prophylaxis in HIV patients in third world countries may lead to high level resistance.
Thus more research is required.
Level of evidence
This is a narrative review hence level V.
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, PCP in immunocompromised individuals.
Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodefi ciencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen.
With the AIDS pandemic PCP emerged as the most common.
The peak incidence of PCP was observed in the late 1980s and early 1990s.
There has been a decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens.
PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis The organism
Pneumocystis were identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini.
These investigators mistakenly considered the organisms as a new form of Trypanozoma cruzi.
Pneumocystis organisms have been identified in most mammalian species in which it has been searched for.
The level of genetic divergence between Pneumocystis organisms infecting different mammals is greater than the degree of divergence observed between certain fungi classified as distinct species .
Hominis for Pneumocystis infecting humans and P. carinii f.sp.
Carinii for one of the two species infecting rats .
pneumosyctic jirovesii , in honor of Otto Jirovec, who was among the fi rst to describe the microbe in humans. Transmission and infection
Since P. jirovecii organism cannot be cultured in vitro, knowledge about its biology has been difficult to obtain.
Antibody and PCR fi ndings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that.
When the organism is obtained initially as a primary infection, it is not clear whether an immunocompetent host develops a transient disease.
Suggests that human hosts can be infected with more than one strain of pneumosystic jirovesii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms .
Adherence is primarily mediated by the major surface glycoprotein (MSG),
This protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family.
Several genes, which in other fungi are involved in mating, pheromone responsiveness, and responses to environmental changes, have been demonstrated in Pneumocystis, suggesting that the organism has a sexual replication cycle that responds to environmental changes in the lung. Drug treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
1977, studies led by Hughes et al established that the combination of trimethoprim—sulfamethoxazole (TMP—SMX) is effective for both treatment and prophylaxis of murine and human PCP .
TMP—SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Trimethoprim, atovaquone and aerosolized pentamidine are effective for prophylaxis.
There are other drugs that have in vitro activity or anecdotal anti-PCP activity in humans and could have a role in managing human disease if all other alternatives were not feasible.
Prophylaxis
Among HIV-infected patients, the occurrence of PCP is closely related to the CD4 count: With lower CD4 counts, the risk of PCP increases.
While a count of 200 cells/mm is often used as an indicator or susceptibility, HIV-infected patients do develop PCP at counts higher than.
X-linked immunodeficiency with hyper-immunoglobulin M and SCID, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP.
After the publication of a convincing study by Fischl et al, PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm in 1989.
HIV-1 infected patients with oral candidiasis or a CD4 count less than 200 cells/μL, should be offered primary prophylaxis. Treatment PCP
Mortality rates have dropped to 5—15%.
This appears to be a consequence of earlier recognition of the infection, the introduction of adjuvant corticosteroids to patients with moderate-to-severe PCP as defined by a PaO2 of less than.
Drug toxicity occurs in 24—57% of HIV-infected patients treated with TMP—SMX.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP—SMX
This drug is only available orally, and does not appear to be as potent as TMP—SMX (66).
Many patients experience progressive oxygen desaturation during the first 4—5 days of therapy
This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
On the basis of these results, adjunctive steroids are recommended for all patients with severe disease (PaOs < 70 mmgh)
Sulphonamide resistance
The widespread use of TMP—SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa resistance could develop in P. jirovecii.
By site-directed mutagenesis, the in vitro effects of mutations identical to the DHPS mutations in P. jirovecii can be investigated
Using this model, two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding.
Several studies have reported a significant association of DHPS mutations with failure of low-dose sulfa prophylaxis
While initial case reports suggested that patients with mutant DHPS strains had increased risk of failing sulfa therapy or prophylaxis, subsequent studies have not supported such a conclusion.
Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance DHFR resistance
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dehydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8-tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids
They are used in combination with sulfonamides.
Several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Clinical resistance is classically defined as the persistence or progression despite the administration of appropriate antimicrobial treatment
This definition is problematic when applied to PCP.
Clinical resistance has been investigated by genotyping of P. jirovecii isolates from patients who develop PCP in spite of prescribed chemoprophylaxis.
In theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure
Atovaquone
1,4-hydroxynaphthoquinone) is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., toxoplasma gondii and Bebesia .
Atovaquone is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc complex.
Binding of atovaquone to the ubiquinol oxidation pocket of the bc complex and the Rieske iron—sulphur protein disrupts electron transport and leads to collapse of the mitochondrial membrane potential.
This presumably results in the depletion of ATP within Pneumocystis and leads to killing of the organism.
In vitro studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.
In vitro studies of the saccharomyces cerevisiae cytochrome bc complex and atovaquone have demonstrated binding to the ubiquitol pocket.
These findings are consistent with the development of atovaquone resistance after selective pressure is exerted Conclusion
In spite of the inability to culture the organisms, it is clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
It is possible that if additional mutations arise, high-level sulfa resistance could emerge and lead to diminished efficacy of TMP—SMX.
This would lead to the loss of the most effi cient and inexpensive therapy for PCP.
These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually lead to the development of a culture system
Drug Resistance in Pneumocystis jirovecii: Introduction:
Pneumocystis jiorveci is serious infection cause pneumonia in immunocompromised patients. The peak incidence of infection appear in 1980-1990 but in recent years it is decline because introduction of prophylaxis of PCP and treatment of HIV-1 antiviral therapy. Microorganisms:
Pneumocystis jirovecii previously named as Pneumocystis carinii and classified as a protozoa. Currently, it is considered a fungus based on nucleic acid and biochemical analysis and named as P. jirovecii organism. Transmission and Infection:
It’s type of fungus, Environmental cause of pneumocystis still not identified and transmission from person to persons by air. Drug Treatment:
The main drug used in prophylaxis of pneumocystis jiorvecii is:
Antifolate drugs
Diamines
Atovaquone
Macrolides
In 1958, the first drug of choice was pentamidine isethionate.
In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystosis in Iran.
In 1966, sulfadiazine and pyrimethamine was used as trials.
Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP. TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
These drugs like sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine shows effective therapy against pneumocystis jiorvecii. Not all drugs are effective for therapy it’s also effective for chemoprophylaxis.
Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis. Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
There are some drugs have activity in vitro like azithromycin, doxycycline, and caspofungin. Prophylaxis:
Patients with HIV
Congenital immunodeficiency
Patients with long term corticosteroids
Patients on chemotherapy such as fludarabine, ATG.
Primary prophylaxis should be considered in patients with HIV-1 with candidiasis or CD4 count less than 200 cell/ul.
Secondary prophylaxis against PCP should be considered in all patients exposed to PCP.
In non-HIV infected individuals, conditions such as organ transplantation, high dose steroid treatment and/or high dose chemotherapy may has high risk of PCP. Prophylaxis should be stared.
The best one and cheaper is TMP–SMX.
Dose of TMP–SMX (septrin), 400/80 mg daily is effective and is associated with few side effects than 160/800mg daily.
Side effects of septrin is skin rash, fever, anemia , neutropenia Hyperkalemia Hepatitis Nephritis and Anaphylactoid reaction. Treatment of PCP:
PCP is serious condition may be fatal if not treated. Mortality rate reached to 30-40% of cases and to 70-80% in cases with respiratory failure. adjuvant steroid to patients with moderate to severe PCP with PaO2 of less than 70mmHg or patients with HIV with CD4 less than 200cell/ ul. The treatment of PCP should be stared as early as possible even symptoms non specific ( dry cough, low grade fever and dyspnea), with presence of risk factors in immunocompromised patients or chest X ray abnormal and the first drug of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase or dihydrofolate reductase.
Pentamidine is very toxic associated with nephritis and pancreatitis and hypoglycemia and it’s may prolongs the QT interval, and cause torsades de pointe in some reported cases.
Alternative to o septrin and pentamidine include dapsone pyrimethamine, clindamycin primaquine, and atovaquone.
Clindamycin associated with high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
Atovaquone is used alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Dapsone pyrimethamine is used in mild to moderate cases with PCP.
Many patients shows progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration is caused by the drug induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. This inflammation can be reduced by corticosteroids. Sulfonamide Resistance:
Resistance develop due to wide use of septrin as prophylaxis and treatment of PCP, Falciparum malaria and bacterial infection. There’s marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and Enterobacteriaceae. This resistance against bacterial infection occur due to mutations of primary sequence of the DHPS gene. Many clinical studies investigated the frequency and significance of DHPS mutation in P jiorvecii. There’s large geographical variations in resistance to sulfa associated with DHPS mutations and some studies shows significant association with the failure of pyrimethamine–sulfadoxine prophylaxis and the Pro57Ser mutation. Also the major cause of resistance is poor adherence to chemoprophylaxis and mutation of DHPS. DHFR Resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR); so mutations to DHFR in Pneumocystis DHFR lead to resistance septrin but still no definitive evidence. Atovaquone:
It’s used to treat and prevent P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. It’s structural near to mitochondrial protein and competitively binds to the cytochrome bc1. However mutations of cytochrome bc1 gene in Plasmodium spp., Toxoplasma gondii and Pneumocystis leading to unresponse to Atovaquone but Survival from PCP did not differ between patients with or without mutations. Pentamidine and Clindamycine–Primaquine:
Pentamidine and clindamycine primaquine are used for prevention and treatment of PCP, and resistance to these agents can be happen but still rare.
What is the level of evidence provided by this article?
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia.
Pneumocystis were identified early in the last century in guinea pigs.
Pneumocystis was first established as a human pathogen when Jirovec in 1952.
P. jirovecii organism cannot be cultured in vitro.
Transmission of infection:
P. jirovecii organisms are ubiquitous.
Its environmental source is unknown. Organisms may be coming from inanimate environmental sources, or may be spread by healthy humans.
The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extra-pulmonary sites.
Prophylaxis:
PCP prophylaxis became a standard of care for HIV-infected patients and Immuno-compromised patients.
The most efficient, cheap and widely used regimen is daily cotimoxazole. It is relatively well tolerated.
To be noted that not all drugs that are effective for therapy are also effective for chemoprophylaxis.
Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
In kidney transplantation:
-The risk depends on the intensity of IS and occurrence of host versus graft
disease or rejection.
-Prophylaxis is recommended for at least 6 months. Treatment of PCP:
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
The optomal duration has never been tested. In HIV patients, at least 2 weeks.
1- First choice: Trimethoprim– sulfamethoxazole
can be given orally (2 DS/8hrs) or IV.
Adverse effects generally occur after 7 days of therapy
Trimethroprim can be associated with hyperkalemia.
fatal cases of Stevens–Johnson syndrome have occurred.
2- Alternative drugs:
Dapsone plus trimethoprim: oral doses.
effective in mild and moderate cases
Clindamycin plus primaquine
IV pentamidine: toxicity is common
rapid infusion associated with hypotension and even death
oral Atovaquone: expensive , well tolerated and effective in mild cases.
3- Adjunctive therapy: Prednisone in patients with room air PaO2 < 70 mmhg
Standard of care for moderate and severe case to counteract the
alveolar inflammation induced by PCP death by treatment.
Sulfonamide resistance:
sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 and 57.
Large geographical variation in the prevalence of DHPS mutations has been reported, ranging from 7 to 69% of isolates.
mutation was linked to previous exposure to sulfa drugs and non-adherence to prophylaxis. yet, it was identified without previous exposure.
sulfonamide resistance is associated with failure od low dose of sulfa prophylaxis.
The majority of patients with mutant DHPS strains have been successfully treated with trimethoprim–sulfamethoxazole or dapsone–trimethoprim.
DHFR resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR).
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
The study of drug resistance in P. jirovecii has been and continues to be difficult. due to failure of in vitro culture which precludes standard susceptibility testing and has greatly limited.
Another problem is that no consistent definition of clinical failure exists.
Pneumocystis jirovecii -fungal organism cause PCP in immunocompromised patients
Incidence increased with the era of definite diagnosis of HIV
Incidence decreased dramatically with era of chemoprophylaxis against PCP, and HIV antiretroviral treatment.
Organism
Identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini and was considered as a new form of Trypanozoma cruzi.
first described in humans in 1942 by two Dutch investigators, van der Meer and Brug
first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
Twentieth century, it was considered as a protozoon and single species based on its morphologic features, but has resistance to classical antifungal agents and the effectiveness of certain drugs used to treat protozoan infections.
1988-analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom was done. Phylogenetic data suggest thatPneumocystis is an ancient organism without any close relatives, Pneumocystis species represent an early divergent line in the fungal kingdom.
Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
2002-because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was among the first to describe the microbe in humans. Transmission and Infection
Primary infection happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
becomes latent, and reactivated only in immunocompromised patients, and antibodies against it usually formed in the first year of life, also it may lead to sudden infant death.
has specific tropism to the lung, where it exists, but may found in other organs.
When inhaled, it attach to type 1 alveolar cells, this adherence is encoded by major surface protein in the organism which is abundant on its surface and it is polymorphic escaping immune response. Drug treatment
Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP.
TMP–SMX
is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.Prophylaxis
CD4 count is usually used as indicator for PCP susceptibility in HIV patientsif less than 200, PCP can be developed but also can be developed in count more than 200, so it is unreliable marker for PCP in HIV patients.
Chemoprophylaxis used as a primary prophylaxis to HIV patient with CD4 less than 200 and can be interrupted at any time when CD4 raised more than 200 FOR 3 months after anti-retroviral treatment.
Secondary prophylaxis can be offered to all patients after attack of PCP.
TMP-SMX has much side effects in HIV patients than non-HIV patients like rash and myelosuppression.
In non-HIV patients like cancer, SOT, patients with high dose steroid-TMP-SMX can be given as a prophylactic therapy Treatment of PCP
The treatment of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
TMP–SMX-Adverse effects
generally occur after 7 days of therapymost commonly include rash, fever, and leukopenia.Hepatotoxicity characterized by elevated transaminases also occurs.There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported.TMP-SMX – associated with hyperkalaemia.These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.Pentamidine
associated with a high frequency of toxicities, like hypotension and death, it is related to rate and route of administration,should be given as iv infusion, pentamidine is nephrotoxic and also has pancreatic toxicity.dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone.
Duration of treatment 2 weeks in non-HIV patients and 3 weeks in HIV patients.
PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
The Organism:
Identified early and classification and name evolving from protozoon to fungal microorganism and fro PCP to PJP after scientist who classify and discover them. Genetic divergence between Pneumocystis organisms infecting different mammals is greater than the degree of divergence observed between certain fungi classified as distinct species.
Transmission and Infection:
Primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
Following primary infection, the organism becomes latent, later manifesting clinically if the patient becomes profoundly immunosuppressed. Acquisition of an airborne pathogen may also lead to infection.
Drug Therapy:
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP.
Proven activity for therapy, including sulfadiazine plus pyrimethamine, Atovaquone, clindamycin plus pyrimethamine, trimetrexate, Dapsone and aerosolized pentamidine.
Not all drugs that are effective for therapy are also effective for chemoprophylaxis.
Dapsone, Dapsone– trimethoprim, Atovaquone and aerosolized pentamidine are also effective for prophylaxis.
Other could have a role in managing human disease if all other alternatives were not feasible. These include azithromycin, doxycycline, and caspofungin.
PCP chemoprophylaxis:
HIV patient:
Primary Prophylaxis
–HIV infected patients with oral candidiasis or a CD4 count less than 200 cells/Μl.
Secondary prophylaxis:
Should be offered to all patients following an episode of PCP. In HIV patients receiving prophylaxis; prophylaxis can safely be interrupted if immune function is improved above a CD4 count of 200 cells/μL for at least 3 months following antiretroviral therapy.
If the patient subsequently fails antiretroviral therapy and the CD4 declines to below 200 cells/μL, prophylaxis should be restarted.
Non-HIV infected individuals:
Conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP.
Regimen is daily TMP–SMX: 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily.
For patients, who have reacted to TMP–SMX, it has been shown to be safe to reintroduce TMP–SMX by dose escalation (. A variety of dosing regimens can be used with similar efficacy.
Tolerability may improve with the lower dose or the intermittent regimens.
Drug regimens for the treatment of PCP:
First choice:
Trimethoprim– sulfamethoxazole:
Dose:
Trimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h.
ADR:
Rash and fever Anemia and neutropenia Hyperkalemia, Hepatitis Nephritis AND Anaphylactoid reaction.
Alternatives Dapsone plus trimethoprim:
Dose
100 mg daily, trimeth 320 mg every 8 h.
ADR:
Rash, nausea and vomiting and fever Methemoglobinemia, leukopenia and hemolytic anemia, Liver function abnormalities; headache.
Clindamycin plus primaquine:
Dose:
300–450 mg every 6 h, 30 mg daily primaquine.
ADR:
Clostridium difficile diarrhea, nausea and vomiting. Primaquine may cause hemolysis in patients with G-6PD deficiency.
Atovaquone:
Dose:
By mouth 750 mg twice daily.
ADR:
Rash, nausea, diarrhea and headache (20%), Fever, increased transaminases and neutropenia.
Pentamidine:
Dose:
Intravenous 4 mg/kg day.
ADR:
High incidence of adverse effects, particularly hypoglycemia and nephrotoxicity Pancreatitis and IDDM. Hypotension with short infusion time Pancytopenia Q-T prolongation.
The optimal duration of therapy for PCP:
HIV-negative patients should receive 2 weeks and HIV positive patients three weeks of drug treatment.
Drug resistance:
Sulfa and Atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
Currently, the clinical effect of the described mutations seems modest.
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
Introduction
– PCP is a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
– It was rare disease and its prevalence increased with AIDS pandemic and subsequently decline with wide spread availability of chemoprophylaxis.
– PCP carries a high mortality rate.
The Organism
– Initially, Pneumocystis was considered as a protozoon.
– Recently it was re-classified as fungi entitled the Archiascomycetes.
– It is unique as it has only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
– It includes a broad family of organisms, with species specificity and genetic divergence.
– There is no cross species infection
– The organism infecting humans was renamed Pneumocystis jirovecii.
Transmission and Infection
– The organisms are ubiquitous, however; its environmental source is unknown.
– Primary infection with happens in early childhood.
– The clinical infection resulted from reactivation of latent organism or recent new infection in immunocompromised hosts.
– Likely an airborne pathogen.
– It has specific tropism for the lung (alveoli) and rarely cause extrapulmonary diseases.
– The life cycle and the mode of replication is not fully established.
Drug Treatment
-The major drug classes used for treatment and prophylaxis of PCP include: antifolate drugs, diamines, atovaquone, and macrolides.
– Pentamidine isethionate was the first drug used to successfully treat PCP
-The combination of trimethoprim–sulfamethoxazole (TMP–SMX) is treatment of choice and the most effective
chemoprophylaxis for PCP.
-Other drugs including; sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
– Not all drugs that are effective for therapy are also effective for chemoprophylaxis
Prophylaxis – In patients without HIV, CD4 counts are not a reliable marker of susceptibility.
– Primary prophylaxis recommended for HIV-patients with CD4 counts < 200 cells/mm3 with oral candidiasis till CD4 count > 200 for at least 3 months then can be interrupted, to resume treatment if count drop to < 200.
– PCP chemoprophylaxis should be offered in: SOT, Caner, high-dose steroid treatment and/or high-dose chemotherapy.
– Secondary prophylaxis should be offered to all patients following an episode of PCP.
– Several regimens are available for prophylaxis.
– TMP–SMX The most efficient, cheap and widely and relatively well tolerated by most non-HIV patients.
Treatment of PCP
-Once there is a high suspicion therapy should be instituted promptly if the diagnostic procedures will be delayed.
– Antifolate drugs: Most potent drugs for PCP treatment.
-Act by blocking de novo synthesis of folates through inhibition of dihydroperoate reductase DHPR, which catalyzes (PABA) to produce dihydropteroate.
– Sulfa drugs are structural analogs of PABA and inhibit DHPS.
– TMP/SMT; first choice; Superior efficacy, Inexpensive Oral and IV
– Drug toxicity occurs in 24–57%: Rash and fever , myelosuppression, hepatitis, interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis. Trimethroprim can be associated with hyperkalemia. Fatal SJS may occurs.
– It is associated with a better survival than pentamidine
–Pentamidine is associated with treatment-limiting toxicities occur in 13–80% of patients, toxicities, also related to route of administration, particularly hypoglycemia and nephrotoxicity, pancreatitis and IDDM. Hypotension with short infusion time, pancytopenia and Q-T prolongation.
– Alternatives therapy include:
–Dapsone should not be used alone for treatment. Dapsone–trimethoprim is effective in mild to moderate PCP , and potency comparable to TMP–SMX. Cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP–SMX.
–Clindamycin–primaquine in moderate- to-severe PCP has equivalent effect with TMP–SMX. Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
-Atovaquone; only available orally, and does not appear to be as potent as TMP–SMX. This is a good alternative to
TMP–SMX for patients with mild disease only who cannot tolerate TMP–SMX.
-Adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh) to reduce inflammation. As patients may deteriorate initially with hypoxia secondary to death of the organism, alveolar damage and the associated inflammation.
Duration of therapy
Usual recommendations are that HIV-negative patients should receive 2 weeks ,while in HIV patients 3 weeks.
Sulfonamide Resistance – Widespread use of sulfa drugs has produced high rates of resistance , and the resistance of many pathogen related to mutation in DHPD gene.
– Double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding in a consequent reduction in sulfa drug sensitivity.
– Clear association between previous exposure to sulfa drugs and DHPS mutations has been shown in all studies. Mutations were also found in patients without previous drug exposure.
– The clinical significance of DHPS mutations, specifically with regard to response to prophylaxis and therapy using a sulfa based regimen has been controversial.
– Despite the emergence of mutant DHPS strains TMP/SMX is effective prophylaxis when taken regularly and majority of patients with mutant DHPS strains have been successfully treated with TMP/SMT or dapsone–trimethoprim.
– Studies suggested that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis.
– The major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis
DHFR Resistance
-Trimetrexate is much more potent against PCP than trimethoprim in vitro.
-The combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.
– There is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of
clinical significant resistance to DHFR inhibitors.
Atovaquone – It is used to prevent and treat P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
– Competitively binds to the cytochrome bc1 complex.
– Mutation in cytochrome bc complex may confer resistance to atovaquone.
Pentamidine and Clindamycine–Primaquine
Resistance mechanisms not yet discovered.
Conclusion
-Wide spread use of PCP prophylaxis resulted inmutations involved in sulfa and atovaquone drug resistance in P. jirovecii .
– DHPS mutations are implicated in the failure of low-dose sulfa prophylaxis , but no significant resistance to high-dose sulfa therapy.
– Investigations the mechanisms of drug resistance and identification of new molecular targets and promising treatment.
Pneumocystis Jirovechii initially remains a relatively rare disease until the early 1980s when the AIDS pandemic hit the world making it one of the most common defining illnesses of AIDS. It then gained a reputation as a serious illness particularly among the immunocompromised individual until the routine use of prophylaxis slows down the incidence.
PJP classification has gone through from being initially known as a protozoan and now to being a fungus even though it has been found to be resistant to antifungal treatment. In 2002, it was named Pneumocytis Jirovechii in honour of Otto Jirovec.
Transmission and Infection
It is a ubiquitous organism that can not be cultured in-vitro.
The infection has been shown to occur in childhood and with the possibility of different strains at times
Following primary infection, the organism may remain dormant until the immune-depressive state
Pneumocystis has a tropism for lung tissue and does not know to cause infection in other organs even if found
The life cycle and mode of replication are not known till now
Drug for prophylaxis
-First choice
TMP-SMX – 480mg daily
-Alternative
Dapsone – 50mg BID or 100mg twice weekly
Dapson with Pyrimethaamine (50mg OD + 100mg weekly)
Leucovorin 25mg weekly
Pentamidine aerosolized 200mg monthly
Atovaquone – 1500mg daily
Drug Treatment
-First choice
TMP- SMX – 2 double doses TID orally, or I.V TMX-SMX (5mg/kg – 20mg/kg)
Wide-spread of TMP-SMX as prophylaxis among HIV patients with CD4 coun t less than 200cells/mm3
Widespread use as antimalaria
Wide-spread use as antibacterial
The resistance is caused by a mutation in the primary sequence of the DHPS gene codons 55 and 57
Conclusion
The growing incidence of the mutation of sulfonamide and atovaquone resistance due to the increase in the use of the drug in HIV-AIDS and the use of low doses for prophylaxis needs to be steamed by growing research into the mechanism of development of the resistance.
Introduction: Pneumocystis jirovecii, a fungal infection leads to pneumocystis pneumonia (PCP) in immunocompromised patients, especially those not receiving any chemoprophylaxis.
The organism: Pneumocystis was initially considered to be a protozoon, but later found to be a fungi. It is an ancient organism with only one copy of nuclear ribosomal RNA locus, with fragile cell wall, and miniscule ergosterol. Pneumocystis infecting humans is named Pneumocystis jirovecii.
Transmission and infection: It is ubiquitous, its environmental source is unknown, and it cannot be cultured in vitro. Primary infection occurs in early childhood causing upper of lower respiratory tract infection, or sudden infant death syndrome (SIDS). The organism becomes latent after primary infection. The organism has affinity for alveoli of lungs. Reactivation of latent infection, or recent acquisition of the airborne pathogen can lead to clinical PCP. The organism gets associated with type I alveolar call surface through MSG (major surface glycoprotein).
Drug treatment: 4 major classes of drugs available for PCP treatment include antifolates, diamines, atovaquone, and macrolide agents. Drugs might be useful for treatment but may not be useful as chemoprophylaxis.
Prophylaxis: Drugs used as prophylaxis for PCP include trimethoprim-sulfamethoxazole (TMP-SMX), the first choice, and alternative medications like Dapsone, Dapsone with pyrimethamine and leucovorin, aerosolized pentamidine, atovaquone, or pyrimethamine with sulfadiazine. Prophylaxis is important for at-risk patients like those with congenital immunodeficiency, HIV patients with oral candidiasis or CD4 count <200 cells/mm3, on high-dose, long-term steroids, on cancer chemotherapy, transplant recipients, or having received fludarabine, Alemtuzumab, or antithymocyte globulin (ATG). Prophylaxis in HIV patients can be stopped if CD4 count increases to >200 for at least 3 months, and needs to be restarted if the CD4 count falls below 200. In transplant recipients, prophylaxis should be given for 6-12 months post-transplant.
Treatment of PCP: PCP, if untreated, leads to mortality. Hence it is important to treat PCP at an early stage. Treatment of PCP should be given for 3 weeks in HIV positive patients, and for 2 weeks in HIV negative patients. Medications used for PCP treatment include:
a) TMP-SMX: It is the drug of choice, can be used orally or parenterally, is inexpensive, and has superior efficacy. It may cause rash, fever, neutropenia, hepatitis, nephritis, and hyperkalemia, pancreatitis, renal calculi, and anaphylactoid reaction. The antifolates inhibit dihydroperoate synthase (DHPS) and dihydrofolate reductase (DHFR).
b) Dapsone plus TMP: It can be used as an alternative, but may cause rash, nausea, fever, vomiting, hepatotoxicity, and hemolysis in G6PD deficiency.
c) Clindamycin plus Primaquine: It may cause diarrhea, nausea, vomiting, hepatitis, and rash. Disadvantage includes non-availability of oral primaquine.
d) Pentamidine: Given as slow intravenous infusion, it is highly effective, but has toxicity including nephrotoxicity, hypoglycemia, pancreatitis, pancytopenia, and Q-T prolongation.
e) Atovaquone: It is expensive, given orally, and is useful only for mild disease in patients who cannot tolerate TMP-SMX.
f) Dapsone plus pyrimethamine: It is given orally, and can be used for mild to moderate PCP.
g) Adjunctive steroids (Prednisone): Used in moderate to severe PCP with low pAO2 (<70 mm Hg), although associated with metabolic effects like glucose and electrolyte abnormalities.
TMP-SMX, pentamidine, and Dapsone plus TMP have similar efficacy.
Sulfonamide resistance: Prior exposure to sulfa drugs leads to development of resistance, primarily due to mutation in DHPS gene. DHPS mutation takes place at 165 and 171 nucleotide position, leading to amino acid changes at position 55 and 57, giving rise to Thr55Ala, and Pro57Ser mutations. DHPS mutations in absence of prior sulfa drug exposure have also been seen due to spread of mutant strain form person to person. DHPS mutation is associated with failure of low-dose sulfa PCP prophylaxis. Poor compliance with respect to chemoprophylaxis lead to PCP breakthrough. DHPS mutation is associated with increased 3 month mortality.
DHFR resistance: TMP and pyrimethamine inhibit DHFR, which is responsible for purine/ pyrimidine nucleotide. DHFR resistance occurs due to selective pressure by DHFR inhibitors (TMP, pyrimethamine, and trimetrexate). Trimetrexate is most potent amongst the DHFR inhibitors. There is no evidence to show that prior use of TMP or pyrimethamine increases resistance to them.
Atovaquone: It binds to Cytbc1 complex, which inhibits ATP generation.
Pentamidine and Clindamycine-Primaquine resistance patterns have not been documented.
Conclusion: Widespread use of sulfa drugs leads to mutations. DHPS mutations are associated with failure of low-dose prophylaxis, but do not show any resistance to high-dose treatment. It is difficult to study drug resistance in Pneumocystis due to absence of invitro culture system, absence of clear-cut definition for treatment failure, presence of inflammatory response (leading to alveolar damage and respiratory failure), high incidence of adverse effects like fever, effect of non-adherence (which might be the reason for resistance mutation rather than treatment failure).
2. What is the level of evidence provided by this article?
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection that cause severe lung injury, and is associated with increased morbidity and mortality
P. jirovecii is transmitted by airborne route, most of cases had the organism since early childhood which become latent and can be reactivated once the immunity is compromised, on the other hand some of cases may not acquire the organism in childhood and acquire it later in life through person to person airborne transmission, and this may explain infection with more than one strain of Pneumocystis jirovecii in one patient
Pneumocystis is exclusively present within the lung alveoli, and once infection develop it presents with alveolitis with subsequent lung damage, no extrapulmonary affection occur
Diagnosis of PCP depends on the detection of the cystic or trophic forms in respiratory secretions by immunofluorescent staining (the organism cannot be cultured) , PCR has a disadvantage of not differentiating between infection and colonization
Prophylaxis
Prophylaxis reduce the risk of PCP dramatically in patients at risk including HIV-positive patients with CD4+ counts < 200 cells/mm3, organ transplant recipients and patients with rheumatologic disease on immunosuppression, cancer patients on certain chemotherapy and patients with congenital immunodeficiencies, particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID
Regimens used for prophylaxis
First line
One single strength TMP-SMX tablet daily (TMP-SMX 80-400 mg) or
One double-strength TMP-SMX tablet daily (TMP-SMX 160-800 mg)
Daily administration of single strength TMP-SMX may have the advantage of lower side effects.
2nd line
One double-strength TMP-SMX tablet every other day.
Dapsone 50 twice daily or 100 mg once daily
Atovaquone suspension 1500 mg orally once daily given with food
Aerosolized pentamidine 300 mg monthly (via Respirgard II nebulizer)
Treatment
Severe disease
First line : IV TMP-SMX, and it should be given whenever possible in all cases except in patients with history of severe allergy. The standard dose of TMP-SMX is 15 to 20 mg/kg/day (based upon the TMP component) intravenously in three or four divided doses.
Second line : clindamycin-oral primaquine, patient should tolerate oral when using his regimen
3rd line : IV pentamidine and due to its side effects, switching to less toxic oral therapy is recommended once patient can tolerate oral
Non severe disease
First line : oral TMP-SMX and it should be given whenever possible in all cases except in patients with history of severe allergy. The standard dose of TMP-SMX is 15 to 20 mg/kg/day (based upon the TMP component) intravenously in three or four divided doses.
Second line : dapsone plus trimethoprim or clindamycin plus primaquine
3rd line : atovaquone which is limited to patients with mild disease to complete the course of therapy after TMP-SMX (if the patient develop side effects related to this drug)
Inductions of adjuvant steroid therapy
PaO2 of <70 mmHg on room air
Monitoring patients on treatment –
Monitoring of side effects of the drugs given
Monitoring for the response
Duration of therapy
Treatment should be given for 2 weeks in non HIV cases and for 21 days in patients with HIV
Secondary prophylaxis
After completion of 21 days of treatment, immunosuppressed patients should receive secondary prophylaxis
Side effects of the most important drugs used in prophylaxis and treatment
TMP-SMX : Fever, rash, BM suppression, gastrointestinal toxicity, hepatitis, renal impairment, and hyperkalemia and it should be avoided in patietns with G6PD deficiency
Dapson : Fever, rash, gastrointestinal upset, methemoglobinemia, hemolytic anemia (in patients with G6PD deficiency)
Atovaquone : Gastrointestinal upsets, rash
Primaquine rash, gastrointestinal upset, hemolytic anemia (in patients with G6PD deficiency)
Clindamycin causes hepatitis, rash and diarrhea (associated with pseudomembranous colitis)
IV pentamidine : hypoglycemia, hypotension, pancreatitis, pancytopenia, renal failure, it is contraindicated if GFR < 60 ml/min, prolonged QT interval
Aerosolized pentamidine : Cough andwheezing
Sulphonamide resistance
Sulphonamides are both cheap and very effective treatment of PCP
Occur due to widespread use of sulpha drugs in the prophylaxis in HIV patients and in the treatment of malaria
Resistance is caused by mutations at codon 55 and 57of the DHPS gene, it is associated with resistance to low dose sulfa, but its link to the resistance to the higher dose is not well documented, this means it has a high impact in the use of prophylactic rather than therapeutic regimen using sulfa drugs
What is the level of evidence provided by this article?
Introduction
Although there is a decline in the incidence of PCP because of the widespread PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens, PCP still remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis
The organism
It is a fungal infection and possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
Transmission and Infection
o Ubiquitous infection with primary infection occurs in early childhood with a high incidence in all geographic areas
o Following primary infection, it becomes latent, later manifesting clinically if the patient becomes immunosuppressed
o Has specific tropism for the lung (alveoli) with rare cases detected in other organs (seldom causes disease at extrapulmonary sites). Adhere to the surface of type I alveolar cells [mediated by the major surface glycoprotein (MSG)]
o MSG protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family (it represents a family of proteins that are highly polymorphic, repeated and distributed among all the chromosomes of Pneumocystis)
Drug Treatment Drugs used for treatment and prophylaxes of PCP include:
1. TMP–SMX: first choice
2. Pentamidine intravenous (only for treatment)
3. Pentamidine aerosolized
4. Sulfadiazine plus pyrimethamine
5. Atovaquone
6. Clindamycin plus pyrimethamine
7. Clindamycin–primaquine (only for treatment)
8. Dapsone
9. Others: azithromycin, doxycycline, and caspofungin
Prophylaxis Risk factors of PJP:
1. Patients with congenital immunodefi ciencies (particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID
2. Long-term and high-dose corticosteroid therapy
3. Certain chemotherapeutic regimens (cancer therapy or transplantation) Recommendations for PCP prophylaxis:
1. HIV-1 infection (lifelong unless CD4 count >200 × >3 months due to antiretroviral therapy)
2. Organ transplantation: minimum 6 month after transplantation
3. Malignancy ((ALL, CLL, and lymphoma)
Treatment of PCP Trimethoprim– sulfamethoxazole
o First choice
o Dose 2 DS every 8 h (oral), rimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h (intravenous)
o Side effects: rash and fever, anemia and neutropenia, hyperkalemia, hepatitis, nephritis, anaphylactoid reaction
Dapsone plus trimethoprim
o Dose 100 mg daily/ 320 mg every 8 h (oral)
o Side effects: rash, nausea and vomiting, fever, methemoglobinemia, leukopenia and haemolytic anemia. Liver function abnormalities; headache. Dapsone may cause hemolysis in patients with G-6PD
Clindamycin plus primaquine
o By mouth, intravenous (300–450 mg every 6 h 30 mg daily)
o Side effects: clostridium difficile diarrhea, nausea and vomiting. Primaquine may cause hemolysis in patients with G-6PD deficiency
Pentamidine
o Intravenous 4 mg/kg day
o High incidence of adverse effects, particularly hypoglycemia and nephrotoxicity, pancreatitis and IDDM, hypotension with short infusion time, pancytopenia and Q-T prolongation
Atovaquone
o By mouth 750 mg twice daily Well tolerated Expensive
o Side effects: Rash, nausea, diarrhea and headache (20%), fever, increased transaminases and neutropenia
Adjunctive therapy (prednisone)
o In patients with room air pAO2 < 70 mmhg (9.3 kPa)
o By mouth, intravenous
o 40 mg twice daily for 5 days 40 mg daily, days 6 through 11 20 mg daily, days 12 through 21 while on anti-PCP therapy
o For moderate or severe disease
o Metabolic problems, especially glucose and electrolyte changes
Sulfonamide Resistance
o Sulfonamide resistance is caused by mutations in the primary sequence of the dihydroperoate synthase (DHPS) gene
o The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser)
DHFR Resistance
o The diaminopyrimidines (trimethoprim and pyrimethamine) are competitive inhibitors of dihydrofolate reductase (DHFR)
o DHFR catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and c ertain amino acids
o Resistance to DHFR inhibitors has arised as a consequence of selective pressure by DHFR inhibitors
o Only few DHFR mutations has been identified in Pneumocystis DHFR
o No evidence that use of trimethoprim or pyrimethamine cause clinical significant resistance to DHFR inhibitors
Pentamidine and clindamycine–Primaquine
o Used for prevention and treatment of PCP
o Possible resistance mechanisms not discovered yet
Atovaquone
o Competitively binds to the cytochrome bc1 complex
o Mutations of the cytochrome b gene lead to atovaquone resistance
Limitations of the study
1. Absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism
2. No consistent definition of clinical resistance (the classic definition of resistance may not be applied to PJP)
3. Difficult assessment of nonadherence of prophylaxis (resistance may be higher with inadequate or interrupted dosing)
Conclusion
o Mutations involved in sulfa and atovaquone drug resistance have arised in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis
o DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy
o The risk of high-level resistance in the third world is due to increasing HIV epidemic and use of TMP–SMX and therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing
o Pneumocystis Genome Project (initiated in 1997) is promising
What is the level of evidence provided by this article?
Level V (narrative review)
The organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was among the first to describe the microbe in humans.
Infection and transmission:
Pneumocystis has specific tropism for the lung, where it exists in the alveoli.After inhalation, the organism attaches tightly to the surface of type I alveolar cells. Managemnent:
For prophylaxis:
Drug of choice: Trimethoprim–sulfamethoxazole 1 DS or SS daily for 6 months for kidney transplantantifolate drugs, diamines, atovaquone, and macrolides80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg dailyBecause of its efficacy, ease of administration and cost, every effort should be tried to maintain patients at risk of PCP on TMP–SMX.Treatment of PCP:
Drug of choice: Trimethoprim–sulfamethoxazole 2 DS 8 hourly per oralTrimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 hourly intravenous Alternative:Dapsone + trimethoprimClindamycin + primaquinePentamidineAtovaquoneAdjunctive : Prednisone in patients with room air pAO2 < 70 mmHg (9.3 kPa)dyspnea, cough, or low-grade fever can be the initial manifestation of PCP, especially in patients with CD4+ T lymphocyte counts below 200 cells/mm3.
Thus, clinicians should not wait for all the features of PCP to be present, or for the chest radiograph to be abnormal, before initiating a workup for PCP.
Sulfonamide Resistance
The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).The currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. DHFR Resistance
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
TMP-DMX = IV TMP 5mg/kg with DMX 20 mg/kg every 8 hrs with hepatitis, nephritis, and anaphylactic reaction, it has anti-bacterial and anti-toxoplasmosis activity.
Dapsone plus TMP, 100 mg daily PO, with side effects (rash, nausea, and vomiting, fever, methemoglobinemia, leukopenia, and hemolytic anemia, advantage; inexpensive, with no IV formulation, OR 320 mg /8hrs with liver dysfunction, headache.
Clindamycin plus primaquine 300-450 mg /6hrs OR 30 mg OD, causes clostridium difficele infection, diarrhea, nausea, vomiting, and hemolysis, but no IV form for primaquine.
Pentamidine; 4mg/kg OD IV, with hypoglycemia and nephrotoxicity, pancreatitis and IDMM, hypotension with short infusion time, pancytopenia, and Q-T prolongation.
Atovaquone; 750 mg BD, with rash, nausea, diarrhea, and headache, fever, elevated transaminases, and neutropenia, well tolerated and useful in mild diseases, but expensive.
Adjunctive therapy (prednisolone) oral or IV 40 mg BD for 5 days, OR 20 mg daily while on anti-PCP therapy. for moderate to severe disease, may cause glucose and electrolyte changes.
Conclusion
Resistance to sulfa and atovaquone in P.jrovecii as a result of selective pressure by widespread PCP prophylaxis.
DHPS mutations at codons 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but no evidence of significant resistance.
Drug resistance against TMP-DMX may rise due to pandemic use as prophylaxis in HIV patients.
Pneumocystis Genome Project initiated in 1997 may give a promising advance in treating PCP.
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP? Typing whole article in italics defeats the purpose of typing in italics meant for specific emphasis!
Pneumocystis jirvocii is a fungus can cause pneumonia in immunocompromised patients.
Peak of PCP occur in late 1990s & early 1990 (AIDS pandemic).
P. jirvocii recognized in human for first time at 1942, & established as human pathogen in 1952.
In 1988, P. jirvocii classified as a fungus, but it differ from other fungi by presence of only one copy of ribosomal RNA.
Mammalian is a specific host of pneumocystis.
Transmission:
P. jirvocii can’t be cultured in vitro.
Antibodies & PCR finding show that primary infection occurs in early childhood with high incidence in all geographical ares.
Unknown environmental source.
Primary infection in immunocompetent person may presented as upper or lower respiratory manifestation or sudden infant death syndrome.
Recent data suggest that infection can be acquired in multiple occasions.
Clinical disease can be as an activation of latent pathogen or recent infection of airborne pathogens.
P. jirvocii has specific tropism for lung, but other can can be affected rarely.
Drug treatment:
Antifolate drugs, diamines, atovaquone & macrolide used in prophylaxis & treatment of PCP.
Most anti fungal have no activity against P. jirvocii.
In 1958 pentamidine was used successfully in treatment of PCP.
In 1960 combination of sulfadoxine & pyrimethine used as prophylaxis & treatment.
Using TMP-SMX as prophylaxis & treatment was in 1977..
Not all drugs effect in treatment are effective for prophylaxis.
Iv pentamidine & clindamycine-primaquine are not effective as prophylaxis.
Prophylaxis:
In HIV patient with CD4 <200cell/mm2 should receive TMP-SMX as prhlaxis, which can be discontinue after rising of CD4 count for at least 3 months after starting antiretroviral therapy.
In SOT recipients low dose of TMP-SMX(80/400mg/day) is effective as prophylactic with low incidence of adverse effects.
Treatment:
CPC mortality reduced in the last decade due to early diagnosis & proper treatment in addition to use of corticosteroid in moderate-severe disease.
Clinician should start workup for CPC diagnosis even if CXR is normal & symptoms are mild.
Most potent drugs are antifolates act by inhibition of DHPS or DHFR.
TMP-SMX & pentamidine have comparable efficacy in treatment of PCP.
IV pentamidine use abandon due to hypotension & death. IM can cause sterile abcess & inhalation is well tolerated but poor efficacy.
Dapsone & MTP combination is effective in treatment but cross react wth sola in 50% of allergic patients.
Clindamycine-primaquine comparable effect to TMP-SMX in moderate-severe disease.
Atovaquone well tolerated & can be used as alternative to TMP-SMX in mild disease.
Corticosteroid used as adjunctive treatment in all patients with severe cases (PaO2<7mmhg).
Sulfonamide resistance:
High rate of resistance occur due to widespread sulfur use in malaria treatment(P. flaciparum) prophylaxis in HIV patients(PCP).
in E.coli, N. meningitides, M. leprae sulfa resistance caused by mutation of DHPS gene.
Documented resistance is very difficult because P. jirvocii can’t be cultured & functional enzymes are unavailable.
There is large geographical variation in prevalence of DHPS mutation.
DHPS mutation observed in patient without previous exposure to sulfa.
Despite DHPS mutation, TMP-SMX prophylaxis effective when taken regularly.
DHFR resistance:
Despite widespread use of TMP-SMX in treatment & prevention of CPC, only few DHFR mutations are identified.
No evidence that widespread use of TMP cause clinical significant resistance to DHFR inhibitors.
Atovaquone:
Used in prevention & treatment of P. jirvocii, plasmodium spp, Toxoplama gondi & Besesia spp.
Patient exposed to atovaquone had more mutations compared to patients not exposed.
Survival from PCP didn’t differ between with or without mutation.
Pentamidine & clindamycine-primaquine:
The mechanism of possible resistance not reported or discovered yet.
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
The Introduction;
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals .
Transmission and Infection ;
1-Studies have not conclusively demonstrated the environmental niche.
2-Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
3-The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
4-Pneumocystis has specific tropism for the lung, where it exists in the alveoli.
Drug Treatment;
The major drug classes used for treatment and prophylaxis of PCP include;
1-Antifolate drugs. 2-Diamines. 3-Atovaquone . 4- Macrolides .
Prophylaxis;
A-High risk groups ;
1-HIV infected individuals .
2-Organ transplanted individuals .
3-Those who received high-dose steroid treatment and/or high-dose chemotherapy.
B-Several prophylactic regimens are available.
C- The most efficient, cheap and widely used regimen is daily TMP—SMX. TMP—SMX prophylaxis is relatively well tolerated by most non-HIV patients; in contrast, HIV patients have a high frequency of adverse effects, in particular rash and myelosuppression.
D- 80/400 mg TMP—SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily.
Treatment of PCP;
1-Untreated PCP is invariably fatal.
2- The optimal duration of therapy for PCP has never been properly tested. Usual recommendations are that HIV-negative patients should receive 2 weeks and HIV- positive patients three weeks of drug treatment.
3- Adjuvant corticosteroids to patients with moderate-to-severe PCP as defined by a PaO2 of less than 70 mmHg.
4- TMP—SMX was associated with a better survival than pentamidine.
5- Pentamidine is associated with a high frequency of toxicities, some of which are treatment-limiting.
6-lternatives for the therapy to TMP—SMX and pentamidine include dapsone pyrimethamine, clindamycin—primaquine, and atovaquon .
7- Dapsone—trimethoprim is effective, however, and probably has potency that is comparable to TMP—SMX. However, since this combination does not come as a fixed-dose combination, is only available orally, and cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP—SMX.
8- Clindamycin—primaquine appears to work on a metabolic pathway different from that of TMP—SMX. Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
9- Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP—SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP—SMX . This is a good alternative to TMP—SMX for patients with mild disease who cannot tolerate TMP—SMX.
10- Efficacy of dapsone—pyrimethamine has only been demonstrated for mild-to-moderate PCP and for atovaquone only for mild PCP . Both must be administered orally.
Sulfonamide Resistance;
1-The widespread use of TMP—SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
2-The mutations that confer resistance are localized within a highly conserved active site of the DHPS protein.
3- DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP—SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
DHFR Resistance;
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Atovaquone;
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
Atovaquone is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q), and competitively binds to the cytochrome bc1 complex.
Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
Survival from PCP did not differ between patients with or without mutations.
Pentamidine and Clindamycine–Primaquine;
Pentamidine and clindamycine—primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Limitations to the study ;
1-The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
2-Most drug development has been empiric and the currently available treatment options for PCP have been unchanged during the last 15 years.
2- Experimental systems have mainly relied on immuno- suppressed animal, in particular the rat model of Pneumocystis.
2-No consistent definition of clinical failure exists.
What is the level of evidence provided by this article
—————————————————————————–
Level V
II. Drug Resistance in Pneumocystis jirovecii 1. Please summarise this article. Introduction
PJP continues to be a significant opportunistic infection in severely immunosuppressed patients who are not getting the proper chemoprophylaxis.
Based on morphological characteristics, its resistance to conventional antifungal medications, & the efficacy of some medications used to treat protozoan infections, Pneumocystis was once thought to be a protozoon & a single species. Later on, analysis of rRNA sequences & observations of genome size placed it in the fungal kingdom.
Pneumocystis infecting humans was initially named P. carinii.Subsequently, based on recognition of its genetic & functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii.
Transmission & Infection
Primary infectionoccurs in early childhood.
P. jirovecii organisms are ubiquitous with a high incidence in all geographic areas; however, its environmental source is unknown (probably inanimate sources or spread by healthy humans).Nonhuman animals are not the source.
Pneumocystis jirovecii can infect human hosts with various strains, reflecting that an infection could be acquired more than once & result in latency with a range of different organisms.
The clinical disease PCP may occur as a reactivation of a prior latent organism, or as a result of recent exposure.
Pneumocystis particularly affects the lung, where it is seen in the alveoli. Extra-pulmonary locations are rarely affected.
Upon inhalation, the organism firmly binds to the type I alveolar cells’ surface via the main surface glycoprotein (MSG).
The most prevalent antigen on Pneumocystis’ surface, MSG, is encoded by a multi-copy gene family.
High levels of antigenic variation are present in MSG. The organisms probably benefit from this antigenic diversity to avoid the host immune response.
No clear knowledge of the life cycle & the mode of replication is not well established.
Drug Treatment
Antifolate drugs, diamines, atovaquone, & macrolides are the main classes used for PCP prophylaxis & treatment.
The majority of antifungal medications have no effect in Pneumocystis.
Initially, Pneumocystis was thought to be a protozoon, hence anti-protozoal medications were the main focus of pharmacological trials.
Regimens for prophylaxis against Pneumocystis pneumonia First choice:
Trimethoprim–sulfamethoxazole 1 DS or SS daily
Alternatives:
Trimethoprim–sulfamethoxazole 1 DS three times/ week
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone with 50 mg daily
Pyrimethamine plus Leucovorin 50/25 mg weekly
Dapsone 200 mg weekly with pyrimethamine plus Leucovorin 75/25 mg weekly
Pentamidine aerosolized 300 mg monthly.
Atovaquone 1,500 mg daily
Pyrimethamine (25–75 mg qd) plus Sulfadiazine (0.5–2.0 g q6h)
Drug regimens for the treatment of PCP First choice Trimethoprim–sulfamethoxazole:
P/O (2 DS/8 h) or IV (Trimethoprim 5 mg/kg; sulfamethoxazole 20 mg/kg/8 h)
—————————————- Adjunctive therapy Prednisone in patients with room air pAO2 < 70 mmHg (9.3 kPa):
PO/IV
40 mg twice daily for 5 days
40 mg daily, days 6 through 11
20 mg daily, days 12 through 21 while on anti-PCP therapy
Toxicity:
Metabolic problems, especially glucose & electrolyte changes.
—————————————- DHFR Resistance
DHFR mutations have been the subject of numerous research; however, there is currently no proof that the widespread use of trimethoprim or pyrimethamine has contributed to the development of clinically significant resistance to DHFR inhibitors.
Atovaquone
Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii & Pneumocystis.
In vitro studies of Plasmodium &Toxoplasma show that these mutations confer resistance toatovaquone.
Since Pneumocystis cannot be propagated invitro, similar susceptibility testing cannot be done.
In vitrostudies of the Saccharomyces cerevisiae cytochrome bc1complex & atovaquone have demonstrated binding to theubiquitol pocket. Introduction of mutations near the bindingpocket led to decreased activity of atovaquone.
Introduction of seven mutations observed in isolates of
Pneumocystis from atovaquone-experienced patients into S.cervisiae cytochrome b increased the inhibitory concentration from 25 to >500 nM.
In one study, sequencing of the cytochrome b gene of Pneumocystis from 10 patients showed sequence variations in 4 patients. Three of four patients receiving atovaquone as prophylaxisdemonstrated such variations. Two of themhad non-synonymous changes leading to amino acid substitutionswithin the ubiquitol pocket. Similar mutations in othermicroorganisms are associated with resistance to atovaquone.
In another study, significantly more patients who previously had been exposed to atovaquone (5/15 patients) had mutations compared to unexposed patients (3/45). Five different mutations near the ubiquitol pocket were described.
Survival from PCP did not differ between patients with or without mutations.
Overall, these findings are consistent with the development of atovaquone resistance after selective pressure is exerted.
Pentamidine & Clindamycin–Primaquine
Possible resistance mechanisms have yet to be discovered & reported.
========================== 2. What is the level of evidence provided by this article?
Drug Resistance in Pneumocystis jirovecii. 1-Please summarise this article. Treatment of PCP;
-Untreated PCP is invariably fatal so early recognition of the disease is important to save life, especially in immunocompromised patient. -Patients with low grade fever and dry cough with shortness of breath and hypoxia is highly suspicion for PCP so early diagnosis and treatment should be started soon.
-The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR). TMP–SMX;
-Associated with a better survival than pentamidine. However, when all the trials are considered, TMP–SMX and pentamidine appear to have roughly comparable efficacy.
-Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX.
-Adverse effects generally occur after 7 days of therapy including; rash, fever and leukopenia , Hepatotoxicity characterized by elevated transaminases.
-There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis.
-Trimethroprim can be associated with hyperkalemia. Pentamidine;
-Associated with a high frequency of toxicities, some of which are treatment-limiting.
-Treatment-limiting toxicities with pentamidine treatment occur in 13–80% of patients.
-Rapid infusions of pentamidine associated with hypotension and death.
-Intramusuclar injections were better tolerated in terms of blood pressure, but they caused a high frequency of sterile abscesses , so that slow intravenous infusion is the best tolerated route.
-Inhaled pentamidine has been used for therapy, and is well tolerated, but efficacy is poor.
-Pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney.
-Pentamidine is toxic to the pancreas; its initial effects cause a surge of insulin release that often manifests as hypoglycemia, which can occur days or weeks after starting therapy, and may occur many days after stopping therapy.
-Leukopenia can also occur.
-Pentamidine prolongs the QT interval, and cases of torsades de pointe have been reported. Alternatives for the therapy to TMP–SMX and pentamidine include;
Dapsone , Pyrimethamine , Clindamycin , Primaquine, and Atovaquone.
-Clindamycin–primaquine appears to work on a metabolic pathway different from that of TMP–SMX.
-Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
-Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX.
-However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX.
-The optimal duration of therapy for PCP has never been properly tested.
-Usual recommendations are that HIV-negative patients should receive 2 weeks and HIV-positive patients three weeks of drug treatment.
-Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy, this deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
-This inflammation can be reduced by corticosteroids, That could reduce mortality in patients with moderate or severe disease.
-Adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh). Sulfonamide Resistance;
-The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
-Sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
-The mutations that confer resistance are localized within a highly conserved active site of the DHPS protein at nucleotide positions 165 and 171. Conclusion;
-Although inability to culture the organisms, it is clear that mutations involved in sulfa and atovaquone, drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
-DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
-However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX.
-This would lead to the loss of the most efficient and inexpensive therapy for PCP.
-The increasing HIV epidemic and use of TMP–SMX in the third world may significantly increase the risk for the development of high-level resistance.
-Therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. Limitation;
-The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
-The knowledge of the metabolic pathways is limited, most drug development has been empiric and the currently available treatment options for PCP have been unchanged during the last 15 years.
-Experimental systems have mainly relied on immunosuppressed animal, in particular the rat model of Pneumocystis.
-No consistent definition of clinical failure exists. In other fungal infections, clinical resistance is classically defined as the persistence or progression despite the administration of appropriate antimicrobial treatment.
-The contribution of nonadherence in presumed failure of prophylaxis may be difficult to assess. The most important reason for prophylaxis failure continues to be nonadherence to prescribed prophylaxis.
-In theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure.
2-What is the level of evidence provided by this article? This narrative review considering level V evidence.
Thanks; our Prof.
actually, I didn’t have experience of sulfa resistance of PCP, I have experience with pt had Adverse reaction to TMP-SMX (rash , leukopenia) and after review by I.D. we shifted him to inhaled pentamidine.
Introduction:
In immunocompromised people, Pneumocystis jirovecii (formerly Pneumocystis carinii) causes pneumonia, known as PCP. Before 1982, PCP was uncommon and mostly diagnosed in congenital immunodeficiencies and people on powerful immunosuppressive medication for cancer.
Organisms:
Chagas discovered Pneumocystis in guinea pigs and Carini in rat lungs early in the 20th century. These researchers misidentified the organisms as a novel Trypanosoma cruzi strain. Pneumocystis, named after Carini, was discovered in 1912.
Prophylaxis:
Daily TMP–SMX is the most cost-effective, extensively utilized regimen. Most non-HIV patients handle TMP–SMX prophylaxis well, however, HIV patients have rash and myelosuppression.
Treatment of PCP:
TMP–SMX outlived pentamidine.
TMP–SMX and pentamidine seem to have similar efficacy when all studies are examined. TMP–SMX toxicity affects 24–57% of HIV-positive individuals.
Pentamidine has several toxicities, some of which are treatment-limiting. Rapid pentamidine infusions caused hypotension and mortality, thus, they were discontinued. Intramuscular injections were beneficial for blood pressure but generated many sterile abscesses.
Dapsone–pyrimethamine, clindamycin–primaquine, and atovaquone are TMP–SMX and pentamidine alternatives.
Sulfonamide Resistance:
Because of the extensive use of TMP–SMX and dapsone for the treatment and prevention of PCP in HIV patients, there is a growing fear that P. jirovecii might acquire resistance to sulfa (sulfonamide or sulfone) medications.
DHFR Resistance:
However, despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only a relatively small number of DHFR mutations have been identified in Pneumocystis DHFR. This is the case despite the fact that trimethoprim is used in combination with sulfamethoxazole.
Conclusion:
The extensive use of PCP prophylaxis has been selected for mutations in P. jirovecii that cause sulfa and atovaquone medication resistance, notwithstanding the inability to grow the organisms.
The mutations’ clinical impact is limited. Low-dose sulfa prophylaxis fails due to DHPS mutations at codons 55 and 57, although there is little indication that they cause significant resistance to high-dose treatment. TMP–SMX efficacy may decrease if new mutations cause high-level sulfa resistance. The most effective and affordable PCP treatment would be lost.
Pneumocystis identified in guinea pigs by Chagas and in rat lungs by Carini
mistakenly considered the organisms as a new form of Trypanozoma cruzi.
In 1912, Pneumocystis was recognized as a new species and named in honor of Carini
Pneumocystis was first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages
Phylogenetic data suggest that Pneumocystis is an ancient organism without any close relatives
The organism has recently been placed in a group of fungi entitled the Archiascomycetes
In contrast to most other fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
in 2002,because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms
Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
Regimens for prophylaxis against Pneumocystis pneumonia
First choice Trimethoprim–sulfamethoxazole 1 DS or SS daily
Alternatives
Trimethoprim–sulfamethoxazole 1 DS three times per week
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone with 50 mg daily
Pyrimethamine plus 50 mg weekly
Pentamidine aerosolized 300 mg monthly via nebulizer
Atovaquone 1,500 mg daily
Several prophylactic regimens are available. The most efficient, cheap and widely used regimen is daily TMP–SMX.
Adverse effect TMP–SMX.
Rash and fever Anemia and neutropenia Hyperkalemia if given oral
Intravenous Hepatitis Nephritis Anaphylactoid reaction if given iv
Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX
Treatment-limiting toxicities with pentamidine treatment occur in 13–80% of patients
adverse effects, hypoglycemia and nephrotoxicity Pancreatitis and IDDM. Hypotension with short infusion time -Pancytopenia -Q-T prolongation
Untreated PCP In the beginning of the HIV epidemic, the mortality rate of PCP was reported to be 30–40% increasing to 70–90% among patients who progressed to respiratory failure
Recommendations for PCP prophylaxis
HIV-1 infection Lifelong unless CD4 count >200 × >3 months due to ART
Kidney heart -lung liver transplant minimum 6 month after transplantation
Antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase
DHPS catalyzes the condensation of p-aminobenzoic acid (PABA) and hydroxymethyl dihydropterin–pryophospate to produce dihydropteroate, which is later converted to dihydrofolate by dihydrofolate synthase. Subsequently, dihydrofolate is reduced by dihydrofolate reductase (DHFR) into tetrahydrofolate
Sulfa drugs are structural analogs of PABA and inhibit DHPS
Sulfonamide Resistance
widespread use of sulfa drugs for prophylaxis of PCP
DHPS mutations have also been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
On the basis of a genetic analysis of multiple loci, it appears that the mutations arose independently in multiple strains of Pneumocystis
Moreover, even in studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprim– sulfamethoxazole or dapsone–trimethoprim.
These observations suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. Given that Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance.
DHFR Resistance
several studies have reported DHFR mutations
For the human Pneumocystis derived DHFR yeast strain, trimethoprim and pyrimethamine were both weak inhibitors, with IC50s in the micromolar range; trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively Given that trimetrexate is much more potent against PCP than trimethoprim in vitro, the combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.Limitations to the study of drug resistance in Pneumocystis
Atovaquone
. is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q), and competitively binds to the cytochrome bc1 complex.
Binding of atovaquone to the ubiquinol oxidation pocket of the bc1 complex and the Rieske iron–sulphur protein disrupts electron transport and leads to collapse of the mitochondrial membrane potential
Eventually, this presumably results in the depletion of ATP within Pneumocystis and leads to killing of the organism
Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
In vitro studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.
Since Pneumocystis cannot be propagated in vitro, similar susceptibility testing cannot be done.
Similar mutations in other microorganisms are associated with resistance to atovaquone.
Limitations to the study of drug resistance in Pneumocystis Compared to other pathogenic fungi,
In spite of many attempts there exists no in vitro culture system for propagation of Pneumocystis. The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
clinical resistance is classically defi ned as the persistence or progression despite the administration of appropriate antimicrobial treatment.
Studies using repeat bronchoscopy during and immediately after successful treatment of PCP have shown that clearance of organisms is slow, with approximately half of patients still harboring Pneumocystis at the end of three weeks of treatment in spite of a successful treatment response
Although infection is eventually cleared and the viability of organisms detected at the end of treatment is uncertain, it is clear that the detection of organisms during or at the end of treatment cannot be interpreted as a proxy for resistance. Second, host infl ammatory response, rather than resistance to antimicrobial drug treatment, may cause an apparent absence of response to treatment.
Clinical resistance has been investigated by genotyping of P. jirovecii isolates from patients who develop PCP in spite of prescribed chemoprophylaxis. However, in most studies assessment of adherence to prophylaxis has been based on chart reviews, which may fail to disclose nonadherence to a drug regimen.
The likelihood of developing P. jirovecii resistance within a patient is likely to be higher with inadequate or interrupted dosing. Hence, in theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure
Introduction
Pneumocystis jirovecii is a fungus that causes interstitial pneumonia mainly in immunosuppressed patients (HIV, SOT, and BMT) and whose number of cases is reduced when using chemoprophylaxis, where the main drug is sulfa drugs.
This document is a narrative review, with level of evidence V.
Organism
Originally identified in different animals by Chagas and Carini. Jiroveci later described it in humans. Due to its intrinsic resistance to classic antifungals, it was not established as a fungus, but with the introduction of DNA, its phylogenetics confirms it in this kingdom.
Transmission and Infection
It is difficult to perform cultures, but there are molecular methods using RT PCR and serologies that may suffer interference from the environment or the immunological status of the patient. That’s why there are two theories of reactivation of the disease and new airborne contamination. Lung and alveolus tropism can trigger sexual replication.
Drug treatment
The drugs of choice are based on sulfa drugs, but in their absence, whether due to resistance or intolerance, less effective medications may be available. Antifungals have intrinsic resistance, the alternatives being Atovaquone, aerosolized Pentamidine, or combinations of sulfa drugs.
Prophylaxis
CD4 values below 200, primary immunosuppression, use of anti-lymphocytes, and high doses of corticosteroids are situations that require prophylaxis.
Treatment
The time depends on the patient’s immunosuppression. CMV co-infections or need for anti-lymphocytes for a rejection or graft disease.
Pneumocystis mutations have brought greater resistance to its pharmacological treatment.
Alternative regimens without sulfates use Clindamycin, Primaquine, Atovaquone and their combinations.
Conclusion
The limitation in performing cultures for a broad investigation of pharmacological sensitivity and its mutations hinders a broader study of pharmacoeffectiveness against Pneumocystis. HIV infections and inappropriate use of Sulfas have increased this resistance.
Introduction: Pneumocystis jerovecii is an opportunistic fungus that causes pneumonia in immunocompromised patients who are not receiving prophylaxis. the organism is everywhere, primary infections occur in childhood mostly with upper respiratory tract symptoms, then become latent till profound immunosuppression. recent airborne infection may also occur. Drug treatment: Most traditional antifungal agents have no activity against Pnemocystis. Regimens for prophylaxis: Duration of prophylaxis PKT: minimum is 6 months, extended prophylaxis depends may be needed depending on the clinical situation. HIV infection: lifelong prophylaxis unless CD4 count >200 for > 3months due to Antiretroviral therapy First choice Trimethoprim–sulfamethoxazole 1 DS or SS daily Alternatives – Trimethoprim–sulfamethoxazole 1 DS three times per week – Dapsone 50 mg twice daily or 100 mg twice weekly – Pentamidine aerosolized 300 mg monthly via nebulization – Atovaquone 1,500 mg daily – Pyrimethamine 25–75 mg qd plus Sulfadiazine 0.5–2.0 g q6h Drug regimens for the treatment: 1st choice, TMP/sulfamethoxazole: – IV:5mg/kg/TMP with 80 mg/kg sulfamethoxazole every 8 hrs – Oral: 2-tab DS every 8 hrs – S/E: anemia &neutropenia Rash & fever Increase creatinine, interstitial nephritis & hyperkalemia Hepatitis & anaphylactoid reaction. – Advantages: Superior efficacy, inexpensive, oral & IV Alternatives: – Dapsone plus trimethoprim (oral only, inexpensive, S/E: cause haemolysis in G6PD deficiency, rash, nausea, vomiting, methemoglobinemia & leukopenia) – Clindamycin plus primaquine (oral 300-50 mg every 6 hrs or IV 30 mg daily) (primaquine is oral only, can cause hemolysis in G6PD deficiency) – IV pentamidine4mg/kg/d (highly effective but toxicity is common, S/E: hypoglycemia, nephrotoxicity, pancreatitis, hypotension if short time infusion, pancytopenia &Q-T prolongation) – Oral Atovaquone 750 mg BID (well tolerated, expensive) – Adjunctive therapy with prednisolone 40 mg twice daily (standard care for moderate or severe disease & if hypoxemia <70 mmhg on room air) Resistance: Resistance develops due to the widespread use of PCP prophylaxis. The clinical effects of mutations till now seem mild. It can cause failure to low-dose supfaprophylaxis but high dose still will be effective. It is possible if more mutation will happen it will cause resistance to high-dose TMP/SMX. Conclusion: Resistance to high-dose TMP/SMX may occur with further mutations. The completion of the Pneumocystis Genome Project, which was initiated in 1997, will be a significant step forward. Complete physical maps and gene sequences are being determined for P. carinii’s genomes. These data will facilitate the identification of new polymorphic regions and drug targets, and may eventually lead to the development of a culture system. level of evidence:
level V
·PCP is an opportunistic fungus that causes pneumonia in immunocompromised individuals,
· PCP is now the most common AIDS-defining diagnosis in industrialized countries.
·PCP has declined due to chemoprophylaxis and HIV-1 antiretroviral regimens but remains a serious opportunistic infection in heavily immunosuppressed patients..
2 The Organism
·Pneumocystis was first identified in humans in 1942 by van der Meer and Brug, and Jirovec in 1952 identified it as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
·Pneumocystis was previously classified as a protozoon, but phylogenetic analysis in 1988 placed it in the fungal kingdom.
·Pneumocystis is an ancient organism without any close relatives, suggesting it is an early divergent line in the fungal kingdom.
·Pneumocystis is a broad family of organisms with species specificity among its mammalian hosts, with greater genetic divergence than other fungi.
3 Transmission and Infection
·Early childhood is the most common age for P. jirovecii primary infection, which has a uniformly high prevalence across all geographic regions and an unidentified environmental cause.
·Results from PCR analysis point to a more nuanced picture of infection and transmission.
·Nonetheless, it is assumed that the organism becomes dormant and appears clinically if the patient develops substantial immunosuppression. Initial infection might result in temporary illness.
·Several Pneumocystis jirovecii strains can infect humans, causing latency with a wide range of species.
·Nonhuman animals are not the source of Pneumocystis since there is no cross-species infection and each animal species has a separate strain of the disease.
·Pneumocystis has a distinct lung tropism, although extrapulmonary areas are seldom affected by the illness.
·The main surface glycoprotein (MSG), which is highly variable, repetitive, and dispersed throughout all chromosomes, is the mechanism by which Pneumocystis clings to the surface of type I alveolar cells.
· This antigenic variant most likely works to prevent the host’s immunological reaction.
4 Drug Treatment
·Antifolate medications, diamines, atovaquone, and macrolides are the main pharmacological classes utilized in the treatment and prevention of PCP.
·The majority of conventional antifungal medications have little effect in Pneumocystis.
·The first medication to successfully treat PCP was pentamidine isethionate in 1958.
Research has shown that the drug combination trimethoprim-sulfamethoxazole (TMP-SMX) is efficient for treating and preventing PCP in both mice and humans.
·Several medications, such as sulfadiazine with pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone, and aerosolized pentamidine, have had therapeutic efficacy.
·Not all medications that work well for treatment also work well for chemoprophylaxis.
·Azithromycin, doxycycline, and capsaicin may be used to treat human illness.
5 Prophylaxis
·Those with HIV who have PCP have cell counts of more than 200 cells/mm3.
·Those with HIV who are taking corticosteroids, receiving chemotherapy, or have congenital immunodeficiencies are at risk of getting PCP.
·CD4 numbers are not a trustworthy indicator.
·When some supporting data was published, PCP prophylaxis became the norm of therapy for HIV-infected patients with CD4 levels under 200 cells/mm3 in 1989.
·In transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP.
·TMP-SMX is the most efficient, cheap, and widely used regimen for PCP prevention, and is well tolerated by non-HIV patients. 80/400 mg TMP–SMX daily is equally effective and associated with fewer side effects than 160/800 mg daily.
6 Treatment of PCP
·Untreated PCP always results in death.
·Early diagnosis, adjuvant corticosteroids, increased diagnostic and therapeutic capabilities, and enhanced ICU supporting measures have all contributed to a drop in PCP death rates.
·Patients and healthcare workers must be aware that PCP may first appear as mild symptoms such as dyspnea, coughing, or low-grade fever and should seek treatment as soon as possible.
·The most successful PCP therapy is antifolate medications.
·To create dihydrofolate, which is then converted into tetrahydrofolate by DHFR, DHPS catalyzes the condensation of PABA and dihydropteroate.
·While DHFR inhibitors are more effective than other commercially available sulfonamide formulations, sulfamethoxazole is nonetheless just as strong.
·Similar to pentamidine in effectiveness, TMP-SMX also causes medication toxicity in 24-57% of HIV-infected individuals.
·Rash, fever, leukopenia, renal calculus development, anaphylactoid responses, and pancreatitis are among the side effects of trimethoprim.
·Pentamidine is linked to a high frequency of toxicities, including leukopenia, nephrotoxicity, and hypoglycemia, some of which are treatment-limiting. 13–80% of individuals have toxicity that is treatment-limiting.
· Atovaquone, clindamycin-primaquine, and dapsone-pyrimethamine are substitutes for TMP-SMX and pentamidine. There is no longer a commercial supply of trimetrexate.
·TMP-SMX and clindamycin-primaquine appear to function differently, however, both studies lacked sufficient power.
·For moderate PCP, atovaquone is a decent substitute for TMP-SMX, although it can only be taken orally and doesn’t seem to be as effective.
·All patients with PaOs 70 mm.gh should get supplementary steroids, which can lower mortality in patients with severe illness.
7Sulfonamide Resistance
·Since TMP-SMX and dapsone are commonly used to treat and prevent PCP in HIV patients, there is concern that P. jirovecii may acquire sulfa (sulfonamide or sulfone) resistance, which would increase trimethoprim-sulfamethoxazole resistance among isolates of Staphylococcus aureus and Enterobacteriaceae.
·Sulfonamide resistance is brought on by changes in the main sequence of the DHPS gene in pathogens including Escherichia coli, Neisseria meningitide, Mycobacterium leprae, and Plasmodium falciparum.
·Non-synonymous DHPS mutations in Pneumocystis jirovecii, which occur at nucleotide positions 165 and 171, were initially discovered by Lane and colleagues.
·It is believed that the mutations change the way Arg56 binds to sulfa medications, lowering its affinity and lowering Arg56’s sensitivity to sulfa medicines.
·The lack of functioning enzymes and the inability to grow Pneumocystis make it difficult to show resistance to sulfa exposure.
·The incidence and importance of DHPS mutations in Pneumocystis jirovecii have been examined in a number of clinical trials.
·Up to 69% of isolates revealed a significant regional variation.
·Clinical isolates collected before the early 1990s had very few mutations, but subsequently there seems to have been a rise in their occurrence.
·A transition from wild-type to mutant DHPS occurred in five of seven individuals who had undergone therapy or secondary prophylaxis with trimethoprim-sulfamethoxazole or dapsone in a genotyping analysis of 13 European HIV patients with recurring episodes of PCP. This implies that sulfa drug pressure may be used to select DHPS mutations in vivo.
·The degree of this connection between DHPS mutations and low-dose sulfa prophylaxis failure is unclear. The effectiveness of trimethoprim-sulfamethoxazole when taken consistently is currently supported by clinical data.
8. DHFR Resistance·Diaminopyrimidines are competitive inhibitors of DHFR, essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and amino acids. ·Human Pneumocystis-derived DHFR had a 10-fold increase in sensitivity to trimetrexate and trimethoprim. ·Trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim and pyrimethamine for PCP prevention and treatment, but only few DHFR mutations have been identified in Pneumocystis DHFR.
Limitations of the study:
·Due to the absence of a culture system and the lack of a comprehensive understanding of metabolic pathways, studying medication resistance in Pneumocystis has proven difficult. · Another issue is that there is no accepted definition of clinical failure. · The contribution of nonadherence in presumed failure of prophylaxis may be difficult to assess.
9. Atovaquone ·Atovaquoneis used to prevent and treat disease caused by P. jirovecii, Plasmodium spp. Toxoplasma gondii and Bebesia spp. ·Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii, and Pneumocystis. ·Similar vitro susceptibility testing cannot be done like Plasmodium spp., Toxoplasma gondii ·Survival from PCP did not differ between patients with or without mutations. Overall, these findings are consistent with the development of atovaquone resistance after selective pressure is exerted. 10 Pentamidine and Clindamycine–Primaquine·Pentamidine and clindamycine-primaquine are used to treat PCP, but resistance is unknown.
11 Conclusion
·P. jirovecii mutations have arisen due to selective pressure from PCP prophylaxis, but their clinical impact is minimal.
·The most effective and affordable treatment for PCP is not affected by the disclosed mutations.
·The Pneumocystis Genome Project is a promising step towards understanding drug resistance.
=================================================== What is the level of evidence provided by this article?
I like your analysis of the level of evidence, and summary. I appreciate the mention of limitations.
Would have any personal experience of sulfa resistance of PCP?
Pneumocystis jirovecii is a fungus that leads to Pneumocystis pneumonia (PCP) in immunocompromised patients as AIDS cases.
Now days the incidence is decreasing compared to late 1980s in HIV patients due widespread use of prophylaxis and the availability of anti-retroviral treatment.
The organism:
Initially it was thought to be a protozoa.
In 1952 Jirovec was the first to discover it as human pathogen.
Recently it is classified as a fungi with a different characteristics, it has only one copy of ribosomal RNA, fragile cell wall, and had minimal no ergosterol.
Transmission & infection:
P.Jirovecii are ubiquitous but the source is not clear.
Primary infection occurs in early childhood worldwide.
Transmission may occur through reactivation or recent exposure to an airborne pathogen.
P.JP enters the lung and adhere to type I alveolar cells by the major surface glycoprotein (MSG) which is a highly polymorphic protein. This is to avoid host responses. Drug Treatment: important milestones:
Pentamidine in 1958
Sulfadoxine plus pyrimethamine 1960s
Sulfadiazine plus pyrimethamine in 1966
Trimethoprim plus sulfamethoxazole (TMP-SMX) between 1974 & 1977
Other agents: atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone, and aerosolized pentamidine Prophylaxis:
Primary; HIV with oral candidiasis or CD4 < 200
Secondary; all patients after an episode of PCP
At the TMP-SMX is the standard care for prevention against PJP Treatment of PJP:
PJP is fatal If Untreated => respiratory failure and death, so early suspicion and
recognition of the disease is very important to save life, as in immunocompromised
patient with low grade fever and dry cough with shortness of breath and hypoxia on
exertion => raise suspicion of PJP so early diagnosis and treatment should be started
soon to reduce the morbidity & mortality.
TMP-SMX:
The treatment of choice is antifolate drugs, which act by blocking de novo.
synthesis of folates through inhibition of dihydroperoate synthase (DHPS)
or dihydrofolate reductase (DHFR).
Toxic in 24 to 57% of HIV after 7 days.
May cause rash, fever, leukopenia, hepatic toxicity, hyperkalemia, interstitial nephritis and renal stones.
Pentamidine:
Administer by slow IV infusion over a period of at least 60–120 minutes at a final
concentration of administration not to exceed 2 mg/ml. Maintain patient lying down
during infusion. Rapid infusion causes hypotension. If hypotension occurs, increase
infusion time to 2–3 hours Nephrotoxic
Pancreatic toxicity; hypoglycemia
Hematologic toxicity; leukopenia
Dapsone-trimethoprim:
Oral drug, effective.
cross-react with sulfa in 50% of allergic patient.
Clindamycin-primaquine:
Clindamycin may cause rash, hepatitis, & diarrhea in HIV subject.
Atovaquone:
Oral medicine not effective as TMP-SMX.
May be use in mild disease when TMP-SMX is contraindicated or not available.
Adjunct therapy:
Hypoxia :
Oxygen saturation deteriorated in 1st 4-5 days of therapy due to death of organism
induced by the drug which leads to more inflammation which can be reduced by steroid,
so, adjunctive steroids are now recommended for all patients with severe disease (PaO2
< 70 mmgh).
Steroids if POa is < 70 mmHg i.e., moderate to severe disease.
Sulfonamide resistance:
Previous exposure to sulpha drugs due to prophylaxis.
DHPS mutations at nucleotide positions 165 and 171 and amino acid change at positions
55 & 57.
Occurs in 7 to 69% of isolates.
No effects on double strength TMP-SMX.
DHFR resistance:
May be due to selective pressure by DHFR inhibitors but so far, no strong evidence.
Atovaquone:
It works by depletion of ATP in the organism leading to death.
Resistance may occur through mutation of cytochrome b gene.
Pentamidine and Clindamycin-Primaquine:
Resistance mechanisms are not yet discovered.
Limitation to the study of drug resistance in pneumocystis jirovecii;
Pneumocystis jirovecii cannot be cultured.
No definition of clinical failure in pneumocystis jirovecii.
Severe inflammatory response may cause treatment failure and not necessarily drug resistance.
Non-adherence issues in presumed failure of prophylaxis may be difficult to assess.
Conclusion:
Sulfa and atovaquone drug resistance mutations occurred in P. jirovecii due to their
widespread use of PCP prophylaxis meanwhile their actual clinical effect is not much
Complete physical maps and gene sequences are being determined for the genomes of P. carinii.
Mechanisms of drug resistance and identification of new molecular targets are continuing under investigations.
What is The Level Of Evidence Provided By This Article?
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia in immunocompromised individuals, becoming the most common AIDS-defining diagnosis in industrialized countries.
2- The Organism
Pneumocystis was first identified in humans in 1942 by van der Meer and Brug, but was first established as a human pathogen in 1952 by Jirovec.
Pneumocystis is an ancient organism without any close relatives, suggesting it is an early divergent line in the fungal kingdom.
It has one copy of the nuclear ribosomal RNA locus, a fragile cell wall, and little ergosterol.
Pneumocystis is a broad family of organisms with species specificity among its mammalian hosts, with greater genetic divergence than other fungi.
Pneumocystis jirovecii was renamed in honor of Otto Jirovec, the first to describe the microbe in humans.
3 -Transmission and Infection
P. jirovecii is a ubiquitous organism with a uniform high incidence in all geographic areas, but its environmental source is unknown.
PCR findings support a more complex picture of transmission and infection.
Primary infection can lead to transient disease, but the presumption is that the organism becomes latent and manifests clinically if the patient is profoundly immunosuppressed.
Humans can be infected with multiple strains of Pneumocystis jirovecii, leading to latency with different organisms.
Non human animals are not the source of Pneumocystis, as each animal species is infected with a different strain and there is no crossspecies infection.
Pneumocystis has a specific tropism for the lung, where it attaches tightly to type I alveolar cells and is mediated by the major surface glycoprotein (MSG).
This protein is highly polymorphic, repeated and distributed among all the chromosomes, and is likely used to avoid the host immune response.
4-Drug Treatment
Drugs used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides, with pentamidine isethionate being the first to successfully treat PCP.
TMP-SMX is effective for both treatment and prophylaxis of PCP, and is the standard for prevention.
Drugs have proven activity for therapy and prophylaxis, but not all are effective for chemoprophylaxis.
Dapsone, trimethoprim, atovaquone, and aerosolized pentamidine are effective for prophylaxis, while intravenous pentamidine and clindamycin are not.
5- Prophylaxis
HIV-infected patients develop PCP at higher levels than 200 cells/mm3.
Patients with congenital immunodeficiencies, long term corti-costeroid therapy, chemothera-peutic regimens, and CD4 counts are at risk of PCP.
Systemic chemoprophylaxis against PCP was introduced by Dutz in the 1950s and Hughes et al. in the 1980s, with PCP prophylaxis becoming a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989.
Prophylaxis should be offered to all HIV-1 infected patients with oral candidiasis and CD4 count below 200 cells/μL for at least 3 months following antiretroviral therapy.
Prophylaxis should be offered for non-HIV infected individuals with a high risk of PCP, with daily TMP-SMX being the most efficient, cheap and widely used regimen.
6- Treatment of PCP
PCP mortality rates have decreased due to earlier recognition, adjuvant corticosteroids, better diagnostic and therapeutic abilities, and improved ICU supportive measures.
Patients and health care professionals must recognize that mild symptoms of PCP can be the initial manifestation, and should seek medical attention early.
Antifolate drugs are the most effective PCP treatment, blocking de novo synthesis of folates.
DHPS catalyzes the condensation of PABA-pryophospate to produce dihydropteroate, which is converted to dihydrofolate by DHFR.
Sulfamethoxazole is as potent as other commercially available sulfonamide preparations against pneumocystis, but trimethoprim is not as potent.
TMP-SMX is associated with better survival than pentamidine, but drug toxicity occurs in 24-57% of HIV-infected patients.
Adverse effects of trimethroprim include rash, fever, leukopenia, hepatotoxicity, renal calculus formation, anaphylactoid reactions, and pancreatitis.
Pentamidine is associated with a high frequency of toxicties, some of which are treatment-limiting. Intravenous infusion is the best tolerated route, but inhaled pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney.
Treatment limiting toxicities occur in 13-80% of patients.
Alternatives to TMP-SMX and pentami-dine include dapsone, trimethoprim, and atovaquone.
Clindamycin/primaquine has a metabolic pathway different from TMP-SMX, but both trials were underpowered.
Atovaquone is a good alternative to TMP-SMX for mild PCP, but dapsone and atovaquone must be administered orally.
Corticosteroids can reduce mortality in patients with severe disease (PaOs < 70 mmgh).
7- Sulfonamide Resistance
Sulfonamide resistance in Pneumocystis jirovecii is caused by mutations in the primary sequence of the DHPS gene, which are localized within a highly conserved active site of the protein.
Lane and co-workers were the first to identify non-synonymous (resulting in changes in the encoded amino acid) DHPS mutations in the virus.
Pneumocystis can not be cultured, so Saccharomyces cerevisiae has been used as a model to study P. jirovecii DHPS resistance.
Two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being asso-ciated with altered substrate binding.
However, one study showed an increase in sensitivity of the double mutations to sulfame thoxazole, suggesting that this approach may not accurately reflect the effect of these mutations.
Several clinical studies have investigated the frequency and significance of DHPS mutations in P. jirovecii.
Table 4 provides a summary of the studies reporting frequencies of mutations in sulfa-exposed and sulfa-unexposed patients.
There is a clear association between previous exposure to sulfa drugs and DHPS mutations, ranging from 7 to 69% of isolates.
Mutations have rarely been found in clinical isolates obtained prior to the early 1990s, but have increased recently due to selective pressure caused by the widespread use of sulfa drugs for prophylaxis.
The emergence of DHPS mutations in multiple strains of Pneumocystis jirovecii has been controversial.
In a genotype study of 13 European HIV patients with recurrent episodes of PCP, a switch from wild-type to mutant DHPS occurred in five of seven patients.
This suggests that DHPS mutants may be selected in vivo (within a given patient) under the pressure of trimethoprim-sulfamethoxazole or dap-sone.
However, there is evidence to suggest a contributory role for DHPSmutations in breakthrough PCP in patients using alternative sulfa prophylaxis.
Hauser et al. found a significant association with the failure of pyrimethamine and the Pro57Ser mutation.
Studies assessing the impact of DHPS mutations on response to therapeutic, high-dose trimethoprim have been conflicting, with initial case reports suggesting an increased risk of failing sulfa therapy or prophy-laxis.
However, two more recent studies have found no effect or a trend for lower death rate when comparing patients with DHPS mutation to wild-type.
This suggests that DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs.
However, additional mutations may develop that produce high-level resistance.
8 – DHFR Resistance
Trimethoprim and pyrimethamine are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of 7,8-dihyfrofolate to 5,6,7,8-tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides.
In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
However, despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR. Ma et al. detected only a single synonymous DHFR mutation in specimens obtained from 32 patients, of whom 22 had previous exposure to TMP—SMX therapy or prophylaxis .
Takahashi et al. found four mutations in P. jirovec iDHFR from 27 patients, two of which were not associated with prior exposure.
Nahimana et al. documented non-synonymous substitutions in 9 of 15 patients receiving a DHFR inhibitor as part of their prophylactic regimen, suggesting a greater selective pressure of this drug.
Matos and coworkers from Portugal recently reported a 27% rate of DHFR mutations in 128 PCP episodes, without association to failure of PCP prophylaxis.
However, there is so far no evidence that the widespread use has caused emergence of clinical significant resistance.
8.1 Atovaquone
Atovaquone is used to prevent and treat pneumocystis caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
It is structurally similar to the mitochondrial protein ubiquinone and competitively binds to the cytochrome bc1 complex, disrupting electron transport and leading to depletion of ATP.
Mutations near the binding pocket lead to decreased activity of atovaquone.
Two clinical studies have found that sequencing of the cytochrome b gene of Pneumocystis from ten patients showed sequence variations in four patients, two of which had nonsynonymous changes leading to amino acid substitutions within the ubiquitol pocket.
These findings suggest that selective pressure can lead to the development of resistance to atovaquone.
9- Pentamidine and
Clindamycine–Primaquine
Pentamidine and clindamycine-primaquine are used for prevention and treatment of PCP, but resistance mecha-nisms remain unknown.
Limitations to the study of drug resistance in Pneumocystis
The study of drug resistance in Pneumocystis jirovecii has been difficult due to the lack of an in vitro culture system and lack of standard susceptibility testing.
Experimental systems have mainly relied on immunosuppressed animal, and no consistent definition of clinical failure exists.
Studies using repeat bronchoscopy during and immediately after successful treatment of PCP have shown that clearance of organisms is slow and that infection is eventually cleared and the viability of organisms detected at the end of treatment is uncertain.
PCP is characterized by marked pulmonary inflammation, which can lead to alveolar damage and respiratory failure.
Treatment of PCP is associated with a high incidence of adverse effects, and it is difficult to know whether a slow treatment response with continuing fever is caused by the infection or by the treatment.
Nonadherence to prescribed prophylaxis is the most important reason for failure, and clinical resistance may be markers of poor adherence, rather than the direct cause of treatment failure.
10 -Conclusion
Mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii, but the clinical effect is modest.
Investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing.
Complete physical maps and gene sequences are being determined for the genomes of P. carinii.
-Introduction
Pneumocystis jirovecii is a fungus that leads to Pneumocystis pneumonia (PCP) in immunocompromised patients as AIDS cases.
PCP chemoprophylaxis and potent HIV-1 antiretroviral regimens lowered it’s incidence. Organism
Pneumocystis was first notified as a human pathogen in 1952 when Jirovec discovered it in premature malnourished infants causing interstitial plasma cell pneumonia .
The organism has been categorized as a fungus entitled under the Archiascomycetes
In 1994, P. carinii f.sp. hominis is named for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats and in 2002 the organism infecting humans was renamed Pneumocystis jirovecii.
Primary infection with P. jirovecii happens in early childhood, the clinical infection results from reactivation in immunocompromised cases Transmission
It was supposed that primary infection can lead to respiratory tract infection or sudden infant death syndrome then the organism remains latent and is reactivated when the host is immunocompromised.
It was supposed that multiple strains of P.jirovecii can infect the individual on multiple occasions.
The environmental source of Pneumocystis is unknown.
It has specific tropism for the lung.
It adhere to the surface of type I alveolar cells after inhalation of the organism , this process is mediated by the major surface glycoprotein (MSG) which harbours extensive variable antigens as a defensive mechanism in front of host immunity .
It was suggested that the organism has a sexual replication cycle that reacts to environmental pulmonary changes . Drug treatment
Classic antifungal drugs are inactive against Pneumocystis pneumonia
Antifolate drugs, diamines, atovaquone, and macrolides are the main drug groups used for prophylaxis and treatment.
TMP–SMX is the treatment and prophylaxis of choice.
Other therapeutic drugs include sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine are used for prophylaxis. Prophylaxis
PCP risk increases with lower CD4 counts. 200 cells/mm3is used as an indicator of susceptibility for PCP in HIV infected cases meanwhile patients can develop PCP at higher CD4 counts .
Immunocompromised status congenital immunodeficiency , long standing steroids intake ,chemotherapeutics render the patient at risk for PCP.
TMP–SMX prophylaxis can prevent PCP occurrence.
HIV-1 infected patients with oral candidiasis or a CD4 count < 200 cells/μL, need primary prophylaxis. Cases with an episode of PCP need secondary prophylaxis .
TMP–SMX prophylaxis is tolerated by non-HIV patients opposite to HIV cases particularly with lower doses or intermittent regimens. PCP treatment
PCP mortality rates decreased to 5–15%.
Adjuvant corticosteroids given to patients with moderate-to-severe PCP with PaO2< 70 mmHg improves outcome.
Early detection of mild symptoms and immediate introduction of therapy without delay improves the prognosis.
Chemotherapy choice is crucial.
The most efficient drugs for PCP treatment are antifolate drugs which acts through inhibition of dihydroperoate synthase (DHPS) or dihydrofoslate reductase. TMP–SMX
It’s intake was associated with better survival compared to pentamidine.
TMP–SMX adverse effects can happen after 1 week of drug intake including rash, fever , leukopenia ,hepatotoxicity , interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis .
They are not life threatening although fatal Stevens–Johnson syndrome was reported . Pentamidine
Slow intravenous infusion is the best tolerated route for pentamidine adminstartion.
It’s side effects include nephrotoxicity ,pancreatic injury ,leucopenia ,long OT interval ,torsade de pointe.
Dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone are another therapeutic options.
Clindamycin has multiple adverse effects as hepatitis, rash and diarrhea.
Primaquine and Atovaquone are only orally given.
Dapsone–pyrimethamine was suitable for mild-to-moderate PCP and atovaquone for mild PCP.
Recommendation of therapy for HIV-negative cases is 2 weeks and HIV positive patients for 3 weeks.
Adjunctive steroids are recommended for all patients with severe disease (PaOs< 70 mmgh). Sulfonamide resistance
Extensive use of sulfa drugs for therapy and prophylaxis for PCP in HIV cases ,malaria and bacterial infection in Africa increased resistance rate .
In E coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
Double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, leading to resistance with altered substrate binding.
Previous exposure to sulfa drugs for prophylaxis had been associated with DHPS mutations .
DHPS mutations was detected in cases without any previous exposure to sulfa drugs, raising the possibility of person-to-person spread of mutant strains.
The actual drug resistance association with prescribed prophylaxis is unknown.
In spite of presence of mutant DHPS strains, the efficacy of trimethoprim–sulfamethoxazole prophylaxis is still noticed.
A study detected failure of pyrimethamine–sulfadoxine prophylaxis association with the Pro57Ser mutation.
DHPS mutations was associated with dapsone prophylaxis.
Therefore DHPS mutations contribute to low-level sulfa resistance and failure of second-line sulfa
prophylaxis.
Lack of compliance on chemoprophylaxis is responsible for PCP outbreak.
The effect of DHPS mutations on response to therapeutic, high-dose trimethoprim was controversial. DHFR resistance
The combination of trimetrexate and sulfamethoxazole are more efficient in vitro than the combination of trimethoprim plus sulfamethoxazole.
Relatively few DHFR mutations are detected in Pneumocystis DHFR inspite of the extensive use of trimethoprim and sulfamethoxazole for prevention and treatment of PCP,
There is no evidence that extensive trimethoprim or pyrimethamine use ,leads to clinical significant resistance to DHFR inhibitors. Atovaquone
It is used for prophylaxis and treatment of diseases caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
Mutations of the cytochrome b gene detected in Plasmodium spp., Toxoplasma gondii and Pneumocystis in vitro studies were associated with resistance to atovaquone. Pentamidine and Clindamycine–Primaquine
They are used for prophylaxis and treatment of PCP, but possible resistance mechanisms are under study Conclusion
Sulfa and atovaquone drug resistance mutations occurred in P. jirovecii due to thier widespread use of PCP prophylaxis meanwhile their actual clinical effect is not much.
No evidence that DHPS mutations is accompanied with significant resistance to high dose of sulfa treatment.
Pneumocystis Genome Project completion and physical maps and gene sequences are studied for the genomes of P. carinii which will be crucial for detection of new polymorphic regions and drug targets.
Pneumocystis jirovecii is a form of pneumonia in immune compromised hosts.
Now days the incidence is decreasing compared to late 1980s in HIV patients due widespread use of prophylaxis and the availability of anti-retroviral treatment.
The organism
Initially it was thought to be a protozoa.
In 1952 Jirovec was the first to discover it as human pathogen and his name was honored for this.
Recently it is classified as a fungi with a different characteristics, it has only one copy of ribosomal RNA, fragile cell wall, and had minimal no ergosterol.
Transmission & infection
P.Jirovecii are ubiquitous but the source is not clear.
Primary infection occur in early childhood world wide.
Transmission may occur through reactivation or recent exposure to an airborne pathogen.
P.J enters the lung and adhere to type I aveloar cells by the major surface glycoprotein(MSG) which is a highly polymorphic protein. This is in order to avoid host responses.
Drug Treatment: important mile stones
Pentamidine in 1958
Sulfadoxine plus pyrimethamine 1960s
Sulfadiazine plus pyrimethamine in 1966
Trimethoprim plus sulfamethoxazole(TMP-SMX) between 1974 & 1977
Other agents: atovocaquone, clindamycin plus pyimethamine, trimetrexate, dapsone, and aerosolized pentamidine
Prophylaxis
Primary; HIV with oral candidiasis or CD4 < 200
Secondary; all patients after an episode of PCP
At the TMP-SMX is the standard care for prevention against PJP
Treatment of PJP
Early diagnosis is essential due reduce the morbidity & mortality.
Do not wait until late.
1.TMP-SMX
Toxic in 24 to 57% of HIV after 7 days.
May cause rash,fever, leukopenia, hepatic toxicity, hyperkalemia, interstitial nephritis & renal stones.
2 Pentamidine
Given by slow IV infusion to avoid adverse events.
Nephrotoxic
Pancreatic toxicity; hypoglycemia
Hematologic toxicity; leukopenia
3.Dapsone-trimethoprime
Oral drug, effective.
cross-react with sulfa in 50% of allergic patient.
4.Clindamycin-primaquine
Clindamycin may cause rash, hepatitis,& diarrhea in HIV subject.
5.Atovaquone
Oral medicine not effective as TMP-SMX.
May be use in mild disease when TMP-SMX is contraindicated or not available.
6.Adjunct therapy
Steroids if POa is < 70 mmHg i.e moderate to severe disease.
Sulfonamide resistance
Previous exposure to sulpha drugs due to prophylaxis.
DHPS mutations at nucleotide positions 165 and 171 and amino acid change at positions 55 & 57.
Occurs in 7 to 69% of isolates.
No effects on double strength TMP-SMX.
DHFR resistance
May be due to selective pressure by DHFR inhibitors but so far no strong evidence.
Atovaqupone
It works by depletion of ATP in the organism leading to death.
Resistance may occur through mutation of cytochrome b gene.
Pentamidine and Clindamycin-Primaquine
Resistnace mechanisms are not yet discovered.
Limitation to the study of drug resistance in pneumocystis jirovecii;
Pneumocystis jirovecii cannot be cultured.
No definition of clinical failure in pneumocystis jirovecii.
Severe inflammatory response may cause treatment failure and not necessarily drug resistance.
Non-adherence issues in presumed failure of prophylaxis may be difficult to assess.
What is the level of evidence provided by this article?
Drug Resistance in Pneumocystis jirovecii Introduction
1- Pneumocystis jirovecii is fungal organism cause pneumonia PCP in immunocompromised patients, previously called Pneumocystis carinii.
2- Its incidence increased with the era of definite diagnosis of HIV.
3- Its incidence decrease dramatically with era of chemoprophylaxis against PCP, and also with introduction with HIV antiretroviral treatment. Organism 1- It was identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini They considered the organisms as a new form of Trypanozoma cruzi. 2- Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug, who described it in three cases. 3- Pneumocystis was fi rst established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages. 4- In the twentieth century, Pneumocystis was considered as a protozoon and single species based on its morphologic features, but has resistance to classical antifungal agents and the effectiveness of certain drugs used to treat protozoan infections. 5- in 1988, analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom was done. Phylogenetic data suggest that Pneumocystis is an ancient organism without any close relatives, Pneumocystis species represent an early divergent line in the fungal kingdom. 6- The organism has recently been placed in a group of fungi entitled the Archiascomycetes. In contrast to most other fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol. 7- In 1994, an interim trinomial name change was adopted with the name P. carinii f.sp. hominis for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats. 8- In 2002, because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was among the fi rst to describe the microbe in humans. Transmission and Infection
1- Primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
2- Organism becomes latent, and reactivated only in immunocompromised patients, and antibodies against it usually formed in the first year of life, also it may lead to sudden infant death.
3- The organism has specific tropism to the lung, where it exists, but may found in other organs.
4- When the organism inhaled, it attach to type 1 alveolar cells, this adherence is encoded by major surface protein in the organism which is abundant on its surface and it is polymorphic escaping immune response. Drug treatment
1- In 1958, pentamidine isethionate was the fi rst drug used to successfully treat PCP.
2- In the 1960s, the combination of sulfadoxine and pyrimethamine was used.
3- In 1966, sulfadiazine and pyrimethamine were used.
4- Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP.
5- TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
6- TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
7- Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine. Prophylaxis
1- CD4 count is usually used as indicator for PCP susceptibility in HIV patients, if less than 200 , PCP can be developed but also can be developed in count more than 200, so it is unreliable marker for PCP in HIV patients.
2- Chemoprophylaxis used as a primary prophylaxis to HIV patient with CD4 less than 200 and can be interrupted at any time when CD4 raised more than 200 FOR 3 months after anti-retroviral treatment.
3- Secondary prophylaxis can be offered to all patients after attack of PCP.
4- TMP-SMX has much side effects in HIV patients than non-HIV patients like rash and myelosuppression.
5- In non-HIV patients like cancer, SOT, patients with high dose steroid, TMP-SMX can be given as a prophylactic therapy and it is well tolerated, cheap and available. Treatment of PCP
1- Untreated PCP is fatal, respiratory failure and death is the end, so, early suspicion and recognition of the disease is very important to save life, as in immunocompromised patient with low grade fever and dry cough with shortness of breath and hypoxia raise suspicion of PCP so early diagnosis and treatment should be started soon.
2- The treatment of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
3- TMP–SMX, Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Hepatotoxicity characterized by elevated transaminases also occurs. There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported. Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.
4- Pentamidine is associated with a high frequency of toxicities, like hypotension and death, it is related to rate and route of administration, so, should be given as iv infusion, pentamidine is nephrotoxic and also has pancreatic toxicity.
5- dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone.
6- Duration of treatment 2 weeks in non-HIV patients and 3 weeks in HIV patients.
7- Oxygen saturation deteriorated in 1st 4-5 days of therapy due to death of organism induced by the drug which leads to more inflammation which can be reduced by steroid, so, adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh).
8- Increase epidemic of HIV and other immunosuppressive state like cancer and SOT, and patients using high dose of steroid, all these increase need for PCP prophylaxis which also increase resistance to sulpha, so, increase chance to other drugs to be introduced.
Pneumocystis jirovecii is an opportunistic fungus that causes PCP in immunocompromised individuals. PCP is a serious problem in immunocompromised who are not received prophylaxis.
Pneumocystitis organisms have been identified in most mammalian species. They include a broad family of organisms, with species specificity among their mammalian hosts.
Transmission
Human to human .. airborne infection
Or environmental, but environmental source is unknown
Non human are not the source, it is species specific.
Human hosts can be infected with more than one strain of PJ leading to latent infection
The clinical disease PCP may occur as a reactivation of a prior latent or as a recent acquisition of an airborne pathogen.
Drug treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines,atovaquone and macrolides.
First drug used successfully for treatment was pentamidine
Then the studies showed that combination of Trimethoprim-sulfamethoxazole is effective in treatment and prophylaxis of murine then human PCP and is as effective as IV pentamidine.
TMP-SMX is still the treatment of choice and the most effective chemo prophylaxis for PCP.
The widespread use of TMP-SMX and dapsone for therapy and prophylaxis among HIV patients has led to the concern that sulfa resistance could develop in P.jirovecii.
Sulfonamide resistance is caused by mutation in the primary sequence of the DHPS gene. The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at position 55 and 57.
DHPS mutations of codon 55 and 57 are implicated in the failure of low dose sulfaprophylaxis , but there is no firm evidence that DHPS mutations result in significant resistance to high dose sulfa therapy.
However, it is possible that if additional mutations arise,then high level sulfa resistance could emerge and lead to diminished efficacy of TMP-SMX. This would be loss of the most efficient and inexpensive therapy for PCP.
Level of evidence 5
The prolonged use of TMP/SMX in PCP prophylaxis has produced some mutations like dihydrofolate reductase (DHFR),also sulfonamide resistance
Level of evidence :5
In other fungal infections, clinical resistance is classically defined as the persistence or progression despite the administration of appropriate antimicrobial treatment. However, persistence of Pneumocystis organisms may happen in spite of a successful treatment response and the host inflammatory response, rather than resistance to antimicrobial drug treatment, may cause an apparent absence of response to treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides
Sulfonamide Resistance is due to the widespread use of TMP–SMX and dapsone for therapy and prophylaxis of P. jirovecii, malaria and bacterial infection in Africa.
In San Francisco, the increasing use of PCP prophylaxis among HIV patients led to a marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and seven genera of Enterobacteriaceae. In pathogens such as Escherichia coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene .the available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. However, the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides. Despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR . although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical signifi cant resistance to DHFR inhibitors.
level of evidence 5
Please summarise this article.
Post-transplantation, kidney transplant patients are prescribed TMP-SMX prophylaxis. The treatment by blocking dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
Treatment for PCP:
Resistance
What is the level of evidence provided by this article?
Level 5
Introduction:
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodeficiencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen, but increased after AIDS discovery.
Organism:
The Organism Pneumocystis were identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini. These investigators mistakenly considered the organisms as a new form of Trypanozoma cruzi. In 1912, Pneumocystis was recognized as a new species and named in honor of Carini . Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug.
Drug Treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
Sulfonamide Resistance
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
In 1997, Lane and co-workers were the first to identify nonsynonymous (resulting in changes in the encoded amino acid) DHPS mutations in Pneumocystis jirovecii. The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).
Conclusion: In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis. Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
level of evidence: 5
PCP is an opportunistic infection that carries a high mortality rate among immunosuppressed and HIV patients who are not on appropriate chemoprophylaxis.
-Antifolate drugs: inhibition of dihydropteroate reductase (DHPR)-TMP/SMT is the drug of choice
-Pentamidine It’s 2nd line after TMP/SMT- in patients with sulfa sensitivity.
-Clindamycin–primaquine
DHFR Resistance
-Trimetrexate
-Atovaquone
-Pentamidine and Clindamycin–Primaquine
-Narrative review of level 5 evidence
Level 5 evidence
It is now known that P. jirovecii mutations related to sulfa and atovaquone medication resistance have arisen as a result of selective pressure from the widespread use of PCP prophylaxis, notwithstanding the difficulty to culture the organisms. The clinical impact of the disclosed mutations currently appears to be minimal. The failure of low-dose sulfaprophylaxis is linked to DHPS mutations at codons 55 and 57, however there is no conclusive proof that DHPS mutations cause significant resistance to high-dose sulfa treatment. However, it’s probable that if more mutations occur, high-level sulfa resistance could appear and reduce TMP-SMX’s efficacy. This would result in the loss of the most effective and affordable treatment for PCP.
The danger of high-level resistance developing could be significantly increased by the growing HIV epidemic and the use of TMP-SMX in developing nations. As a result, research into medication resistance mechanisms and the identification of new molecular targets is ongoing. The completion of the Pneumocystis Genome Project, which was started in 1997, is a promising development. For the genomes of P. carinii , complete physical maps and gene sequences are being determined. The identification of new polymorphic areas and therapeutic targets, as well as the potential construction of a culture system, will all be made possible by these data, which are essential for advancing our understanding of the illness.
Drug Resistance in Pneumocystis jirovecii
Its narrative review (level 5) was published in January 2009 In the book Antimicrobial Drug Resistance discussing PCP and pathogen-related mutation in the DHPD gene which results in only a reduction in sulfa drug sensitivity.
Introduction
– PCP is a serious opportunistic infection that carries a high mortality rate among immunosuppressed and HIV patients who are not on appropriate chemoprophylaxis.
PCP was re-classified as fungi that have only one copy of the nuclear ribosomal RNA locus surrounded by a fragile cell wall.
– There is no cross-species infection and the organism infecting humans was renamed Pneumocystis jirovecii.
Transmission and Infection
–Most likely it’s an airborne pathogen but reactivation of latent organisms is still suspected in immunocompromised hosts.
Drug Treatment
-The major drug classes used for the treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
1. Antifolate drugs: these blocks the de novo synthesis of folates through the inhibition of dihydropteroate reductase (DHPR), which catalyzes (PABA) to produce dihydropteroate. Sulfa drugs are structural analogs of PABA and inhibit DHPS.TMP/SMT is the drug of choice
2. Pentamidine is an IV drug that needs to be administrated on a monthly basis associated with hypoglycemia and nephrotoxicity, pancreatitis, and IDDM. Hypotension with short infusion time, pancytopenia, and Q-T prolongation. It’s 2nd line after TMP/SMT, especially in patients with sulfa sensitivity.
3. Dapsone: it should not be used alone for treatment. Usually used as Dapsone–trimethoprim combination. There are cross-reacts with sulfa in 50% of allergic patients which is why it’s not offering any advantages over TMP–SMX.
4. Clindamycin–primaquine in moderate- to-severe PCP has an equivalent effect with TMP–SMX.
5. Atovaquone; This is a good alternative to TMP–SMX for patients with mild disease only who cannot tolerate TMP–SMX.
Sulfonamide Resistance
Double DHPS mutations (Thr55Ala and Pro57Ser) result in a reduction in sulfa drug sensitivity that’s why the only clinical significance of DHPS mutations will be in prophylaxis regimens. Therapy using a sulfa-based regimen has been controversial.
. there is a clear association between previous exposure to sulfa drugs and DHPS mutations have been shown in all studies.
DHFR Resistance
1. Trimetrexate is much more potent against PCP than trimethoprim in vitro so a combination of trimetrexate and sulfamethoxazole may be a good option but there is no clinical data to support this.
2. Atovaquone: Competitively binds to the cytochrome bc1 complex. It can be used for DHPS mutations but mutation in cytochrome bc complex may confer resistance to atovaquone.
Pentamidine and Clindamycin–Primaquine: Resistance mechanisms not yet
Introduction:
Pneumocystis jirovecii, previously known as Pneumocystis carinii, is a fungal pathogen that causes pneumonia in immunocompromised patients. Despite a reduction in its incidence due to prophylaxis and antiretroviral therapy, Pneumocystis pneumonia (PCP) remains a serious opportunistic infection among heavily immunosuppressed individuals. This article discusses various aspects of Pneumocystis jirovecii, including its discovery, transmission, clinical manifestations, and treatment.
Pneumocystis jirovecii was first discovered in guinea pigs and rat lungs in the early 20th century. Its identification as a human pathogen occurred in 1942, and in 2002, it was officially named Pneumocystis jirovecii. The organism is believed to have a tropism for the lungs and is predominantly found in the alveoli.
Transmission and Infection:
Primary infection with Pneumocystis jirovecii is thought to occur during early childhood, and the organism is considered ubiquitous. The exact source of infection is unknown, but it is hypothesized to be an environmental source. Infection may correlate with respiratory symptoms or sudden infant death syndrome. It is possible for individuals to be infected with multiple strains of Pneumocystis jirovecii, leading to latency with different organisms.
Prophylaxis and Treatment:
Pneumocystis jirovecii has limited susceptibility to traditional antifungal agents, and initial drug testing focused on drugs with activity against protozoan infections. Trimethoprim-sulfamethoxazole (TMP-SMX) is the most commonly used and effective therapy for both treatment and prophylaxis of PCP. Other drug classes used include antifolate drugs, diamines, atovaquone, and macrolides.
Prophylaxis against PCP is crucial, particularly in high-risk populations such as organ transplant recipients and individuals receiving high-dose steroid treatment or chemotherapy. TMP-SMX is the preferred prophylactic regimen, while alternative regimens include dapsone, pentamidine, and atovaquone. Untreated PCP is almost always fatal, and the first-line treatment is trimethoprim-sulfamethoxazole. Alternative treatment options include dapsone plus trimethoprim, clindamycin plus primaquine, pentamidine, and atovaquone.
There are concerns about the development of sulfa resistance in Pneumocystis jirovecii due to the widespread use of sulfonamide drugs for PCP treatment and prophylaxis. Resistance to sulfonamides can limit their efficacy. Additionally, resistance to DHFR inhibitors, such as trimethoprim, has emerged in various bacterial and parasitic species. However, the occurrence of resistance in Pneumocystis jirovecii is relatively low.
Limitations of the Study:
Studying drug resistance in Pneumocystis jirovecii is challenging due to the absence of a culture system for susceptibility testing. The lack of a consistent definition for clinical failure and the difficulty in assessing non-adherence to prophylaxis pose additional challenges. Treatment of PCP can also be associated with side effects, making it challenging to differentiate between treatment-related effects and persistent infection.
Level of Evidence:
This article provides Level V evidence.
Please summarise this article.
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).DHPS catalyzes the condensation of p-aminobenzoic acid (PABA) and hydroxymethyl dihydropterin–pryophospate to produce dihydropteroate, which is later converted to dihydrofolate by dihydrofolate synthase. Subsequently, dihydrofolate is reduced by dihydrofolate reductase (DHFR) into tetrahydrofolate. Sulfa drugs are structural analogs of PABA and inhibit DHPS.
Sulfonamide Resistance-
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.. A clear association between previous exposure to sulfa drugs (primarily for prophylaxis rather than therapy) and DHPS mutations has been shown in all studies.. Large geographical variation in the prevalence of DHPS mutations has been reported, ranging from 7 to 69% of isolates. The clinical significance of DHPS mutations, specifically with regard to response to prophylaxis and therapy using a sulfabased regimen (primarily trimethoprim– sulfamethoxazole or dapsone), has been controversial. Several studies have reported a significant association of DHPS mutations with failure of low-dose sulfa prophylaxis However, the extent to which this association refl ects actual drug resistance or failure to comply with prescribed prophylaxis is unknown.Hence, in spite of the emergence of mutant DHPS strains, current clinical experience supports the efficacy of trimethoprim– sulfamethoxazole prophylaxis when taken regularly. Available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. However, the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
While initial case reports suggested that patients with mutant DHPS strains had increased risk of failing sulfa therapy or prophylaxis , subsequent studies have not supported such a conclusion.Moreover, even in studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprim– sulfamethoxazole or dapsone–trimethoprim. These observations suggest that the currently identifi ed DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
The diaminopyrimidines, trimethoprim and pyrimethamine,are competitive inhibitors of dihydrofolate reductase (DHFR).In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical signifi cant resistance to DHFR inhibitors.
Atovaquone
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia sp. Development of atovaquone resistance can occur after selective pressure is exerted.. Survival from PCP did not differ between patients with or without mutations.
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
What is the level of evidence provided by this article?
Level 5
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodefi ciencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen. However, with the AIDS pandemic PCP emerged as the most common AIDS-defi ning diagnosis in industrialized countries. The peak incidence of PCP was observed in the late 1980s and early 1990s. Subsequently, there has been a decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens. However, PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis. Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no fi rm evidence that DHPS mutations result in signifi cant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished effi – cacy of TMP–SMX. This would lead to the loss of the most effi cient and inexpensive therapy for PCP. The increasing HIV epidemic and use of TMP–SMX in the third world may signifi cantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identifi cation of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Complete physical maps and gene sequences are being determined for the genomes of P. carinii (111). These data will be crucial for further understanding of the infection and will enable identifi cation of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
The level of evidence is 5
Summary :
Pneumocystis jirovecii is ubiquitous fungus which causes opportunistic infection (Pneumocystis pneumonia – PCP), in the immunocompromised. Pneumocystis jirovecii infection when acquired, can remain latent for long time. The clinical presentation may appear due to reactivation of previous latent infection, or due to new acquisition of an airborne pathogen.
Drug treatment:
First line – Trimethoprim-sulfamethoxazole.
Alternative protocol: Dapsone + Trimethoprim. Clindamycin + Primaquine, Pentamidine, Atovaquone.
Resistance to sulphonamide:
– use of sulfa drugs for malaria and bacterial infections in Africa led to high incidence of resistance in P. falciparum and several bacterial species
– Mutations related to resistance are located in a highly conserved active site of the DHPS protein.
Resistance of DHFR :
The diaminopyrimidines; trimethoprim & pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) that is related to catalysis of reduction of inactive 7,8-dihyfrofolate to the active form 5,6,7,8- tetrahydrofolate with presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used combined with sulfonamides.
It is not clear whether high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors.
Atovaquone:
Atovaquone is used for prevention and treatment of disease caused by P. jirovecii, Plasmodium spp, Toxoplasma gondii and Bebesia spp .Structurally ,it is similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex. Studies involving Plasmodium and Toxoplasma showed that these mutations lead to resistance to atovaquone. Studies of cytochrome b gene of Pneumocystis, were in harmony with the development of atovaquone resistance
Pentamidine – Primaquine – Clindamycin:
No resistance mechanisms have yet to been reported.
Conclusion
DHPS mutations at codon 55 and 57 are involved in the failure of low-dose sulfa prophylaxis, but no solid evidence that DHPS mutations cause significant resistance to high-dose sulfa therapy. However, it is probable that if more mutations occur, high-level sulfa resistance could develop and result in reduced efficacy of TMP–SMX. This could lead to not using the most efficient and inexpensive therapy for PCP.
The increasing HIV incidence and use of TMP–SMX in the third world may markedly lead to increase of the risk for the development of high-level resistance. So, studies of the mechanisms of drug resistance and detection of new molecular targets are needed. A potential advance will be the achievement of the Pneumocystis Genome Project.
-Level of evidence: V .
Summary:
Introduction
This article has a narrative theme, and is based on drug resistance in pneumocystis jirovecii. In the past, PCP was a rare infection, however, after the spread of HIV AIDs, this infection has become more prevalent, causing severe respiratory distress and eventually death. However, chemoprophylaxis has a good outcome when fighting against PCP.
Discussion
There are four different classes of drugs that can be used in treatment and prophylaxis of PCP. These include
antifolate drugsdiaminesatovaquonemacrolidesThe specific drugs under these classes that can be used along with their dosage includes :
Trimethoprim-sulfamethoxazole OD – single or double doseDapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorine 25 mg weeklyDapsone 200 mg weekly + pyrimethamine 75 mg weekly + leucovorin 25 mg weeklyatovaquone 1500 mg dailyOutbreaks of PCP can be controlled with sulfadoxine plus pyrimethamine.
Other than HIV, other factors such as organ transplant, high dose steroids and high dose chemotherapy can increase the risk of PCP.
The most effective and safe prophylactic regimen is daily TMP-SMX. However, it can be toxic in 25-50% of patients. Adverse effects include fever, rashes and leucopenia, with possibility of anaphylaxis in some patients. Hyperkalemia is also a concern which should be monitored for in these patients. Hepatotoxicity is seen in some patients, in which case we can see elevated transaminases. More serious possible complications include pancreatitis, Stevens Johnson syndrome, interstitial nephritis, and renal calculus formation.
Atovaquone is generally well tolerated in comparison with TMP SMX, but is only available orally. It can be used for patients with mild disease.
The common use of TMP SMX has led to sulfonamide resistance. Mutations in the DHPS gene, in nucleotide positions 165 and 171 leading to amino acid position changes at 55 and 57. These mutations are found in patients with previous exposure to sulfa drugs, which suggests person to person spread of mutant strains.
It is possible that DHPS mutations are due to low dose sulfa prophylaxis. DHPS mutations may be an independent predictor of decreased survival in PCP patients.
The other mutation possible leading to antibiotic resistance is DHFR gene mutation. However, this is not thought to be impacted heavily by use of trimethoprim or pyrimethamine.
Nonadherence to medication during the prophylactic phase can be a big reason for failure of prophylaxis. This can lead to bad outcome post transplant for both the graft and the patient. Monitoring may be essential in more rapid intervals for patients who are suspected of non adherence to medication.
Conclusion
PCP is a fatal disease if not treated adequately. Adherence to treatment regimen along with completion of treatment will allow better chances for success in infection resolution. In addition, kidney transplant patients may need lowering of immunosuppressive drug doses in order to allow PCP to resolve satisfactorily. The best method would be to prevent the infection from impacting the patient in the first place, through aggressive prophylaxis for 3 to 6 months post kidney transplant.
Level of evidence:
This is a narrative study, and this level of evidence is 5.
Introduction:
Pneumocystis jiorveci is serious infection cause pneumonia in immunocompromised patients. The peak incidence of infection appear in 1980-1990 but in recent years it is decline because introduction of prophylaxis of PCP and treatment of HIV-1 antiviral therapy.
Microorganisms:
Pneumocystis jirovecii previously named as Pneumocystis carinii and classified as a protozoa. Currently, it is considered a fungus based on nucleic acid and biochemical analysis and named as P. jirovecii organism.
Transmission and Infection:
It’s type of fungus, Environmental cause of pneumocystis still not identified and transmission from person to persons by air.
Drug Treatment:
The main drug used in prophylaxis of pneumocystis jiorvecii is:
In 1958, the first drug of choice was pentamidine isethionate.
In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystosis in Iran.
In 1966, sulfadiazine and pyrimethamine was used as trials.
Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP. TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
These drugs like sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine shows effective therapy against pneumocystis jiorvecii. Not all drugs are effective for therapy it’s also effective for chemoprophylaxis.
Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis. Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
There are some drugs have activity in vitro like azithromycin, doxycycline, and caspofungin.
Prophylaxis:
Patients with HIV
Congenital immunodeficiency
Patients with long term corticosteroids
Patients on chemotherapy such as fludarabine, ATG.
Primary prophylaxis should be considered in patients with HIV-1 with candidiasis or CD4 count less than 200 cell/ul.
Secondary prophylaxis against PCP should be considered in all patients exposed to PCP.
In non-HIV infected individuals, conditions such as organ transplantation, high dose steroid treatment and/or high dose chemotherapy may has high risk of PCP. Prophylaxis should be stared.
The best one and cheaper is TMP–SMX.
Dose of TMP–SMX (septrin), 400/80 mg daily is effective and is associated with few side effects than 160/800mg daily.
Side effects of septrin is skin rash, fever, anemia , neutropenia Hyperkalemia Hepatitis Nephritis and Anaphylactoid reaction.
Treatment of PCP:
PCP is serious condition may be fatal if not treated. Mortality rate reached to 30-40% of cases and to 70-80% in cases with respiratory failure. adjuvant steroid to patients with moderate to severe PCP with PaO2 of less than 70mmHg or patients with HIV with CD4 less than 200cell/ ul. The treatment of PCP should be stared as early as possible even symptoms non specific ( dry cough, low grade fever and dyspnea), with presence of risk factors in immunocompromised patients or chest X ray abnormal and the first drug of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase or dihydrofolate reductase.
Pentamidine is very toxic associated with nephritis and pancreatitis and hypoglycemia and it’s may prolongs the QT interval, and cause torsades de pointe in some reported cases.
Alternative to o septrin and pentamidine include dapsone pyrimethamine, clindamycin primaquine, and atovaquone.
Clindamycin associated with high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
Atovaquone is used alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Dapsone pyrimethamine is used in mild to moderate cases with PCP.
Many patients shows progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration is caused by the drug induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. This inflammation can be reduced by corticosteroids.
Sulfonamide Resistance:
Resistance develop due to wide use of septrin as prophylaxis and treatment of PCP, Falciparum malaria and bacterial infection. There’s marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and Enterobacteriaceae. This resistance against bacterial infection occur due to mutations of primary sequence of the DHPS gene. Many clinical studies investigated the frequency and significance of DHPS mutation in P jiorvecii. There’s large geographical variations in resistance to sulfa associated with DHPS mutations and some studies shows significant association with the failure of pyrimethamine–sulfadoxine prophylaxis and the Pro57Ser mutation. Also the major cause of resistance is poor adherence to chemoprophylaxis and mutation of DHPS.
DHFR Resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR); so mutations to DHFR in Pneumocystis DHFR lead to resistance septrin but still no definitive evidence.
Atovaquone:
It’s used to treat and prevent P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. It’s structural near to mitochondrial protein and competitively binds to the cytochrome bc1. However mutations of cytochrome bc1 gene in Plasmodium spp., Toxoplasma gondii and Pneumocystis leading to unresponse to Atovaquone but Survival from PCP did not differ between patients with or without mutations.
Pentamidine and Clindamycine–Primaquine:
Pentamidine and clindamycine primaquine are used for prevention and treatment of PCP, and resistance to these agents can be happen but still rare.
Level V
Drug Resistance in Pneumocystis jirovecii
Jannik Helweg-Larsen, Thomas Benfi eld, Joseph Kovacs, and Henry Masur
Summary of the article:
Introduction:
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is ubiquitous fungus that causes opportunistic pulmonary infection (Pneumocystis pneumonia – PCP), in immunocompromised patient. Pneumocystis jirovecii infection can be acquired on multiple occasions, remain latent for long time. The clinical disease may occur as reactivation of prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Drug used for PCP:
1st line – Trimethoprim-sulfamethoxazole.
Alternative regimen: Dapsone + Trimethoprim. Clindamycin + Primaquine, Pentamidine, Atovaquone.
Sulphonamide resistance:
TMP-SMX for prophylaxis and treatment of PCP has raised the development of sulfa (sulfonamide or sulfone) resistance.
– use of sulfa drugs for malaria and bacterial infections in Africa has resulted in high rates of resistance in P. falciparum and many bacterial species
– the mutations that confer resistance are located within a highly conserved active site of the DHPS protein.
DHFR resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) which catalyses the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
Whether high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors, is not clear.
Atovaquone:
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp, Toxoplasma gondii and Bebesia spp. It is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex. Studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone. Studies of cytochrome b gene of Pneumocystis, were consistent with the development of atovaquone resistance
Pentamidine – Primaquine – Clindamycin:
Possible resistance mechanisms have yet to be discovered and reported.
Conclusion
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
The increasing HIV epidemic and use of TMP–SMX in the third world may significantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997.
Level of evidence:
Level of evidence is 5 – (narrative study)
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. It was diagnosed among patients with congenital immunodeficiencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen, however, with the AIDS pandemic PCP emerged. Subsequently, there has been a decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens . But, PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
P. jirovecii organism cannot be cultured in vitro, knowledge about its biology has been diffi cult to obtain. Antibody and PCR fi ndings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extrapulmonary sites.
DRUGS AND TREATMENTS
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
– TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
– Dapsone has not been studied as a single drug and thus should not be used alone for treatment. Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX. However, since this combination does not come as a fixed dose combination, is only available orally, and cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP–SMX.
– Clindamycin–primaquine appears to work on a metabolic pathway different from that of TMP–SMX. Two comparative trials of clindamycin/primaquine with TMP–SMX in moderate to severe PCP demonstrated apparent equivalence for clindamycin–primaquine, but both trials were underpowered
– Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX.
PROPHLAXIS
Are patients at risk for developing PCP:
– Among HIV-infected patients, the occurrence of PCP is closely related to the CD4 count: With lower CD4 counts, the risk of PCP increases. While a count of 200 cells/mm3 is often used as an indicator or susceptibility.
– Patients with congenital immunodefi ciencies ( particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID)
– patients receiving long-term and high-dose corticosteroid therapy,
– patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation;
The most effi cient, cheap and widely used regimen is daily TMP–SMX. This prophylaxis is relatively well tolerated by most non-HIV patients; in contrast, HIV patients have a high frequency of adverse effects, in particular rash and myelosuppression. Fortunately, 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily.
RESISTENCE
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
Several clinical studies have investigated the frequency and signifi cance of DHPS mutations in P. jirovecii, reporting frequencies of mutations in sulfa-exposed and sulfa-unexposed patients. Mutations have rarely been found in clinical isolates obtained prior to the early 1990s, but seem to have increased in frequency recently, presumably as a consequence of increasing selective pressure caused by the widespread use of sulfa drugs for prophylaxis. These observations suggest that the currently identifi ed DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors, however, despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR.
This is a narrative review – level 05.
For most of the twentieth century, Pneumocystis was considered as a protozoan. However, in 1988, based on the work by Edman and colleagues, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.
In 1994, an interim trinomial name change was adopted with the name P. carinii f.sp. hominis for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats.
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides .
Most traditional antifungal agents have no activity against Pneumocystis. As Pneumocystis was originally believed to be a protozoon.
Pentamidine was the first used drug for successful treatment of PCP in 1958.
In the 1960s, sulfadoxine and pyrimethamine as combination was used for the prevention of epidemic infantile pneumocystosis in Iran .
In 1966, Rifkind treated two patients with sulfadiazine and pyrimethamine; both patients died, but two patients were successfully treated 4 years later.
Between 1974 and 1977, studies led by Hughes et al. established that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP.
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Also TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore used for prevention.
despite this some drugs can develop resistance like:
1- Sulfonamide Resistance.
2- DHFR Resistance
Introduction:
PCP is an oppurtunistic fungus that causes pneumonia… PCP in immunocompromised host can cause Pneumonia… It used to be on of AIDS defining illness… It is a serious oppurtunistic infection and the incidence is on the decreasing trend in the last few years due to institution of all prophylaxis agents …
Originally PCP was mistaken for Trypanazoma…. It was described in humans in 1942 and was then on known to be protozoan organism….Genetic analysis and antigenic analysis have shown that Pneumocystis includes a broad family of organisms with species specificity among the mammalian host….The Organism was renamed as Pneumocystitis Jiroveci in honor of Jirovec, who was first to describe the microbe in humas…
It is a difficult organism to isolate by cultures and invitro techniques….Biopsy specimens have to be stained with special stains like Geimsa stain, toulidiene blue and Calcoflour white for demonstration…antibody and PCR techniques indicate that infection happens in childhood … PCP has specific tropism for lungs and it lives in the alveoli….It is rare that it is found in other organs…The Major surface glycoprotein found on the organism attaches firmly to the alveoli… There are known asexual and sexual life cycle of the organism described….
Treatment:
Makor drug classes used for treatment and prophylaxsis of PCP are antifolate drugs, Diamines, Atovaquone and macrolides..
Pentamidine esthionate was the first drug used to treat PCP… Most of the drugs used for treatment of PCP are effective for prophylaxis also except intravenous pentamidine and clindamycin – primaquine are not used for prophylaxsis
Prophylaxsis:
Systemic chemoprohylaxis agaisnt PCP was introduced in 1950 and became a standard of care for HIV infected patients in 1989.. Secondary prophylaxsis should be offered after an episode of PCP to prevent re infection.. In kidney transplant patients all patients are offered prophylaxis against PCP in the form of Trimethoprim sulfamethoxazole SS daily or double strength tablet alternate day…
Alternative drugs for prophylaxis are Dapsone 50mg twice daily or 100 mg twice weekly….Dapsone 50mg daily with pyrimethamine 50mg plus leucovorin 25mg weekly, Dapsone 200 mg weekly with pyremethamine 75mg weekly plus leucovorin 25 mg weekly or aerosolized pentamidine 300mg via a nebulizer…
Treatment of PCP:
Untreated PCP is fatal, but the improved mortality rates have been achieved is used to better treatment facilities in the last 2 decades…
TMP-SMX is the first line of treatment of choice for PCP…. 2 DS tablets every 8th hourly is the most common dose used….the commenst side effect is due to sulfa allergy and skin rash…. Intravenous Trimethoprim 5mg/kg with sulfamethoxazole 20mg/kg is used in severe cases…
If the patient is allergic to TMP-SMX, Available options are Dapsone 100mg Plus trimethoprim 320mg every eight hourly both used per orally, clindamycin 300-450mg every 6th hourly plus primaquine intravenous 30mg daily has been used….Intravenous Pentamidine 4mg/kg day has been used but there is high incidence of adverse events like rash, hepatotoxicity and neutropenia..
Atovoquone 750mg twice daily is also well tolerated….
wide spread use of TMP-SMX and dapsone among HIV patients has led to sulfanomide resistance could develop in P.Jirovecii…. Non synonomous DHPS mutations in pneumocystis and Sacchormyces have been found to be in increasing frequency… Studies show that DHPS mutations contribute to low level sulfa resistance.. but poor adhrence to chemoprophylaxsis is one of the reasons for sulfonamide resistance…
DHFR resistance: Trimethoprim and pyrimethamine are competitive inhibitors of DHFR which catalyzes the reduction of dihydrofolate to tetrahydrofolate…DHFR resistance is widespread but few mutations are identified in pneumocystis DHFR….
Atovoquone binds to cytochrome BC1 complex and disrupts the electron transport chain…Resistance to clindamycin primaquine and Atovoquone have not yet been reported..
but the lack of in vitro culture system makes evaluation of drug resistance in PCP difficult….Non adherence to prophylaxsis is the most important reason for PCP failure rather than evolution of drug resistance…
Atovaquone binds to the cytochrome bc1 complex and disrupts electron transport, leading to depletion of ATP and killing of Pneumocystis
The level of evidence is 5 ..It is a narrative review
The Organism
●Pneumocystis was recognized as a new species and named in honor of Carini
●It was first described in humans in 1942
●Pneumocystis was first established as a human pathogen when Jirovec in 1952
●in 1988, analysis of (rRNA) and observations of genome size placed P. carinii in the fungal kingdom.
● It has recently been placed in a group of fungi Archiascomycetes.
Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall
● in 2002,the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec,
●It cannot be cultured in vitro
● primary infection with P. jirovecii happens in early childhood
● clinical infection was a result of reactivation in immunocompromised hosts.
●primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome
●human hosts can be infected with more than one strain of Pneumocystis jirovecii,
●nonhuman animals are not the source
Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
●the organism attaches tightly to the surface of type I alveolar cells
● Adherence is primarily mediated by the (MSG)
●MSG shows high level of antigenic variation by switching the expression of multiple MSG genes, with a system that resembles the antigenic system used for antigenic variation in Trypanozoma cruzi
●It is likely that this antigenic variation in MSG serves for avoiding the host immune response.
Drug Treatment
The major drug classes used for treatment and prophylaxis of PCP include
1- antifolate drugs,
2- diamines,
3- atovaquone, and
4- macrolides
□ Pentamidine isethionate was the fi rst drug used to successfully treat PCP
□Between 1974 and 1977, studies led by Hughes et al. established that the combination of (TMP–SMX) is effective for both treatment and prophylaxis
□Other drugs have proven activity for therapy,
sulfadiazine plus pyrimethamine,
atovaquone,
clindamycin plus pyrimethamine,
trimetrexate,
dapsone and aerosolized pentamidine.
effective for prophylaxis
1- Dapsone,
2- dapsone trimethoprim,
3- atovaquone and aerosolized pentamidine
There are other drugs that have in vitro activity or anecdotal anti-PCP activity in humans
1- azithromycin,
2- doxycycline,
3- caspofungin.
Prophylaxis
With lower CD4 counts, the risk of PCP increases. a count of 200 cells/mm3 is often used as an indicator.
●In HIV patients receiving prophylaxis; prophylaxis can safely be interrupted if immune function is improved above a CD4 count of 200 cells/μL for at least 3 months following antiretroviral therapy.
● In non-HIV infected individuals, conditions such as organ transplantation, Prophylaxis should be offered . daily TMP–SMX.
80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
Treatment of PCP
●Corticosteroids to patients with moderate-to-severe PCP as defi ned by a PaO2 of less than70 mmHg,
●Both patients and health care professionals must recognize that mild symptoms such as dyspnea, cough, or low-grade fever can be the initial manifestation of PCP
1—– □The most potent drugs for PCP treatment are antifolate drugs,
2—- □The earliest clinical trials to treat PCP were performed with sulfadiazine plus pyrimethamine
□TMP–SMX and pentamidine appear to have roughly comparable effi cacy
Adverse effects
generally occur after 7 days of therapy
● most commonly include rash, fever and leukopenia.
● Hepatotoxicity [ elevated transaminases ]
● sulfamethoxazole-induced interstitial nephritis, renal calculus formation
●Trimethroprim can be associated with hyperkalemia
●Stevens–Johnson syndrome have occurred.
● rapid infusions of pentamidine were associated with hypotension and death, so this route of administration was abandoned.
● Pentamidine is nephrotoxic (glomerular and tubular damage) and it is toxic to the pancreas;
●Pentamidine prolongs the QT interval, and cases of torsades de pointe
3—- □dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone
4—- □Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
Primaquine can only be given orally.
Atovaquone is also only available orally,
Effi cacy of dapsone–pyrimethamine has only been demonstrated for mild-to-moderate PCP
atovaquone only for mild PCP
Sulfonamide Resistance
●Widespread use of sulfa drugs has produced high rates of resistance
●In Pneumocystis, the DHPS protein is part of a trifunctional protein that together are encoded by the multidomain FAS gene
●The most frequent DHPS mutations occur at nucleotide positions 165 and 171
● these variants appear to represent true mutations rather than allelic polymorphisms.
Either mutation can occur alone.
● Using this model, two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance
● a summary of the studies reporting frequencies of mutations in sulfa-exposed and sulfa-unexposed patients.
● a clear association between previous exposure to sulfa drug and DHPS mutations has been shown in all studies.
●The prevalence of DHPS mutations ranging from 7 to 69% of isolates.
In the US, the incidence of mutations was lower in Indianapolis and Denver compared to San Francisco 《80%》
Wide variations have also been observed in studies from Europe with a particularly low incidence in Italy (8% frequency)
● DHPS mutations have also been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
● The emergence of DHPS mutations appears to be specifi c for P. jirovecii
●Several studies have reported a signifi cant association of DHPS mutations with failure of low-dose sulfa prophylaxis
●Hence, in spite of the emergence of mutant DHPS strains, current clinical experience supports the effi cacy of TMP-SMX prophylaxis when taken regularly.
● Some observations suggest that the currently identifi ed DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
■ diaminopyrimidines, trimethoprim and pyrimethamine,
■They are used in combination with sulfonamides.
■Ma and Kovacs observed that the human Pneumocystis-derived DHFR had ~10-fold increase in sensitivity than rat
■ Trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively
■ there are currently no clinical data to support the combination of trimetrexate and sulfamethoxazole
■ In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
■only relatively few DHFR mutations have been identifi ed in Pneumocystis DHFR
■Ma et al. detected only a single synonymous DHFR mutation in specimens obtained from 32 patients, of whom 22 had previous exposure to TMP–SMX therapy or prophylaxis
■In studies, patients were successfully treated with TMP–SMZ.
In conclusion, although
♤Nahimana et al.
♤A South African study
,♤ Matos and coworkers
studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical signifi cant resistance to DHFR inhibitors.
Atovaquone
○It is used to prevent and treat disease.
○ It is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q),
○Introduction of mutations near the binding pocket led to decreased activity of atovaquone
○Introduction of seven mutations
Results from two clinical studies have been published.
■In the fi rst, Three of four patients receiving atovaquone as prophylaxis demonstrated such variations.
Notably, two of them had mutation .
.
■In the second study, a nested case- control study, signifi cantly more patients who previously had been exposed to atovaquone (5 of 15 patients) had mutations compared to unexposed patients
■ Five different mutations near the ubiquitol pocket were described bringing the total number to seven.
■Overall, these fi ndings are consistent with the development of atovaquone resistance after selective pressure is exerted.
Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine
are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Limitations
●there exists no in vitro culture system for propagation of Pneumocystis
● no consistent defi nition of clinical failure exists
●contribution of nonadherence in presumed failure of prophylaxis may be diffi cult to assess.
Level v
1. Please summarise this article.
Pneumocystis jirovecii has remain a serious opportunistic infection and has been the main stay in loss of graft function in renal transplantation.
Since 1980s and 1990 the PCP has higher incidence of infection, then it was seen decreasing trend with better use of prophylaxes.
Transmission and infection;
PCP is a ubiquitous organism, the primary infection occurs mostly in childhood, and spread by healthy humans. The primary infection can manifest in child hood with upper and lower respiratory infection and infant death syndrome, because it has specific tropism for lung parenchyma and alveoli.
There is no such detailed life cycle of PCP, mode of transmission, but both sexual and asexual cycles have been proposed, and suggest sexual replication with in the lungs with environmental changes in the lung like immunosuppression.
Drug treatment;
In 1958, pentamidine was the first drug used successfully to treat PCP.
The major classes of drugs used for treatment of the PCP included anti-folate, diamines, atovaquone, and microlides.
In 1960s, the combination of sulfadoxine and pyriamide used in Iran.
In 1974-1977, TMP-SMX used effectively, and since now the most effective drug being used.
Other drugs being used are dapsone, aerosolized pentamidine, clindamycine plus pyeramethamine. The mortality has decreased in recent decade’s up-to 10 to 15% due to prophylaxes and treatment, otherwise, there was 70-90% mortality. Due to better diagnostic tools, early treatment and use of corticosteroids use.
Prophylaxes;
Opportunistic infection has been the main stay of mortality in immunocompromissed patients and loss of graft function in renal transplantation.
Chemoprophylaxis was initially used by Dutz by 1950s in Iran. In high risk patients with HIV, and other immunosuppressive medication for SOT are at high risk for PCP.
Conclusion;
There is no firm evidence that DHPS mutation has result in significant resistance and failure, however, there is possible codon 55-57 mutation.
Pneumocystis genome project started at 1997, its completion may enable for some new prophylaxes, understanding, and identification of new polymorphism.
Level of evidence V
Introduction
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals. Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodefi ciencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen.
The Organism
Pneumocystis was fi rst described in humans in 1942 by two Dutch investigators, van der Meer and Brug, who described it in three cases: a 3-month-old infant with congenital heart disease and in 2 of 104 autopsy cases – a 4-month-old infant and a 21-year-old adult
Pneumocystis organisms have been identifi ed in most mammalian species in which it has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species specifi city among its mammalian hosts
Transmission and Infection
It was previously though that the infection was carried life-long and that clinical infection was a result of reactivation in immunocompromised hosts. PCR fi ndings have questioned this view and support a more complex picture of transmission and infection.
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms .The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Drug Treatment
In 1958, pentamidine isethionate was the fi rst drug used to successfully treat PCP
In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystosis in Iran
In 1966, Rifkind treated two patients with sulfadiazine and pyrimethamine; both patients died, but two patients were successfully treated 4 years later
(TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis. There are other drugs that have in vitro activity or anecdotal anti-PCP activity in humans and could have a role in managing human disease if all other alternatives were not feasible. These include azithromycin, doxycycline, and caspofungin.
Prophylaxis
Patients with congenital immunodefi ciencies, particularly
X-linked immunodefi ciency with hyper-immunoglobulin M and SCID, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP.
Systemic chemoprophylaxis against PCP was introduced by Dutz in Iran in the early 1950s. He showed that outbreaks of PCP could be aborted with the use of sulfadoxine plus pyrimethamine . Hughes et al. followed this observation with a classic study of children with acute lymphocytic leukemia (ALL); they showed that PCP could be virtually eliminated by TMP–SMX prophylaxis
In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP. Prophylaxis should be offered
Treatment of PCP
Untreated PCP is invariably fatal. In the beginning of the HIV epidemic, the mortality rate of PCP was reported to be 30–40% increasing to 70–90% among patients who progressed to respiratory failure
Over the past decade, mortality rates have dropped to 5–15%
The importance of educating patients to seek medical attention early, when symptoms are still mild, must be an emphasis of patient management programs. Both patients and health care professionals must recognize that mild symptoms such as dyspnea, cough, or low-grade fever can be the initial manifestation of PCP, especially in patients with CD4+ T lymphocyte counts below 200 cells/mm3
The choice of specifi c chemotherapy is also important. The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
The earliest clinical trials to treat PCP were performed with sulfadiazine plus pyrimethamine on the assumption that these drugs would have synergistic action against pneumocystis, as against plasmodia.
Pentamidine is associated with a high frequency of toxicities, some of which are treatment-limiting. Early experiences with rapid infusions of pentamidine were associated with hypotension and death, so this route of administration was abandoned. Intramusuclar injections were better tolerated in terms of blood pressure, but they caused a high frequency of sterile abscesses.
Alternatives for the therapy to TMP–SMX and pentamidine include dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone
Trimetrexate has activity, but is no longer commercially available. Dapsone has not been studied as a single drug and thus should not be used alone for treatment. Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX. However, since this combination does not come as a fi xed-dose combination, is only available orally, and cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP–SMX.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX
This is a good alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Many patients experience progressive oxygen desaturation during the fi rst 4–5 days of therapy. This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar infl ammation. This infl ammation can be reduced by corticosteroids. Four randomized, controlled trials demonstrated that corticosteroids could reduce mortality in patients with moderate or severe disease
On the basis of these results, adjunctive steroids are now recommended for all patients with severe disease (PaOs
< 70 mmgh).
Sulfonamide Resistance
In many pathogenic bacteria and parasites, resistance to sulfonamides has increased as a consequence of selective pressure, and has limited the effi cacy of sulfonamides
Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many bacterial species
In pathogens such as Escherichia coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene
In 1997, Lane and co-workers were the fi rst to identify nonsynonymous (resulting in changes in the encoded amino acid) DHPS mutations in Pneumocystis jirovecii
Large geographical variation in the prevalence of DHPS mutations has been reported, ranging from 7 to 69% of isolates. In the US, the incidence of mutations was lower in Indianapolis and Denver compared to San Francisco, where one study reported that more than 80% of patients were infected with mutant strains
Wide variations have also been observed in studies from Europe with a particularly low incidence in Italy; in one study, an 8% frequency of mutations was found among 107 HIV patients between 1994 and 2001
DHFR Resistance
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
Recently, Ma and Kovacs evaluated the activity of DHFR inhibitors by using a yeast assay expressing P. jirovecii DHFR and observed that the human Pneumocystis-derived DHFR had ~10-fold increase in sensitivity to trimetrexate and trimethoprim compared to rat Pneumocystis-derived DHFR. For the human Pneumocystisderived DHFR yeast strain, trimethoprim and pyrimethamine were both weak inhibitors, with IC50 s in the micromolar
range; trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively (Table 5). Given that trimetrexate is much more potent against PCP than trimethoprim in vitro, the combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.
South African study found nonsynonymous DHFR mutations in samples obtained between 2001 and 2003 in 3 of 27 patients. None had long-term exposure to TMP–SMX before developing PCP
Finally, Matos and coworkers from Portugal recently reported a 27% rate of DHFR Atovaquone (2-[trans-4-(4´-chlorphenyl)cyclohexyl]-3-hydroxy1,4-hydroxynaphthoquinone) is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.mutations in 128 PCP episodes, without association to failure of PCP prophylaxis
Atovaquone
Atovaquone is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q), and competitively binds to the cytochrome bc1
complex. The bc1 complex catalyzes electron transfer from ubiquinone
to cytochrome c and thereby proton translocation across the mitochondrial membrane resulting in the generation of ATP.
Results from two clinical studies have been published. In the fi rst, sequencing of the cytochrome b gene of Pneumocystis from ten patients showed sequence variations in four patients .Three of four patients receiving atovaquone as prophylaxis demonstrated such variations. Notably, two of them had nonsynonymous changes leading to amino acid substitutions within the ubiquitol pocket. Similar mutations in other microorganisms are associated with resistance to atovaquone. One patient, who had not received atovaquone prophylaxis, had a synonymous change that did not confer any change in amino acid sequence.
Conclusion
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no fi rm evidence that DHPS mutations result in signifi cant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished effi cacy of TMP–SMX. This would lead to the loss of the most effi cient and inexpensive therapy for PCP.
The increasing HIV epidemic and use of TMP–SMX in the third world may signifi cantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identifi cation of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997.
Level 5
Summary :
Introduction:
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised patient.
P. jirovecii organisms are ubiquitous.Pneumocystis jirovecii infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms. The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
Drug used for PCP :1st line :Trimethoprim-sulfamethoxazole.
Alternative regimn:Dapsone plus trimethoprim.Clindamycin plus primaquine ,Pentamidine,Atovaquone.
Sulphonamide resistance:
TMP-SMX for prophylaxis and treatment of PCP has raised the development of sulfa (sulfonamide or sulfone) resistance.
– use of sulfa drugs for malaria and bacterial infections in Africa has resulted in high rates of resistance in P. falciparum and many bacterial species
– the mutations that confer resistance are located within a highly conserved active site of the DHPS protein.
DHFR resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and c ertain amino acids. They are used in combination with sulfonamides.
There is no data that using high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors.
Atovaquone
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. Atovaquone is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1 complex..Studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.Studies of cytochrome b gene of Pneumocystis, were consistent with the development of atovaquone resistance
Pentamididine-Primaquine -clindamycine:
Possible resistance mechanisms have yet to be discovered and reported.
Level of evidence :
This is a narrative study, and this level of evidence is 5
Summary
Introduction
This article has a narrative theme, and is based on drug resistance in pneumocystis jirovecii. In the past, PCP was a rare infection, however, after the spread of HIV AIDs, this infection has become more prevalent, causing severe respiratory distress and eventually death. However, chemoprophylaxis has a good outcome when fighting against PCP.
Discussion
There are four different classes of drugs that can be used in treatment and prophylaxis of PCP. These include
antifolate drugsdiaminesatovaquonemacrolidesThe specific drugs under these classes that can be used along with their dosage includes :
Trimethoprim-sulfamethoxazole OD – single or double doseDapsone 50 mg daily + pyrimethamine 50 mg weekly + leucovorine 25 mg weeklyDapsone 200 mg weekly + pyrimethamine 75 mg weekly + leucovorin 25 mg weeklyatovaquone 1500 mg dailyOutbreaks of PCP can be controlled with sulfadoxine plus pyrimethamine.
Other than HIV, other factors such as organ transplant, high dose steroids and high dose chemotherapy can increase the risk of PCP.
The most effective and safe prophylactic regimen is daily TMP-SMX. However, it can be toxic in 25-50% of patients. Adverse effects include fever, rashes and leucopenia, with possibility of anaphylaxis in some patients. Hyperkalemia is also a concern which should be monitored for in these patients. Hepatotoxicity is seen in some patients, in which case we can see elevated transaminases. More serious possible complications include pancreatitis, Stevens Johnson syndrome, interstitial nephritis, and renal calculus formation.
Atovaquone is generally well tolerated in comparison with TMP SMX, but is only available orally. It can be used for patients with mild disease.
The common use of TMP SMX has led to sulfonamide resistance. Mutations in the DHPS gene, in nucleotide positions 165 and 171 leading to amino acid position changes at 55 and 57. These mutations are found in patients with previous exposure to sulfa drugs, which suggests person to person spread of mutant strains.
It is possible that DHPS mutations are due to low dose sulfa prophylaxis. DHPS mutations may be an independent predictor of decreased survival in PCP patients.
The other mutation possible leading to antibiotic resistance is DHFR gene mutation. However, this is not thought to be impacted heavily by use of trimethoprim or pyrimethamine.
Nonadherence to medication during the prophylactic phase can be a big reason for failure of prophylaxis. This can lead to bad outcome post transplant for both the graft and the patient. Monitoring may be essential in more rapid intervals for patients who are suspected of non adherence to medication.
Conclusion
PCP is a fatal disease if not treated adequately. Adherence to treatment regimen along with completion of treatment will allow better chances for success in infection resolution. In addition, kidney transplant patients may need lowering of immunosuppressive drug doses in order to allow PCP to resolve satisfactorily. The best method would be to prevent the infection from impacting the patient in the first place, through aggressive prophylaxis for 3 to 6 months post kidney transplant.
Level of evidence
This is a narrative study, and this level of evidence is 5.
DRUG RESISTANCE IN PJP
BACKGROUND
PCP can’t be cultured in lab
we have limited knowledge of metabolic pathways so drug development is empirical
NO clear definition of clinical failure , meaning PCP can persist in body samples even after successful treatment
Host inflammatory response, rather than resistance to antimicrobial drug treatment, can mimic like absence of response
Fever can be due to ongoing PCP or adverse reaction to drugs
prophylaxis
with TMP-SMX
1DS /SS daily
DS 3 PER WEEK
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone with pyrimethamine and leucoverin / prednisolone
Atovaquone 750 mf twice a day
Pyrimethamine and sulfadiazine
TREATMENT
MECHANISM- ANTIFOLATE
inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
DRUGS
TMP-SMX
DAPSONE IN COMBINATION
CLINDAMYCIN AND PRIMIQUINE
STERIOD IF PO2 less than 70 mm hg on room air
DRUG RESISTANCE
Mutation in DHPS gene is common at codon 55 and 57 ( associated with failure of low dose sulfonamide)
but its clinical relevance is poor as mutated PCP also respond to TMP-SMX
CD4 count is good indicator for susceptibility in HIV and not in organ transplants
DHFR mutation is known but clinically it is not significant when PCP is treated with antifolate drugs
ATOVAQUONE
similar to ubiquinone
survival in patient with mutation is similar , suggesting no clinical significance
CLINDAMYCIN AND PRIMIQUINE
resistance pathways are yet to be known
Pneumocystis Genome Project is the FUTURE
Drug Resistance in Pneumocystis jirovecii
1 Introduction
· The peak incidence of PCP was observed in the late 1980s and early 1990s then declined after introduction of PCP chemoprophylaxis and potent HIV-1 antiretroviral regimens
· PCP still a serious opportunistic infection in heavily immunosuppressed patients who were not given appropriate chemoprophylaxis.
2 The Organism
· Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug
· Pneumocystis was first established as a human pathogen by Jirovec in 1952
· Pneumocystis was considered as a protozoon until 1988, it was placed in the fungal kingdom
· In contrast to most other fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
· The organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, in 2002.
3 Transmission and Infection
· Primary infection with P. jirovecii happens in early childhood and P. jirovecii organisms are ubiquitous.
· Recent data suggests that human hosts can be infected with more than one strain of P. jirovecii.
· Pneumocystis has specific tropism for the lung, where it exists in the alveoli.
· After inhalation, the organism attaches tightly to the surface of type I alveolar cells
4 Drug Treatment
· Hughes et al. found that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP
· TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
· Other drugs have proven activity for therapy: sulfadiazine + pyrimethamine, atovaquone, clindamycin + pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
· Other alternative drugs: azithromycin, doxycycline, and caspofungin.
5 Prophylaxis
· HIV-1 infected patients with oral candidiasis or a CD4 count less than 200 cells/μL, should be offered primary prophylaxis.
· all patients following an episode of PCP should be given secondary prophylaxis
· In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP
· The most efficient, cheap and widely used regimen is daily TMP–SMX
· 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
6 Treatment of PCP
· The most potent drugs for PCP treatment are antifolate drugs
· TMP–SMX found to have better survival than pentamidine but comparable efficacy
· Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX
· Alternatives for the therapy to TMP–SMX and pentamidine include dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone
· Two comparative trials of clindamycin/primaquine with TMP–SMX in moderate-to-severe PCP demonstrated apparent equivalence for clindamycin–primaquine
· Atovaquone is well tolerated but less effective than TMP–SMX and an alternative to patients with mild disease who cannot tolerate TMP–SMX.
· HIV-negative patients should receive 2 weeks and HIV-positive patients three weeks of drug treatment.
· Oxygen desaturation due to alveolar inflammation can be reduced by corticosteroids.
· Adjunctive steroids should be given for all patients with severe disease (PaOs < 70 mmgh).
7 Sulfonamide Resistance
· The use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to resistance to sulfa
· In Africa the use of sulfa drugs for malaria and bacterial infection produced high rates of resistance in P. falciparum and many bacterial species
· In some pathogens, resistance to sulfa is caused by mutations in the primary sequence of the DHPS gene
· The mutations that confer resistance are localized within a highly conserved active site of the DHPS protein.
8 DHFR Resistance
· The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of DHFR
· In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
· Inspite of DHFR mutations, there is no evidence that the widespread use of trimethoprim or pyrimethamine have caused clinically significant resistance to DHFR inhibitors.
8.1 Atovaquone
· is used to prevent and treat diseases caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp
· Mutations of the cytochrome b gene have been identifi ed in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
· Studies found that atovaquone resistance has developed
9 Pentamidine and Clindamycine–Primaquine
· Are used for prevention and treatment of PCP, with possible resistance
10 Conclusion
· mutations involved in sulfa and atovaquone drug resistance have occured in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
· DHPS mutations at codon 55 and 57 are involved in in the failure of low-dose sulfaprophylaxis, but not high dose.
· The use of TMP–SMX in the third world for HIV epidemic may increase the risk for the development of high-level resistance.
· Pneumocystis Genome Project is promising
This is a narrative review level 5
DRUG RESISITANCE IN PCP.
INTRODUCTION.
PCP is a fungus that mostly affects HIV +VE pts and those who are immunocompromised like post transplant pts esp those not not on prophylactic medications.
THE ORGANISM.
P .Carinni f.sp hominis affects humans while P Carinni f.sp carinni infects rats.PCP is pneumocystis jirovecii after Otto Jiroveci who was amongst its pioneer investigators.
TRANSMISSION AND INFECTION.
-Primary infection occurs in early childhood ,becomes latent and later manifests once immunity is compromised. The source of infection is not clear.
-PCP mostly infects and causes pulmonary manifestation with rare extrapulmonary manifestation. PCP lifecycle and replication mode not clear.
DRUG TX.
-Septrin is effective in tx and prophylaxis as parenteral pentamidine and is the treatment of choice.
-Other tx choices ; sulfadiazine + pyrimethamine, atovaquone, clindamycin +pyrimethamine, trimetrexate, dapsone and aerolized pentamidine.
-IV pentamidine and clindamycin – primaquine are not effective chemoprophylaxis.
PROPHYLAXIS.
-In HIV,CD4 <200 increases risk of PCP, other risk factors include ;congenital immunodeficiencies, SCID, long term steroids use and pts on certain chemotherapeutic meds(fludarabine ,ATG)
-In HIV ,prophylaxis is given until CD4 > 200 for at least 3/12.Post transplant it is given for a minimum of 6/12 post sx with possibility of increasing to at least 1 year depending on malignancy and level of immunosuppression.
-Septrin is the cheapest, most available and effective regimen.
-Other options for prophylaxis ; dapsone, dapsone + pyrimethamine+ leucovorine, aerolized pentamidine, atovaquone and pyrimethamine + sulfadiazine.
SULFONAMIDE RESISTANCE.
-This could be secondary to increased use of septrin and dapsone for tx and prophylaxis in PCP in pts with HIV.
-DHPS mutation and non adherence to treatment could lead to resistance and breakthrough PCP respectively.
-PCP infection in those with DHPS mutation have responded to higher doses of septrin or dapsone-trimethoprim signifying that this mutation confers low level sulfa resistance.
DHFR RESISTANCE.
-Despite the aforementioned being seen in studies, we are yet to have enough evidence that widespread use of trimethoprim or pyrimethamine has caused significant DHFR inhibitor resistance.
ATOVAQUONE.
-A number of mutations have been shown to confer resistance to atovaquone but this hasn’t been extensively studied in PCP and has not affected outcome in PCP tx in the few studies done.
PENTAMIDINE AND CLINDAMYCIN -PRIMAQUINE.
-Modes of resistance yet to be studied.
LEVEL OF EVIDENCE – 5
Introduction
● Pneumocystis jirovecii is An opportunistic fungus causes pneumonia in immunocompromised individuals with peak incidence in AIDS pandemic
● Primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome
● Following primary infection it becomes latent, and later manifesting clinically if the patient becomes immunosuppressed.
● Human can be infected with more than one strain of Pneumocystis jirovecii
● The clinical disease may be a reactivation or as acquisition infection
● It has specific tropism “alveoli in lung” although it may detected in other organs, it seldom causes disease at these sites.
● After inhalation it attaches to surface of alveolar cells and adherence by MSG resulting in antigenic variation in MSG that avoiding it the host immune response.
● The organism has a sexual replication cycle that responds to environmental changes in the lung
Drug Treatment
● The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides
● TMP–SMX is effective for both treatment and prophylaxis and is still the treatment of choice.
● Other drugs as sulfadiazine plus pyrimethamine, atovaquone, clindamycin
plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
● Not all drugs that are effective for therapy are also effective for prophylaxis.
● Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis.
● IV pentamidine and clindamycin–primaquine aren’t effective for prophylaxis.
Prophylaxis
● The risk of PCP increases with CD4 lower than 200 cells/mm3 in HIV-infected patients
● High risk patients for PCP :
☆ Congenital immunodeficiencies “hyper-immunoglobulin M and SCID ”
☆ Long-term and high-dose Steroid therapy
☆ Chemotherapeutic regimens for cancer and therapy or transplantation
☆ Some chemotherapeutic agents such as fludarabine or antithymocyte globulin
● In patients without HIV, CD4 counts are not a reliable marker of susceptibility
● Secondary prophylaxis should be offered to all patients following an episode of PCP.
● In HIV patients prophylaxis can safely be interrupted if CD4 count above 200 cells/μL for at least 3 months and should be restarted if antiretroviral therapy fails to increase CD4 above 200 cells/μL
● TMP–SMX is efficient, cheap , and well tolerated by non-HIV patients regimen in contrast, HIV patients have a high frequency of adverse effects
● 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
Treatment of PCP
● Mortality rate of PCP is 30–40% and 70–90% in patients with respiratory failure
● Treatment decreases mortality rates to 5–15%
● Educating patients is essential in management programs.
● TMP–SMX and pentamidine appear to have comparable efficacy
● AEs occur after 7 days of therapy and include rash, fever, Hepatotoxicity and leukopenia.
● SMX can induce interstitial nephritis, renal calculus , anaphylactoid reactions and pancreatitis
● TMP associated with hyperkalemia.
● Stevens–Johnson syndrome have occurred and it may be fatal
● Hypoglycemia can occur after starting therapy, or few days after stopping therapy
● Dapsone–trimethoprim is effective
● Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX it is available only orally
● Recommendations for optimal duration of therapy for PCP are :
☆ HIV-negative patients need 2 weeks
☆ HIV-positive patients need three weeks
● A djunctive steroids are recommended for patients with severe disease (PaOs < 70 mmgh)
● Causes of Sulfonamide Resistance :
☆ The widespread use of TMP–SMX for therapy and prophylaxis of PCP
☆ Mutations in the primary sequence of the DHPS gene
☆ Person-to-person spread of mutant strains
☆ Poor adherence
● Pneumocystis can not be cultured because functional enzymes are unavailable
● An association between previous exposure to sulfa drugs and DHPS mutations has been shown
● DHPS mutations implicated in failure of low-dose sulfa prophylaxis, but not high-dose sulfa therapy. But if additional mutations arise, then high-level sulfa resistance could emerge
● The majority of patients with mutant DHPS strains have been treated with trimethoprimsulfamethoxazole or dapsonetrimethoprim successfully .
● Combination of trimetrexate and sulfamethoxazole is a more potent than trimethoprim plus sulfamethoxazole.
Atovaquone
● It is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
● Pentamidine and Clindamycine–Primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have discovered
Limitations to the study of drug resistance in Pneumocystis
● Absence of a culture system impeded investigations into the mechanisms of drug resistance.
● Most drug development has been empiric as knowledge of the metabolic pathways is limited,
● Experimental mainly relied on immuno-suppressed animal
● There is no consistent definition of clinical failure exists.
● Clinical resistance definition is problematic when applied to PCP because
* Persistence of Pneumocystis organisms
may happen in spite of a successful treatment response.
* Host inflammatory response, rather than resistance to antimicrobial as a severe inflammatory response with respiratory distress, rather than drug resistance, may cause treatment failure.
* Treatment of PCP is associated with a high incidence of AEs
● Level : 5
II. Drug Resistance in Pneumocystis jirovecii
Summarise this article
Introduction
– PCP is a serious opportunistic infection among
immunocompromised patients not receiving chemoprophylaxis
The organism
– pneumocystis carinii belongs to the fungal kingdom and because of its genetic and functional distinctness, the organism infecting man was renamed pneumocystis jirovecii
Transmission and infection
– P. jirovecii is ubiquitous and primary infection occurs in early childhood
– human hosts can be infected by more than one strain of P. jirovecii
– this suggests that PCP can occur as a reactivation of a prior latent organism or as a result of a recently acquired airborne pathogen
– pneumocystis has specific tropism for the lung, it exists in the alveoli, it seldom causes extrapulmonary disease
– following inhalation, the organism attaches tightly to type I alveola cell surface mediated by the major surface glycoprotein (MSG)
– MSG has antigenic variation enabling the organism to escape the host immune response
– the life cycle and mode of replication remains unknown
Drug treatment
– the major classes of drugs used in the treatment and prophylaxis of PCP include antifolate drugs, atovaquone, diamines, macrolides
– trimethoprim-sulfamethoxazole (TMP-SMX) is effective for both prophylaxis and treatment of PCP
– TMP-SMX is as effective as pentamidine and is the most effective/ drug of choice for PCP chemoprophylaxis
– other drugs with activity for therapy against PCP include atovaquone, sulfadiazine plus pyrimethamine, clindamycin plus pyrimethamine, dapsone, aerosolized pentamidine, trimetrexate
– not all drugs used in therapy are effective in chemoprophylaxis
– dapsone, atovaquone, dapsone-primaquine, aerosolized pentamidine are also effective for chemoprophylaxis
– clindamycin-primaquine and IV pentamidine are not effective for chemoprophylaxis
– azithromycin, caspofungin, doxycycline can be considered if other alternatives are not feasible
Prophylaxis
– immunocompromised patients are at an increased risk of developing PCP
– risk factors for PCP warranting chemoprophylaxis include: – SOT, high-dose corticosteroids
– use of ATG portends a higher risk of PCP than other induction regimens
– secondary prophylaxis should be offered following an episode of PCP
– TMP-SMX is the most efficient, cheap and widely used chemoprophylaxis regimen
Treatment of PCP
– if left untreated, PCP is invariably fatal
– prompt initiation of treatment, use of adjuvant corticosteroids in patients with moderate-to-severe PCP (i.e., PaO₂ <70mmHg), better diagnostic tools, therapeutic strategies and improved ICU care has improved the outcomes
– the most potent therapeutic agents for PCP treatment are antifolate drugs
– TMP-SMX is associated with a better survival than pentamidine but both are equally efficacious
– sulfamethoxazole can cause interstitial nephritis and renal calculi
– trimethoprim is associated with hyperkalemia
– pentamidine is nephrotoxic and causes predictable glomerular and tubular damage
– alternatives to TMP-SMX and pentamidine include: – atovaquone, dapsone-pyrimethamine, clindamycin-atovaquone
– trimetrexate is no longer commercially available
– dapsone should not be used as a single agent – no studies to support its use as a single drug
– dapsone-trimethoprim is effective and has similar potency as TMP-SMX; however, it is not available as a single pill and it cross-reacts with sulfa in 50% of allergic patients hence it does not offer many advantages over TMP-SMX
– clindamycin-primaquine is an alternative therapy which acts on a metabolic pathway different from that of TMP-SMX
– Atovaquone is well tolerated, but is not as potent as TMP-SMX, it acts on a metabolic pathway different from that of TMP-SMX, is available as an oral formulation, it is a good alternative for patients with mild PCP who cannot tolerate TMP-SMX
– dapsone-pyrimethamine is efficacious in mild-to-moderate PCP, is administered orally
– optimal duration of PCP treatment has never been well studied but the recommendations suggest 2 weeks for HIV negative patients and 3 weeks for HIV positive patients
– drug-induced death of the pneumocystis organisms causes exacerbation of alveolar inflammation resulting in progressive oxygen desaturation in the first 4-5 days of therapy
– this alveolar inflammation can be reduced by use of corticosteroids
– corticosteroids reduce mortality in patients with moderate or severe PCP therefore, corticosteroids are recommended for all patients with severe disease i.e., PaO₂ <70mmHg
Sulfonamide resistance
– use of TMP-SMX for prophylaxis and treatment of PCP has raised concerns about development of sulfa (sulfonamide or sulfone) resistance in P. jirovecii
– use of sulfa drugs for malaria and bacterial infections in Africa has resulted in high rates of resistance in P. falciparum and many bacterial species
– the mutations that confer resistance are located within a highly conserved active site of the DHPS protein
DHFR resistance
– trimethoprim and pyrimethamine are competitive inhibitors of DHFR (dihydrofolate reductase)
– only few DHFR mutations have been identified in pneumocystis
– there is no evidence that widespread use of trimethoprim or pyrimethamine cause emergence of clinically significant resistance to DHFR inhibitors
Atovaquone
– used for prophylaxis and treatment of P. jirovecii, Plasmodium spp, T. gondii and Bebesia spp
– mutations of the cytochrome b gene have been identified in pneumocystis, plasmodium spp and toxoplasma
– these mutations confer mutations to atovaquone
Pentamidine and clindamycin-primaquine
– are used for prophylaxis and treatment of PCP
– possible resistance mechanisms are yet to be discovered
Conclusion
– selective pressure following widespread use of PCP prophylaxis has led to mutations involved in sulfa and atovaquone drug resistance in P. jirovecii
– DHPS mutations have been implicated in the failure of low-dose sulfa prophylaxis but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy
– with additional mutations, high-level sulfa resistance can emerge leading to reduced efficacy of TMP-SMX – can result in the loss of the most efficient and cheap therapy for PCP
– increased use of TMP-SMX in the HIV population increases the risk of high-level resistance
– completion of the pneumocystis genome project will provide data that will enhance further understanding of the infection
Level of evidence provided by this article
– Level V evidence
Summary:
· Pneumocystis jirovecii is an opportunistic fungus; causes pneumonia in immunocompromised individuals like AIDS, transplant recipients and congenitally immune deficients.
· Source unknown, more than one genotype might infect human being in several times and could stay latent for long time. Reactivated when there is immunosuppression of the host.
· Reservior is uncertain, it might be the infected humen being or trees and grass shedding the fungus.
· Once it enters in to the body through respiratory tract, it dwells in type I alveolar cells attached to its surface, leading to pneumonia in immunocompromised.
· Prophylaxis: TMP-SMX DS (TMP 160+ SMX 800) or SS(TMP 80+ SMX 400) daily
· Treatment: sensitive to antifolate , atovagoune and Macrolides. It was found that Trimethoprim-Sulfamethoxazol is the most effective in prophylaxis and treatment , by inhibiting dihydrofolate reducatse enzymes DHFR and dihydrofolate synthase enzyme.
· In conclusion it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
Level of evidence: level 5
Organism
PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis. In 1988, based on the work by Edman and colleagues, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.In 2002, because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii.
Transmission and Infection
-Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood.
-The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
-Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs,
-After inhalation, the organism attaches tightly to the surface of type I alveolar cells.
-Adherence is primarily mediated by the major surface glycoprotein
Prophylaxis
-TMP–SMX is still the treatment of choice.
-Dapsone, dapsone– trimethoprim, atovaquone, leucovorine and aerosolized pentamidine are also effective for prophylaxis.
-Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
Special risk factor
-With lower CD4 counts, the risk of PCP increases. While a count of 200 cells/mm3 is often used as an indicator or susceptibility,
-Fludarabine or ant thymocyte globulin produce a much higher risk of PCP than other regimens.
Treatment of PCP
First choice
Trimethoprim– sulfamethoxazole
TMP–SMX was associated with a better survival than pentamidine.
Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Trimethroprim can be associated with hyperkalemia.
Alternatives
Dapsone plus trimethoprim
Clindamycin plus primaquine
Pentamidine
Atovaquone
Adjunctive therapy Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
Sulfonamide Resistance
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa resistance could develop in P. jirovecii.
In San Francisco, the increasing use of PCP prophylaxis among HIV patients led to a marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and seven genera of Enterobacteriaceae.
DHPS
Several clinical studies have investigated the frequency and significance of DHPS mutations in P. jirovecii. a clear association between previous exposure to sulfa drugs (primarily for prophylaxis rather than therapy) and DHPS mutations has been shown in all studies.
Studies suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinically significant resistance to DHFR inhibitors.
Atovaquone resistance
-Mutations of the cytochrome b gene have been identified in Pneumocystis.
-Introduction of mutations near the binding pocket led to decreased activity of atovaquone.
-Introduction of seven mutations observed in isolates of Pneumocystis from atovaquone-experienced patients into S. cervisiae cytochrome b increased the inhibitory concentration from 25 to >500 nM
-Pentamidine and Clindamycine resistantance–not reported.
Conclusion
-In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
-There is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
-These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
Limitation
No vitro culture system for propagation of Pneumocystis
Since the knowledge of the metabolic pathways is limited, most drug development has been empiric and the currently available treatment options for PCP have been unchanged during the last 15 years.
No consistent definition of clinical failure exists.
Level of evidence – book chapter not leveled
PJP prophylaxis has lead to markedly low incidence of this fatal disease however emergence of resistance remains alarming. This chapter has shed light on this important aspect.
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia.
Pneumocystis were identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini.Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug.Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extrapulmonary sites.
Transmission and Infection
Since P. jirovecii organism cannot be cultured in vitro. Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. Its environmental source is, however, unknown. Organisms may be coming from inanimate environmental sources, or may be spread by healthy humans.
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms .
This means that PJP May result as reactivation of previous latent infection or as a new airborne infection.
Drug Treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
Most traditional antifungal agents have no activity against Pneumocystis. The the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine. Not all drugs that are effective for therapy are also effective for chemoprophylaxis. Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis.
Prophylaxis.
Among HIV-infected patients, the occurrence of PCP is closely related to the CD4 count: With lower CD4 counts, the risk of PCP increases.
Systemic chemoprophylaxis against PCP was introduced by Dutz in Iran in the early 1950s. He showed that outbreaks of PCP could be aborted with the use of sulfadoxine plus pyrimethamine.Hughes later in his study showed that that PCP could be virtually eliminated by TMP–SMX prophylaxis.
. In non HIV patients like SOT 80/400mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800mg daily . Because of its efficacy, ease of administration and cost, every effort should be tried to maintain patients at risk of PCP on TMP–SMX.
Sulfonamide Resistance
The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
In 1997, Lane and co-workers were the first to identify non- synonymous (resulting in changes in the encoded amino acid) DHPS mutations in Pneumocystis jirovecii.The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).
These observations suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. Given that Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance.
In conclusion, although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
There are findings consistent with the development of atovaquone resistance after selective pressure is exerted.
Conclusion
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in sig- nificant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished effi- cacy of TMP–SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
This is a book chapter which explains about drug resistance in Pneumocystis jirovecii (PJ)
INTRODUCTION
PJ is an opportunistic fungus that causes pneumonia. It was relatively rare before 1982 but emerged severely with onset of AIDS pandemic. But with the starting of PCP prophylaxis, its incidence significantly declined.
But still it is a serious opportunistic infection specially among immunocompromised patients.
ORGANISM
Pneumocystis were identifi ed early in the last century in guinea pigs by Chagas and in rat lungs by Carini . It was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug. However, Pneumocystis was first
established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell
pneumonia among premature or malnourished infants in orphanages. Initially it was considered as protozoan but based on the work by Edman and colleagues , phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.
TRANSMISSION
Antibody and PCR fi ndings indicate that primary infection with P. jirovecii happens in early childhood with a uniform
high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. Its environmental
source is, however, unknown. Organisms may be coming from inanimate environmental sources, or may be spread by
healthy humans. Studies have not conclusively demonstrated the environmental niche.
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions.
The organism is being shed into the environment regularly by healthy hosts, or whether the organism is introduced into the environment from an inanimate environmental source such as trees or grass is unknown. However, non human animals are not the source, because, as mentioned above, each animal species is infected with a different strain of Pneumocystis, and there is no cross species infection that has been identified.
DRUG TREATMENT
Main drug classes used for the treatment and prophylaxis are antifolates, diamines, atovaquone and macrolides. Usual anftifungals dont work against PJ. Various drugs have been studied and tried. But TMP–SMX is the most effective
chemoprophylaxis for PCP, and therefore the standard for prevention.
PROPHYLAXIS
For the first time systemic chemoprophylxis was proposed by Dutz in iran in 1950s. He showed that PCP could be virtually eliminated by TMP–SMX prophylaxis.
SULFONAMIDE RESISTANCE
Widespread use of sulfa group of drugs in various conditions have increased the risk of drug resistance.
CONCLUSION
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug
resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Complete physical maps and gene sequences are being determined for the genomes of P. carinii . These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
LEVEL OF EVIDENCE 5
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals.
Transmission and Infection
Since P. jirovecii organism cannot be cultured in vitro, knowledge about its biology has been difficult to obtain.
Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
When the organism is obtained initially as a primary infection, it is not clear whether an immunocompetent host develops a transient disease. Various investigators have proposed that primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome (21–23). Following primary infection, the presumption, based on murine models, has been that the organism becomes latent, later manifesting clinically if the patient becomes profoundly immunosuppressed.
most infants acquire antibody against Pneumocystis during the first year of life, the organism must be ubiquitous.
Pneumocystis has specific tropism for the lung, where it exists in the alveoli. In rare cases organism have been detected in other organs, but it seldom causes disease at extrapulmonary sites. After inhalation, the organism attaches tightly to the surface of type I alveolar cells .
Adherence is primarily mediated by the major surface glycoprotein (MSG).
This protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family.
Drug Treatment
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Dapsone, dapsonetrimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis. Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
Prophylaxis
In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP.
The most efficient, cheap and widely used regimen is daily TMP–SMX. TMP–SMX prophylaxis is relatively well tolerated by most non-HIV patients; in contrast, HIV patients have a high frequency of adverse effects, in particular rash and myelosuppression.
TMP–SMX 80/400 mg daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily
Treatment of PCP
Untreated PCP is invariably fatal. In the beginning of the HIV epidemic, the mortality rate of PCP was reported to be 30–40% ,increasing to 70–90% among patients who
progressed to respiratory failure .Over the past decade, mortality rates have dropped to 5–15% .
This appears to be a consequence of earlier recognition of the infection, the introduction of adjuvant corticosteroids to patients with moderate-to-severe PCP as defined by a P PaO 2 of less than 70 mmHg, better diagnostic and therapeutic abilities related to concomitant processes, and improved ICU supportive measures.
The choice of specific chemotherapy is also important. The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR)
TMP–SMX was associated with a better survival than pentamidine. However, when all the trials are considered, TMP–SMX and pentamidine appear to have roughly comparable efficacy .
Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX.
Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Hepatotoxicity characterized by elevated transaminases also occurs. There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported. Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.
Pentamidine is associated with a high frequency of toxicities, some of which are treatment-limiting. Early experiences with rapid infusions of pentamidine were associated with hypotension and death, so this route of administration was abandoned. Intramusuclar injections were better tolerated in terms of blood pressure, but they caused a high frequency of sterile abscesses. Therapy was then administered by slow intravenous infusion, which is the best tolerated route. Inhaled pentamidine has been used for therapy, and is well tolerated, but efficacy is poor. Pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney. Pentamidine is toxic to the pancreas; its initial effects cause a surge of insulin release that often manifests as hypoglycemia. Hypoglycemia can occur days or weeks after starting therapy, and may occur many days after stopping therapy. Leukopenia can also occur. Pentamidine prolongs the QT interval, and cases of torsades de pointe have been reported.
Alternatives for the therapy to TMP–SMX and pentamidine include dapsone–pyrimethamine, clindamycinprimaquine, and atovaquone
Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX.
Clindamycin–primaquine appears to work on a metabolic pathway different from that of TMP–SMX. Two comparative trials of clindamycin/primaquine with TMP–SMX in moderate-to-severe PCP demonstrated apparent equivalence for clindamycin–primaquine, but both trials were underpowered .
Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX .
This is a good alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Efficacy of dapsone–pyrimethamine has only been demonstrated for mild-to-moderate PCP and for atovaquone only for mild PCP .Both must be administered orally.
Usual recommendations are that HIV-negative patients should receive 2 weeks and HIVpositive patients three weeks of drug treatment.
Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
adjunctive steroids are now recommended for all patients with severe disease (PaO s < 70 mmgh).
Sulfonamide Resistance
In San Francisco, the increasing use of PCP prophylaxis among HIV patients led to a marked increase in trimethoprimsulfamethoxazole resistance among isolates of Staphylococcus aureus and seven genera of Enterobacteriaceae .
In a retrospective study, trimethoprim–sulfamethoxazole resistance was more than twice as likely in blood culture isolates from HIV patients receiving trimethoprim–sulfamethoxazole compared to patients not receiving this prophylaxis.
Several clinical studies have investigated the frequency and significance of DHPS mutations in P. jirovecii.
On the basis of a genetic analysis of multiple loci, it appears that the mutations arose independently in multiple strains of Pneumocystis .
In a genotype study of 13 European HIV patients with recurrent episodes of PCP, a switch from wild-type to mutant DHPS occurred in five of seven patients who had a recurrence of the otherwise same molecular type of P. jirovecii .
All patients had received treatment or secondary prophylaxis with trimethoprimsulfamethoxazole or dapsone. These findings suggest that DHPS mutants may be selected in vivo (within a given patient) under the pressure of trimethoprim–sulfamethoxazole or dapsone. The emergence of DHPS mutations appears to be specific for P. jirovecii because only wild-type Pneumocystis DHPS has been found in other primate species .
a relatively high number of prophylaxis failures associated with DHPS mutations have been described in patients receiving dapsone prophylaxis. Thus, available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis. However, the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis.
Moreover, even in studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprimsulfamethoxazole or dapsone–trimethoprim. These observations suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. Given that Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance.
DHFR Resistance
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8-tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
Given that trimetrexate is much more potent against PCP than trimethoprim in vitro, the combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.
In conclusion, although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Limitations to the study of drug resistance in Pneumocystis
The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
Another problem is that no consistent definition of clinical failure exists.
PCP is characterized by marked pulmonary inflammation that in severe cases results in alveolar damage and respiratory failure. Although an efficient immune response is required to control the infection, it has also been demonstrated that an excessive inflammatory response, rather than direct effects of Pneumocystis organisms, is crucial for the pulmonary injury
Third, treatment of PCP is associated with a high incidence of adverse effects including fever. In clinical practice, it may be difficult to know whether a slow treatment response with continuing fever is caused by the infection or by the treatment. Given the difficulties in defining clinical failure, reported failure rates for primary trimethoprim–sulfamethoxazole treatment in AIDS patients have varied considerably, ranging from 10 to 40% of cases
In addition, the contribution of nonadherence in presumed failure of prophylaxis may be difficult to assess. The most important reason for prophylaxis failure continues to be nonadherence to prescribed prophylaxis
In theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure.
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Conclusion
In spite of the inability to culture the organisms, it is now clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis. Currently, the clinical effect of the described mutations seems modest. DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
The increasing HIV epidemic and use of TMP–SMX in the third world may significantly increase the risk for the development of high-level resistance. Therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. A promising advance will be the completion of the Pneumocystis Genome Project, which was initiated in 1997. Complete physical maps and gene sequences are being determined for the genomes of P. carinii (111). These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually also lead to the development of a culture system.
level of evidence 5
PPlease summarise this article
pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals.in the past define as infection in AIDS defining diagnosis or post malignancy treaments.it is serious opportunistc infection but decline recently after prophylactic treatments.
organism
The history of identifying the PCP is very old in last century mistake as trypanzoma .
In 1942 first describe in human,then considered as protozoa . Pneumocystis organisms have been identifi ed in most mammalian species in which it has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species specifi city among its mammalian host.
The organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was the first describe the microbe in humans.
Transmission and Infection
The difficulties in isolated or obtaining the Pneumocytis jirovecii that is not live invetro and no way to be cultured.
Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas.the PCR solved many questions about transmissions and infections.
When the infection of PCP occure ,may be new or from latent ,as PCP can come from multiple strains. Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
It is rare that P Jirovicii detect in other organ.
The glycoprotein is first attached to alveoli when the pt inhaled the organism.
This glycoprotein is major surface glycoprotein (MSG).
It is not yet to know what is life cycle and mode of replication but asexual and sexual life cycle has been proposed.
The PCP suggesting that the organism has a sexual replication cycle that responds to environmental changes in the lung.
Drug Treatment
Trimethoprim-slfamethoxazole (TMP–SMX )is the most effective chemoprophylaxis for PCP, and the best for prevention.
Befor discovering of TMP-SMX ,pentamidine firstly discovered to treat PCP.
There are many drugs using in treatment of PCP :
sulfadiazine plus pyrimethamine
atovaquone
clindamycin plus pyrimethamine
trimetrexate,
dapsone
aerosolized pentamidine.
Prophylaxis
The risk of PCP infection:
HIV-infected patients with low CD4 count.
congenital immunodefi ciencies.
Patients who receiving long-term and high-dose corticosteroid therapy.
Patients who receiving certain chemotherapeutic regimens for cancer therapy or transplantation.
PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989.
The most effective regimen is daily TMP–SMX. TMP–SMX prophylaxis is relatively well tolerated by most non-HIV patients.
HIV patients TMP–SMX have a high frequency of adverse effects.
Other prophylactic drugs that use apart from TMP–SMX :
Dapsone 50 mg twice adaily.
Dapon with pyremethamine and leucovorin
Pentamidine aerosolized 300mg monthly.
Treatment of PCP
PCP if not treated is fatal.
The drug of choice is TMP-SMX .
There are some Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia,hepatotoxicity.drug toxicity also can occur.
Pentamidine is other choice ,other drugs:
dapsone–pyrimethamine
clindamycin– primaquine.
atovaquone.
Sulfanomide resistance
The wide use of sulfanomide which in TMP-SMX and dapsone in treatment of PCP resistance can easily occur.
In many pathogenic bacteria and parasites, resistance to sulfonamides has increased as a consequence of selective pressure, and has limited the efficacy of sulfonamides.
Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many bacterial species.
The association with sulfa exposure is consistent with the concept that these mutations represent resistance that developed under drug pressure, documenting resistance is very difficult partly because Pneumocystis cannot be cultured, and partly because functional enzymes are unavailable.
In some bacteria. such as Escherichia coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
This gene discovered that all mutation gene that responsible of resistance are in this DHPS.
Several studies have reported a significant association of DHPS mutations with failure of low-dose sulfa prophylaxis.
majority of patients with mutant DHPS strains have been successfully treated with trimethoprim– sulfamethoxazole or dapsone–trimethoprims.
DHFR Resistance.
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR) which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and c ertain amino acids. They are used in combination with sulfonamides.
There is no data that using high dose trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors.
Atovaquone.
is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
The resistance to atovaquone is related to mutation in cytochrome b detected in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
Pentamidine and clindamycine–primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Conclusion
mutations involved in sulfa and atovaquone drug
resistance have emerged in P. Jirovecii .
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis.
The increasing HIV epidemic and use of TMP–SMX in the third world may signifi cantly
increase the risk for the development of high-level resistance.
What is the level of evidence provided by this article? Level V.
Introduction
Pneumocystis organisms have been identified in most mammalian species which has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species-specific among its mammalian hosts.Since P. jirovecii organism cannot be cultured in vitro the advance of molecular and immunological techniques has acceptable large insight into this organism and how it interacts with its many animal hosts. It was previously thought that the infection was carried life-long and that clinical infection was a result of reactivation in immunocompromised hosts. PCR findings have questioned this view and support a more complex picture of transmission and infection. More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms (24).
The clinical disease PCP may happen as a reactivation of a past latent organism, or as a result of the new gaining of an airborne pathogen.
Pneumocystis has a specific tropism for the lung, where it exists in the alveoli. After inhalation, the organism attaches tightly to the surface of type I alveolar cells (25). Adherence is primarily mediated by the major surface glycoprotein (MSG)
Treatment and prophylaxis of PCP
The major drug classes used for the treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides Most traditional antifungal agents have no activity against Pneumocystis. As Pneumocystis was originally believed to be a protozoon, the initial drug testing focused on drugs with activity against protozoan infection.In 1958, pentamidine isethionate was the first drug used to successfully treat PCP.In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystis in Iran.
In 1977, Hughes et al. established that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP (37–39). TMP–SMX is the most effective
chemoprophylaxis for PCP, and therefore the standard for prophylaxis and treatment pentamidine. However, when all the trials are considered, TMP–SMX and
pentamidine appears to have roughly comparable efficacy (59). Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX (63)
Pentamidine is associated with a high rate of toxicities, especially with IV or IM routes with some reports of IV rapid infusions of pentamidine associated with hypotension and death, IM route also can be associated with sterile abscesses but inhaled pentamidine is more tolerated with poor efficacy and more nephrotoxic including glomerular and tubular damage, also toxic to the pancreas and can results in profound hypoglycemia even after stopping the treatment lecupenia and can induced tordaes depoint due to prolong QT interval. its use is limited due to the wide range of side effects , alternative second-line therapy for PCP includes dapsone–pyrimethamine, clindamycin–primaquine, and atovaquone
What is the level of evidence provided by this article?
level 5 narrative review article
Introduction
Pneumocysitis jirovecii is an opportunistic fungus that causes Pneumocystis pneumonia (PCP) in immunocompromised individuals. The incidence of PCP has reduced due to the introduction of PCP chemoprophylaxis. PCP still causes significant mortality.
The organism
Pneumocystis was identified in the lungs of rats by Carini. It was first established as a human pathogen by Jirovecii in 1952, when it was identified as the organism causing interstitial plasma cell pneumonia among premature or malnourished infants. In 1988, Edman et al analyzed its ribosomal RNA and categorized it as a fungus. However, unlike other fungi, Pneumocystis only has one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
Transmission & infection
P. jiroveciicannot be cultured in vitro. Antibody and PCR findings indicate that primary infection with P. jiroveciioccurs in early childhood. It has a uniform incidence in all geographical areas. Its environmental source is unknown. Following primary infection, the organism becomes latent and manifests clinically if the patient becomes immunosuppressed. Pneumocystis moves in the direction of the lung, where it exists in the alveoli. After inhalation, the organism attaches tightly to the surface of type I alveolar cells, mediated by the major surface glycoprotein (MSG). It is an abundant antigen on the surface of pneumocystis. It shows a high level of antigenic variation, which helps in avoiding the host immune response. Recent studies have shown that pneumocystis has a sexual replication cycle that responds to the environmental changes in the lung.
Drug treatment
Anti-folate drugs, diamines, atovaquone and macrolides are the major drug classes used for the treatment and prophylaxis of PCP. In 1977, the combination of trimethoprim-sulfamethoxazole (TMP-SMX) was shown to be effective for both the treatment and prophylaxis of PCP. It is as effective as intravenous pentamidine for therapy and is the most effective chemoprophylaxis for PCP, therefore the standard for prevention.
Other drugs that can be used for treatment include sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine. Drugs that are effective as prophylaxis include dapsone, dapsone-trimethoprim, atovaquone and aerosolized pentamidine.
Prophylaxis
Among patients infected with HIV, the lower the CD4 counts, the risk of PCP increases. Other patients at an increased risk of developing PCP include patients with congenital immune deficiencies (especially X-linked immunodeficiency with hyper-immunoglobulin M and SCID) and patients receiving long-term and high-dose corticosteroid therapy or transplantation. It has been observed that PCP can be eliminated by TMP-SMX prophylaxis. It is a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3since 1989. Prophylaxis should also be offered to the following patients at risk of PCP: patients with oropharyngeal candidiasis, organ transplant recipients, patients with leukemia and lymphoma. The most widely used, cheap and efficient regimen is daily TMP-SMX.
Treatment of PCP
Untreated PCP can be fatal. Better diagnostic and therapeutic abilities have significantly decreased mortality rates. It is important for both health care professionals and patients to recognize that mild symptoms such as dyspnea, cough or low-grade fever can be the initial manifestation of PCP. The most potent medications for PCP are anti-folate drugs. They work by blocking de novo synthesis of folate through inhibition of dihydroperoate synthase dihydrofolate reductase (DHFR). First choice for the treatment is TMP-SMX, alternatives include dapsone plus trimethoprim, clindamycin plus primaquin, pentamidine and atovaquone. It has been shown that TMP-SMX has been associated with better survival than pentamidine. Drug toxicity occurs in 24 to 57% of HIV-infected patients treated with TMP-SMX. The adverse effects usually occur after 7 days of treatment. The most common adverse effects include rash fever, leukopenia and hepatotoxicity. Some cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis have been reported.
Treatment-limiting toxicities with pentamidine treatment occur in 13 to 80% of patients. Intramuscular injections are better tolerated in terms of blood pressure, but they can cause sterile abscesses. The best tolerated route is slow intravenous infusion. It is nephrotoxic, toxic to the pancreas, can cause leukopenia and prolong the QT interval.
The optimal duration of PCP treatment has never been properly tested. Usual recommendations are 2 weeks for HIV-negative patients and three weeks for patients infected with HIV. Exacerbation of alveolar inflammation can occur initially after initiating treatment. The inflammation can be reduced by the use of corticosteroids.
Sulfonamide resistance
As TMP-SMX and dapsone has been used extensively for the treatment and prophylaxis of PCP, there are concerns regarding the development of sulfonamide resistance in P. jirovecii. The use of sulfa drugs for the treatment of malaria and bacterial infections has led to high rates of resistance in P. falciparum and many bacterial species. Several clinical studies have investigating the frequency and significance of variations in P. jirovecii. The mutations have also been found in patients not exposed sulfa drugs, suggesting person-to-person spread of mutant strains. It has been noted that the major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis. A study showed that patients with the mutations, still responded to TMP-SMX treatment, indicating that the mutations may confer to a low-level of resistance to sulfonamides. Knowing that P. jirovecii has the ability to undergo variations, brings about the concern that further mutations may result in high-level resistance.
Dihydrofolate reductase (DHFR) resistance
Diaminopyrimidine, trimethoprim and pyrimethamine are competitive inhibitors of DHFR. In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors. However, despite the widespread use of TMP-SMX for the prevention and treatment of PCP, only a few DHFR mutations have been identified in P. jirovecii DHFR. The mutations elicited were not associated with prior TMP-SMX, and were successfully treated with the same.
Atovaquone
Atovaquone is similar in structure to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc1complex. Binding of atovaquone to the ubiquinol oxidation pocket of the bc1complex and the Rieske iron-sulphur protein disrupts electron transport and leads to collapse of the mitochondrial membrane potential. Eventually, this results in the depletion of ATP within P. jirovecii and leads to the killing of the organism. Mutations of the cytochrome b gene have been identified in P. jirovecii. Survival of the patients with or without the mutations has not shown to be significantly different.
Pentamidine and clindamycin-primaquine
Possible resistance mechanisms of P. jiroveciiagainst pentamidine and clindamycin-primaquine have not been discovered or reported.
Conclusion
Despite the inability to culture the organisms, it has been noted that the mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii,due to the selective pressure by the widespread use of PCP prophylaxis. Currently, the effect of the mutations are modest, but high-level sulfa drug resistance may emerge, leading to a reduced efficacy of TMP-SMX. This may lead to the loss of the most efficient and inexpensive treatment for PCP. The increasing incidence of HIV and the use of TMP-SMX may lead to an increased risk for the development of high-level resistance.
Level of Evidence: Level V
Thank you All
Please summarise this article.
# Introduction:
*Pneumocystis jirovecii earlier it is called Pneumocystis carinii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia in immunocompromised patients.
*The rate of PCP has been reduced due to initiation of PCP chemoprophylaxis and potent HIV-1 antiretroviral regimens, but it is still considered as a serious opportunistic infection between heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
# The Organism:
*It was discovered early in the last century in guinea pigs by Chagas and in rat lungs by Carini, and they considered it as a new form of Trypanozoma cruzi.
*It was described first in humans in 1942 in 3 cases by two Dutch investigators, van der Meer and Brug.
*Pneumocystis was first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in
Orphanages
*In 1994, an interim trinomial name change was adopted with the name P. carinii f.sp. hominis for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats, then in 2002 the organism infecting humans was renamed Pneumocystis jirovecii.
# Transmission and Infection
*The antibody and PCR findings indicate that primary infection happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous. It’s may be environmental source, but unknown
* It is proposed that primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome.
*The human hosts can be infected with more than one strain of P. jirovecii, indicating that infection can occur on multiple occasions, leading to latency with a variety of organisms.
*The clinical disease of PCP may occur as a reactivation of a prior latent organism, or due to recent acquisition of an airborne pathogen.
*The organism has specific c tropism to the lung, where it exists in the alveoli, but n rare cases have been detected at extrapulmonary sites.
# Drug Treatment:
* The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
* Most traditional antifungal agents have no activity against Pneumocystis.
*It was originally believed to be a protozoon, initial drug testing focused on drugs with activity against protozoan infections.
*(TMP–SMX) is still effective therapy for both treatment and prophylaxis
# Regimens for prophylaxis against Pneumocystis pneumonia
First choice
1DS of Trimethoprim(160mg)–sulfamethoxazole(800) or SS daily TMP 80 + SMX 400)
Alternatives
Trimethoprim–sulfamethoxazole 1 DS three times per week
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone 50 mg daily with Pyrimethamine 50 mg weekly plus Leucovorin 25 mg weekly
Dapsone 200 mg weekly with pyrimethamine 75 mg weekly plus Leucovorin 25 mg weekly
Pentamidine aerosolized 300 mg monthly via nebulizer system
Atovaquone 1,500 mg daily
Pyrimethamine 25–75 mg qd plus Sulfadiazine 0.5–2.0 g q6h
*In organ transplantation, high-dose steroid treatment and/or high-dose
chemotherapy may confer a high risk of PCP.
*The most efficient, cheap and widely used regimen is daily TMP–SMX, it well tolerated by most non-HIV patients.
# Drug regimens for the treatment of PCP
*Untreated PCP is invariably fatal.
First choice
Trimethoprim– sulfamethoxazole
Alternatives
*Dapsone plus trimethoprim
*Clindamycin plus primaquine
*Pentamidine
*Atovaquone
*Adjunctive therapy Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
# Sulfonamide Resistance
*The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa resistance could develop in P. jirovecii.
*In many pathogenic bacteria and parasites, resistance to sulfonamides has increased as a consequence of selective pressure, and has limited the efficacy of sulfonamides.
*Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many bacterial species
*In pathogens such as E. coli, N.meningitidis, M. leprae and P. falciparum, sulfonamide
resistance is caused by mutations in the primary sequence of the DHPS gene.
*Studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprim–sulfamethoxazole or dapsone–trimethoprim.
# DHFR Resistance
*In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors.
*Despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only relatively few DHFR mutations have been identified in Pneumocystis DHFR
# The limitation of the study:
The study of drug resistance in P. jirovecii has been and continues to be difficult.
*The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
*No consistent definition of clinical failure exists
*The contribution of non adherence in presumed failure of prophylaxis may be difficult to assess.
*treatment of PCP is associated with S/E including fever, so it may be difficult to know whether a slow treatment response with continuing fever is caused by the infection or by the treatment.
What is the level of evidence provided by this article?
Level V
Please summarise this article.
Introduction
-Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised
individuals.
Transmission and Infection
– P. jirovecii organism cannot be cultured in vitro, so knowledge about its biology has been diffi cult to obtain.
-Primary infection might correlate with the development of upper or lower respiratory manifestations, or with the development of sudden infant death syndrome .
-Following primary infection, the organism becomes latent, later manifesting clinically if the patient becomes profoundly immunosuppressed.
– The clinical disease PCP may, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
-As noted above, the environmental source of Pneumocystis
has not been identified.
-Pneumocystis has specific tropism for the lung, where it
exists in the alveoli. After inhalation, the organism attaches
tightly to the surface of type I alveolar cells .
Drug Treatment
-The major drug classes used for treatment and prophylaxis of
PCP include antifolate drugs, diamines, atovaquone, and
macrolides .
– TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
-Other drugs have proven activity for therapy, including
sulfadiazine plus pyrimethamine, atovaquone, clindamycin
plus pyrimethamine, trimetrexate, dapsone and aerosolized
pentamidine.
-Not all drugs that are effective for therapy are
also effective for chemoprophylaxis.
– Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis
Prophylaxis
-Among HIV-infected patients, the occurrence of PCP is
closely related to the CD4 count: With lower CD4 counts,
the risk of PCP increases.
-Patients with congenital immunodefi ciencies, particularly X-linked immunodefi ciency with hyper-immunoglobulin M, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP.
– Secondary prophylaxis should be offered to all patients following an
episode of PCP.
-80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily .
Treatment of PCP
-It is important educate patients to seek medical attention early, when symptoms are still mild, must be an emphasis of patient management programs.
-Both patients and health care professionals must recognize that mild symptoms such as dyspnea, cough, or low-grade fever can be the
initial manifestation of PCP, especially in patients with
CD4+ T lymphocyte counts below 200 cells/mm3.
– Once there is a high suspicion therapy should be instituted promptly if the diagnostic procedures will be delayed.
-The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR) .
– Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX .
-Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Hepatotoxicity characterized by elevated transaminases also occurs. There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported.
-Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.
-Pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney. Pentamidine is toxic to the pancreas; its initial effects cause a surge of insulin release that often manifests as hypoglycemia.Leukopenia can also occur. Pentamidine prolongs the QT
interval, and cases of torsades de pointe have been reported.
-Usual recommendations are that HIV-negative patients should receive 2 weeks and HIV positive patients three weeks of drug treatment.
-Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. This inflammation can be reduced by corticosteroids.
Sulfonamide Resistance
-DHPS mutations have been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
– The emergence of DHPS mutations appears to be specific for P. jirovecii because only wild-type Pneumocystis DHPS has been found in other primate species .
-In spite of the emergence of mutant DHPS strains, current clinical experience supports the effi cacy of trimethoprim– sulfamethoxazole prophylaxis when taken regularly.
– There is evidence to suggest a contributory role for DHPS
mutations in breakthrough PCP in patients using alternative
sulfa prophylaxis.
-Available data currently suggest that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis.
DHFR Resistance
-The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the bio synthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids. They are used in combination with sulfonamides.
-Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Atovaquone
-It is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention
and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
What is the level of evidence provided by this article?
Level 5.
Please summarise this article.
Introduction:
Pneumocystis jirovecii (PCP) is an opportunistic fungus that causes pneumonia in immunocompromised individuals, with increased incidence in the late 1980’s.
Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug, who described it in three cases, However, Pneumocystis was first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
In the most of the 20th century, Pneumocystis was considered as a protozoon and single species based on its morphologic features, its resistance to classical antifungal drugs, in 1988, based on the work by Edman and colleagues, phylogenetic analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom.
Transmission of PCP:
The primary infection approved by antibody testing and PCR, occurs in early childhood with demographic variations, indicates environmental source of infection.
Airborne ?
Inanimate environmental source such as trees or grass?
Drug prophylaxis and treatment:
Anti-folate drugs: trimethoprim sulfamethoxazole, dapsone
Diamines: pentamidine isethionate, pyrimethamine.
Atovaqoune.
Macrolides.
Regimens for prophylaxis against Pneumocystis pneumonia:
First choice is TMP/SMX double strength (800/160 mg) or single strength (400/80mg) daily for 6 months.
Or:
– Double strength every other day for 6 months.
– Dapsone 50 mg twice daily or 100 mg twice weekly for 6 months.
– Dapsone with 50 mg daily/ 200 mg weekly+ Pyrimethamine 50 mg weekly+ Leucovorin 25 mg weekly.
– Pentamidine aerosolized 300 mg monthly via nebulizer.
– Atovaquone 1,500 mg daily
– Sulfadiazine 0.5–2.0 g q6h
– Pyrimethamine plus 25–75 mg qd only used when concurrent toxoplasmosis.
Drug regimens for the treatment of PCP:
Drug of first choice is double strength TMP/SMX 2 tabs x3/day, or IV Trimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 hrs.
Or:
– Oral Dapsone 100 mg x1/day + oral trimpethoprim 360 mg q 8hrs.
– Oral clindamycin 300-450 mg q 6 hrs + IV primaquine 30 mg daily.
– IV pentamidine 4mg/kg/day.
– Oral Atovaqoune 750 mg q 12 hrs.
Adjunctive therapy with prednisolone 40 mg twice daily for 5 days then 40 mg daily till day 11 and 20 mg to day 21 (the completion of treatment course), is indicted when PaO2 < 70 mmHg/9.3kPa.
Drug resistance:
Limitation to the study of drug resistance in PCP:
Conclusion:
In spite of absence of organism culture, resistance to low dose TMP/SMX and Atovaqoune have been identified due to sequence mutations in (DHPS) gene, additional mutations could emerge leading to failure of response to TMP/SMX (the most efficient and inexpensive therapy for PCP).
A promising Pneumocystis Genome Project, with Complete physical maps and gene sequences are being determined for the genomes of P. carinii, may lead to identification of new polymorphic regions, new drugs target for treatment and facilitate culture system development.
What is the level of evidence provided by this article?
The level of evidence is V – erratic review.
Introduction
Pneumocystis jirovecii is a fungal infection causing Pneumocystis pneumonia (PCP) in immunocompromised patients.
PCP chemoprophylaxis in immunocompromised host and potent HIV antiretroviral regimens have lowered its incidence significantly.
Organism
Notified first in human as a pathogen in 1952 by Jirovec in premature malnourished infants causing interstitial plasma cell pneumonia.
The organism is categorized as a fungus (Archi ascomycetes)
In 2002 the organism infecting humans was renamed Pneumocystis jirovecii.
Primary infection with P. jirovecii happens in early childhood, the clinical infection results from reactivation in immunocompromised hosts.
Transmission
The primary infection leads to respiratory tract infection or some time sudden infant death syndrome or it remains latent and is reactivated when the host is immunocompromised due to any reason. Multiple strains of P.jirovecii could infect an individual on different occasions.
It has specific tropism for the lung tissue by adherence to the surface of type I alveolar cells after inhalation. This process is mediated by the major surface glycoprotein (MSG) with multiple variable antigens as a defense mechanism.
Drug treatment
The usual antifungal drugs are ineffective against Pneumocystis pneumonia.
The drugs groups like Antifolate drugs, diamines, atovaquone, and macrolides are used for prophylaxis and treatment.
Prophylaxis
TMP–SMX prophylaxis can prevent PCP occurrence. therefore HIV-1 infected patients with CD4 count < 200 cells/μL, need primary prophylaxis. Cases treated for PCP infection also needs secondary prophylaxis.
PCP treatment
TMP–SMX
Its intake was associated with better survival compared to pentamidine.
Adverse effects recorded rash, fever, leukopenia, hepatotoxicity, interstitial nephritis, renal calculus formation, anaphylactoid reactions and sometime Stevens–Johnson syndrome has been reported.
Pentamidine
Intravenous infusion is the tolerated route for pentamidine administration. With main side effects of nephrotoxicity, pancreatic injury, leucopenia, torsade de pointe.
Dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone are alternative.
Dapsone–pyrimethamine was suitable for mild-to-moderate PCP and atovaquone for mild PCP. Recommendation of therapy for HIV-negative cases is 2 weeks and HIV positive patients for 3 weeks.
Adjunctive steroids are recommended for all patients with severe disease (PaOs< 70 mmgh).
Sulfonamide resistance
Double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, leading to resistance with altered substrate binding. Previous exposure to sulfa drugs for prophylaxis had been associated with DHPS mutations.
In spite of presence of mutant DHPS strains, the efficacy of trimethoprim–sulfamethoxazole prophylaxis is still noticed.
A study detected failure of pyrimethamine–sulfadoxine prophylaxis association with the Pro57Ser mutation. DHPS mutations was associated with dapsone prophylaxis.
The effect of DHPS mutations on response to therapeutic, high-dose trimethoprim was controversial.
DHFR resistance
The combination of trimetrexate and sulfamethoxazole are more efficient in vitro than the combination of trimethoprim plus sulfamethoxazole.
There is no evidence that extensive trimethoprim or pyrimethamine use leads to significant resistance to DHFR inhibitors.
Atovaquone
Used for Prophylaxis and treatment of P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. Resistance to atovaquone is due to Mutations of the cytochrome b gene detected in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
Pentamidine and Clindamycine–Primaquine
They are used for prophylaxis and treatment of PCP.
Conclusion
Sulfa and atovaquone drug resistance mutations occurred in P. jirovecii.
No evidence that DHPS mutations is accompanied with significant resistance to high dose of sulfa treatment.
Pneumocystis Genome Project completion and physical maps and gene sequences are studied for the genomes of P. carinii which will be crucial for detection of new polymorphic regions and drug targets.
Level of evidence is V
Introduction :
Pneumocystis jirovecii is an opportunistic pathogen that causes serious lung infections in immunocompromised individuals. The incidence of P. jirovecii pneumonia (PCP) ranges from 0.6 to 14% in renal transplant recipients who do not receive prophylaxis despite active antibiotic treatment. Mortality from it reaches 50%. PCP remains a serious opportunistic infection among severely immunosuppressed patients who do not receive adequate chemoprophylaxis.
The Organism:
Transmission and Infection:
–The Pneumocystis jirovecii organism cannot be cultured in vitro, but the development of molecular and immunological techniques has provided insight into its biology and how it interacts with its various animal hosts.
-Antibody and PCR findings suggest that primary infection with the organism occurs in early childhood, and its environmental source is unknown. PCP may occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
PCP has a specific tropism for the lung, where it attaches tightly to the surface of type I alveolar cells. Adherence is mediated by the major surface glycoprotein (MSG) which is highly polymorphic, repeated and distributed among all the chromosomes. Several genes have been demonstrated to be involved in mating, pheromone responsiveness, and responses to environmental changes in the lung.
Drug treatment :
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides, with pentamidine isethionate being the first to successfully treat PCP.
Drugs that are effective for therapy are also effective for prophylaxis, but intravenous pentamidine and clindamycin-primaquine are not.
Prophylaxis :
-Trimethoprim–sulfamethoxazole 1 DS three times per week
-Dapsone 50 mg twice daily or 100 mg twice weekly
-Dapsone 50 mg daily with pyrimethamine 50 mg weekly plus leucovorin 25 mg weekly
-Dapsone 200 mg weekly with pyrimethamine 75 mg weekly plus leucovorin 25 mg weekly
-Pentamidine aerosolized 300 mg monthly via nebulizer
Treatment of PCP:
Untreated PCP is fatal, but over the past decade, mortality rates have decreased due to earlier recognition and the introduction of adjuvant corticosteroids.
The importance of educating patients to seek medical attention early, when symptoms are still mild, and choosing antifolate drugs for PCP treatment is important .
Treatment options for PCP include :
Trimethoprim–sulfamethoxazole Is the first choice 2 DS tabs PO every 8 h common side effect is skin rash. Intravenous Trimethoprim 5 mg/kg with sulfamethox-azole 20 mg/kg every 8 h (in severe cases ) .
Alternatives:
-Dapsone 100 mg plus trimethoprim 320 mg every 8 h both used PO on a daily basis .
– Clindamycin PO 300–450 mg every 6 h plus primaquine intravenous 30 mg daily.
– Pentamidine Intravenous 4 mg/kg day (High incidence of adverse effects,)
– Atovaquone By mouth 750 mg twice daily( well tolerated but expensive )
Adjunctive therapy:
Prednisone in patients with room air pAO< 70 mmhg (9.3 kPa) – used orally 40 mg twice daily for 5 days ,40 mg daily, from day (6 to 11) ,20 mg daily, from day (12 to 21 ) while on anti-PCP therapy. IV pulse methylprednisolone also can be used in severe cases .
Sulphonamide resistant :
The widespread use of TMP–SMX and dapsone among HIV patients has led to concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii. Lane and co-workers were the first to identify nonsynonymous DHPS mutations in Pneumocystis and Saccharomyces cerevisiae, which have increased in frequency recently.
DHPS mutations may contribute to low-level sulfa resistance, but the major reason for PCP breakthrough is poor adherence to chemoprophylaxis. Clinical evidence supports trimethoprim-sulfamethoxazole or dapsone.
DHFR Resistance:
Trimethoprim and pyrimethamine are competitive inhibitors of DHFR, which catalyzes the reduction of 7,8-dihyfrofolate to 5,6,7,8- tetrahydrofolate.
DHFR resistance to trimetrexate and sulfamethoxazole is widespread, but only few DHFR mutations have been identified in Pneumocystis DHFR.
Several studies have reported DHFR mutations, but there is no evidence that the widespread use of trimethoprim or pyrimethamine has caused clinical significant resistance to DHFR inhibitors.
Atovaquone binds to the cytochrome bc1 complex and disrupts electron transport, leading to depletion of ATP and killing of Pneumocystis
Pentamidine and Clindamycine–Primaquine
Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Limitation to the study :
Conclusion :
Mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii, but the clinical effect is modest. Investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing. Complete physical maps and gene sequences are being determined for the genomes of P. carinii.
What is the level of evidence provided by this article?
level 5 ( narrative review )
*Introduction
Pneumocystis jirovecii is an opportunistic fungus that
causes Pneumocystis pneumonia (PCP), in immunocompromised individuals.
Was mainly diagnosed patients with congenital immuno-deficiencies, and
patients receiving immunosuppression as antineoplastic
treatment and patients with AIDS.
*The organism
Pneumocystis was frst described in humans in 1942
It was considered as a protozoon and based on its morphologic features, and
the effectiveness of drugs used to treat protozoan infections.
In 1988, analysis of ribosomal RNA (rRNA) sequences and observations of
genome size placed P. Carinii in the fungus
There is great level of genetic divergence between Pneumocystis organisms
infecting different mammals
The organism infecting humans was renamed Pneumocystis jirovecii, in honor
of Otto Jirovec.
*Transmission and Infection
Primary infection with P. Jirovecii occurs in early childhood.
Its environmental source is still unknown.
It may come from inanimate environmental sources, or may be spread by
healthy humans. Studies didn’t demonstrate the environmental niche.
investigators proposed that early childhood infection may cause upper or
lower respiratory manifestations, or sudden infant death syndrome.
After initial infection the organism becomes latent, to be reactivated in
immunosuppressed host .
recent data, suggests that more than
one strain may infect the human and the infection can be acquired on multiple
occasions, leading to latency with a variety of distinct organisms.
The clinical disease PCP may, occur
as a reactivation, or as a result of recent airborne pathogen.
Pneumocystis has specific tropism for the lung, where it exists in the
alveoli.
Organism attaches to the surface of type I alveolar cells through a major
surface glycoprotein (MSG).
This protein is the most abundant
antigen on the surface of Pneumocystis and is encoded by a multicopy gene
family.
MSG shows high level of antigenic variation allowing resistance to host
immune response.
*Drug Treatment
-The major drug classes used for treatment and prophylaxis of PCP include
antifolate drugs, diamines, atovaquone, and macrolides with no effect for
antifungal agents .
-trimethoprim–sulfamethoxazole (TMP–SMX) is as effective as intravenous
pentamidine for therapy, and is still the treatment of choice.
-TMP–SMX is the most effective
chemoprophylaxis for PCP, and therefore the standard for prevention.
-Other effective drugs for therapy includes:
sulfadiazine plus pyrimethamine,
atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and
aerosolized pentamidine.
-Effective drugs for prophylaxis includes:
Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine .
-azithromycin, doxycycline, and
caspofungin were used if other alternatives were not feasible.
*Prophylaxis
Immunocompromised patients as Transplant
recipients are at the risk of
developing PCP and induction with ATG was associated with higher risks.
In contrast to HIV patients CD4 counts are not a reliable marker of susceptibility in this group of
patients.
TMP–SMX is effective
in prophylaxis used for primary prophylaxis in HIV-1 infected patients
with oral candidiasis or a CD4 count less than 200 cells/μL.
And
for Secondary prophylaxis for all patients following an episode of PCP and In
immunocompromised patients (organ transplantation, high-dose steroid treatment
and/or high-dose chemotherapy ).
Several prophylactic regimens are available.
The most efficient, cheap, well tolerated and widely used regimen is daily
TMP–SMX.
* Treatment of PCP
Mortality rates due to PCP had markedly declined due to Early
recognition of the infection, the introduction of adjuvant corticosteroids to
patients with moderate-to-severe PCP as defined by a PaO2 of less than 70 mmHg,
better diagnostic and therapeutic abilities, and improved ICU supportive
measures.
In high risk patients and patients with
with CD4+ counts below 200
cells/mm3 mild symptoms as dyspnea, cough, or
low-grade fever can be the initial manifestation of PCP.
Clinicians should start Treatment
early when suspecting infection and not wait for all the features of PCP to be
present, or for the chest radiograph to be abnormal.
-TMP–SMX is effective Treatment ,the trials showed TMP–SMX and pentamidine appear to have
roughly comparable efficacy.
Adverse effects occur after 7 days of therapy and commonly include rash,
fever and leukopenia, hepatotoxicity.
There are cases of sulfamethoxazole-induced
interstitial nephritis, renal calculus formation, anaphylactoid reactions and
pancreatitis reported, hyperkalemia, and rare cases of Stevens–Johnson syndrome
have occurred.
-Pentamidine is associated with a high level of side effects which may be Treatment
limiting.
Other Treatment options includes dapsone–pyrimethamine, clindamycin–
primaquine, and atovaquone .
-Dapsone–trimethoprim is effective,
and it has potency that is comparable to TMP–SMX and it cross-reacts with sulfa
in 50% of allergic patients, so it does not offer many advantages over TMP–SMX.
-Atovaquone is well tolerated
It is available orally only , and does not appear to be as potent as
TMP–SMX and it is mainly for mild cases .
-Dapsone–pyrimethamine has only been demonstrated for mild-to-moderate PCP.
-Recommended duration for ttt are that for HIV-negative patients should
receive 2 weeks and HIV-positive patients 3 weeks of drug treatment.
-Corticosteroids could reduce mortality in patients with moderate or severe
disease with exacerbation of alveolar inflammation and desaturation in the
first days after ttt.
On the basis of these results,
adjunctive steroids are now recommended for all patients with severe disease
(PaOs < 70 mmgh).
*Sulfonamide Resistance
Widespread use of sulfa drugs for treatment and prophylaxis of PCP resulted
in resistance due to DHPS mutations.
DHPS mutations have also been found in patients without any previous
exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
In spite of the emergence of mutant DHPS strains, Current clinical
experience supports the efficacy of trimethoprim– sulfamethoxazole prophylaxis
when taken regularly.
data suggests that DHPS mutations
contribute to low-level sulfa resistance, and may be the most important in
failure of second-line sulfa prophylaxis.
And the major reason for PCP breakthrough continues to be the poor
adherence to chemoprophylaxis.
*DHFR Resistance
Despite the widespread use of trimethoprim in combination with
sulfamethoxazole for the prevention and treatment of PCP, only relatively few
DHFR mutations have been identified in Pneumocystis DHFR.
*Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but
possible resistance mechanisms have yet to be discovered and reported.
*Conclusion
-it is now clear that mutations involved in sulfa and atovaquone drug
resistance have emerged in P. Jirovecii .
– the clinical effect of the described mutations seems modest.
-no evidence that DHPS mutations result in significant resistance to
high-dose sulfa therapy.
– it is possible that if additional mutations arise, then high-level sulfa
resistance could emerge.
What is the level of evidence provided by this article?
Narrative review level of evidence 5
Please summarise this article.
Pneumocystis jirovecii
Drugs for prophylaxis: Minimum 6 months
First line:
Alternatives:
Drugs for treatment:
First line:
Alternative:
Adjunctive therapy:
Sulfonamide resistance
TMP resistance:
What is the level of evidence provided by this article?
Thank you
Drug Resistance in Pneumocystis jirovecii.
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), which is usually associated with immunocompromised patients such as AIDs or patient receiving potent immunosuppressive therapy, but it is incidence now decreased due to prophylactic treatment.
Pneumocystis jirovecii leads to primary infection that might be correlate with the development of upper or lower respiratory manifestations which becomes latent and later manifesting clinically if the patient becomes profoundly immunosuppressed, till now the environmental source of Pneumocystis has not been identified.
Drug Treatment.
Most traditional antifungal agents have no activity against Pneumocystis and the major drug classes used for treatment and prophylaxis of PCP include ant folate drugs, diamines, Atovaquone, and macrolides.
Studies, shown that the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP, other proven active therapy including sulfadiazine plus pyrimethamine, Atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Prophylaxis of PCP.
PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989, many prophylactic regimens are available but the most efficient, cheap and widely used regimen is daily TMP–SMX. TMP–SMX prophylaxis.
Treatment of PCP.
1-TMP–SMX and Pentamidine appear to have roughly comparable efficacy and drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX such as rash, fever and leukopenia.
Hepatotoxicity and others, and Pentamidine also is nephrotoxic
and causes predictable glomerular and tubular damage to the
kidney, has toxic effect to the pancreas lead to hypoglycemia and leukopenia can also occur.
2-Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX, but this combination does not come as a fixed-dose combination.
3-Clindamycin–primaquine, some studies compare this combination with TMP–SMX in moderate-to-severe PCP and demonstrated apparent equivalence for clindamycin–primaquine.
4-Atovaquone is well tolerated but does not appear to be as potent as TMP–SMX, but used as alternative with mild disease who cannot tolerate TMP–SMX.
Usually the treatment duration should be for 2 weeks and in HIV positive patients three weeks of drug treatment, oxygen desaturation during the first 4–5 days of therapy which caused due to drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. Finally many studies proven that corticosteroids could reduce mortality in patients with moderate or severe disease.
Sulfonamide Resistance.
Two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding, there is a clear association between previous exposure to sulfa drugs (primarily for prophylaxis rather than therapy) and DHPS mutations has been shown in all studies.
DHFR Resistance.
In several bacterial and parasitic species, resistance to DHFR inhibitors has emerged as a consequence of selective pressure by DHFR inhibitors and there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Atovaquone.
Survival from PCP did not differ between patients with or without mutations. Overall, these findings are consistent with the development of Atovaquone resistance after selective pressure is exerted.
Pentamidine and Clindamycin–Primaquine.
Possible resistance mechanisms have yet to be discovered and reported.
Conclusion.
The widespread use of PCP prophylaxis such as sulfa and Atovaquone is considered the clear cause of that mutations and involved in the occurrence of resistance, DHPS mutations not result in significant resistance to high-dose sulfa therapy, hence, investigations into the mechanisms of drug resistance and identification of new molecular targets are required.
What is the level of evidence provided by this article?
Narrative review=Level V.
Thank you
Summary of the article
Drug Resistance in Pneumocystis jirovecii
Pneumocystis jirovecii
1. Pneumocystis was first established as a human pathogen by Jirovec in 1952 and was renamed Pneumocystis jirovecii, in honor of Otto Jirovec.
2. Pneumocystis species represent an early divergent line in the fungal kingdom, has recently been placed in a group of fungi entitled the Archiascomycetes.
3. Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
Transmission and Infection of PCP
1. P. jirovecii organism cannot be cultured in vitro and It’s environmental source is, however, unknown.
2. Non-human animals are not the source and there is no cross- species infection that has been identified.
3. Since most infants acquire antibody against Pneumocystis during the first year of life, the organism must be ubiquitous.
4. The clinical disease PCP may occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
5. Pneumocystis has specific tropism for the lung, where it exists in the alveoli. It seldom causes disease at extrapulmonary sites.
Risk factors for developing PCP
1. Patients with congenital immunodeficiencies, particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID.
2. HIV infected patients.
3. Patients on immunosuppression for SOT.
4. Long-term and high-dose corticosteroid therapy.
5. Patients receiving certain chemotherapeutic regimens for cancer therapy (fludarabine or antithymocyte globulin produce a much higher risk of PCP than other regimens).
Drug Treatment for PCP
1. Most traditional antifungal agents have no activity against Pneumocystis.
2. The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
a) Pentamidine isethionate was the first drug used to successfully treat PCP.
b) TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
c) Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
d) other drugs that have anti-PCP activity in humans and could have a role in managing human disease include azithromycin, doxycycline, and caspofungin.
3. Drug treatment options for PCP:
a) The first choice: trimethoprim-sulfam ethoxazoleat a dose of 2tablets DS every 8h or IVTrimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h.
b) Alternatives:
I. Dapsone( 100 mg daily) plus trimethoprim(320 mg every 8 h).
II. Clindamycin(PO 300–450 mg every 6 h) plus primaquine (IV 30 mg daily).
III. Pentamidine IV at 4mg/kg/day.
IV. Atovaquone PO 750 mg BID.
c) Adjunctive therapy: Prednisone in patients with room air pAO2 < 70 mmhg (9.3 kPa)
· 40 mg twice daily for 5 days.
· 40 mg daily; days 6 through 11.
· 20 mg daily, days 12 through 21 while on anti-PCP therapy.
d) Dapsone has not been studied as a single drug and thus should not be used alone for treatment. Dapsone–trimethoprim is effective, however, and probably has potency that is comparable to TMP–SMX.
4. The optimal duration of therapy for PCP has never been properly tested. Usual recommendations are that:
· HIV-negative patients should receive 2 weeks of drug treatment.
· HIV- positive patients should receive 3 weeks of drug treatment.
Prophylaxis for PCP
Several prophylactic regimens are available:
1. The most efficient, cheap and widely used regimen is daily TMP–SMX.
2. The combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis.
3. Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis.
4. Not all drugs that are effective for therapy are also effective for chemoprophylaxis.
5. Regimen for prophylaxis:
A. First choice Trimethoprim-sulfamethoxazole 1 DS or SS daily.
B. Alternatives Trimethoprim-sulfamethoxazole(1 DS three times per week) Dapsone (50 mg twice daily or 100 mg twice weekly).
C. Dapsone(50 mg daily) with Pyrimethamine(50 mg weekly) plus Leucovorin(25 mg weekly).
D. Dapsone(200 mg weekly) with pyrimethamine(75 mg weekly) plus Leucovorin(25 mg weekly)Pentamidine aerosolized (300 mg monthly via nebulizer system).
E. Atovaquone(1500 mg daily) Pyrimethamine(25-75 mg qd) plus Sulfadiazine(0.5-2.0 g q6h):This regimen only for use in case of concurrent toxoplasmosis.
Drug resistance in PCP
A. Sulfonamide Resistance
a. Due to widespread use of sulfa drugs for malaria and bacterial infection.
b. Causes of resistance:
c. Mutations in the primary sequence of the DHPS gene as in E.coli and and other pathogen.
d. Non- synonymous (resulting in changes in the encoded amino acid) DHPS mutations as in Pneumocystis jirovecii.
B. DHFR resistance
a. Few DHFR mutations have been identified in Pneumocystis despite of widespread use of trimethoprim or pyrimethamine.
b. For the human Pneumocystis- derived DHFR yeast strain, trimethoprim and pyrimethamine were both weak inhibitors.
c. Trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively.
C. Atovaquone resistance
a. Overall, findings are consistent with the development of atovaquone resistance after selective pressure is exerted.
D. Pentamidine and Clindamycine-Primaquine
a) Pentamidine and clindamycine–primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Stud’s limitations
1. The absence of a culture system precludes standard susceptibility testing.
2. No in vitro culture system for propagation of Pneumocystis.
3. No consistent definition of clinical failure exists.
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
Thank you
Pneumocystis Jirovecii PJ :
Is the most common opportunistic infection encountered in immune-compromized patients such as HIV ,transplant recipients and congenitally immune deficient.
Its associated with Pneumocystis Jirovecii pneumonia PJP as the cardinal presentation of this fungal infection.
PJ:
its difficult to culture this fungi. its extremely ubiquitous that most of the infants are tested antibodies positive towards the end of first year.
The source of infection is not clearly identified, as the it was discovered that more than one genotype might infect human being several times and could stay latent for long time before being reactivated by immune suppression of the host.
Reservior is uncertain, it might be the infected humen being or trees and grass shedding the fungus.Animal sourse is not proved as different species are causing infection in varied animals.
Rout of infection:
Its either a current infection or reactivation of latent infection.
Tropisim:
once it enters the body through respiratory pathway, it dwells in type I alveolar cells attached to its surface.Without treatment its fatal when causing pneumonia.
In HIV patients its commonly encountered when CD4 T-lymphocytes below 200.
This factor is not applicable in other conditions such as kidney transplant on immune suppressants.
Treatment:
Its sensitive to antifolate , atovagoune and Macrolides. It was found that Trimethoprim-Sulfamethoxazol is the most effective in prophylaxis and treatment , by inhibiting dihydrofolate reducatse enzymes DHFR and dihydrofolate synthase enz. DHFS.
PJ was reported to show resistance to Sulfa and Atovagoune resultant fron selective pressure. owing to extended usage of the same particularly with lower doses of 80/400 per day ,mutation of DHFS was reported to cause resistance as well.
Better understanding of genomic system and development of culture system is promising for better understanding of this micro-organism.
It is a narrative study with level of evidence 5.
Thank you
Please summarise this article.
Introduction
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia.
There is decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of HIV-1 antiretroviral regimens
The organism
Initially considered as a new form of Trypanozoma cruzi
Pneumocystis was first established as a human pathogen by Jirovec in 1952
As compared to fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
Transmission and Infection
P. jirovecii organism cannot be cultured in vitro
Human hosts can be infected with more than one strain of Pneumocystis jiroveci
Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
It attaches tightly to the surface of type I alveolar cells
Adherence is primarily mediated by the major surface glycoprotein (MSG)
The antigenic variation in MSG serves for avoiding the host immune response
Drug Treatment
The main agents include antifolate drugs, diamines, atovaquone, and macrolides
Pentamidine isethionate was the fi rst drug used to successfully treat PCP in 1958.
Combination of sulfadoxine and pyrimethamine was used in 1960
Trimethoprim–sulfamethoxazole (TMP–SMX) for both treatment and prophylaxis of murine and then human PCP in 1977
Other drugs include – sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine
Prophylaxis
Primary in patients with HIV and oral candidiasis. Secondary in all those who had who had first episode.
Trimethoprim and sulphamethoxazole stanadard of care for treatment and prevention.
Treatment
Trimethoprim and sulphamethoxazole
Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX
Side effects-rash, fever and leukopenia, Hepatotoxicity , interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis. Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred
Pentamidine
Given by slow IV. It has renal hepatic, pancreatic and haematological toxicity.
Dapsone- Trimethoprim
Quite effective
Can have allergic reactions
Clindamycim- Primaquine
Can have side effects like rash , diarrhoea and liver toxicity.
Atovaquone
Can be used in mild disease
Sulphonamide resistance
Exposure to sulpha drugs
DHPS mutations occur at nucleotide positions 165 and 171 leading to amino acid change
Currently identified DHPS mutations may confer only low-level sulfa resistance
DHFR Resistance
There is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors
Atovaqupone
It depletes ATP leading to death of organism
Drug resistance can develop
Pentamidine and Clindamycine–Primaquine
These are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered
Limitations
The absence of a culture system precludes standard susceptibility testing
No consistent definition of clinical failure
Nonadherence in presumed failure of prophylaxis can be difficult to assess
It may difficult to know that slow treatment response with continuing fever is caused by the infection or by the treatment
What is the level of evidence provided by this article?
Narrative review
Level V
Thank you
Introduction :
Pneumocystis jirovecii is an opportunistic pathogen that causes serious lung infections in immunocompromised individuals. The incidence of P. jirovecii pneumonia (PCP) ranges from 0.6 to 14% in renal transplant recipients who do not receive prophylaxis despite active antibiotic treatment. Mortality from it reaches 50%. PCP remains a serious opportunistic infection among severely immunosuppressed patients who do not receive adequate chemoprophylaxis.
The Organism:
Pneumocystis was considered as a protozoon and single species based on its morphologic features, its resistance to classical antifungal agents and the effectiveness of certain drugs used to treat protozoan infections.
The organism has recently been placed in a group of fungi entitled the Archiascomycetes Pneumocystis organisms have been identified in most mammalian species in which it has been searched for. Genetic and antigenic analyses have shown that Pneumocystis includes a broad family of organisms, with species specificity among its mammalian hosts
Transmission and Infection:
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen. Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli In rare cases organism have been detected in other organs, After inhalation, the organism attaches tightly to the surface of type I alveolar cells Adherence is primarily mediated by the major surface glycoprotein (MSG) . This protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family. MSG is a family of highly polymorphic proteins that are repetitive and distributed throughout the Pneumocystis chromosome.
Therapy:
The main drugs used to treat and prevent PCP include antifolates, diamines, atobaquone, and macrolides. Between 1974 and 1977 Hughes et al. We found that the combination trimethoprim-sulfamethoxazole (TMP-SMX) is effective for both treatment and prevention of murine and late-stage human PCP (37-39). TMP-SMX is as effective for treatment as intravenous pentamidine and is still used for treatment. select. In addition, TMP-SMX is the standard for prevention as it is the most effective chemical prophylaxis against Pneumocystis pneumonia.
Prophylaxis:
HIV-infected patients develop PCP at CD4 counts higher than 200 cells/mm3 Patients with congenital immune deficiencies, particularly X-linked immunodefi ciency with hyper-immunoglobulin M and SCID, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm3 in 1989 Secondary prophylaxis should be offered to all patients following an episode of PCP. In HIV patients receiving prophylaxis; prophylaxis can safely be interrupted if immune function is improved above a CD4 count of 200 cells/ìL for at least 3 months following antiretroviral therapy In non-HIV infected individuals, conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP. Prophylaxis should be offered TMP–SMX prophylaxis is relatively well tolerated
Treatment of PCP:
The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR) The earliest clinical trials to treat PCP were performed with sulfadiazine plus pyrimethamine on the assumption that these drugs would have synergistic action against pneumocystis, as against plasmodia Sulfonamide Resistance The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii. Widespread use of sulfa drugs for malaria and bacterial infection in Africa has produced high rates of resistance in P. falciparum and many types of bacteria Recently, Saccharomyces cerevisiae was used as a model to study P. jirovecii resistance to DHPS.
Limitations of Pneumocystis parasitic drug resistance studies
Standard culture systems are lacking. There is no clear definition of clinical failure. Contribution of non-compliance due to prophylaxis failure .
Conclusion :
Mutations of resistance to sulfanilamide drugs and atovaquone in P. jirovecii as a result of the selective pressure resulting from the widespread use of PCP prophylaxis. The clinical effects of currently described mutations are You look humble. DHPS mutations in codons 55 and 57 are associated with failure of low-dose sulfa prophylaxis, but there is no conclusive evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
This article is level v
I like your analysis of the level of evidence, and summary.
Would have any personal experience of sulfa resistance of PCP? Please use bold or underline for headings or sub-headings to make it easier to read
Introduction
Pneumocystis jirovecii, formerly known as Pneumocystis carinii, is a fungus that causes PCP in immunocompromised patients. Its prevalence increased throughout the era of HIV diagnosis. The advent of PCP chemoprophylaxis and the emergence of HIV antiretroviral treatment have led to a remarkable decline in the disease’s occurrence.
Organism
Chagas discovered it in Guinea pigs and Carini in rat lungs early in the 20th century. The organisms were a new Trypanozoma cruzi strain. In 1942, Dutch researchers van der Meer and Brug recorded three occurrences of pneumocystis in humans. In 1952, Jirovec discovered that pneumocystis caused interstitial plasma cell pneumonia in premature or malnourished orphans.
Based on its morphology, Pneumocystis was regarded a protozoon and single species in the 20th century, although it resists standard antifungals and several protozoan infection medicines. rRNA sequences and genome size placed P. carinii in the fungal kingdom in 1988. Pneumocystis species are an early divergent fungal line, according to phylogenetic evidence. The Archiascomycetes fungi now include the organism. Pneumocystis has a weak cell wall, one nuclear ribosomal RNA locus, and little or no ergosterol, unlike most fungi.
Pneumocystis jirovecii, named after Otto Jirovec, who first described the microorganism in humans, was renamed in 2002 due to its genetic and functional uniqueness.
Transmission & infection
Early childhood infection with P. jirovecii occurs with a high incidence in all geographic regions, suggesting that P. jirovecii organisms are widespread. The organism becomes dormant and is only awakened in immunocompromised people; antibodies against it are typically generated in the first year of life; and it can cause rapid newborn death. The organism has a specific tropism towards the lung, where it is located, but it can also be discovered in other organs. When an organism is inhaled, it adheres to type 1 alveolar cells. This adhesion is encoded by a large surface protein that is abundant on the organism’s surface and is polymorphic, so evading immune reaction.
Treatment/Drugs history
Pentamidine isethionate was the first PCP treatment in 1958. Sulfadoxine-pyrimethamine was utilized in the 1960s. Sulfadiazine and pyrimethamine were used 1966. Trimethoprim–sulfamethoxazole (TMP–SMX) was effective for treatment and prevention of mouse and human PCP between 1974 and 1977. TMP–SMX is as effective as intravenous pentamidine for treatment. TMP–SMX prevents PCP best. Sulfadiazine, atovaquone, clindamycin, trimetrexate, dapsone, and aerosolized pentamidine are other effective treatments.
Prophylaxis
PCP can occur in HIV patients with a CD4 count below 200, but it can also develop with a count above 200, making it an inconsistent predictor for PCP susceptibility.
Chemoprophylaxis is used as main prophylaxis for HIV patients with CD4 less than 200 and can be stopped when CD4 rises above 200 for 3 months after anti-retroviral treatment.
All PCP patients can receive secondary prophylaxis.
HIV individuals get more TMP-SMX adverse effects include rash and myelosuppression.
TMP-SMX is well-tolerated, inexpensive, and available for preventative treatment of cancer, SOT, and high-dose steroid patients.
Treatment of PCP
Untreated PCP causes respiratory failure and mortality, thus early detection and treatment are crucial to save lives. Immunocompromised patients with low-grade fever, dry cough, shortness of breath, and hypoxia should be tested for PCP.
Antifolate medications block de novo folate synthesis by inhibiting dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR). TMP–SMX use may cause rashes, fever, and leukopenia which usually appear after 7 days of treatment. Transaminase-raising hepatotoxicity occurs. Sulfamethoxazole has caused interstitial nephritis, renal calculus, anaphylactoid responses, and pancreatitis. Trimethroprim can cause hyperkalemia. These toxins rarely kill, although Stevens–Johnson syndrome can.
Pentamidine is nephrotoxic, pancreatic, and has a high rate of toxicities such hypotension and mortality. It should be given as an intravenous infusion.
HIV treatment lasts 3 weeks, non-HIV 2 weeks.
HIV, cancer, SOT, and high-dose steroid users enhance the requirement for PCP prophylaxis, which increases sulpha resistance and the probability of alternative medications being introduced.
Level of evidence
Review article- level V
I like your analysis of the level of evidence, and summary.
Drug resistant PCP
Summary
· PCP is one of the most common opportunistic infection, fungal in nature, that occurs among immunocompromised individuals as HIV with WBC< 200 cells/mm3, cancer patients with chemotherapy and transplant recipients with immunosuppressive medications.
· It was previously considered from the protozoa, however it is now classified as fungal infection.
· It is unique from fungi that has RNA and lack strong dell wall with excess ergosterol.
· Pneumocystis carinii found only in rates, while in human it is called Jirovecii.
· Mode of transmission are air borne, may be nosocomial or reactivation of old infection.
· It has lung tropism and attacks type I alveolar cells.
· Pentamidine can be given either IV or aerolized, while SMX-TMP can be given either oral or intravenous.
· ⭐Not all drugs that can be used for PCP treatment are effective for chemoprophylaxis.
o Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine can be used for both prophylaxis and treatment.
o ⭐ IV pentamidine and clindamycin–primaquine are not effective for chemoprophylaxis.
· 👉 Standard prophylaxis is indicated for 3-6 months after kidney transplantation.
· 👉 SMX-TMP is the most effective and cheap chemoprophylaxis agent, with relatively few side effects as neutropenia, hepatitis and interstitial nephritis. Single strength is better than double strength formulation (same efficacy with fewer adverse effects).
· 👉 Alternatives to SMX-TMP in treatment of PCP:
o Oral dapsone + trimethoprim.
o Oral clindamycin +primaquine.
o IV pentamidine.
· 👉Adjuvant steroid therapy (either oral or IV) is indicated in moderate-severe cases if hypoxemia and PaO2 is <70 mmHg.
· Wide spread use of SMX-TMP has increased its resistance through certain mutations involved in sulfa and atovaquone drug resistance.
· 👉 Definition of resistance is difficult, as clearance of the organism is not evident in all cases after ttt (persistent detection of PCP in BAL).
.. 👉Sulfonamide. Resistance
👉 several resistance mechanisms have been identified in penatmidine and primaquine.
👌Level of evidence : narrative review (level V).
I like your analysis of the level of evidence, and summary.
Would have any personal experience of sulfa resistance of PCP? Typing whole sentence in bold or capitals equals to shouting !
Thanks dear professor
I will take care of my writing next time.
I really don’t have any experience in Sulfa resistant PCP.
Drug Resistance in Pneumocystis jirovecii
Summary of the article
Introduction
The Organism
Transmission and Infection
Drug Treatment
Prophylaxis
Treatment of PCP
Sulfonamide Resistance
DHFR Resistance
Atovaquone
Pentamidine ,Clindamycine–Primaquine
Conclusion
level of evidence is v , it is a review article
I like your analysis of the level of evidence, detailed summary.
SUMMARY
Introduction
PCP is a serious opportunistic infection in healthy immunosuppressed individuals not on prophylaxis.
Primary infection occurs in childhood with equal geographic distribution and can lead to upper or lower respiratory tract manifestations.
The organism can remain latent, later manifesting with disease when the host is immunosuppressed.
Recent studies also show that humans can be infected with more than one strain. Therefore the clinical disease can be due to reactivation of the latent organism or infection with a new strain.
Transmission and infection
Its environmental source is not known though transmission is thought to be airborne and there is no cross-infection with animal host.
The fungi has tropism for the lungs and it rarely causes extra-pulmonary disease.
Drug treatment
Drugs used to treat and prophylaxis include antifolate drugs, diamines, atovaquone, and macrolides.
Anti-fungal have no activity against it.
TMP-SMX is as effective as iv pentamidine and is the drug of choice for treatment and chemoprophylaxis.
Not all drugs used for treatment are effective chemoprophylaxis.
Dapsone, dapsone– trimethoprim, atovaquone and aerosolised pentamidine are effective for prophylaxis, however, iv pentamidine and clindamycin–primaquine are not.
Prophylaxis
Low CD4 counts <200cells/ml is associated with increased risk of PCP in HIV patients and they should be offered primary prophylaxis. Once the CD4 counts >200cells/ml for at least 3 months then the prophylaxis can be stopped. Secondary prophylaxis should be offered after treatment for PCP.
Other patients at risk of PCP are patients on longterm steroids, patients on chemotherapy, transplant recipients on immunosuppressive agents and patients with acquired and congenital immunodeficiencies.
HIV patients have a high frequency of adverse effects eg myelosuppression and rash with TMP-SMX.
TMP/SMX 80/400mg daily is as effective as 160/800mg daily.
Treatment
The beginning of HIV pandemic the mortality of PCP was 30-40% rising to 70-90% in respiratory failure, this has decreased to 5-15% due to early recognition, better diagnostic and treatment.
Antifolate drugs are the most potent drugs for treatment of PCP, they block denovo synthesis of folate via inhibition of DHPS or DHFR.
HIV infected patients have drug toxicity with TMP-SMX ranging between 24-57% and usually occurs within 7 days after initiation. Some adverse effects are less life threatening like rash and leucopenia, though it can cause SJS which is life threatening. TMP-SMX in the kidneys can cause interstitial nephritis, renal calculus formation and hyperkalemia
Pentamidine on the other hand has been associated with treatment limiting toxicities in the ranges of 13-80%. The rapid IV infusion is associated with hypotension, while IM injections was associated with sterile abscesses, the inhaled pentamidine is associated with poor efficacy thus its given as slow infusion.
Pentamidine is also toxic to several organs, in the kidneys it causes glomerular and tubular damage, in the pancreas it causes an insulin surge leading to hypoglycaemia, and in the heart can prolong the QT leading to torsades de pointe.
Other treatment alternatives are dapsone-pyrimethamine, clindamycin-primaquine and atovaquone.
Dapsone has not been studied as a single drug thus should not be used alone.
Dapsone-pyrimethamine is potent as TMP-SMX, however its efficacy is only demonstrated in mild -moderate PCP. It also cross reacts in 50% sulphur allergic patients thus doesn’t offer much advantage over TMP-SMX.
Clindamycin-primaquine works in a different metabolic pathway, however clindamycin leads to a high incidence of hepatitis, rash and diarrhoea.
Atovaquone though it also works in a different metabolic pathway it is not as potent as TMP-SMX and its efficacy has only been demonstrated in mild PCP.
Duration of treatment has not been tested however it is recommended that HIV patients should be treated for 2 weeks and non-HIV for three weeks.
Sulfonamide resistance
Resistance to sulphonamides has increased in both bacteria and parasites this has limited its efficacy.
Resistance is caused in mutations in the DHPS gene.
However documenting this resistance is difficult because P.Jivorecii can’t be cultured.
A clear association between prior sulpha exposure and presence of DHPS mutations has been shown in several studies.
Interestingly some studies have documented the presence of DHPS mutation and no prior sulpha exposure, this could be due to transmission of a mutant strain.
The significance of the mutant strain in terms of drug resistance and failure to comply to treatment is unknown.
This is further supported by the fact that patients with mutant strains have been successfully treated with TMP-SMX.
This DHPS mutations could thus only confer low level strain resistance that allows the organism to survive in low prophylactic dose. This can be overcome by use of high dose TMP-SMX.
DHFR resistance
Diaminopyrimidines, trimethoprim and pyrimethamine are competitive inhibitors of DHFR.
Some bacteria and parasitic species like plasmodium falciparum have developed resistance to DHFR.
However despite widespread use of TMP-SMX use there are few DHFR mutations in P.jivorecii.
Currently there is no evidence that widespread use of TMP-SMX has lead to DHFR resistance with clinical significance.
Atovaquone
It’s used to treat and prevent diseases caused by P. jirovecii, Plasmodium, Toxoplasma gondii and Bebesia.
Mutations in plasmodium and toxoplasma have been identified in vitro and this confers resistance to atovaquone.
Since P.jivorecii can’t be cultured resistance testing have not be done.
Presence of PCP mutation to atovaquone have been found not to affect survival of the patients.
Pentamidine and Clindamycine–Primaquine
Possible resistance mechanism are yet to be discovered and reported.
Conclusion
Mutations to sulpha and atovaquone have developed in P.Jivorecii via selective pressure by widespread use of prophylaxis.
DHPS mutation is implicated in low dose sulpha prophylaxis but this can be overcome by high dose sulpha.
Use of PCP prophylaxis in HIV patients in third world countries may lead to high level resistance.
Thus more research is required.
Level of evidence
This is a narrative review hence level V.
I like your analysis of the level of evidence, and detailed summary.
Introduction
Pneumocystis jirovecii is an opportunistic fungus that causes pneumonia, PCP in immunocompromised individuals.
Before 1982, PCP was relatively rare and primarily diagnosed among patients with congenital immunodefi ciencies, and patients receiving potent immunosuppressive therapy as part of an antineoplastic regimen.
With the AIDS pandemic PCP emerged as the most common.
The peak incidence of PCP was observed in the late 1980s and early 1990s.
There has been a decline in the incidence of PCP because of the widespread introduction of PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens.
PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis
The organism
Pneumocystis were identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini.
These investigators mistakenly considered the organisms as a new form of Trypanozoma cruzi.
Pneumocystis organisms have been identified in most mammalian species in which it has been searched for.
The level of genetic divergence between Pneumocystis organisms infecting different mammals is greater than the degree of divergence observed between certain fungi classified as distinct species .
Hominis for Pneumocystis infecting humans and P. carinii f.sp.
Carinii for one of the two species infecting rats .
pneumosyctic jirovesii , in honor of Otto Jirovec, who was among the fi rst to describe the microbe in humans.
Transmission and infection
Since P. jirovecii organism cannot be cultured in vitro, knowledge about its biology has been difficult to obtain.
Antibody and PCR fi ndings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that.
When the organism is obtained initially as a primary infection, it is not clear whether an immunocompetent host develops a transient disease.
Suggests that human hosts can be infected with more than one strain of pneumosystic jirovesii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms .
Adherence is primarily mediated by the major surface glycoprotein (MSG),
This protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family.
Several genes, which in other fungi are involved in mating, pheromone responsiveness, and responses to environmental changes, have been demonstrated in Pneumocystis, suggesting that the organism has a sexual replication cycle that responds to environmental changes in the lung.
Drug treatment
The major drug classes used for treatment and prophylaxis of PCP include antifolate drugs, diamines, atovaquone, and macrolides.
1977, studies led by Hughes et al established that the combination of trimethoprim—sulfamethoxazole (TMP—SMX) is effective for both treatment and prophylaxis of murine and human PCP .
TMP—SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Trimethoprim, atovaquone and aerosolized pentamidine are effective for prophylaxis.
There are other drugs that have in vitro activity or anecdotal anti-PCP activity in humans and could have a role in managing human disease if all other alternatives were not feasible.
Prophylaxis
Among HIV-infected patients, the occurrence of PCP is closely related to the CD4 count: With lower CD4 counts, the risk of PCP increases.
While a count of 200 cells/mm is often used as an indicator or susceptibility, HIV-infected patients do develop PCP at counts higher than.
X-linked immunodeficiency with hyper-immunoglobulin M and SCID, patients receiving long-term and high-dose corticosteroid therapy, and patients receiving certain chemotherapeutic regimens for cancer therapy or transplantation are at the risk of developing PCP.
After the publication of a convincing study by Fischl et al, PCP prophylaxis became a standard of care for HIV-infected patients with CD4 counts less than 200 cells/mm in 1989.
HIV-1 infected patients with oral candidiasis or a CD4 count less than 200 cells/μL, should be offered primary prophylaxis.
Treatment PCP
Mortality rates have dropped to 5—15%.
This appears to be a consequence of earlier recognition of the infection, the introduction of adjuvant corticosteroids to patients with moderate-to-severe PCP as defined by a PaO2 of less than.
Drug toxicity occurs in 24—57% of HIV-infected patients treated with TMP—SMX.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP—SMX
This drug is only available orally, and does not appear to be as potent as TMP—SMX (66).
Many patients experience progressive oxygen desaturation during the first 4—5 days of therapy
This deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
On the basis of these results, adjunctive steroids are recommended for all patients with severe disease (PaOs < 70 mmgh)
Sulphonamide resistance
The widespread use of TMP—SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa resistance could develop in P. jirovecii.
By site-directed mutagenesis, the in vitro effects of mutations identical to the DHPS mutations in P. jirovecii can be investigated
Using this model, two recent studies reported that the double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding.
Several studies have reported a significant association of DHPS mutations with failure of low-dose sulfa prophylaxis
While initial case reports suggested that patients with mutant DHPS strains had increased risk of failing sulfa therapy or prophylaxis, subsequent studies have not supported such a conclusion.
Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance
DHFR resistance
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dehydrofolate reductase (DHFR), which catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8-tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and certain amino acids
They are used in combination with sulfonamides.
Several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Clinical resistance is classically defined as the persistence or progression despite the administration of appropriate antimicrobial treatment
This definition is problematic when applied to PCP.
Clinical resistance has been investigated by genotyping of P. jirovecii isolates from patients who develop PCP in spite of prescribed chemoprophylaxis.
In theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure
Atovaquone
1,4-hydroxynaphthoquinone) is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., toxoplasma gondii and Bebesia .
Atovaquone is structurally similar to the mitochondrial protein ubiquinone, and competitively binds to the cytochrome bc complex.
Binding of atovaquone to the ubiquinol oxidation pocket of the bc complex and the Rieske iron—sulphur protein disrupts electron transport and leads to collapse of the mitochondrial membrane potential.
This presumably results in the depletion of ATP within Pneumocystis and leads to killing of the organism.
In vitro studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.
In vitro studies of the saccharomyces cerevisiae cytochrome bc complex and atovaquone have demonstrated binding to the ubiquitol pocket.
These findings are consistent with the development of atovaquone resistance after selective pressure is exerted
Conclusion
In spite of the inability to culture the organisms, it is clear that mutations involved in sulfa and atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
It is possible that if additional mutations arise, high-level sulfa resistance could emerge and lead to diminished efficacy of TMP—SMX.
This would lead to the loss of the most effi cient and inexpensive therapy for PCP.
These data will be crucial for further understanding of the infection and will enable identification of new polymorphic regions and drug targets and may eventually lead to the development of a culture system
Drug Resistance in Pneumocystis jirovecii:
Introduction:
Pneumocystis jiorveci is serious infection cause pneumonia in immunocompromised patients. The peak incidence of infection appear in 1980-1990 but in recent years it is decline because introduction of prophylaxis of PCP and treatment of HIV-1 antiviral therapy.
Microorganisms:
Pneumocystis jirovecii previously named as Pneumocystis carinii and classified as a protozoa. Currently, it is considered a fungus based on nucleic acid and biochemical analysis and named as P. jirovecii organism.
Transmission and Infection:
It’s type of fungus, Environmental cause of pneumocystis still not identified and transmission from person to persons by air.
Drug Treatment:
The main drug used in prophylaxis of pneumocystis jiorvecii is:
In 1958, the first drug of choice was pentamidine isethionate.
In the 1960s, the combination of sulfadoxine and pyrimethamine was used for the prevention of epidemic infantile pneumocystosis in Iran.
In 1966, sulfadiazine and pyrimethamine was used as trials.
Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP. TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
These drugs like sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine shows effective therapy against pneumocystis jiorvecii. Not all drugs are effective for therapy it’s also effective for chemoprophylaxis.
Dapsone, dapsone– trimethoprim, atovaquone and aerosolized pentamidine are also effective for prophylaxis. Intravenous pentamidine and clindamycin–primaquine have not been shown to be effective for chemoprophylaxis.
There are some drugs have activity in vitro like azithromycin, doxycycline, and caspofungin.
Prophylaxis:
Patients with HIV
Congenital immunodeficiency
Patients with long term corticosteroids
Patients on chemotherapy such as fludarabine, ATG.
Primary prophylaxis should be considered in patients with HIV-1 with candidiasis or CD4 count less than 200 cell/ul.
Secondary prophylaxis against PCP should be considered in all patients exposed to PCP.
In non-HIV infected individuals, conditions such as organ transplantation, high dose steroid treatment and/or high dose chemotherapy may has high risk of PCP. Prophylaxis should be stared.
The best one and cheaper is TMP–SMX.
Dose of TMP–SMX (septrin), 400/80 mg daily is effective and is associated with few side effects than 160/800mg daily.
Side effects of septrin is skin rash, fever, anemia , neutropenia Hyperkalemia Hepatitis Nephritis and Anaphylactoid reaction.
Treatment of PCP:
PCP is serious condition may be fatal if not treated. Mortality rate reached to 30-40% of cases and to 70-80% in cases with respiratory failure. adjuvant steroid to patients with moderate to severe PCP with PaO2 of less than 70mmHg or patients with HIV with CD4 less than 200cell/ ul. The treatment of PCP should be stared as early as possible even symptoms non specific ( dry cough, low grade fever and dyspnea), with presence of risk factors in immunocompromised patients or chest X ray abnormal and the first drug of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase or dihydrofolate reductase.
Pentamidine is very toxic associated with nephritis and pancreatitis and hypoglycemia and it’s may prolongs the QT interval, and cause torsades de pointe in some reported cases.
Alternative to o septrin and pentamidine include dapsone pyrimethamine, clindamycin primaquine, and atovaquone.
Clindamycin associated with high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
Atovaquone is used alternative to TMP–SMX for patients with mild disease who cannot tolerate TMP–SMX.
Dapsone pyrimethamine is used in mild to moderate cases with PCP.
Many patients shows progressive oxygen desaturation during the first 4–5 days of therapy. This deterioration is caused by the drug induced death of Pneumocystis organisms with exacerbation of alveolar inflammation. This inflammation can be reduced by corticosteroids.
Sulfonamide Resistance:
Resistance develop due to wide use of septrin as prophylaxis and treatment of PCP, Falciparum malaria and bacterial infection. There’s marked increase in trimethoprim– sulfamethoxazole resistance among isolates of Staphylococcus aureus and Enterobacteriaceae. This resistance against bacterial infection occur due to mutations of primary sequence of the DHPS gene. Many clinical studies investigated the frequency and significance of DHPS mutation in P jiorvecii. There’s large geographical variations in resistance to sulfa associated with DHPS mutations and some studies shows significant association with the failure of pyrimethamine–sulfadoxine prophylaxis and the Pro57Ser mutation. Also the major cause of resistance is poor adherence to chemoprophylaxis and mutation of DHPS.
DHFR Resistance:
The diaminopyrimidines, trimethoprim and pyrimethamine, are competitive inhibitors of dihydrofolate reductase (DHFR); so mutations to DHFR in Pneumocystis DHFR lead to resistance septrin but still no definitive evidence.
Atovaquone:
It’s used to treat and prevent P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp. It’s structural near to mitochondrial protein and competitively binds to the cytochrome bc1. However mutations of cytochrome bc1 gene in Plasmodium spp., Toxoplasma gondii and Pneumocystis leading to unresponse to Atovaquone but Survival from PCP did not differ between patients with or without mutations.
Pentamidine and Clindamycine–Primaquine:
Pentamidine and clindamycine primaquine are used for prevention and treatment of PCP, and resistance to these agents can be happen but still rare.
I like your analysis of the level of evidence, and detailed summary.
I -Summary:
Transmission of infection:
Prophylaxis:
-The risk depends on the intensity of IS and occurrence of host versus graft
disease or rejection.
-Prophylaxis is recommended for at least 6 months.
Treatment of PCP:
1- First choice: Trimethoprim– sulfamethoxazole
2- Alternative drugs:
effective in mild and moderate cases
rapid infusion associated with hypotension and even death
3- Adjunctive therapy: Prednisone in patients with room air PaO2 < 70 mmhg
Standard of care for moderate and severe case to counteract the
alveolar inflammation induced by PCP death by treatment.
Sulfonamide resistance:
DHFR resistance:
The study of drug resistance in P. jirovecii has been and continues to be difficult. due to failure of in vitro culture which precludes standard susceptibility testing and has greatly limited.
Another problem is that no consistent definition of clinical failure exists.
II- level of evidence: V
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
Pneumocystis jirovecii -fungal organism cause PCP in immunocompromised patients
Incidence increased with the era of definite diagnosis of HIV
Incidence decreased dramatically with era of chemoprophylaxis against PCP, and HIV antiretroviral treatment.
Organism
Identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini and was considered as a new form of Trypanozoma cruzi.
first described in humans in 1942 by two Dutch investigators, van der Meer and Brug
first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
Twentieth century, it was considered as a protozoon and single species based on its morphologic features, but has resistance to classical antifungal agents and the effectiveness of certain drugs used to treat protozoan infections.
1988-analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom was done. Phylogenetic data suggest thatPneumocystis is an ancient organism without any close relatives, Pneumocystis species represent an early divergent line in the fungal kingdom.
Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
2002-because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was among the first to describe the microbe in humans.
Transmission and Infection
Primary infection happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
becomes latent, and reactivated only in immunocompromised patients, and antibodies against it usually formed in the first year of life, also it may lead to sudden infant death.
has specific tropism to the lung, where it exists, but may found in other organs.
When inhaled, it attach to type 1 alveolar cells, this adherence is encoded by major surface protein in the organism which is abundant on its surface and it is polymorphic escaping immune response.
Drug treatment
Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP.
TMP–SMX
is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.Prophylaxis
CD4 count is usually used as indicator for PCP susceptibility in HIV patientsif less than 200, PCP can be developed but also can be developed in count more than 200, so it is unreliable marker for PCP in HIV patients.
Chemoprophylaxis used as a primary prophylaxis to HIV patient with CD4 less than 200 and can be interrupted at any time when CD4 raised more than 200 FOR 3 months after anti-retroviral treatment.
Secondary prophylaxis can be offered to all patients after attack of PCP.
TMP-SMX has much side effects in HIV patients than non-HIV patients like rash and myelosuppression.
In non-HIV patients like cancer, SOT, patients with high dose steroid-TMP-SMX can be given as a prophylactic therapy
Treatment of PCP
The treatment of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
TMP–SMX-Adverse effects
generally occur after 7 days of therapymost commonly include rash, fever, and leukopenia.Hepatotoxicity characterized by elevated transaminases also occurs.There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported.TMP-SMX – associated with hyperkalaemia.These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.Pentamidine
associated with a high frequency of toxicities, like hypotension and death, it is related to rate and route of administration,should be given as iv infusion, pentamidine is nephrotoxic and also has pancreatic toxicity.dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone.
Duration of treatment 2 weeks in non-HIV patients and 3 weeks in HIV patients.
This was narrative review, level 5.
I like your analysis of the level of evidence, and summary.
Introduction:
PCP remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
The Organism:
Identified early and classification and name evolving from protozoon to fungal microorganism and fro PCP to PJP after scientist who classify and discover them. Genetic divergence between Pneumocystis organisms infecting different mammals is greater than the degree of divergence observed between certain fungi classified as distinct species.
Transmission and Infection:
Primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
Following primary infection, the organism becomes latent, later manifesting clinically if the patient becomes profoundly immunosuppressed. Acquisition of an airborne pathogen may also lead to infection.
Drug Therapy:
TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice. Additionally, TMP–SMX is the most effective chemoprophylaxis for PCP.
Proven activity for therapy, including sulfadiazine plus pyrimethamine, Atovaquone, clindamycin plus pyrimethamine, trimetrexate, Dapsone and aerosolized pentamidine.
Not all drugs that are effective for therapy are also effective for chemoprophylaxis.
Dapsone, Dapsone– trimethoprim, Atovaquone and aerosolized pentamidine are also effective for prophylaxis.
Other could have a role in managing human disease if all other alternatives were not feasible. These include azithromycin, doxycycline, and caspofungin.
PCP chemoprophylaxis:
HIV patient:
Primary Prophylaxis
–HIV infected patients with oral candidiasis or a CD4 count less than 200 cells/Μl.
Secondary prophylaxis:
Should be offered to all patients following an episode of PCP. In HIV patients receiving prophylaxis; prophylaxis can safely be interrupted if immune function is improved above a CD4 count of 200 cells/μL for at least 3 months following antiretroviral therapy.
If the patient subsequently fails antiretroviral therapy and the CD4 declines to below 200 cells/μL, prophylaxis should be restarted.
Non-HIV infected individuals:
Conditions such as organ transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP.
Regimen is daily TMP–SMX: 80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily.
For patients, who have reacted to TMP–SMX, it has been shown to be safe to reintroduce TMP–SMX by dose escalation (. A variety of dosing regimens can be used with similar efficacy.
Tolerability may improve with the lower dose or the intermittent regimens.
Drug regimens for the treatment of PCP:
First choice:
Trimethoprim– sulfamethoxazole:
Dose:
Trimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h.
ADR:
Rash and fever Anemia and neutropenia Hyperkalemia, Hepatitis Nephritis AND Anaphylactoid reaction.
Alternatives Dapsone plus trimethoprim:
Dose
100 mg daily, trimeth 320 mg every 8 h.
ADR:
Rash, nausea and vomiting and fever Methemoglobinemia, leukopenia and hemolytic anemia, Liver function abnormalities; headache.
Clindamycin plus primaquine:
Dose:
300–450 mg every 6 h, 30 mg daily primaquine.
ADR:
Clostridium difficile diarrhea, nausea and vomiting. Primaquine may cause hemolysis in patients with G-6PD deficiency.
Atovaquone:
Dose:
By mouth 750 mg twice daily.
ADR:
Rash, nausea, diarrhea and headache (20%), Fever, increased transaminases and neutropenia.
Pentamidine:
Dose:
Intravenous 4 mg/kg day.
ADR:
High incidence of adverse effects, particularly hypoglycemia and nephrotoxicity Pancreatitis and IDDM. Hypotension with short infusion time Pancytopenia Q-T prolongation.
The optimal duration of therapy for PCP:
HIV-negative patients should receive 2 weeks and HIV positive patients three weeks of drug treatment.
Drug resistance:
Sulfa and Atovaquone drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
Currently, the clinical effect of the described mutations seems modest.
DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
Level of evidence V.
It is really resistance of bug or an intolerance of host to the drug?
Introduction
– PCP is a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis.
– It was rare disease and its prevalence increased with AIDS pandemic and subsequently decline with wide spread availability of chemoprophylaxis.
– PCP carries a high mortality rate.
The Organism
– Initially, Pneumocystis was considered as a protozoon.
– Recently it was re-classified as fungi entitled the Archiascomycetes.
– It is unique as it has only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
– It includes a broad family of organisms, with species specificity and genetic divergence.
– There is no cross species infection
– The organism infecting humans was renamed Pneumocystis jirovecii.
Transmission and Infection
– The organisms are ubiquitous, however; its environmental source is unknown.
– Primary infection with happens in early childhood.
– The clinical infection resulted from reactivation of latent organism or recent new infection in immunocompromised hosts.
– Likely an airborne pathogen.
– It has specific tropism for the lung (alveoli) and rarely cause extrapulmonary diseases.
– The life cycle and the mode of replication is not fully established.
Drug Treatment
-The major drug classes used for treatment and prophylaxis of PCP include: antifolate drugs, diamines, atovaquone, and macrolides.
– Pentamidine isethionate was the first drug used to successfully treat PCP
-The combination of trimethoprim–sulfamethoxazole (TMP–SMX) is treatment of choice and the most effective
chemoprophylaxis for PCP.
-Other drugs including; sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
– Not all drugs that are effective for therapy are also effective for chemoprophylaxis
Prophylaxis
– In patients without HIV, CD4 counts are not a reliable marker of susceptibility.
– Primary prophylaxis recommended for HIV-patients with CD4 counts < 200 cells/mm3 with oral candidiasis till CD4 count > 200 for at least 3 months then can be interrupted, to resume treatment if count drop to < 200.
– PCP chemoprophylaxis should be offered in: SOT, Caner, high-dose steroid treatment and/or high-dose chemotherapy.
– Secondary prophylaxis should be offered to all patients following an episode of PCP.
– Several regimens are available for prophylaxis.
– TMP–SMX The most efficient, cheap and widely and relatively well tolerated by most non-HIV patients.
Treatment of PCP
-Once there is a high suspicion therapy should be instituted promptly if the diagnostic procedures will be delayed.
– Antifolate drugs: Most potent drugs for PCP treatment.
-Act by blocking de novo synthesis of folates through inhibition of dihydroperoate reductase DHPR, which catalyzes (PABA) to produce dihydropteroate.
– Sulfa drugs are structural analogs of PABA and inhibit DHPS.
– TMP/SMT; first choice; Superior efficacy, Inexpensive Oral and IV
– Drug toxicity occurs in 24–57%: Rash and fever , myelosuppression, hepatitis, interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis. Trimethroprim can be associated with hyperkalemia. Fatal SJS may occurs.
– It is associated with a better survival than pentamidine
–Pentamidine is associated with treatment-limiting toxicities occur in 13–80% of patients, toxicities, also related to route of administration, particularly hypoglycemia and nephrotoxicity, pancreatitis and IDDM. Hypotension with short infusion time, pancytopenia and Q-T prolongation.
– Alternatives therapy include:
–Dapsone should not be used alone for treatment. Dapsone–trimethoprim is effective in mild to moderate PCP , and potency comparable to TMP–SMX. Cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP–SMX.
–Clindamycin–primaquine in moderate- to-severe PCP has equivalent effect with TMP–SMX. Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients.
-Atovaquone; only available orally, and does not appear to be as potent as TMP–SMX. This is a good alternative to
TMP–SMX for patients with mild disease only who cannot tolerate TMP–SMX.
-Adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh) to reduce inflammation. As patients may deteriorate initially with hypoxia secondary to death of the organism, alveolar damage and the associated inflammation.
Duration of therapy
Usual recommendations are that HIV-negative patients should receive 2 weeks ,while in HIV patients 3 weeks.
Sulfonamide Resistance
– Widespread use of sulfa drugs has produced high rates of resistance , and the resistance of many pathogen related to mutation in DHPD gene.
– Double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, consistent with resistance being associated with altered substrate binding in a consequent reduction in sulfa drug sensitivity.
– Clear association between previous exposure to sulfa drugs and DHPS mutations has been shown in all studies. Mutations were also found in patients without previous drug exposure.
– The clinical significance of DHPS mutations, specifically with regard to response to prophylaxis and therapy using a sulfa based regimen has been controversial.
– Despite the emergence of mutant DHPS strains TMP/SMX is effective prophylaxis when taken regularly and majority of patients with mutant DHPS strains have been successfully treated with TMP/SMT or dapsone–trimethoprim.
– Studies suggested that DHPS mutations contribute to low-level sulfa resistance, and may be the most important in failure of second-line sulfa prophylaxis.
– The major reason for PCP breakthrough continues to be the poor adherence to chemoprophylaxis
DHFR Resistance
-Trimetrexate is much more potent against PCP than trimethoprim in vitro.
-The combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.
– There is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of
clinical significant resistance to DHFR inhibitors.
Atovaquone
– It is used to prevent and treat P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
– Competitively binds to the cytochrome bc1 complex.
– Mutation in cytochrome bc complex may confer resistance to atovaquone.
Pentamidine and Clindamycine–Primaquine
Resistance mechanisms not yet discovered.
Conclusion
-Wide spread use of PCP prophylaxis resulted in mutations involved in sulfa and atovaquone drug resistance in P. jirovecii .
– DHPS mutations are implicated in the failure of low-dose sulfa prophylaxis , but no significant resistance to high-dose sulfa therapy.
– Investigations the mechanisms of drug resistance and identification of new molecular targets and promising treatment.
Level of evidence : narrative review level 5.
I like your analysis of the level of evidence, limitations of study and summary.
SUMMARY
Introduction
Pneumocystis Jirovechii initially remains a relatively rare disease until the early 1980s when the AIDS pandemic hit the world making it one of the most common defining illnesses of AIDS. It then gained a reputation as a serious illness particularly among the immunocompromised individual until the routine use of prophylaxis slows down the incidence.
PJP classification has gone through from being initially known as a protozoan and now to being a fungus even though it has been found to be resistant to antifungal treatment. In 2002, it was named Pneumocytis Jirovechii in honour of Otto Jirovec.
Transmission and Infection
Drug for prophylaxis
-First choice
-Alternative
Drug Treatment
-First choice
-Alternative
Sulfonamide Resistance
Conclusion
The growing incidence of the mutation of sulfonamide and atovaquone resistance due to the increase in the use of the drug in HIV-AIDS and the use of low doses for prophylaxis needs to be steamed by growing research into the mechanism of development of the resistance.
The level of evidence is 5
I like your analysis of the level of evidence, limitations of study and summary.
It is really resistance of bug or an intolerance of host to the drug?
1. Please summarise this article.
Introduction: Pneumocystis jirovecii, a fungal infection leads to pneumocystis pneumonia (PCP) in immunocompromised patients, especially those not receiving any chemoprophylaxis.
The organism: Pneumocystis was initially considered to be a protozoon, but later found to be a fungi. It is an ancient organism with only one copy of nuclear ribosomal RNA locus, with fragile cell wall, and miniscule ergosterol. Pneumocystis infecting humans is named Pneumocystis jirovecii.
Transmission and infection: It is ubiquitous, its environmental source is unknown, and it cannot be cultured in vitro. Primary infection occurs in early childhood causing upper of lower respiratory tract infection, or sudden infant death syndrome (SIDS). The organism becomes latent after primary infection. The organism has affinity for alveoli of lungs. Reactivation of latent infection, or recent acquisition of the airborne pathogen can lead to clinical PCP. The organism gets associated with type I alveolar call surface through MSG (major surface glycoprotein).
Drug treatment: 4 major classes of drugs available for PCP treatment include antifolates, diamines, atovaquone, and macrolide agents. Drugs might be useful for treatment but may not be useful as chemoprophylaxis.
Prophylaxis: Drugs used as prophylaxis for PCP include trimethoprim-sulfamethoxazole (TMP-SMX), the first choice, and alternative medications like Dapsone, Dapsone with pyrimethamine and leucovorin, aerosolized pentamidine, atovaquone, or pyrimethamine with sulfadiazine. Prophylaxis is important for at-risk patients like those with congenital immunodeficiency, HIV patients with oral candidiasis or CD4 count <200 cells/mm3, on high-dose, long-term steroids, on cancer chemotherapy, transplant recipients, or having received fludarabine, Alemtuzumab, or antithymocyte globulin (ATG). Prophylaxis in HIV patients can be stopped if CD4 count increases to >200 for at least 3 months, and needs to be restarted if the CD4 count falls below 200. In transplant recipients, prophylaxis should be given for 6-12 months post-transplant.
Treatment of PCP: PCP, if untreated, leads to mortality. Hence it is important to treat PCP at an early stage. Treatment of PCP should be given for 3 weeks in HIV positive patients, and for 2 weeks in HIV negative patients. Medications used for PCP treatment include:
a) TMP-SMX: It is the drug of choice, can be used orally or parenterally, is inexpensive, and has superior efficacy. It may cause rash, fever, neutropenia, hepatitis, nephritis, and hyperkalemia, pancreatitis, renal calculi, and anaphylactoid reaction. The antifolates inhibit dihydroperoate synthase (DHPS) and dihydrofolate reductase (DHFR).
b) Dapsone plus TMP: It can be used as an alternative, but may cause rash, nausea, fever, vomiting, hepatotoxicity, and hemolysis in G6PD deficiency.
c) Clindamycin plus Primaquine: It may cause diarrhea, nausea, vomiting, hepatitis, and rash. Disadvantage includes non-availability of oral primaquine.
d) Pentamidine: Given as slow intravenous infusion, it is highly effective, but has toxicity including nephrotoxicity, hypoglycemia, pancreatitis, pancytopenia, and Q-T prolongation.
e) Atovaquone: It is expensive, given orally, and is useful only for mild disease in patients who cannot tolerate TMP-SMX.
f) Dapsone plus pyrimethamine: It is given orally, and can be used for mild to moderate PCP.
g) Adjunctive steroids (Prednisone): Used in moderate to severe PCP with low pAO2 (<70 mm Hg), although associated with metabolic effects like glucose and electrolyte abnormalities.
TMP-SMX, pentamidine, and Dapsone plus TMP have similar efficacy.
Sulfonamide resistance: Prior exposure to sulfa drugs leads to development of resistance, primarily due to mutation in DHPS gene. DHPS mutation takes place at 165 and 171 nucleotide position, leading to amino acid changes at position 55 and 57, giving rise to Thr55Ala, and Pro57Ser mutations. DHPS mutations in absence of prior sulfa drug exposure have also been seen due to spread of mutant strain form person to person. DHPS mutation is associated with failure of low-dose sulfa PCP prophylaxis. Poor compliance with respect to chemoprophylaxis lead to PCP breakthrough. DHPS mutation is associated with increased 3 month mortality.
DHFR resistance: TMP and pyrimethamine inhibit DHFR, which is responsible for purine/ pyrimidine nucleotide. DHFR resistance occurs due to selective pressure by DHFR inhibitors (TMP, pyrimethamine, and trimetrexate). Trimetrexate is most potent amongst the DHFR inhibitors. There is no evidence to show that prior use of TMP or pyrimethamine increases resistance to them.
Atovaquone: It binds to Cytbc1 complex, which inhibits ATP generation.
Pentamidine and Clindamycine-Primaquine resistance patterns have not been documented.
Conclusion: Widespread use of sulfa drugs leads to mutations. DHPS mutations are associated with failure of low-dose prophylaxis, but do not show any resistance to high-dose treatment. It is difficult to study drug resistance in Pneumocystis due to absence of invitro culture system, absence of clear-cut definition for treatment failure, presence of inflammatory response (leading to alveolar damage and respiratory failure), high incidence of adverse effects like fever, effect of non-adherence (which might be the reason for resistance mutation rather than treatment failure).
2. What is the level of evidence provided by this article?
Level of evidence: Level 5 – Narrative review
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
No Professor. I did not see any patient with sulfa resistance.
Please summarise this article.
Diagnosis of PCP depends on the detection of the cystic or trophic forms in respiratory secretions by immunofluorescent staining (the organism cannot be cultured) , PCR has a disadvantage of not differentiating between infection and colonization
Prophylaxis
Regimens used for prophylaxis
First line
2nd line
Treatment
Severe disease
Non severe disease
Inductions of adjuvant steroid therapy
Monitoring patients on treatment –
Duration of therapy
Secondary prophylaxis
Side effects of the most important drugs used in prophylaxis and treatment
Sulphonamide resistance
What is the level of evidence provided by this article?
I like your analysis of the level of evidence, limitations of study and summary.
Please summarise this article.
Introduction
Although there is a decline in the incidence of PCP because of the widespread PCP chemoprophylaxis and the introduction of increasingly potent HIV-1 antiretroviral regimens, PCP still remains a serious opportunistic infection among heavily immunosuppressed patients who are not receiving appropriate chemoprophylaxis
The organism
It is a fungal infection and possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
Transmission and Infection
o Ubiquitous infection with primary infection occurs in early childhood with a high incidence in all geographic areas
o Following primary infection, it becomes latent, later manifesting clinically if the patient becomes immunosuppressed
o Has specific tropism for the lung (alveoli) with rare cases detected in other organs (seldom causes disease at extrapulmonary sites). Adhere to the surface of type I alveolar cells [mediated by the major surface glycoprotein (MSG)]
o MSG protein is the most abundant antigen on the surface of Pneumocystis and is encoded by a multicopy gene family (it represents a family of proteins that are highly polymorphic, repeated and distributed among all the chromosomes of Pneumocystis)
Drug Treatment
Drugs used for treatment and prophylaxes of PCP include:
1. TMP–SMX: first choice
2. Pentamidine intravenous (only for treatment)
3. Pentamidine aerosolized
4. Sulfadiazine plus pyrimethamine
5. Atovaquone
6. Clindamycin plus pyrimethamine
7. Clindamycin–primaquine (only for treatment)
8. Dapsone
9. Others: azithromycin, doxycycline, and caspofungin
Prophylaxis
Risk factors of PJP:
1. Patients with congenital immunodefi ciencies (particularly X-linked immunodeficiency with hyper-immunoglobulin M and SCID
2. Long-term and high-dose corticosteroid therapy
3. Certain chemotherapeutic regimens (cancer therapy or transplantation)
Recommendations for PCP prophylaxis:
1. HIV-1 infection (lifelong unless CD4 count >200 × >3 months due to antiretroviral therapy)
2. Organ transplantation: minimum 6 month after transplantation
3. Malignancy ((ALL, CLL, and lymphoma)
Treatment of PCP
Trimethoprim– sulfamethoxazole
o First choice
o Dose 2 DS every 8 h (oral), rimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 h (intravenous)
o Side effects: rash and fever, anemia and neutropenia, hyperkalemia, hepatitis, nephritis, anaphylactoid reaction
Dapsone plus trimethoprim
o Dose 100 mg daily/ 320 mg every 8 h (oral)
o Side effects: rash, nausea and vomiting, fever, methemoglobinemia, leukopenia and haemolytic anemia. Liver function abnormalities; headache. Dapsone may cause hemolysis in patients with G-6PD
Clindamycin plus primaquine
o By mouth, intravenous (300–450 mg every 6 h 30 mg daily)
o Side effects: clostridium difficile diarrhea, nausea and vomiting. Primaquine may cause hemolysis in patients with G-6PD deficiency
Pentamidine
o Intravenous 4 mg/kg day
o High incidence of adverse effects, particularly hypoglycemia and nephrotoxicity, pancreatitis and IDDM, hypotension with short infusion time, pancytopenia and Q-T prolongation
Atovaquone
o By mouth 750 mg twice daily Well tolerated Expensive
o Side effects: Rash, nausea, diarrhea and headache (20%), fever, increased transaminases and neutropenia
Adjunctive therapy (prednisone)
o In patients with room air pAO2 < 70 mmhg (9.3 kPa)
o By mouth, intravenous
o 40 mg twice daily for 5 days 40 mg daily, days 6 through 11 20 mg daily, days 12 through 21 while on anti-PCP therapy
o For moderate or severe disease
o Metabolic problems, especially glucose and electrolyte changes
Sulfonamide Resistance
o Sulfonamide resistance is caused by mutations in the primary sequence of the dihydroperoate synthase (DHPS) gene
o The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser)
DHFR Resistance
o The diaminopyrimidines (trimethoprim and pyrimethamine) are competitive inhibitors of dihydrofolate reductase (DHFR)
o DHFR catalyzes the reduction of the biologically inactive 7,8-dihyfrofolate to the active 5,6,7,8- tetrahydrofolate in the presence of NADPH and is essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and c ertain amino acids
o Resistance to DHFR inhibitors has arised as a consequence of selective pressure by DHFR inhibitors
o Only few DHFR mutations has been identified in Pneumocystis DHFR
o No evidence that use of trimethoprim or pyrimethamine cause clinical significant resistance to DHFR inhibitors
Pentamidine and clindamycine–Primaquine
o Used for prevention and treatment of PCP
o Possible resistance mechanisms not discovered yet
Atovaquone
o Competitively binds to the cytochrome bc1 complex
o Mutations of the cytochrome b gene lead to atovaquone resistance
Limitations of the study
1. Absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism
2. No consistent definition of clinical resistance (the classic definition of resistance may not be applied to PJP)
3. Difficult assessment of nonadherence of prophylaxis (resistance may be higher with inadequate or interrupted dosing)
Conclusion
o Mutations involved in sulfa and atovaquone drug resistance have arised in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis
o DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy
o The risk of high-level resistance in the third world is due to increasing HIV epidemic and use of TMP–SMX and therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing
o Pneumocystis Genome Project (initiated in 1997) is promising
What is the level of evidence provided by this article?
Level V (narrative review)
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
Introduction:
The organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was among the first to describe the microbe in humans.
Infection and transmission:
Pneumocystis has specific tropism for the lung, where it exists in the alveoli.After inhalation, the organism attaches tightly to the surface of type I alveolar cells.
Managemnent:
For prophylaxis:
Drug of choice: Trimethoprim–sulfamethoxazole 1 DS or SS daily for 6 months for kidney transplantantifolate drugs, diamines, atovaquone, and macrolides80/400 mg TMP–SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg dailyBecause of its efficacy, ease of administration and cost, every effort should be tried to maintain patients at risk of PCP on TMP–SMX.Treatment of PCP:
Drug of choice: Trimethoprim–sulfamethoxazole 2 DS 8 hourly per oralTrimethoprim 5 mg/kg with sulfamethoxazole 20 mg/kg every 8 hourly intravenous Alternative:Dapsone + trimethoprimClindamycin + primaquinePentamidineAtovaquoneAdjunctive : Prednisone in patients with room air pAO2 < 70 mmHg (9.3 kPa)dyspnea, cough, or low-grade fever can be the initial manifestation of PCP, especially in patients with CD4+ T lymphocyte counts below 200 cells/mm3.
Thus, clinicians should not wait for all the features of PCP to be present, or for the chest radiograph to be abnormal, before initiating a workup for PCP.
Sulfonamide Resistance
The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).The currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy.
DHFR Resistance
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Level of evidence: V (Narrative review)
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
Sir, I have no personal experience of the resistance.
Drug-Resistance-in-Pneumocystis-jirovecii
Introduction
PCP is a common opportunistic infection in immunocompromised individuals;
The Organism
Drug treatment
2. Alternatives
Treatment
Conclusion
Level of evidence
Leve ((V))
review article
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP? Typing whole article in italics defeats the purpose of typing in italics meant for specific emphasis!
Introduction:
Transmission:
Drug treatment:
Prophylaxis:
Treatment:
Sulfonamide resistance:
DHFR resistance:
Atovaquone:
Pentamidine & clindamycine-primaquine:
Level of evidence is 5
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP? It is really resistance of bug or an intolerance of host to the drug?
No, I didn’t experience sulfa resistant of PCP.
The Introduction;
Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungus that causes pneumonia, Pneumocystis pneumonia (PCP), in immunocompromised individuals .
Transmission and Infection ;
1-Studies have not conclusively demonstrated the environmental niche.
2-Antibody and PCR findings indicate that primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
3-The clinical disease PCP may, therefore, occur as a reactivation of a prior latent organism, or as a result of recent acquisition of an airborne pathogen.
4-Pneumocystis has specific tropism for the lung, where it exists in the alveoli.
Drug Treatment;
The major drug classes used for treatment and prophylaxis of PCP include;
1-Antifolate drugs.
2-Diamines.
3-Atovaquone .
4- Macrolides .
Prophylaxis;
A-High risk groups ;
1-HIV infected individuals .
2-Organ transplanted individuals .
3-Those who received high-dose steroid treatment and/or high-dose chemotherapy.
B-Several prophylactic regimens are available.
C- The most efficient, cheap and widely used regimen is daily TMP—SMX. TMP—SMX prophylaxis is relatively well tolerated by most non-HIV patients; in contrast, HIV patients have a high frequency of adverse effects, in particular rash and myelosuppression.
D- 80/400 mg TMP—SMX daily appears to be equally effective and is associated with fewer side effects than 160/800 mg daily.
Treatment of PCP;
1-Untreated PCP is invariably fatal.
2- The optimal duration of therapy for PCP has never been properly tested. Usual recommendations are that HIV-negative patients should receive 2 weeks and HIV- positive patients three weeks of drug treatment.
3- Adjuvant corticosteroids to patients with moderate-to-severe PCP as defined by a PaO2 of less than 70 mmHg.
4- TMP—SMX was associated with a better survival than pentamidine.
5- Pentamidine is associated with a high frequency of toxicities, some of which are treatment-limiting.
6-lternatives for the therapy to TMP—SMX and pentamidine include dapsone pyrimethamine, clindamycin—primaquine, and atovaquon .
7- Dapsone—trimethoprim is effective, however, and probably has potency that is comparable to TMP—SMX. However, since this combination does not come as a fixed-dose combination, is only available orally, and cross-reacts with sulfa in 50% of allergic patients, this regimen does not offer many advantages over TMP—SMX.
8- Clindamycin—primaquine appears to work on a metabolic pathway different from that of TMP—SMX. Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
9- Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP—SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP—SMX . This is a good alternative to TMP—SMX for patients with mild disease who cannot tolerate TMP—SMX.
10- Efficacy of dapsone—pyrimethamine has only been demonstrated for mild-to-moderate PCP and for atovaquone only for mild PCP . Both must be administered orally.
Sulfonamide Resistance;
1-The widespread use of TMP—SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
2-The mutations that confer resistance are localized within a highly conserved active site of the DHPS protein.
3- DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfaprophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy. However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP—SMX. This would lead to the loss of the most efficient and inexpensive therapy for PCP.
DHFR Resistance;
Although several studies have reported DHFR mutations, there is so far no evidence that the widespread use of trimethoprim or pyrimethamine have caused emergence of clinical significant resistance to DHFR inhibitors.
Atovaquone;
Atovaquone is used to prevent and treat disease caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
Atovaquone is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q), and competitively binds to the cytochrome bc1 complex.
Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
Survival from PCP did not differ between patients with or without mutations.
Pentamidine and Clindamycine–Primaquine;
Pentamidine and clindamycine—primaquine are used for prevention and treatment of PCP, but possible resistance mechanisms have yet to be discovered and reported.
Limitations to the study ;
1-The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
2-Most drug development has been empiric and the currently available treatment options for PCP have been unchanged during the last 15 years.
2- Experimental systems have mainly relied on immuno- suppressed animal, in particular the rat model of Pneumocystis.
2-No consistent definition of clinical failure exists.
What is the level of evidence provided by this article
—————————————————————————–
Level V
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of clinical failures in PCP?
II. Drug Resistance in Pneumocystis jirovecii
1. Please summarise this article.
Introduction
Transmission & Infection
Drug Treatment
Regimens for prophylaxis against Pneumocystis pneumonia
First choice:
Alternatives:
Drug regimens for the treatment of PCP
First choice
Trimethoprim–sulfamethoxazole:
Toxicity: Rash, fever, anemia, neutropenia, hyperkalemia, hepatitis, nephrits, &
anaphylactoid reaction.
Advantages:
Alternatives
Dapsone (100 mg/d PO) plus trimethoprim (320 mg/8 h PO)
Toxicity:
—————————————-
Clindamycin plus primaquine (300–450 mg/6 h 30 mg/d PO/IV)
Toxicity:
—————————————-
Pentamidine (4 mg/kg/d IV)
Toxicity:
—————————————-
Atovaquone (750 mg twice daily PO)
Toxicity:
—————————————-
Adjunctive therapy
Prednisone in patients with room air pAO2 < 70 mmHg (9.3 kPa):
Toxicity:
—————————————-
DHFR Resistance
Atovaquone
Pentamidine & Clindamycin–Primaquine
==========================
2. What is the level of evidence provided by this article?
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP?
Thank you, dear Prof/Ajay
No, actually I have never seen it; however, we frequently see significant side effects necessating cessation of the drug..
Drug Resistance in Pneumocystis jirovecii.
1-Please summarise this article.
Treatment of PCP;
-Untreated PCP is invariably fatal so early recognition of the disease is important to save life, especially in immunocompromised patient.
-Patients with low grade fever and dry cough with shortness of breath and hypoxia is highly suspicion for PCP so early diagnosis and treatment should be started soon.
-The most potent drugs for PCP treatment are antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
TMP–SMX;
-Associated with a better survival than pentamidine. However, when all the trials are considered, TMP–SMX and pentamidine appear to have roughly comparable efficacy.
-Drug toxicity occurs in 24–57% of HIV-infected patients treated with TMP–SMX.
-Adverse effects generally occur after 7 days of therapy including; rash, fever and leukopenia , Hepatotoxicity characterized by elevated transaminases.
-There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis.
-Trimethroprim can be associated with hyperkalemia.
Pentamidine;
-Associated with a high frequency of toxicities, some of which are treatment-limiting.
-Treatment-limiting toxicities with pentamidine treatment occur in 13–80% of patients.
-Rapid infusions of pentamidine associated with hypotension and death.
-Intramusuclar injections were better tolerated in terms of blood pressure, but they caused a high frequency of sterile abscesses , so that slow intravenous infusion is the best tolerated route.
-Inhaled pentamidine has been used for therapy, and is well tolerated, but efficacy is poor.
-Pentamidine is nephrotoxic and causes predictable glomerular and tubular damage to the kidney.
-Pentamidine is toxic to the pancreas; its initial effects cause a surge of insulin release that often manifests as hypoglycemia, which can occur days or weeks after starting therapy, and may occur many days after stopping therapy.
-Leukopenia can also occur.
-Pentamidine prolongs the QT interval, and cases of torsades de pointe have been reported.
Alternatives for the therapy to TMP–SMX and pentamidine include;
Dapsone , Pyrimethamine , Clindamycin , Primaquine, and Atovaquone.
-Clindamycin–primaquine appears to work on a metabolic pathway different from that of TMP–SMX.
-Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
-Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX.
-However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX.
-The optimal duration of therapy for PCP has never been properly tested.
-Usual recommendations are that HIV-negative patients should receive 2 weeks and HIV-positive patients three weeks of drug treatment.
-Many patients experience progressive oxygen desaturation during the first 4–5 days of therapy, this deterioration appears to be caused by the drug-induced death of Pneumocystis organisms with exacerbation of alveolar inflammation.
-This inflammation can be reduced by corticosteroids, That could reduce mortality in patients with moderate or severe disease.
-Adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh).
Sulfonamide Resistance;
-The widespread use of TMP–SMX and dapsone for therapy and prophylaxis of PCP among HIV patients has led to the concern that sulfa (sulfonamide or sulfone) resistance could develop in P. jirovecii.
-Sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
-The mutations that confer resistance are localized within a highly conserved active site of the DHPS protein at nucleotide positions 165 and 171.
Conclusion;
-Although inability to culture the organisms, it is clear that mutations involved in sulfa and atovaquone, drug resistance have emerged in P. jirovecii as a result of selective pressure by the widespread use of PCP prophylaxis.
-DHPS mutations at codon 55 and 57 are implicated in the failure of low-dose sulfa prophylaxis, but there is no firm evidence that DHPS mutations result in significant resistance to high-dose sulfa therapy.
-However, it is possible that if additional mutations arise, then high-level sulfa resistance could emerge and lead to diminished efficacy of TMP–SMX.
-This would lead to the loss of the most efficient and inexpensive therapy for PCP.
-The increasing HIV epidemic and use of TMP–SMX in the third world may significantly increase the risk for the development of high-level resistance.
-Therefore, investigations into the mechanisms of drug resistance and identification of new molecular targets are continuing.
Limitation;
-The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
-The knowledge of the metabolic pathways is limited, most drug development has been empiric and the currently available treatment options for PCP have been unchanged during the last 15 years.
-Experimental systems have mainly relied on immunosuppressed animal, in particular the rat model of Pneumocystis.
-No consistent definition of clinical failure exists. In other fungal infections, clinical resistance is classically defined as the persistence or progression despite the administration of appropriate antimicrobial treatment.
-The contribution of nonadherence in presumed failure of prophylaxis may be difficult to assess. The most important reason for prophylaxis failure continues to be nonadherence to prescribed prophylaxis.
-In theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure.
2-What is the level of evidence provided by this article?
This narrative review considering level V evidence.
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of sulfa resistance of PCP?
Thanks; our Prof.
actually, I didn’t have experience of sulfa resistance of PCP, I have experience with pt had Adverse reaction to TMP-SMX (rash , leukopenia) and after review by I.D. we shifted him to inhaled pentamidine.
Introduction:
In immunocompromised people, Pneumocystis jirovecii (formerly Pneumocystis carinii) causes pneumonia, known as PCP. Before 1982, PCP was uncommon and mostly diagnosed in congenital immunodeficiencies and people on powerful immunosuppressive medication for cancer.
Organisms:
Chagas discovered Pneumocystis in guinea pigs and Carini in rat lungs early in the 20th century. These researchers misidentified the organisms as a novel Trypanosoma cruzi strain. Pneumocystis, named after Carini, was discovered in 1912.
Prophylaxis:
Daily TMP–SMX is the most cost-effective, extensively utilized regimen. Most non-HIV patients handle TMP–SMX prophylaxis well, however, HIV patients have rash and myelosuppression.
Treatment of PCP:
TMP–SMX outlived pentamidine.
TMP–SMX and pentamidine seem to have similar efficacy when all studies are examined. TMP–SMX toxicity affects 24–57% of HIV-positive individuals.
Pentamidine has several toxicities, some of which are treatment-limiting. Rapid pentamidine infusions caused hypotension and mortality, thus, they were discontinued. Intramuscular injections were beneficial for blood pressure but generated many sterile abscesses.
Dapsone–pyrimethamine, clindamycin–primaquine, and atovaquone are TMP–SMX and pentamidine alternatives.
Sulfonamide Resistance:
Because of the extensive use of TMP–SMX and dapsone for the treatment and prevention of PCP in HIV patients, there is a growing fear that P. jirovecii might acquire resistance to sulfa (sulfonamide or sulfone) medications.
DHFR Resistance:
However, despite the widespread use of trimethoprim in combination with sulfamethoxazole for the prevention and treatment of PCP, only a relatively small number of DHFR mutations have been identified in Pneumocystis DHFR. This is the case despite the fact that trimethoprim is used in combination with sulfamethoxazole.
Conclusion:
The extensive use of PCP prophylaxis has been selected for mutations in P. jirovecii that cause sulfa and atovaquone medication resistance, notwithstanding the inability to grow the organisms.
The mutations’ clinical impact is limited. Low-dose sulfa prophylaxis fails due to DHPS mutations at codons 55 and 57, although there is little indication that they cause significant resistance to high-dose treatment. TMP–SMX efficacy may decrease if new mutations cause high-level sulfa resistance. The most effective and affordable PCP treatment would be lost.
Level 5, Narrative review
I like your analysis of the level of evidence, limitations of study and summary.
Would have any personal experience of clinical failures in PCP?
Pneumocystis identified in guinea pigs by Chagas and in rat lungs by Carini
mistakenly considered the organisms as a new form of Trypanozoma cruzi.
In 1912, Pneumocystis was recognized as a new species and named in honor of Carini
Pneumocystis was first established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages
Phylogenetic data suggest that Pneumocystis is an ancient organism without any close relatives
The organism has recently been placed in a group of fungi entitled the Archiascomycetes
In contrast to most other fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol
in 2002,because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec
More recent data, however, suggests that human hosts can be infected with more than one strain of Pneumocystis jirovecii, raising the possibility that infection can be acquired on multiple occasions, leading to latency with a variety of distinct organisms
Pneumocystis has specifi c tropism for the lung, where it exists in the alveoli.
Regimens for prophylaxis against Pneumocystis pneumonia
First choice Trimethoprim–sulfamethoxazole 1 DS or SS daily
Alternatives
Trimethoprim–sulfamethoxazole 1 DS three times per week
Dapsone 50 mg twice daily or 100 mg twice weekly
Dapsone with 50 mg daily
Pyrimethamine plus 50 mg weekly
Pentamidine aerosolized 300 mg monthly via nebulizer
Atovaquone 1,500 mg daily
Several prophylactic regimens are available. The most efficient, cheap and widely used regimen is daily TMP–SMX.
Adverse effect TMP–SMX.
Rash and fever Anemia and neutropenia Hyperkalemia if given oral
Intravenous Hepatitis Nephritis Anaphylactoid reaction if given iv
Clindamycin causes a relatively high incidence of hepatitis, rash and diarrhea in HIV-infected patients. Primaquine can only be given orally.
Atovaquone is well tolerated and acts on a metabolic pathway different from that of TMP–SMX. However, this drug is also only available orally, and does not appear to be as potent as TMP–SMX
Treatment-limiting toxicities with pentamidine treatment occur in 13–80% of patients
adverse effects, hypoglycemia and nephrotoxicity Pancreatitis and IDDM. Hypotension with short infusion time -Pancytopenia -Q-T prolongation
Untreated PCP In the beginning of the HIV epidemic, the mortality rate of PCP was reported to be 30–40% increasing to 70–90% among patients who progressed to respiratory failure
Recommendations for PCP prophylaxis
HIV-1 infection Lifelong unless CD4 count >200 × >3 months due to ART
Kidney heart -lung liver transplant minimum 6 month after transplantation
Antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase
DHPS catalyzes the condensation of p-aminobenzoic acid (PABA) and hydroxymethyl dihydropterin–pryophospate to produce dihydropteroate, which is later converted to dihydrofolate by dihydrofolate synthase. Subsequently, dihydrofolate is reduced by dihydrofolate reductase (DHFR) into tetrahydrofolate
Sulfa drugs are structural analogs of PABA and inhibit DHPS
Sulfonamide Resistance
widespread use of sulfa drugs for prophylaxis of PCP
DHPS mutations have also been increasingly found in patients without any previous exposure to sulfa drugs, suggesting person-to-person spread of mutant strains.
On the basis of a genetic analysis of multiple loci, it appears that the mutations arose independently in multiple strains of Pneumocystis
Moreover, even in studies reporting an association of DHPS mutations with failure of sulfa therapy, the majority of patients with mutant DHPS strains have been successfully treated with trimethoprim– sulfamethoxazole or dapsone–trimethoprim.
These observations suggest that the currently identified DHPS mutations may confer only low-level sulfa resistance, allowing PCP to occur in the setting of prophylactic doses of sulfa drugs, that is overcome by the higher doses used for therapy. Given that Pneumocystis has already demonstrated an ability to mutate under antibiotic pressure, a major concern is that additional mutations may develop that produce high-level resistance.
DHFR Resistance
several studies have reported DHFR mutations
For the human Pneumocystis derived DHFR yeast strain, trimethoprim and pyrimethamine were both weak inhibitors, with IC50s in the micromolar range; trimetrexate was about 10- and 40-fold more potent than trimethoprim and pyrimethamine, respectively Given that trimetrexate is much more potent against PCP than trimethoprim in vitro, the combination of trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim plus sulfamethoxazole. However, there are currently no clinical data to support this.Limitations to the study of drug resistance in Pneumocystis
Atovaquone
. is structurally similar to the mitochondrial protein ubiquinone (coenzyme Q), and competitively binds to the cytochrome bc1 complex.
Binding of atovaquone to the ubiquinol oxidation pocket of the bc1 complex and the Rieske iron–sulphur protein disrupts electron transport and leads to collapse of the mitochondrial membrane potential
Eventually, this presumably results in the depletion of ATP within Pneumocystis and leads to killing of the organism
Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii and Pneumocystis.
In vitro studies of Plasmodium and Toxoplasma show that these mutations confer resistance to atovaquone.
Since Pneumocystis cannot be propagated in vitro, similar susceptibility testing cannot be done.
Similar mutations in other microorganisms are associated with resistance to atovaquone.
Limitations to the study of drug resistance in Pneumocystis Compared to other pathogenic fungi,
In spite of many attempts there exists no in vitro culture system for propagation of Pneumocystis. The absence of a culture system precludes standard susceptibility testing and has greatly limited the understanding of many fundamental aspects of the organism and impeded investigations into the mechanisms of drug resistance.
clinical resistance is classically defi ned as the persistence or progression despite the administration of appropriate antimicrobial treatment.
Studies using repeat bronchoscopy during and immediately after successful treatment of PCP have shown that clearance of organisms is slow, with approximately half of patients still harboring Pneumocystis at the end of three weeks of treatment in spite of a successful treatment response
Although infection is eventually cleared and the viability of organisms detected at the end of treatment is uncertain, it is clear that the detection of organisms during or at the end of treatment cannot be interpreted as a proxy for resistance. Second, host infl ammatory response, rather than resistance to antimicrobial drug treatment, may cause an apparent absence of response to treatment.
Clinical resistance has been investigated by genotyping of P. jirovecii isolates from patients who develop PCP in spite of prescribed chemoprophylaxis. However, in most studies assessment of adherence to prophylaxis has been based on chart reviews, which may fail to disclose nonadherence to a drug regimen.
The likelihood of developing P. jirovecii resistance within a patient is likely to be higher with inadequate or interrupted dosing. Hence, in theory resistance mutations could be markers of poor adherence, rather than the direct cause of treatment failure
Level of evidence:
level V
I like your analysis of the level of evidence and a very detailed summary.
Would have any personal experience of sulfa resistance of PCP?
Introduction
Pneumocystis jirovecii is a fungus that causes interstitial pneumonia mainly in immunosuppressed patients (HIV, SOT, and BMT) and whose number of cases is reduced when using chemoprophylaxis, where the main drug is sulfa drugs.
This document is a narrative review, with level of evidence V.
Organism
Originally identified in different animals by Chagas and Carini. Jiroveci later described it in humans. Due to its intrinsic resistance to classic antifungals, it was not established as a fungus, but with the introduction of DNA, its phylogenetics confirms it in this kingdom.
Transmission and Infection
It is difficult to perform cultures, but there are molecular methods using RT PCR and serologies that may suffer interference from the environment or the immunological status of the patient. That’s why there are two theories of reactivation of the disease and new airborne contamination. Lung and alveolus tropism can trigger sexual replication.
Drug treatment
The drugs of choice are based on sulfa drugs, but in their absence, whether due to resistance or intolerance, less effective medications may be available. Antifungals have intrinsic resistance, the alternatives being Atovaquone, aerosolized Pentamidine, or combinations of sulfa drugs.
Prophylaxis
CD4 values below 200, primary immunosuppression, use of anti-lymphocytes, and high doses of corticosteroids are situations that require prophylaxis.
Treatment
The time depends on the patient’s immunosuppression. CMV co-infections or need for anti-lymphocytes for a rejection or graft disease.
Pneumocystis mutations have brought greater resistance to its pharmacological treatment.
Alternative regimens without sulfates use Clindamycin, Primaquine, Atovaquone and their combinations.
Conclusion
The limitation in performing cultures for a broad investigation of pharmacological sensitivity and its mutations hinders a broader study of pharmacoeffectiveness against Pneumocystis. HIV infections and inappropriate use of Sulfas have increased this resistance.
Would have any personal experience of sulfa resistance of PCP?
No, Professor. But it is frequent drug intolerance
Introduction:
Pneumocystis jerovecii is an opportunistic fungus that causes pneumonia in immunocompromised patients who are not receiving prophylaxis.
the organism is everywhere, primary infections occur in childhood mostly with upper respiratory tract symptoms, then become latent till profound immunosuppression.
recent airborne infection may also occur.
Drug treatment:
Most traditional antifungal agents have no activity against Pnemocystis.
Regimens for prophylaxis:
Duration of prophylaxis
PKT: minimum is 6 months, extended prophylaxis depends may be needed depending on the clinical situation.
HIV infection: lifelong prophylaxis unless CD4 count >200 for > 3months due to Antiretroviral therapy
First choice
Trimethoprim–sulfamethoxazole 1 DS or SS daily
Alternatives
– Trimethoprim–sulfamethoxazole 1 DS three times per week
– Dapsone 50 mg twice daily or 100 mg
twice weekly
– Pentamidine aerosolized 300 mg monthly via nebulization
– Atovaquone 1,500 mg daily
– Pyrimethamine 25–75 mg qd
plus Sulfadiazine 0.5–2.0 g q6h
Drug regimens for the treatment:
1st choice, TMP/sulfamethoxazole:
– IV:5mg/kg/TMP with 80 mg/kg sulfamethoxazole every 8 hrs
– Oral: 2-tab DS every 8 hrs
– S/E: anemia &neutropenia
Rash & fever
Increase creatinine, interstitial nephritis & hyperkalemia
Hepatitis & anaphylactoid reaction.
– Advantages:
Superior efficacy, inexpensive, oral & IV
Alternatives:
– Dapsone plus trimethoprim (oral only, inexpensive, S/E: cause haemolysis in G6PD deficiency, rash, nausea, vomiting, methemoglobinemia & leukopenia)
– Clindamycin plus primaquine (oral 300-50 mg every 6 hrs or IV 30 mg daily) (primaquine is oral only, can cause hemolysis in G6PD deficiency)
– IV pentamidine4mg/kg/d (highly effective but toxicity is common, S/E: hypoglycemia, nephrotoxicity, pancreatitis, hypotension if short time infusion, pancytopenia &Q-T prolongation)
– Oral Atovaquone 750 mg BID (well tolerated, expensive)
– Adjunctive therapy with prednisolone 40 mg twice daily (standard care for moderate or severe disease & if hypoxemia <70 mmhg on room air)
Resistance:
Resistance develops due to the widespread use of PCP prophylaxis. The clinical effects of mutations till now seem mild. It can cause failure to low-dose supfaprophylaxis but high dose still will be effective.
It is possible if more mutation will happen it will cause resistance to high-dose TMP/SMX.
Conclusion:
Resistance to high-dose TMP/SMX may occur with further mutations.
The completion of the Pneumocystis Genome Project, which was initiated in 1997, will be a significant step forward. Complete physical maps and gene sequences are being determined for P. carinii’s genomes. These data will facilitate the identification of new polymorphic regions and drug targets, and may eventually lead to the development of a culture system.
level of evidence:
level V
I like your analysis of the level of evidence, and summary.
Would have any personal experience of sulfa resistance of PCP?
Please summarise this article
1 Introduction
·PCP is an opportunistic fungus that causes pneumonia in immunocompromised individuals,
· PCP is now the most common AIDS-defining diagnosis in industrialized countries.
·PCP has declined due to chemoprophylaxis and HIV-1 antiretroviral regimens but remains a serious opportunistic infection in heavily immunosuppressed patients..
2 The Organism
·Pneumocystis was first identified in humans in 1942 by van der Meer and Brug, and Jirovec in 1952 identified it as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
·Pneumocystis was previously classified as a protozoon, but phylogenetic analysis in 1988 placed it in the fungal kingdom.
·Pneumocystis is an ancient organism without any close relatives, suggesting it is an early divergent line in the fungal kingdom.
·Pneumocystis is a broad family of organisms with species specificity among its mammalian hosts, with greater genetic divergence than other fungi.
3 Transmission and Infection
·Early childhood is the most common age for P. jirovecii primary infection, which has a uniformly high prevalence across all geographic regions and an unidentified environmental cause.
·Results from PCR analysis point to a more nuanced picture of infection and transmission.
·Nonetheless, it is assumed that the organism becomes dormant and appears clinically if the patient develops substantial immunosuppression. Initial infection might result in temporary illness.
·Several Pneumocystis jirovecii strains can infect humans, causing latency with a wide range of species.
·Nonhuman animals are not the source of Pneumocystis since there is no cross-species infection and each animal species has a separate strain of the disease.
·Pneumocystis has a distinct lung tropism, although extrapulmonary areas are seldom affected by the illness.
·The main surface glycoprotein (MSG), which is highly variable, repetitive, and dispersed throughout all chromosomes, is the mechanism by which Pneumocystis clings to the surface of type I alveolar cells.
· This antigenic variant most likely works to prevent the host’s immunological reaction.
4 Drug Treatment
·Antifolate medications, diamines, atovaquone, and macrolides are the main pharmacological classes utilized in the treatment and prevention of PCP.
·The majority of conventional antifungal medications have little effect in Pneumocystis.
·The first medication to successfully treat PCP was pentamidine isethionate in 1958.
Research has shown that the drug combination trimethoprim-sulfamethoxazole (TMP-SMX) is efficient for treating and preventing PCP in both mice and humans.
·Several medications, such as sulfadiazine with pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone, and aerosolized pentamidine, have had therapeutic efficacy.
·Not all medications that work well for treatment also work well for chemoprophylaxis.
·Azithromycin, doxycycline, and capsaicin may be used to treat human illness.
5 Prophylaxis
·Those with HIV who have PCP have cell counts of more than 200 cells/mm3.
·Those with HIV who are taking corticosteroids, receiving chemotherapy, or have congenital immunodeficiencies are at risk of getting PCP.
·CD4 numbers are not a trustworthy indicator.
·When some supporting data was published, PCP prophylaxis became the norm of therapy for HIV-infected patients with CD4 levels under 200 cells/mm3 in 1989.
·In transplantation, high-dose steroid treatment and/or high-dose chemotherapy may confer a high risk of PCP.
·TMP-SMX is the most efficient, cheap, and widely used regimen for PCP prevention, and is well tolerated by non-HIV patients. 80/400 mg TMP–SMX daily is equally effective and associated with fewer side effects than 160/800 mg daily.
6 Treatment of PCP
·Untreated PCP always results in death.
·Early diagnosis, adjuvant corticosteroids, increased diagnostic and therapeutic capabilities, and enhanced ICU supporting measures have all contributed to a drop in PCP death rates.
·Patients and healthcare workers must be aware that PCP may first appear as mild symptoms such as dyspnea, coughing, or low-grade fever and should seek treatment as soon as possible.
·The most successful PCP therapy is antifolate medications.
·To create dihydrofolate, which is then converted into tetrahydrofolate by DHFR, DHPS catalyzes the condensation of PABA and dihydropteroate.
·While DHFR inhibitors are more effective than other commercially available sulfonamide formulations, sulfamethoxazole is nonetheless just as strong.
·Similar to pentamidine in effectiveness, TMP-SMX also causes medication toxicity in 24-57% of HIV-infected individuals.
·Rash, fever, leukopenia, renal calculus development, anaphylactoid responses, and pancreatitis are among the side effects of trimethoprim.
·Pentamidine is linked to a high frequency of toxicities, including leukopenia, nephrotoxicity, and hypoglycemia, some of which are treatment-limiting. 13–80% of individuals have toxicity that is treatment-limiting.
· Atovaquone, clindamycin-primaquine, and dapsone-pyrimethamine are substitutes for TMP-SMX and pentamidine. There is no longer a commercial supply of trimetrexate.
·TMP-SMX and clindamycin-primaquine appear to function differently, however, both studies lacked sufficient power.
·For moderate PCP, atovaquone is a decent substitute for TMP-SMX, although it can only be taken orally and doesn’t seem to be as effective.
·All patients with PaOs 70 mm.gh should get supplementary steroids, which can lower mortality in patients with severe illness.
7 Sulfonamide Resistance
·Since TMP-SMX and dapsone are commonly used to treat and prevent PCP in HIV patients, there is concern that P. jirovecii may acquire sulfa (sulfonamide or sulfone) resistance, which would increase trimethoprim-sulfamethoxazole resistance among isolates of Staphylococcus aureus and Enterobacteriaceae.
·Sulfonamide resistance is brought on by changes in the main sequence of the DHPS gene in pathogens including Escherichia coli, Neisseria meningitide, Mycobacterium leprae, and Plasmodium falciparum.
·Non-synonymous DHPS mutations in Pneumocystis jirovecii, which occur at nucleotide positions 165 and 171, were initially discovered by Lane and colleagues.
·It is believed that the mutations change the way Arg56 binds to sulfa medications, lowering its affinity and lowering Arg56’s sensitivity to sulfa medicines.
·The lack of functioning enzymes and the inability to grow Pneumocystis make it difficult to show resistance to sulfa exposure.
·The incidence and importance of DHPS mutations in Pneumocystis jirovecii have been examined in a number of clinical trials.
·Up to 69% of isolates revealed a significant regional variation.
·Clinical isolates collected before the early 1990s had very few mutations, but subsequently there seems to have been a rise in their occurrence.
·A transition from wild-type to mutant DHPS occurred in five of seven individuals who had undergone therapy or secondary prophylaxis with trimethoprim-sulfamethoxazole or dapsone in a genotyping analysis of 13 European HIV patients with recurring episodes of PCP. This implies that sulfa drug pressure may be used to select DHPS mutations in vivo.
·The degree of this connection between DHPS mutations and low-dose sulfa prophylaxis failure is unclear. The effectiveness of trimethoprim-sulfamethoxazole when taken consistently is currently supported by clinical data.
8. DHFR Resistance·Diaminopyrimidines are competitive inhibitors of DHFR, essential for the biosynthesis of purine/pyrimidine nucleotides, thymidylate and amino acids.
·Human Pneumocystis-derived DHFR had a 10-fold increase in sensitivity to trimetrexate and trimethoprim.
·Trimetrexate and sulfamethoxazole may be a more potent combination than trimethoprim and pyrimethamine for PCP prevention and treatment, but only few DHFR mutations have been identified in Pneumocystis DHFR.
Limitations of the study:
·Due to the absence of a culture system and the lack of a comprehensive understanding of metabolic pathways, studying medication resistance in Pneumocystis has proven difficult.
· Another issue is that there is no accepted definition of clinical failure.
· The contribution of nonadherence in presumed failure of prophylaxis may be difficult to assess.
9. Atovaquone
·Atovaquoneis used to prevent and treat disease caused by P. jirovecii, Plasmodium spp. Toxoplasma gondii and Bebesia spp.
·Mutations of the cytochrome b gene have been identified in Plasmodium spp., Toxoplasma gondii, and Pneumocystis.
·Similar vitro susceptibility testing cannot be done like Plasmodium spp., Toxoplasma gondii
·Survival from PCP did not differ between patients with or without mutations. Overall, these findings are consistent with the development of atovaquone resistance after selective pressure is exerted.
10 Pentamidine and Clindamycine–Primaquine·Pentamidine and clindamycine-primaquine are used to treat PCP, but resistance is unknown.
11 Conclusion
·P. jirovecii mutations have arisen due to selective pressure from PCP prophylaxis, but their clinical impact is minimal.
·The most effective and affordable treatment for PCP is not affected by the disclosed mutations.
·The Pneumocystis Genome Project is a promising step towards understanding drug resistance.
===================================================
What is the level of evidence provided by this article?
Narrative Review. Level V
I like your analysis of the level of evidence, and summary. I appreciate the mention of limitations.
Would have any personal experience of sulfa resistance of PCP?
Drug Resistance in Pneumocystis jirovecii
1-Please summarize this article:
Introduction:
Pneumocystis jirovecii is a fungus that leads to Pneumocystis pneumonia (PCP) in immunocompromised patients as AIDS cases.
Now days the incidence is decreasing compared to late 1980s in HIV patients due widespread use of prophylaxis and the availability of anti-retroviral treatment.
The organism:
Initially it was thought to be a protozoa.
In 1952 Jirovec was the first to discover it as human pathogen.
Recently it is classified as a fungi with a different characteristics, it has only one copy of ribosomal RNA, fragile cell wall, and had minimal no ergosterol.
Transmission & infection:
P.Jirovecii are ubiquitous but the source is not clear.
Primary infection occurs in early childhood worldwide.
Transmission may occur through reactivation or recent exposure to an airborne pathogen.
P.JP enters the lung and adhere to type I alveolar cells by the major surface glycoprotein (MSG) which is a highly polymorphic protein. This is to avoid host responses.
Drug Treatment: important milestones:
Pentamidine in 1958
Sulfadoxine plus pyrimethamine 1960s
Sulfadiazine plus pyrimethamine in 1966
Trimethoprim plus sulfamethoxazole (TMP-SMX) between 1974 & 1977
Other agents: atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone, and aerosolized pentamidine
Prophylaxis:
Primary; HIV with oral candidiasis or CD4 < 200
Secondary; all patients after an episode of PCP
At the TMP-SMX is the standard care for prevention against PJP
Treatment of PJP:
PJP is fatal If Untreated => respiratory failure and death, so early suspicion and
recognition of the disease is very important to save life, as in immunocompromised
patient with low grade fever and dry cough with shortness of breath and hypoxia on
exertion => raise suspicion of PJP so early diagnosis and treatment should be started
soon to reduce the morbidity & mortality.
TMP-SMX:
The treatment of choice is antifolate drugs, which act by blocking de novo.
synthesis of folates through inhibition of dihydroperoate synthase (DHPS)
or dihydrofolate reductase (DHFR).
Toxic in 24 to 57% of HIV after 7 days.
May cause rash, fever, leukopenia, hepatic toxicity, hyperkalemia, interstitial nephritis and renal stones.
Pentamidine:
Administer by slow IV infusion over a period of at least 60–120 minutes at a final
concentration of administration not to exceed 2 mg/ml. Maintain patient lying down
during infusion. Rapid infusion causes hypotension. If hypotension occurs, increase
infusion time to 2–3 hours Nephrotoxic
Pancreatic toxicity; hypoglycemia
Hematologic toxicity; leukopenia
Dapsone-trimethoprim:
Oral drug, effective.
cross-react with sulfa in 50% of allergic patient.
Clindamycin-primaquine:
Clindamycin may cause rash, hepatitis, & diarrhea in HIV subject.
Atovaquone:
Oral medicine not effective as TMP-SMX.
May be use in mild disease when TMP-SMX is contraindicated or not available.
Adjunct therapy:
Hypoxia :
Oxygen saturation deteriorated in 1st 4-5 days of therapy due to death of organism
induced by the drug which leads to more inflammation which can be reduced by steroid,
so, adjunctive steroids are now recommended for all patients with severe disease (PaO2
< 70 mmgh).
Steroids if POa is < 70 mmHg i.e., moderate to severe disease.
Sulfonamide resistance:
Previous exposure to sulpha drugs due to prophylaxis.
DHPS mutations at nucleotide positions 165 and 171 and amino acid change at positions
55 & 57.
Occurs in 7 to 69% of isolates.
No effects on double strength TMP-SMX.
DHFR resistance:
May be due to selective pressure by DHFR inhibitors but so far, no strong evidence.
Atovaquone:
It works by depletion of ATP in the organism leading to death.
Resistance may occur through mutation of cytochrome b gene.
Pentamidine and Clindamycin-Primaquine:
Resistance mechanisms are not yet discovered.
Limitation to the study of drug resistance in pneumocystis jirovecii;
Pneumocystis jirovecii cannot be cultured.
No definition of clinical failure in pneumocystis jirovecii.
Severe inflammatory response may cause treatment failure and not necessarily drug resistance.
Non-adherence issues in presumed failure of prophylaxis may be difficult to assess.
Conclusion:
Sulfa and atovaquone drug resistance mutations occurred in P. jirovecii due to their
widespread use of PCP prophylaxis meanwhile their actual clinical effect is not much
Complete physical maps and gene sequences are being determined for the genomes of P. carinii.
Mechanisms of drug resistance and identification of new molecular targets are continuing under investigations.
What is The Level Of Evidence Provided By This Article?
Level V === Narrative Review
I like your analysis of the level of evidence, and summary.
Would have any personal experience of sulfa resistance of PCP?
II. Drug Resistance in Pneumocystis jirovecii
===================================================================
Please summarise this article.
1- Introduction
2- The Organism
3 -Transmission and Infection
4-Drug Treatment
5- Prophylaxis
6- Treatment of PCP
7- Sulfonamide Resistance
8 – DHFR Resistance
8.1 Atovaquone
9- Pentamidine and
Clindamycine–Primaquine
Limitations to the study of drug resistance in Pneumocystis
10 -Conclusion
====================================================================
What is the level of evidence provided by this article?
I like your analysis of the level of evidence, and summary.
Many thanks Prof. Sharma
-Introduction
Pneumocystis jirovecii is a fungus that leads to Pneumocystis pneumonia (PCP) in immunocompromised patients as AIDS cases.
PCP chemoprophylaxis and potent HIV-1 antiretroviral regimens lowered it’s incidence.
Organism
Pneumocystis was first notified as a human pathogen in 1952 when Jirovec discovered it in premature malnourished infants causing interstitial plasma cell pneumonia .
The organism has been categorized as a fungus entitled under the Archiascomycetes
In 1994, P. carinii f.sp. hominis is named for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats and in 2002 the organism infecting humans was renamed Pneumocystis jirovecii.
Primary infection with P. jirovecii happens in early childhood, the clinical infection results from reactivation in immunocompromised cases
Transmission
It was supposed that primary infection can lead to respiratory tract infection or sudden infant death syndrome then the organism remains latent and is reactivated when the host is immunocompromised.
It was supposed that multiple strains of P.jirovecii can infect the individual on multiple occasions.
The environmental source of Pneumocystis is unknown.
It has specific tropism for the lung.
It adhere to the surface of type I alveolar cells after inhalation of the organism , this process is mediated by the major surface glycoprotein (MSG) which harbours extensive variable antigens as a defensive mechanism in front of host immunity .
It was suggested that the organism has a sexual replication cycle that reacts to environmental pulmonary changes .
Drug treatment
Classic antifungal drugs are inactive against Pneumocystis pneumonia
Antifolate drugs, diamines, atovaquone, and macrolides are the main drug groups used for prophylaxis and treatment.
TMP–SMX is the treatment and prophylaxis of choice.
Other therapeutic drugs include sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Dapsone, dapsone–trimethoprim, atovaquone and aerosolized pentamidine are used for prophylaxis.
Prophylaxis
PCP risk increases with lower CD4 counts. 200 cells/mm3is used as an indicator of susceptibility for PCP in HIV infected cases meanwhile patients can develop PCP at higher CD4 counts .
Immunocompromised status congenital immunodeficiency , long standing steroids intake ,chemotherapeutics render the patient at risk for PCP.
TMP–SMX prophylaxis can prevent PCP occurrence.
HIV-1 infected patients with oral candidiasis or a CD4 count < 200 cells/μL, need primary prophylaxis. Cases with an episode of PCP need secondary prophylaxis .
TMP–SMX prophylaxis is tolerated by non-HIV patients opposite to HIV cases particularly with lower doses or intermittent regimens.
PCP treatment
PCP mortality rates decreased to 5–15%.
Adjuvant corticosteroids given to patients with moderate-to-severe PCP with PaO2< 70 mmHg improves outcome.
Early detection of mild symptoms and immediate introduction of therapy without delay improves the prognosis.
Chemotherapy choice is crucial.
The most efficient drugs for PCP treatment are antifolate drugs which acts through inhibition of dihydroperoate synthase (DHPS) or dihydrofoslate reductase.
TMP–SMX
It’s intake was associated with better survival compared to pentamidine.
TMP–SMX adverse effects can happen after 1 week of drug intake including rash, fever , leukopenia ,hepatotoxicity , interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis .
They are not life threatening although fatal Stevens–Johnson syndrome was reported .
Pentamidine
Slow intravenous infusion is the best tolerated route for pentamidine adminstartion.
It’s side effects include nephrotoxicity ,pancreatic injury ,leucopenia ,long OT interval ,torsade de pointe.
Dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone are another therapeutic options.
Clindamycin has multiple adverse effects as hepatitis, rash and diarrhea.
Primaquine and Atovaquone are only orally given.
Dapsone–pyrimethamine was suitable for mild-to-moderate PCP and atovaquone for mild PCP.
Recommendation of therapy for HIV-negative cases is 2 weeks and HIV positive patients for 3 weeks.
Adjunctive steroids are recommended for all patients with severe disease (PaOs< 70 mmgh).
Sulfonamide resistance
Extensive use of sulfa drugs for therapy and prophylaxis for PCP in HIV cases ,malaria and bacterial infection in Africa increased resistance rate .
In E coli, Neisseria meningitidis, Mycobacterium leprae and Plasmodium falciparum, sulfonamide resistance is caused by mutations in the primary sequence of the DHPS gene.
Double DHPS mutations Thr55Ala and Pro57Ser result in an absolute requirement for PABA, leading to resistance with altered substrate binding.
Previous exposure to sulfa drugs for prophylaxis had been associated with DHPS mutations .
DHPS mutations was detected in cases without any previous exposure to sulfa drugs, raising the possibility of person-to-person spread of mutant strains.
The actual drug resistance association with prescribed prophylaxis is unknown.
In spite of presence of mutant DHPS strains, the efficacy of trimethoprim–sulfamethoxazole prophylaxis is still noticed.
A study detected failure of pyrimethamine–sulfadoxine prophylaxis association with the Pro57Ser mutation.
DHPS mutations was associated with dapsone prophylaxis.
Therefore DHPS mutations contribute to low-level sulfa resistance and failure of second-line sulfa
prophylaxis.
Lack of compliance on chemoprophylaxis is responsible for PCP outbreak.
The effect of DHPS mutations on response to therapeutic, high-dose trimethoprim was controversial.
DHFR resistance
The combination of trimetrexate and sulfamethoxazole are more efficient in vitro than the combination of trimethoprim plus sulfamethoxazole.
Relatively few DHFR mutations are detected in Pneumocystis DHFR inspite of the extensive use of trimethoprim and sulfamethoxazole for prevention and treatment of PCP,
There is no evidence that extensive trimethoprim or pyrimethamine use ,leads to clinical significant resistance to DHFR inhibitors.
Atovaquone
It is used for prophylaxis and treatment of diseases caused by P. jirovecii, Plasmodium spp., Toxoplasma gondii and Bebesia spp.
Mutations of the cytochrome b gene detected in Plasmodium spp., Toxoplasma gondii and Pneumocystis in vitro studies were associated with resistance to atovaquone.
Pentamidine and Clindamycine–Primaquine
They are used for prophylaxis and treatment of PCP, but possible resistance mechanisms are under study
Conclusion
Sulfa and atovaquone drug resistance mutations occurred in P. jirovecii due to thier widespread use of PCP prophylaxis meanwhile their actual clinical effect is not much.
No evidence that DHPS mutations is accompanied with significant resistance to high dose of sulfa treatment.
Pneumocystis Genome Project completion and physical maps and gene sequences are studied for the genomes of P. carinii which will be crucial for detection of new polymorphic regions and drug targets.
-level of evidence is V
I like your analysis of the level of evidence, and summary.
Please summarize this article.
Introduction
The organism
Transmission & infection
Drug Treatment: important mile stones
Prophylaxis
Treatment of PJP
Early diagnosis is essential due reduce the morbidity & mortality.
Do not wait until late.
1.TMP-SMX
2 Pentamidine
3.Dapsone-trimethoprime
4.Clindamycin-primaquine
5.Atovaquone
6.Adjunct therapy
Sulfonamide resistance
DHFR resistance
Atovaqupone
Pentamidine and Clindamycin-Primaquine
Limitation to the study of drug resistance in pneumocystis jirovecii;
What is the level of evidence provided by this article?
Thankyou well done.
Thnxs prof
Drug Resistance in Pneumocystis jirovecii
Introduction
1- Pneumocystis jirovecii is fungal organism cause pneumonia PCP in immunocompromised patients, previously called Pneumocystis carinii.
2- Its incidence increased with the era of definite diagnosis of HIV.
3- Its incidence decrease dramatically with era of chemoprophylaxis against PCP, and also with introduction with HIV antiretroviral treatment.
Organism
1- It was identified early in the last century in guinea pigs by Chagas and in rat lungs by Carini They considered the organisms as a new form of Trypanozoma cruzi.
2- Pneumocystis was first described in humans in 1942 by two Dutch investigators, van der Meer and Brug, who described it in three cases.
3- Pneumocystis was fi rst established as a human pathogen when Jirovec in 1952 identified the organism as the cause of interstitial plasma cell pneumonia among premature or malnourished infants in orphanages.
4- In the twentieth century, Pneumocystis was considered as a protozoon and single species based on its morphologic features, but has resistance to classical antifungal agents and the effectiveness of certain drugs used to treat protozoan infections.
5- in 1988, analysis of ribosomal RNA (rRNA) sequences and observations of genome size placed P. carinii in the fungal kingdom was done. Phylogenetic data suggest that Pneumocystis is an ancient organism without any close relatives, Pneumocystis species represent an early divergent line in the fungal kingdom.
6- The organism has recently been placed in a group of fungi entitled the Archiascomycetes. In contrast to most other fungi, Pneumocystis possesses only one copy of the nuclear ribosomal RNA locus, has a fragile cell wall and contains little or no ergosterol.
7- In 1994, an interim trinomial name change was adopted with the name P. carinii f.sp. hominis for Pneumocystis infecting humans and P. carinii f.sp. carinii for one of the two species infecting rats.
8- In 2002, because of the recognition of its genetic and functional distinctness, the organism infecting humans was renamed Pneumocystis jirovecii, in honor of Otto Jirovec, who was among the fi rst to describe the microbe in humans.
Transmission and Infection
1- Primary infection with P. jirovecii happens in early childhood with a uniform high incidence in all geographic areas, and suggest that P. jirovecii organisms are ubiquitous.
2- Organism becomes latent, and reactivated only in immunocompromised patients, and antibodies against it usually formed in the first year of life, also it may lead to sudden infant death.
3- The organism has specific tropism to the lung, where it exists, but may found in other organs.
4- When the organism inhaled, it attach to type 1 alveolar cells, this adherence is encoded by major surface protein in the organism which is abundant on its surface and it is polymorphic escaping immune response.
Drug treatment
1- In 1958, pentamidine isethionate was the fi rst drug used to successfully treat PCP.
2- In the 1960s, the combination of sulfadoxine and pyrimethamine was used.
3- In 1966, sulfadiazine and pyrimethamine were used.
4- Between 1974 and 1977, the combination of trimethoprim–sulfamethoxazole (TMP–SMX) is effective for both treatment and prophylaxis of murine and then human PCP.
5- TMP–SMX is as effective as intravenous pentamidine for therapy, and is still the treatment of choice.
6- TMP–SMX is the most effective chemoprophylaxis for PCP, and therefore the standard for prevention.
7- Other drugs have proven activity for therapy, including sulfadiazine plus pyrimethamine, atovaquone, clindamycin plus pyrimethamine, trimetrexate, dapsone and aerosolized pentamidine.
Prophylaxis
1- CD4 count is usually used as indicator for PCP susceptibility in HIV patients, if less than 200 , PCP can be developed but also can be developed in count more than 200, so it is unreliable marker for PCP in HIV patients.
2- Chemoprophylaxis used as a primary prophylaxis to HIV patient with CD4 less than 200 and can be interrupted at any time when CD4 raised more than 200 FOR 3 months after anti-retroviral treatment.
3- Secondary prophylaxis can be offered to all patients after attack of PCP.
4- TMP-SMX has much side effects in HIV patients than non-HIV patients like rash and myelosuppression.
5- In non-HIV patients like cancer, SOT, patients with high dose steroid, TMP-SMX can be given as a prophylactic therapy and it is well tolerated, cheap and available.
Treatment of PCP
1- Untreated PCP is fatal, respiratory failure and death is the end, so, early suspicion and recognition of the disease is very important to save life, as in immunocompromised patient with low grade fever and dry cough with shortness of breath and hypoxia raise suspicion of PCP so early diagnosis and treatment should be started soon.
2- The treatment of choice is antifolate drugs, which act by blocking de novo synthesis of folates through inhibition of dihydroperoate synthase (DHPS) or dihydrofolate reductase (DHFR).
3- TMP–SMX, Adverse effects generally occur after 7 days of therapy and most commonly include rash, fever and leukopenia. Hepatotoxicity characterized by elevated transaminases also occurs. There are cases of sulfamethoxazole-induced interstitial nephritis, renal calculus formation, anaphylactoid reactions and pancreatitis reported. Trimethroprim can be associated with hyperkalemia. These toxicities are usually not life threatening, although fatal cases of Stevens–Johnson syndrome have occurred.
4- Pentamidine is associated with a high frequency of toxicities, like hypotension and death, it is related to rate and route of administration, so, should be given as iv infusion, pentamidine is nephrotoxic and also has pancreatic toxicity.
5- dapsone–pyrimethamine, clindamycin– primaquine, and atovaquone.
6- Duration of treatment 2 weeks in non-HIV patients and 3 weeks in HIV patients.
7- Oxygen saturation deteriorated in 1st 4-5 days of therapy due to death of organism induced by the drug which leads to more inflammation which can be reduced by steroid, so, adjunctive steroids are now recommended for all patients with severe disease (PaOs < 70 mmgh).
8- Increase epidemic of HIV and other immunosuppressive state like cancer and SOT, and patients using high dose of steroid, all these increase need for PCP prophylaxis which also increase resistance to sulpha, so, increase chance to other drugs to be introduced.
level of evidence 5
Thankyou this is an exellent, comprehensive summary.