PCP is the most frequent and serious fungal infection for patients with autoimmune disorders. The incidence of PCP was about 50% in immunocompromised individuals, 20 to 40% in hematological malignancy patients, 5 to 15 % in transplant recipients and 2% in RA.
TMP-SMX has been observed to minimize the incidence of PCP in these patients.
As with other antibiotics,TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration dependent toxicity, necessitating the avoidance of excessive dosage.
In accordance with current dosing guidelines, the recommended therapy for PCP is high dose of TMP-SMX.
Patients receiving recommended high dose of TMP-SMX as first line treatment regimen had higher rates of adverse effects such as skin iirritation, GIT disturbances, bone marrow suppression, renal and hepatoxicity.
Thus requiring optimal dosing strategies of TMP-SMX, therefore to ensure drug safety and there is a high demand to review current evidence in patients with PCP with a focus on dose optimization strategies
Methods
Various databases were searched from Jan 2000 to Dec 2021 for articles in English, focusing on dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria .
Results
Thirteen articles from 857 met the Inclusion criteria for final analysis
Most of studies compared the high dose with the low dose TMP-SMX therapy for PCP
They found that a low dose of TMP-SMX provides satisfactory outcomes while reducing mortality rate and PCP associated adverse effects. This strategy reduces the economic burden of illness and enhances patients compliance .
This systematic review article
They analyzed 13 study (from (857 studies) that match the criteria of their main goal
Main goal of this study is to assess the current dosing strategy of
TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
the studies included PCP in HIV ,kidney transplant ,GCPD patients,rheumatoid arthritis
they recommended that low dose prophylaxis is the best option to avoid PCP infection and possible side effects from Sulfa-trimethoprime
but still need more RCTs for some patient populations like PCP emerging on TMP-SMX prophylaxis in HIV patients ,due to limited data available
This is a systematic search assessing the dosing guidelines of TMP-SMX in patients from 31 studies chosen out of 857 studies. The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group . Although the TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients. Moreover, the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors . Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts . A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia . Therefore, routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes. the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) . Alternative PCP prophylaxis includes one double strength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays . This practice may not provide desired clinical outcomes with the minimal risk of AEs. The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
Study backgroud
Databased from January 2000 to December 2021
Searched for PCP dose optimization of TMP-SMX – 13 studies meet the inclusion and exclusion (9 retrospectives, 2 RCT, 2 case reports)
Comparator: High vs Low dose TMP-SMX
Outcome: Low dose provide a satisfactory outcome – reducing mortality and PCP adverse outcome
Introduction:
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders. The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients
Methods:
Data Sources and Search Strategy The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, etc., were explored for articles in English from January 2000 to December 2021. Reference lists of relevant studies were screened for additional titles
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan. For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
-The incidence of PCP was more than 50% in immunocompromised patients. -The study aimed for dose optimization of TMP-SMX concluding that low dose of TMP-SMX provides satisfactory outcomes with low mortality rate and less side effects but large RCT are needed .
The article discusses the dosing strategy of trimethoprim-sulfamethoxazole (TMP-SMX) for the prevention and treatment of Pneumocystis carinii pneumonia (PCP) in patients with autoimmune disorders. PCP is a fungal infection that is common in immunocompromised patients, and it is a significant cause of morbidity and mortality. The incidence of PCP has been reduced in HIV-positive patients due to advances in diagnostic tools, management strategies, and preventive measures.
TMP-SMX, a combination of trimethoprim and sulfamethoxazole, has been shown to effectively reduce the incidence of PCP. However, the recommended high doses of TMP-SMX can lead to adverse events (AEs) such as skin irritation, gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity, and electrolyte disorders. Therefore, optimizing the dose of TMP-SMX is important to ensure its safety and effectiveness.
The study conducted a systematic search of relevant articles published from 2000 to 2021. A total of 13 studies were included in the analysis, including retrospective cohort studies, case reports, and randomized controlled trials. The studies evaluated the dosing strategy of TMP-SMX in various patient populations, including HIV-positive patients, patients with rheumatoid arthritis, non-HIV patients, kidney transplant recipients, and patients with G6PD deficiency.
Among the included studies, some compared low-dose regimens of TMP-SMX with high-dose regimens and found that low-dose therapy could be considered as a first-line treatment option for preventing PCP and its associated AEs. The low-dose regimen showed satisfactory outcomes in terms of reducing mortality rates and PCP-related AEs while also reducing the economic burden and improving patient compliance.
However, it is important to note that the study has limitations, such as the inclusion of studies from various countries with potential socio-demographic influences and a limited number of studies conducted after 2000. Therefore, further large-scale prospective studies are needed to provide more specific guidelines for dosing strategies in PCP prevention and treatment.
In conclusion, the study highlights the importance of optimizing the dose of TMP-SMX in the prevention and treatment of PCP. Low-dose regimens can be effective in reducing AEs and improving patient outcomes. However, more research is needed to establish clear dosing guidelines for different patient populations and to address the limitations of the current evidence.
level of evidence 3
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX. In randomized trials where various treatment regimen was compared for virus-associated PCP, patients receiving recommended high dose of TMP-SMX as a first-line treatment regimen had higher rates of AEs such as skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs .
Materials and Methods
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines .In total, 857 related published studies were identified from grey literature as well as electronic databases.A total of 13 articles met the inclusion criteria for final analysis . Of the 13 selected studies, nine were retrospective cohort studies two case reports and two randomized controlled trial (RCT).
Dosing Strategy of TMP-SMX in Selected Studies
Of 13 studies, four reported that patients having AIDS received TMP-SMX for prophylaxis, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency. Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen option to prevent occurrence and recurrence of PCP and PCP-associated AEs. Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy Similarly, Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs. Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.In both RCTs, no cases of PCP were documented up to weeks 24 and 52 in low dose group.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
What is the level of evidence provided by this article?
Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the morbidity and mortality of patients, especially those with autoimmune disorders, thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX). Therefore, to ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies; (2) Methods: Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs); (3) Results: Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan; (4) Conclusions: The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan. For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
What is the level of evidence provided by this article?
Pneumocystis pneumonia is a an opportunistic pathogen that affects immunocompromised patient. The incidence is 2-15% IN transplant recipients and about 40% in hematological malignancy cases. Co-trimoxazole is the treatment of choice and the optimum dosage & duration remain questionable .Co-trimoxazole if not given in the proper dose is not effective and may result in antibiotic resistance. High dose of TMP-SMX may cause rashes ;the most common side effect, followed by hepatotoxicity& bone marrow suppression.
TMP-SMX has 2 ingredients: Sulfamethoxazole 75-100 mg/kg/day + trimethoprim 15- 20mg/kg/day for 2 to 3 weeks….
Databases were studied from Jan 2000 to Dec 2021 for articles in English that focused on TMP SMX dose optimization.
13 studies met inclusion criteria for final analysis;9 retrospective studies, 2 case reports & 2 RCTs. Mainly, studies compared high dose with low dose TMP – SMX therapy for PCP. They concluded that low dose TMP-SMX therapy was equal with regard to outcomes in addition to reducing the mortality and reducing the adverse events.
The Cochrane meta analysis revealed a decrease in incidence of PCP up to 91% and mortality reduction up to 83% in comparison to the control group.
It was concluded that prophylactic treatment involved in the immunosuppression regimen, resulted in diminishing the economic burden.
Routine PCP prophylaxis is advised in 1-6 months following transplantation .The study highlighted predisposing factors for PCP eg CMV infections, repeated graft rejections.
Various socio economic categories were included in the study.5 out of 13 studies compared low dose with high dose TMP-SMX protocol with low dose protocol; with the final conclusion that low dose protocol is equally effective as high dose protocol.
●This article is to ensure the safety of TMP-SMX
●there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies
(2) Methods:
■Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
■The data were collected in a specific form with predefined inclusion and exclusion criteria.
■ The quality of each article was evaluated using a (NOS) for retrospective studies, (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
(3) Results:
○Thirteen studies met the inclusion criteria for final analysis.
○Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
○Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
○We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
○This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan;
●The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91%and decrease in mortality rate up to 83%when compared to the control group
prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients.
■Routine PCP prophylaxis is recommended
the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period
■Other predisposing factors include
1- concomitant cytomegalovirus,
2- infections,
3- number of graft rejection episodes,
4- and low CD4+ count lymphocyte counts
5- PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3 [
● The first-line prophylactic agent is
1– one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day)
2– or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
● Alternative PCP prophylaxis includes one
1– double strength TMP-SMX tablet thrice per week
2– administration of dapsone either alone or in combination with leucovorin
3– and pyrimethamine, atovaquone, or pentamidine sprays].
♡The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis Nowadays, patients with PCP differ from the patients that were treated 30–40 years ago
♤The standard doses result in an absolute increase of 18% in the incidence of grade ≥3AEs
♡However, step-down therapy may be a worthy in exploring approaches to improve clinical outcomes This study does have several limitations:
1– Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics
2– Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
3– Thirdly, due to small sample size, this may result in false-negative or false-positive findings.
●Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
● However, Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy ● Similarly,Schildetal. Reported that the patients received an intermediate-dose TMP-SMX (TMP10–15mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AE sand this regimen was deemed to be safe and effective in patients with various immune dysfunctions
●Nakashima et al. reported that the total AEs rate was 58.3%in the low dose group and in conventional-dose group 72.4%of patients experienced AEs
●Similarly, another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group(25.0%)
● A study documented that tTMP-SMX was reported to cause hemolysis in patients with G6PD deficiency
In both RCTs, no cases of PCP were documented up to weeks 24and
4. Conclusions
□The low dose of TMP-SMX provides satisfactory outcomes .
□This strategy also reduces overall economic burden and enhances patients’ compliance.
□Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale,
□ prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%.Pneumocystis jirovecii has 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, primary infection occurs mostly in childhood – manifest with respiratory infection and infant death syndrome, due to its specific tropism for lung parenchyma and alveoli. Life cycle of PCP is not completely understood Mode of transmission – both sexual and asexual cycles proposed; sexual replication with in the lungs; environmental changes due to immunosuppression.
Drug treatment; Pentamidine was the first drug to treat PCP Anti-folate, diamines, atovaquone, and microlides. sulfadoxine and pyriamid, TMP-SMX dapsone, pentamidine, clindamycin plus pyrimethamine. Prophylaxes;. Chemoprophylaxis was initially used . 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
Introduction
The most frequently fatal fungal infection for autoimmune people is Pneumocystis carinii pneumonia. Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%. Immunosuppressive patients die mostly from PCP critical symptoms as tachycardia, hypoxia, tachypnea, shortness of breath, etc. Hence, PCP is an HIV hallmark. Due to enhanced diagnostic technologies, early diagnosis, intensive care management strategies, and preventive measures, PCP in HIV-positive patients has decreased in recent years. Materials and Methods
PRISMA recommendations were used for the systematic search of TMP-SMX dosage guidelines in patients.
This review covered studies on TMP-SMX dose for PCP incidence or recurrence. Based on titles and abstracts, all studies involving TMP-SMX clinical outcomes were screened.
The selected studies provided author, year, design, sample size, patient characteristics, dosage approach, clinical outcomes, and findings. Results
Among a total of more than 857 papers screened, only 13 matched the inclusion criteria for evaluation. Of the 13 selected studies, nine were retrospective designs, two case reports, and two RCTs. Based on the NOS quality of studies evaluation, eight studies received a total score of 7, one study had a score of 6, and four studies received a score of 8. The average score for the included studies was 7. The Cochrane bias test determined that the majority of RCT domains posed a minimal risk of bias. According to the JBI critical checklist, the case report quality in both reports was high. Five out of thirteen studies compared the low-dose regimen of TMP-SMX to the high-dose regimen, and they recommended the low-dose regimen of TMP-SMT as first-line therapy for preventing the recurrence or development of PJP because it was much more tolerable. Ohmura and his colleagues reported in one more research that a low-dose treatment regimen of TMP-SMX with 10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy and was linked with fewer side effects and a lower death rate of 19% compared to >25% in conventional dose.
Low-dose treatments had fewer side effects than conventional regimens. Among 84 kidney transplant recipients with hyperkalemia and 102 with leukopenia, TMP-SMX was reduced in 438 patients. TMP-SMX caused hyperkalemia in another research. Nakashima et al. found that 72.4% of patients in the conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day) and 58.3% in the low-dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day) had AEs. In G6PD-deficient patients, TMP-SMX caused hemolysis. Up to weeks 24 and 52, neither RCT reported PCP. Discussion
PCP has a significant impact on patient mortality and morbidity, especially in immunocompromised individuals.
According to this analysis, low-dose TMP-SMX should be the first-line treatment because it reduces mortality and PCP-related side effects.
Compared to the control group, there was a 91% reduction in the incidence of PCP and an 83% reduction in the mortality rate.
Due to TMP-SMX-associated adverse effects and medication intolerance induced by neutropenia and G6PD deficiency, it is usually necessary to move to second-line therapies (dapsone, atovaquone, and pentamidine).
Conclusion
The low dose of TMP-SMX produces good results while decreasing mortality and PCP-associated adverse events.
This approach decreases the overall economic load and increases patient adherence to their daily prescription.
What is the level of evidence provided by this article?
3. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review Abdul Haseeb 1,* , Mohammed A. S. Abourehab 2 , Wesam Abdulghani Almalki 1 Int. J. Environ. Res. Public Health 2022, 19, 2833. https://doi.org/10.3390/ijerph19052833 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, primary infection occurs mostly in childhood – manifest with respiratory infection and infant death syndrome, due to its specific tropism for lung parenchyma and alveoli.
Life cycle of PCP is not completely understood Mode of transmission – both sexual and asexual cycles proposed; sexual replication with in the lungs; environmental changes due to immunosuppression. Drug treatment;
Pentamidine was the first drug used in 1958, to treat PCP successfully.
The major class 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 used are dapsone, aerosolized pentamidine, clindamycin plus pyrimethamine. The mortality has reduced from 70-90% to 10-15% in recent decades due to universal prophylaxes, better diagnostic tools, early effective treatment and use of corticosteroids use.
Prophylaxes; Opportunistic infection has been the main cause of mortality in immune-compromised patients, with loss of graft function in renal transplantation. Chemoprophylaxis was initially used by Dutz by 1950s in Iran. HIV patients and those with 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
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders [1,2]. The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases.
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family. TMP-SMX has been observed to substantially minimize the incidence of PCP in patients. As with other antibiotics, TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage.
The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections. In accordance with current dosing guidelines, the recommended therapy for PCP is high-dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks). There is a high incidence of adverse events (AE) in patients receiving recommended high doses of TMP-SMX.
Among the main results, we have:
– the meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
– the most common cause for second-line treatment are associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency
– The following are predisposing factors to PCP and therefore conditions that indicate prophylaxis:
· patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients
· transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors
· patients with concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts ( HIV-positive patients who have CD4+ counts less than 200 cells/mm3, because HIV-negative CD4+ count levels do not interfere)
· The incidence of occurrence of PCP is the most frequent in patients with systemic rheumatoid arthritis disease taking steroids and immunosuppressive agents. The risk factors for PCP in patients with rheumatoid disorders include age group (elderly > 65 years), use of glucocorticoids, and existing comorbidities
– the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
– Alternative PCP prophylaxis includes dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays
What is the level of evidence provided by this article?
Pneumocystis pneumonia is a an opportunistic fungal pathogen which causes disease in immunocompromised patients… the incidence is 2-15% among transplant recipients… and around 40% in hematological malignancy patients…. Cotrimoxazole has been the treatment of choice in many individuals and the optimum dosage and duration remains a question… cotrimoxazole if not given in the proper dose may not be effective for the treatment of PCP and may pave way for antibiotic resistance also…. High dose of TMP-SMX may cause rashes (most common side effect) followed by hepatotoxicity, bone marrow suppression…
TMP-SMX has 2 components – Sulfamethoxazole 75-100 mg/kg/day + trimethoprim 15-20mg/kg/day for 2 to 3 weeks….
The various databases were searched from Jan 2000 to Dec 2021 for articles in English that focused on the optimization of the dose of TMP SMX… The data were collected in a proforma with inclusion and exclusion criteria….
13 studies were met inclusion criteria for final analysis… 9 were retrospective studies, 2 case reports and 2 RCT…. Most of the studies compared the high dose with low dose TMP – SMX therapy for PCP…. they analyzed and found out that low dose TMP-SMX therapy was equal with respect to outcomes while reducing the mortality and reducing the adverse events….
The Cochrane meta analysis reported a decrease in incidence of PCP unto 91% and mortality reduction upto 83% when compared to the control group…..
Based on the meta analysis they concluded that prophylactic drugs are included in the crucial immunosuppression regimen, resulting in reducing the economic burden of the patient…
The routine PCP prophylaxis is recommended in 1-6 months post transplantation…the study also defined other predisposing factors for PCP namely CMV, Infections, number of graft rejection episodes…..
The study included all patients from various socio economic categories…. 5 out of 13 studies compared low dose with high dose TMP-SMX regimen with low dose regimen…. they concluded that low dose regimen is as effective as high dose regimen..
●there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies
(2) Methods:
■Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
■The data were collected in a specific form with predefined inclusion and exclusion criteria.
■ The quality of each article was evaluated using a (NOS) for retrospective studies, (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
(3) Results:
○Thirteen studies met the inclusion criteria for final analysis.
○Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
○Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
○We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
○This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan;
●The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91%and decrease in mortality rate up to 83%when compared to the control group
prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients.
■Routine PCP prophylaxis is recommended
the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period
■Other predisposing factors include
1- concomitant cytomegalovirus,
2- infections,
3- number of graft rejection episodes,
4- and low CD4+ count lymphocyte counts
5- PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3 [
● The first-line prophylactic agent is
1– one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day)
2– or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
● Alternative PCP prophylaxis includes one
1– double strength TMP-SMX tablet thrice per week
2– administration of dapsone either alone or in combination with leucovorin
3– and pyrimethamine, atovaquone, or pentamidine sprays].
♡The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
Nowadays, patients with PCP differ from the patients that were treated 30–40 years ago
♤The standard doses result in an absolute increase of 18% in the incidence of grade ≥3AEs
♡However, step-down therapy may be a worthy in exploring approaches to improve clinical outcomes
This study does have several limitations.
1– Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics
2– Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
3– Thirdly, due to small sample size, this may result in false-negative or false-positive findings.
●Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
● However, Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
● Similarly,Schildetal. Reported that the patients received an intermediate-dose TMP-SMX (TMP10–15mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AE sand this regimen was deemed to be safe and effective in patients with various immune dysfunctions
●Nakashima et al. reported that the total AEs rate was 58.3%in the low dose group and in conventional-dose group 72.4%of patients experienced AEs
●Similarly, another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group(25.0%)
● A study documented that tTMP-SMX was reported to cause hemolysis in patients with G6PD deficiency
In both RCTs, no cases of PCP were documented up to weeks 24and
1. Please summarise this article. PCP is a opportunistic infection usually involves those patient immunocompromissed. The incidence of PCP was around 50% in immunocompromissed patients, and it has a substantial impact on the mortality and morbidity of patients. Currently the most effective drugs for treatment and prophylaxes is TMP-SMX, so there is high demand to review regularly the dose optimization. Co-trimoxazole is a combination of trimethoprim and sulfamthoxazole, it’s being used for PCP, and as antibiotic as single or as combination of other antibiotic. Recommended dose in bacterial infection is 320-640mg/day bid, while its TMP 15-20mg/kg, SMX 75-100mg tds 6 to 8 hourly for PCP IV then orally. Due to its safety issues there is high demands to review the current dose to prevent toxicity. Material and methods; This is randomize and retrospective studies and case reports were included. 1. Those studies were included done after 2000 to before 2021. 2. Assessing the dosing guidelines used were PRISMA. 3. Selection criteria were—- all those articles included with titles abstract containing TMP-SMX, 4. Article quality evaluated using different methods. 5. Data extraction was performed using Microsoft Word 2013, and information retrieved. Result; Total 857 related published studies were identified. On the bases of quality assessment of studies the outcomes based on the NOS, and scored accordingly out of 13, eight scored 7, one scored 6 and the remaining scored 8. Overall the score included studies was 7. Second, the dosing strategy regimen documented that low dose regimen of TMP-SMX must be considered as a first line treatment option prevent occurrence and recurrence of PCP and PCP associated AEs. The studies shows fewer side effects. Discussion and conclusion; This review has revealed the low dosing strategy regimen showed be first line treatment option. They documented that low dose regimen of TMP-SMX must be considered as a first line treatment option prevent occurrence and recurrence of PCP and PCP associated AEs. The risk PCP is high at 1-6 month post-transplantation, other risk factors are CMV infection, number of rejections. The low dose of drug provides satisfactory outcomes while reducing the mortality rate and PCP associated AEs. However, they failed to identify significant differences b/w the full dose and low dose of TMP-SMX for the recurrence and prophylaxes of PCP. level of evidence III
Introduction
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders . The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases
PCP is considered a hallmark disorder indicating human immunodeficiency virus (HIV) infection
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine
analog, and sulfamethoxazole (SMX), which is from the sulfonamide family . TMP-SMX has been observed to substantially minimize the incidence of PCP in patients. There have been some published data on this topic.
As with other antibiotics, TMP-SMX must be administered in an appropriate way
to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX. Due to insufficient data on the optimal dose of TMP-SMX, its use is limited. In randomized trials where various treatment regimen was compared for virus-associated PCP, patients receiving recommended high dose of TMP-SMX as a first-line treatment regimen had higher rates of AEs such as skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs
Materials and Methods Data Sources and Search Strategy
The systematic search assessing the dosing guidelines of TMP-SMX in patients was
carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines . Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, etc., were explored for articles in English from January 2000 to December 2021.
Selection Criteria and Procedure
The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study. The studies published before January 2000 or having inappropriate and incomplete information were excluded from the study. Titles and abstracts of all included articles collected through the search were screened by two reviewers independently. In case of uncertainty as to whether selected studies met inclusion criteria, they discussed with a third reviewer.
Data Extraction
Data extraction was performed using the predesigned data collection form for this
review using MicrosoftWord 2013. Information retrieved from the selected articles included author and year, design, sample size, characteristics of patients, dosing strategy, clinical outcomes, and findings. Data extraction was performed by one of the reviewers and reviewed by another co-author. Any discrepancies were resolved by a third reviewer.
Article Quality Assessment
The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs) . Two of the reviewers assessed the quality of each included study independently. They compared their results and disagreements were resolved by detailed discussion.
Dosing Strategy ofTMP-SMX in Selected Studies
Low-dose treatment regimens usually reported fewer side effects compared to the
conventional dosing regimens. However, a study reported that a in a total of 438 patients, the dose of TMP-SMX was reduced in 84 kidney transplant recipients for hyperkalemia, and 102 for leukopenia Another study reported side effects, such as hyperkalemia, with the use of TMP-SMX. Nakashima et al. reported that the total AEs rate was 58.3% in the lowdose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), 72.4% of patients experienced AEs
Discussion
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
Over the past few years, various preventive treatment options are available for opportunistic infections in immunocompromised and transplanted patients . Although highly recommended by the healthcare community, prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients
Extrapolated from previous data, the first-line prophylactic agent is one single strength
TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) . Alternative PCP prophylaxis includes one doublestrength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays
Nowadays, patients with PCP differ from the patients that were treated 30–40 years
ago .The standard doses result in an absolute increase of 18% in the incidence of grade ≥3 AEs
However, step-down therapy may be a worthy in exploring approaches to improve clinical outcomes . The incidence of occurrence of PCP is the most frequent in patients with systemic rheumatoid arthritis disease taking steroids and immunosuppressive agents
This study does have several limitations. Firstly, the selected articles included patients
from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment. Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria. Thirdly, although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention
and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan. For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
This article is focussed around the drug treatment of PCP, in particular, TMP SMX known popularly as Bactrim.
The importance of PCP and its effects on patients, especially auto immune and immunosuppressed patients. PCP was a rare infection in the past, and has now become more common. It causes significant damage to the allograft and mortality rate of patients even when treated aggressively with antibiotics.
TMP SMX is part of the first line therapy for PCP and can help to a great extent. However, dosage has to be decided carefully since it has to be balanced with the immunosuppressive regimen. This article is an attempt to look further into dose optimization to achieve maximum effect and good outcome.
Discussion
This article is a systematic review. The baseline of the study was to find out how to optimize dosage of TMP SMX in such a way as to give good outcome for the patient in terms of life span as well as quality of life.
The authors of the study found that low dose TMP SMX is better as first line management, since it reduced mortality rate and adverse events incidence associated with PCP. This reduction was found to be significant by the Cochrane meta analysis up-to 90%.
The side effects of TMP SMX such as neutropenia and G6PD deficiency made it difficult to use it as a first line drug despite its efficacy against PCP. However, with the use of lower dosage, we are able to prevent or reduce the intensity of these side effects and effectively treat or prevent PCP at the same time.
PCP prophylaxis so far includes TMP SMX and other drugs such as atovaquone, dapsone, etc being given in double or triple strength two or three times a week. In contrast to this, administration of single strength TMP SMX daily may help prevent not only PCP, but other post transplant infectious diseases such as toxoplasmosis.
Conclusion
The main theme of this article has been to assess what strategies would work best to optimize TMP SMX regimen so that it would yield the best results for the patient. This study concluded that low dose TMP SMX has the upper hand, in comparison with high dose. Low dosage of TMP SMX was able to achieve lower mortality rates along with reduced incidence of PCP associated adverse events. These benefits in turn lower the economic burden of the disease and allow the patients to adhere better to their daily drug regimen.
Further study is needed in this area to develop proper clinical practice and standardized dosing regimen for different patients. Large scale RCTs would help to prevent occurrence of PCP in itself in immunocompromised patients, in comparison with treating the disease once it has affected the patient.
Level of evidence
This article is a systematic review, and thus level of evidence is 1.
Q1- Summary
Abstract Background : Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the
morbidity and mortality of patients, especially those with autoimmune disorders, thus requiring
optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX).
Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the
mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of
illness and enhances patients’ compliance to daily regimen plan. Conclusions: The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
1. Introduction
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia
has remained the most frequent and highly morbid fungal infection for patients with
autoimmune disorders .
The incidence was more than 50% in immunocompromised patients,
22–45% with hematological malignancy,
5–15% in transplant recipients
2% with rheumatoid diseases .
PCP is considered a hallmark disorder indicating (HIV) infection .
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family .
TMP-SMX has ability to substantially minimize the incidence of PCP in patients.
The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections . In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) .
There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
There is an insufficient data on the optimal dose of TMP-SMX .
In randomized trials where various treatment regimen was compared for virus-associated PCP, patients receiving recommended high dose had higher AEs such as skin irritation ( rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs . The therapeutic option for treatment of PCP requires a dose of more than 16 mg/kg of TMP-SMX with risk of hepato-renal AEs .
Materials and Methods
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.
Dosing Strategy of TMP-SMX in Selected Studies.
The included studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associatedAEs.
Ohmura and his colleagues reported that a low-dose treatment regimen of
TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose
Schild et al. reported that the patients received an intermediate-dose
TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose
TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in
patients with various immune dysfunctions .
Low-dose treatment regimens usually reported fewer side effects compared to the
conventional dosing regimens.
Nakashima et al. reported that the total AEs rate was 58.3% in the low dose
group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose
group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), 72.4% of patients experienced
AEs .
another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%) . Discussion:
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
second-line treatment include : such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency .
Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients . The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors, concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts.
PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3 . this failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP. This strategy reduces economic burden of illness and enhances patients’ compliance to daily regimen plan.
Extrapolated from previous data, the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) . Alternative PCP prophylaxis includes one doublestrength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays . The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis .
This study does have several limitations. Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics . Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria. Thirdly, although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions :
The low dose of TMP-SMX provides satisfactory outcomes while
reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall
economic burden and enhances patients’ compliance to daily regimen plan. For
STUDY DESIGN
13 articles were reviewed, including 2 RCT
DOSE
LOW-TMP-SMX 10 MG/KG/DAY OF TMP
INTERMEDIATE – 10-15 MG/KG/DAY OF TMP
HIGH >15 MG/KG/DAY OF TMP
Out of 13 study , 2 had kidnet transplant recipients patients
Lod dose of TMP-SMX is associated with less AE and dose reduction in kidney transplants were done for hyperkalemia and leucopenia
Prophylaxis
1 SS or DS per day
1 DS 3 times a week
Duration 6-12 months
Prophyalaxis decrease the incidence of PCP up to 91% and decrease in mortality rate up to
83% when compared to the control group
Second line like dapsone and other durgs are chosen in case of AE due to TMP-SMX and in G6PD deff patients
Introduction
· Pneumocystis jirovecii pneumonia still a common cause of morbidity from fungal infections
In patients with autoimmune diseases.
· TMP-SMX reduce the incidence of PJP and may reduce mortality.
· High dose of TMP-SMX used in the treatment regimen associated with higher rates of adverse effects.
Materials and Methods
· Data used from Systematic Reviews and Meta-analysis guidelines and articles in English from January 2000 to December 2021.
· Inclusion criteria: studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP
· Exclusion criteria: The studies published before January 2000 or having inappropriate and incomplete information
Discussion
· The goal of this study is evaluation of dose of TMP-SMX to prevent PJP in immunocompromised patients.
· This study found that low-dose TMP-SMX therapy should be the first-line treatment option, as it reduced mortality and PCP-associated AEs.
· TMP-SMX can be switched to dapsone, atovaquone, or pentamidine in case of TMP-SMX associated AEs and drug intolerance caused by neutropenia and G6PD deficiency
· Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients
· the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, (neutropenia, steroids, ATG, or CNI)
· Other risk factors for PJP: concomitant CMV, infections, rejections, and low CD4+ count lymphocyte counts
· PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3
· There was no difference between the full-dose and low-dose PJP prophylaxis regimen of TMP-SMX.
· Nowadays the standard doses of TMP-SMX have increased risk of AEs.
· The incidence of PCP is the most frequent in patients with Rheumatoid arthritis on steroids and immunosuppressive agents
Limitations of the study
· Articles were selected from different countries with possible different socio-demographic characteristics
· limited number of studies after January 2000.
· small sample size may result in false-negative or false-positive findings.
Conclusions
· The low dose of TMP-SMX has accepted outcomes while reducing the mortality rate and PCP-associated AEs.
· prophylactic treatment regimen is warranted in HIV-patients
INTRODUCTION
PCP has become one of the most frequent opportunistic infections in immunocompromised patients. It accounts for about 50% of the total infections. It usually manifests with respiratory symptomatology like tachypnoea, shortness of breath, hypoxia with other symptoms including fever and tachycardia.
It significantly affects morbidity and mortality of patients . This is even more significant in post transplant patients. The usual drug of choice is cotrimoxazole (TMP-SMX).
Hence, there is need to ensure the safety of TMP-SMX. Dose optimization is the key methods in antimicrobial stewardship programs and very effective to ensure therapeutic outcome of antimicrobial therapy as like in management of PCP.
MATERIALS AND METHODS
Databases were searched from period of January 2000 to December 2021 to find the studies focusing on dose optimisation of TMP-SMX. A set of inclusion and exclusion criteria were applied and 13 articles were included in the study.
The main objective was to assess and analyse the dosing strategies of TMP-SMX followed by various centers to manage PCP.
RESULTS
A total of 13 articles met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective
cohort studies , two case reports and two randomized controlled trial (RCT).
The outcomes based on the NOS, eight studies were rated as a total score of 7, one study scored 6, and the remaining four studies scored 8. Overall, the score of included studies was 7. The Cochrane bias tool assessed that almost all the domains for RCT were at low risk of bias. As per the JBI critical checklist, the quality of case reports in
both reports were of good quality.
Of 13 studies, four reported that patients having AIDS received TMP-SMX for prophylaxis, four reported
patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency.
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
DISCUSSION
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Over the past few years, various preventive treatment options are available for opportunistic infections in immunocompromised and transplanted patients . Although highly recommended by the healthcare community, prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients.
CONCLUSION
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
LIMITATIONS
1. Socio-demographic characteristics of patients are different as studies are included from different countries.
2. Although the quality of the included studies is good, the sample sizes were small.
Pneumocystis jirovecii pneumonia is serious fungal infection in autoimmune disease patients causing significant
mortality.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in hematological malignancy, 5–15% in transplant recipients
and around 2% in patients with rheumatoid diseases .
Using TMP-SMX showed decrease in the incidence of PCP in patients.
appropriate dosing is important to achieve adequate effect with lowest toxicities.
The TMP-SMX dosing recommendations is oral 320–640 mg/day/12 h, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections.
current dosing guidelines, the recommended therapy for PCP is high-dose TMP-SMX (TMP 15–20
mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
AEs include skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow
suppression, renal impairment, hepatotoxicity and electrolyte disorder .
Therefore dose optimization is mandatory to achieve optimal therapeutic effects with minimal AEs.
*Materials and Methods
-All studies reporting the dosing and
outcomes of TMP-SMX in patients with PCP were included in this
review from January 2000 to December
2021.
-Of all studies, 13 articles including 2663 patients met the inclusion criteria for final analysis.
-5 studies compared the low-dose with high dose regimen of TMP-SMX and documented
that low-dose therapy should be used as a first-line treatment to prevent occurrence and recurrence of PCP and to minimize AEs.
-hyperkalemia and leukopenia occurred in some KTR even on low dose required
more dose reduction.
-Nakashima et al. Reported that the total AEs rate was 58.3% in the low-dose group (TMP,
4–10 mg/kg/day; SMX 20–50 mg/kg/day).and AEs rate was 72.4% in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day).
– mortality rate was lower in the low-dose group (19.5%) compared to the
conventional-dose group (25.0%) .
*Discussion
-PCP is a leading cause of mortality and
morbidity in immunocompromised patients
.
-this is a systematic review done to assess different dosing strategy of TMP-SMZ to
reduce the risk of PCP in immunocompromised patients.
-Thereview recommended low-dose TMP-SMX as the first-line treatment option, to reduce
AEs.
-The Cochrane meta-analysis reported that there was a decrease in the incidence of
PCP up to 91% and decrease in mortality rate up to 83% when compared to the
control group.
-second-line treatment such as dapsone, atovaquone, and atomized
pentamidine can be used in case of intolerance due AEs or resistance to drug.
-routine prophylaxis of PCP is required during the early post-transplant month
and after therapy of rejection episodes due to higher risk of PCP among transplant recipients
The risk is greater in 1–6 month
post-transplantation period, during prolonged neutropenia, or in patients
receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
– this review found no significant
differences between the full-dose and low-dose regimen of TMP-SMX for the
occurrence or recurrence of PCP.
– using TMP-SMX double-strength is effective either daily or 3/week , but
daily administration of TMP-SMX prevents other post-transplant infectious
diseases such as toxoplasmosis.
-there were no proper
guidelines on PCP prophylaxis in patients treated with immunosuppressive drugs,
and high-dose steroids for immune-mediated dermatologic conditions.
BACTRIM DOSE OPTIMIZATION IN PCP MGT;A SYSTEMATIC REVIEW.
INTRODUCTION.
-Incidence of PCP ;50% in immunocompromised,22-455 in hematological malignancies,5-15% in KTR and 2% in RA pts.
-As per guidelines ,bactrim is dosed at 15-20mg/kg 6-8 hrly fpr PCP tx.Effective dose for PCP tx is >16 mg/kg of Bactrim which is associated with side effects which should be closely monitored.
MATERIALS AND METHODS.
Data sources and search strategy – Dosing guidelines for bactrim were done with PRISMA guidelines. Articles in English were assessed from varied databases from jan 2000 to dec 2021.
Selection criteria and procedure – Inclusion criteria ; Studies reporting septrin dosing strategy for PCP, studies with data on clinical outcome of septrin and RCTS in English. Exclusion criteria ;Studies published before 2000 and studies with inappropriate or incomplete information.
Microsoft word 2013 was used for data extraction by the reviewers.
Quality was assessed using NOS, Joanna Briggs Institute and University of Adelaide critical check list for case reports.
RESULTS.
-13 Studies met inclusion criteria,9 were retrospective while 2 were RCTS.2663 pts were recruited.
-From studies comparing low vs high dose septrin recommended low dose for 1st line tx for PCP to prevent recurrence, occurrence of PCP and minimize SE.The low dose group had fewer side effects, less mortality in comparison to conventional group.(TMP – SMX 4-10mg/kg/day/20-50mg/kg/day vs 10-20mg/kg/day/20-50mg/kg/day)
DISCUSSION.
-Low dose septrin should be considered 1st line to achieve low SE and mortality rate. In the event of SE from septrin, we should switch to 2nd line ;dapsone, atovaquone and atomized pentamidine. Routine prophylaxis should be administered early post transplant due to high immunosuppressive medications used then.
-Options for 1st line prophylaxis ;x1 single strength septrin OD,x1 double strength septrin OD,X1 double strength septrin x3/week, Dapsone, dapsone +leucovorin+ pyrimethamine, atovaquone or pentamidine sprays.
-All pts with rheumatological conditions, autoimmune dysfunction, HIV and any immunosuppression need PCP prophylaxis.
STUDY LIMITATIONS.
-Varied sources of article and pts from different countries hence they might have been affected by sociodemographic xtics.
-Limited studies after jan 2000 thus some low quality studies were included.
-Small sample sizes thus some false +VEs and -VEs occurred.
III. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Summarise this article
Introduction
– Trimethoprim-Sulfamethoxazole (TMP-SMX) substantially reduces the incidence of Pneumocystis jirovecii pneumonia (PCP)
– optimal dosing of TMP-SMX is crucial since PCP has a significant impact on the morbidity and mortality of immunocompromised patients
– the recommended treatment for PCP is high-dose TMP-SMX i.e., TMP 15-20mg/kg/day and SMX 75-100mg/kg/day for 2-3weeks
– a higher incidence of adverse events has been reported among patients receiving the recommended high-dose TMP-SMX
Methods
– various databases were searched from January 2000 to December 2021 focusing on TMP-SMX dose optimization
– there was a predefined inclusion and exclusion criteria
– studies reporting the TMP-SMX dosing strategy in patients for PCP occurrence or recurrence were included
– studies looking at clinical outcomes of TMP-SMX regimens were included
– studies published before January 2000, studies with inappropriate and incomplete information were excluded
– a predesigned data collection form was used to extract data
– quality of each article was evaluated
Results
– 13 studies met the inclusion criteria for final analysis, 9 were retrospective cohort studies, 2 case reports and 2 RCTs
– a total of 2663 patients were recruited in the included studies
– most studies compared the high-dose with low-dose TMP-SMX treatment for PCP
– out of the 13 studies, 5 compared low-dose TMP-SMX with a high-dose regimen
– these studies documented that low-dose TMP-SMX therapy must be considered as the 1st line therapy to prevent the occurrence and recurrence of PCP as well as PCP-associated adverse events
– low-dose TMP-SMX was well-tolerated and effective as high-dose therapy
– low-dose TMP-SMX regimens were associated with fewer adverse events and lower mortality rates compared to the conventional dosing regimens
– this low-dose strategy enhances patients’ adherence to the daily regimen plan and reduces the economic burden of the illness
Discussion
– PCP has a significant impact on morbidity and mortality among immunocompromised patients
– low-dose TMP-SMX therapy should be considered s the 1st line treatment option resulting in a reduction in the mortality and adverse events associated with PCP
– 2nd line options in case of TMP-SMX intolerance and adverse events include dapsone, pentamidine and atovaquone
– risk factors for PCP include the first 6 months post-transplant, neutropenia, use of corticosteroids, antithymocyte antibodies, CNIs, CMV, infections, number of rejection episodes, low CD4 counts
– routine prophylaxis is recommended in the early post-transplant period and following treatment for graft rejection
– low-dose TMP-SMX therapy enhances patients’ compliance to daily regimen plan and reduces the economic burden of the illness
– one single strength or one double strength TMP-SMX tablet daily is considered as the first-line prophylactic agent
– alternative PCP prophylaxis includes: – one double strength TMP-SMX tablet given thrice weekly, dapsone monotherapy, dapsone combined with leucovorin and pyrimethamine, atovaquone or pentamidine
– daily administration of TMP-SMX prevents other post-transplant infections like toxoplasmosis
Study limitations
– patients included in the study were from different countries hence the findings could be affected by the different sociodemographic characteristics
– limited number of studies
– false positive or negative findings due to the small sample size of the studies included
Conclusion
– low-dose TMP-SMX therapy provides satisfactory outcomes while reducing the mortality and PCP-associated adverse events
– low-dose TMP-SMX dosing strategy also reduces the economic burden of PCP and enhances patients’ adherence to the daily regimen plan
– large-scale RCTs and cohort studies looking at TMP-SMX dosing strategies are required to improve the dosing strategies to prevent the initial occurrence of PCP and to prevent recurrence of PCP in immunocompromised patients
What is the level of evidence provided by this article?
Introduction:
Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders. The incidence of PCP is high among immunocompromised patients and it is more than 50%. Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family . TMP-SMX has been observed to substantially minimize the incidence of PCP.
Method Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Result:
Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. This study has found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan. Conclusion: The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy also reduces economic burden. The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immunocompromised patient. Level of evidence: level 1
Pneumocystis Jirovecii pneumonia PJP: Is the most common pathogen encountered in immune compromised patients causing pneumonia. It’s mainly targeted by cell mediated immunity, hence its prevalent in rheumatoid patients, HIV, particularly when C4D count is less than 200, and solid organ transplant recipients. It begets increased morbidity and mortality. Therefore, prophylaxis against PJP was an essential part of management of immune compromised patients. Risk factors for PJP infection include:
no. of rejections, use of ATG, prolonged lymphopenia, concomitant CMV infection, and use of CNi. Trimethoprime- Sulphamethoxasol TMP-SMX: Is the drug of first choice for prophylaxis and treatment of PJP. Trimethoprim is a derivative of Pyrimethamine and sulphamethoxazol is sulfa antibiotic. It’s used in a single or double strengths.
single strength is 80/400 and double strength is 160/800 mg. In practice both of the strengths were in use. Nevertheless, double dose TMP-SMX was linked to several significant complications, reported in 27% of renal allograft recipients, these AEs including:
1] Bone marrow suppression.
2] Hepatotoxicity.
3] Renal toxicity.
4} Contraindicated in G6PD.
5] Electrolytes disturbance
6] Gastrointestinal disturbance.
Regular dose is 16 mg/kg body wt. PJP is higher between 1-6 months and after treatment of acute rejection episodes.
Proper dosing of antibiotic is crucial to prevent and treat the infection with PJP.
Nevertheless, due to the side effects and complications related to double dosing of antibiotics, many patients fall short of adequate medications. single strength TMP-SMX was advocated as safer alternative.
This meta-analysis study tested the hypothesis that low dose TMP-SMX is as efficient and effective with lesser side effects than double dose TMP-SMX. By screening all studies compared the two dosing strategies, conducted between 2000 through 2021.
13 studies were surveyed for the same reason.
Conclusively the study showcased non inferiority of low dose antibiotic in preventing PJP infection, featuring less economic burden, more compliance and lesser side effects.
Its a meta-analysis with level of evidnce 1.
PJP has significant impact on mortality and morbidity of immunocompromised patients.
What is the optimum dosing strategy for these patients is an unanswered question which has been explored in this review.
Methods:
Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen These studies documented that low-dose TMP-SMX therapy must be considered as a first- line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs. However, Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy. Similarly, Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions.
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
Introduction
Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the morbidity and mortality of patients, thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX). TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage.
Method
This systemic review was done from various databases, from January 2000 to December 2021 with articles in English, the systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP were included in this review.
Result
-Thirteen studies met the inclusion criteria, nine were retrospective cohort studies two case reports [31] and two randomized controlled trial (RCT)
-In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of hepato-renal AEs
-Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
-Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen. These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs
-Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
-Nakashima et al. reported that the total AEs rate was 58.3% in the lowdose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), 72.4% of patients experienced AEs
-This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AE
The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Conclusion
The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immunocompromised patient.
Limitation
-Study failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP
-Mixed homogenous data
-small sample size Level of evidence is -level 1- systemic review of RCT
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization
in Pneumocystis jirovecii Pneumonia (PCP) Management
Introduction
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia
has remained the most frequent and highly morbid fungal infection for patients with
autoimmune disorders.
The incidence of PCP classified as follow
* 50% in immunocompromised patients
* 22–45% in patients with hematological malignancy
* 5–15% in transplant recipients
* around 2% in patients with rheumatoid diseases
A retrospective study reported that the incidence
of PCP and PCP-associated mortality was lower in patients with rheumatoid arthritis who
received high-dose of glucocorticoids.
Another study reported that PCP developed
in up to 40% of patients with the lymphoproliferative disease or acute lymphoblastic
leukemia, and about 50% of patients experience hepatotoxicity .
Moreover, the incidence of adverse events (AEs) was decreased in non-HIV patients who
received TMP-SMX prophylactically
TMP-SMX must be administered in an appropriate way
to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities,
necessitating the avoidance of excessive dosage . Specifically, in the era of
antimicrobial resistance, optimal antibiotics usage is very crucial to ensure effectiveness
of therapy.
The TMP-SMX dosing recommendations 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections .
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX
(TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks)
the occurnace of AE is associated more with high doses .
The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of
hepato-renal AEs .
Therefore, to ensure the safety of TMP-SMX, there is a high demand
to review current evidence in PCP patients with a focus on dose optimization strategies.
Dose optimization is the key methods in antimicrobial stewardship programs and very
effective to ensure therapeutic outcome of antimicrobial therapy as like in management of
PCP
Dosing Strategy of TMP-SMX in Selected Studies
Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen
These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option
to prevent occurrence and recurrence of PCP and PCP-associated AEs.
However, Ohmura and his colleagues reported that a low-dose treatment regimen of
TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose
therapy
Low-dose treatment regimens usually reported fewer side effects compared to the
conventional dosing regimens.
Discussion
The main goal of this systematic review was to assess the current dosing strategy of
TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
The impact of PCP on mortality and morbidity of the patients especially
immunosuppressive patients is significant
his review has revealed that low-dose
TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of
mortality rate and PCP-associated AEs
Routine PCP prophylaxis is recommended for patients
treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients
A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with
other medications experienced AEs such as cytopenia
Therefore, routine prophylaxis
is mainly required during the early post-transplant month and after therapy of rejection
episodes. PCP prophylaxis is highly recommended in HIV-positive patients who have
CD4+ counts less than 200 cells/mm3
However, we failed to identify significant
differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or
recurrence of PCP
extrapolated from previous data, the first-line prophylactic agent is one single strength
TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP
160 mg/day; SMX 800 mg/day) .
Alternative PCP prophylaxis includes one double strength TMP-SMX tablet thrice per week,
administration of dapsone either alone or in
combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays .
This practice may not provide desired clinical outcomes with the minimal risk of AEs
This study does have several limitations.
Firstly, the selected articles included patients
from various countries, so the findings could have been affected by socio-demographic
characteristics such as ethnicity, region, lifestyle, and environment.
Secondly, the limited number of studies conducted after January 2000
forced us to include all studies that met inclusion criteria.
Thirdly, although the quality of the majority of the included studies was
good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention
and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while
reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall
economic burden and enhances patients’ compliance to daily regimen plan. For some
patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it
may still warrant to start prophylactic treatment regimen. Due to limited data available on
the optimal dose of TMP-SMX, these findings would support the conduct of large-scale,
prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies
for the PCP.
Name of the study: Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization
in Pneumocystis jirovecii Pneumonia (PCP) Management:A Systematic Review Year of the study: 2022 journal: Int. J. Environ. Res. Public Health, the journal has a 2020 impact factor of 3.390 Introduction:
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases Study Aim:
dose optimization of TMP-SMX to provider satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. Material and methods: Data Sources and Search Strategy Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines
Free-text web searches using Google Scholar, and databases such as
PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews,etc.
The keywordsused for the search were “dose optimization”, “Pneumocystis carinii pneumonia”,“Pneumocystis jirovecii pneumonia”, “HIV-patients”, “immune compromised patients” “Co-trimoxazole”, “trimethoprim/sulfamethoxazole”, and “TMP-SMX” Selection Criteria and Procedure all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening. The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study.
results as showen in figure 1 conclusion
The low dose of TMP-SMX provides satisfactory outcomes with low mortality rate and less side effects but large RCT still needed to clarify, confirm and provide guidelines regarding the dosing strategies for the PCP. limitations
–diagnosis of PCP and difference between treatment and prophylactic unclear
–RCT are done in rheumatology patient which already have the lowest incidence -mixed non homogeneous data level of evidence unclear and difficult to decide
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review. Introduction: PJP is considered the most common fungal infection in immunocompromised patients such as HIV, post kidney transplant and other immunological diseases, the treatment of choice is Trimethoprim-Sulfamethoxazole, and as other antibiotics, TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage and when using The therapeutic option for treatment of PCP requires a dose of _16 mg/kg of TMP-SMX with risk of hepato-renal adverse effects and herein, this systematic review focus on dose optimization to ensure the safety of TMP-SMX. Materials and Methods. Various databases were searched from January 2000 to December 2021 for articles that focusing on the dose optimization of TMP-SMX, the retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included and others having inappropriate and incomplete information were excluded from the study, total included studies are 13 studies. Results: There are13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP or effect of early diagnosis and treatment in prognosis. Most of these studies revealed that low dose of TMP-SMX provides satisfactory outcomes and reducing the mortality rate and PCP-associated adverse events. Conclusion: The low dose of TMP-SMX provides satisfactory outcomes with low mortality rate and less side effects and so this lead to reduces overall economic burden and helps in patients’ compliance to daily medications and large RCT still needed to clarify, confirm and provide guidelines regarding the dosing strategies for the PCP. Level of evidence: I (Systematic review).
III. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Please summarise this article:
Introduction:
PJP is the most frequent and highly morbid fungal infection for patients with autoimmune disorders and is a hallmark disorder indicating human immunodeficiency virus (HIV) infection, Incidence is > 50% in immune compromised hosts.
Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole that has been found to reduce the incidence of PJP in non-HIV patients.
TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration dependent toxicities.
In the era of antimicrobial resistance, optimal antibiotics usage is essential. Current dosing guidelines recommend 320-640 mg/day, administered every 12 h, orally, to treat bacterial infections and 15-20 mg/kg every 6 to 8 h intravenously then orally for PCP infections.
However, there is a high incidence of AEs in patients receiving recommended high doses. To ensure safety, dose optimization strategies are needed.
Methods:
It is a systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using PRISMA guidelines and free-text web searches using Google Scholar, PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews.
Keywords used were “dose optimization”, “Pneumocystis carinii pneumonia”, “HIV-patients”, “immune compromised patients”, “Co-trimoxazole”, “trimethoprim/sulfamethoxazole”.
Selection Criteria and Procedure
Studies reporting the dosing strategy of TMP-SMX in PCP were included for further screening, with retrospective studies, randomized controlled trials, and case reports excluded.
Data extraction was performed by one reviewer and coauthor, with any discrepancies resolved by a third reviewer.
Two reviewers assessed the quality of each included study independently, with disagreements resolved by detailed discussion.
Study Characteristics:
857 related published studies were identified from grey literature and electronic databases, and 163 were evaluated for eligibility criteria.
25 articles were excluded due to no full-text, literature reviews, inappropriate intervention, no required data, and non-English.
13 articles met the inclusion criteria for final analysis, nine of which were retrospective cohort studies.
2663 patients were recruited in selected studies.
Quality Assessment of Studies:
The NOS, Cochrane Bias tool, and JBI critical checklist assessed the quality of studies, with 8 studies rated as 7.2.
Dosing Strategy of TMP-SMX in Selected Studies:
Low-dose TMP-SMX therapy must be considered as a first-line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Low-dose treatment regimens reported fewer side effects than conventional dosing regimens, but hyperkalemia, leukopenia, hemolysis, and PCP were reported.
Results:
After the process of identification, screening, 13 articles made it and accepted for the final assessment.
Their design was retrospective (9 studies), case reports (2 studies), and RCTs (2 studies).
Most of the studies looked at the difference between high-dose and low dose TMP-SMX in treatment of PJP.
This systematic review showed that, low-dose TMP-SMX is effective and associated with decrease mortality, reduced treatment cost, and adherence to daily drug intake.
Discussion:
Low-dose TMP-SMX therapy should be the first-line treatment option to reduce the risk of PCP in immunosuppressive patients, as a Cochrane meta-analysis reported a decrease in the incidence of PCP up to 91% and mortality rate up to 83%.
Routine PCP prophylaxis is recommended for immunocompromised and transplanted patients, as the risk of PCP is greater in 1–6-month post transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
This strategy reduces economic burden of illness and enhances compliance to daily regimen plan.
TMP-SMX is the first-line prophylactic agent for PCP, but alternative prophylaxis may not provide desired clinical outcomes.
PCP is the most frequent in patients with systemic rheumatoid arthritis, and risk factors include age, use of glucocorticoids, and existing comorbidities.
Guidelines for PCP prophylaxis for various cohorts are needed due to limited data on predictors and risk factors.
Small sample size and limited number of studies may lead to false-negative or false positive findings.
Conclusions:
Low-dose TMP-SMX may result in satisfactory outcomes in PJP treatment.
Further RCTs needed for better understanding on the optimal dosage of TMP-SMX in PJP treatment.
What is the level of evidence provided by this article?
The level of evidence provided by this article => level 1
Pneumocystis jirovecii pneumonia (PCP) has significant cause of morbidity and mortality 50% in immunocompromised patient, and 22% to 45% in haematological malignancies and 5% to 15 %in post transplanted one ,and 2% in patients with rheumatoid disease.
For that number of mortality and morbidity ,antibiotics prophylaxis reduce the incidence of PCP.
TMP-SMX it is used for prophylaxis of PCP but adverse effects . like leukemia and hepatic toxicity has been observed that elaborate the need for formulating well-defined guide for its use .
TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage.
In high doses of TMP-SMX many adverse effects:
skin rash
gastrointestinal disturbances
bone marrow suppression
renal impairment
hepatotoxicity as well as electrolyte disorder
for which alternative treatment is required to avoid these adverse effects and optimize treatment. Materials and method
data collected from from January 2000 to December 202 for dose optimization.
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP.
The quality of each article was evaluated using a Newcastle–Ottawa Scale for retrospective studies, Joanna Briggs Institute, The University of Adelaide critical checklist for case reports. Results
13studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen.
Low dose treatment regimens is recommended for treatment and prophylaxis.
Low-dose treatment regimens is effective and less adverse effects. Conclusion
Inspite of limited data available on the optimal dose of TMP-SMX ,the recommendation for treatment and prophylaxis is low dose of TMP-SMX. Level of evidence .III
· PCP is the most frequent and highly morbid fungal infection for patients with autoimmune disorders, with an incidence of 50% in immunocompromised patients, 22-45% in hematological malignancy, 5-15% in transplant recipients, and 2% in rheumatoid diseases.
· PCP in HIV-positive patients has been reduced due to advanced technology and preventive measures.
· Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole that has been found to reduce the incidence of PCP and associated mortality in non-HIV patients.
· PCP and hepatotoxicity were lower in non-HIV patients who received TMP-SMX prophylactically.
· TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities.
· Current dosing guidelines recommend 320-640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15-20 mg/kg every 6 to 8 h intravenously than orally for PCP infections. However, there is a high incidence of AEs in patients receiving recommended high doses.
· To ensure safety, dose optimization strategies are needed.
Method
· Database searches were conducted from 2000 to 2021. focusing on the dose optimization of TMP-SMX. · The quality of articles was evaluated using a Newcastle-Ottawa Scale, JBI critical checklist, and Cochrane bias tool.
Discussion:
· Low-dose TMP-SMX therapy should be the first-line treatment option to reduce the risk of PCP in immunosuppressive patients, resulting in a decrease in mortality rate and PCP-associated AEs.
· Routine PCP prophylaxis is recommended for immunocompromised and transplanted patients, as the risk of PCP is greater in 1-6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, anti-lymphocyte antibodies, or calcineurin inhibitors.
· A study reported that 27% of kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia. This strategy reduces the economic burden of illness and enhances patients’ compliance with daily regimen plans.
· TMP-SMX is the first-line prophylactic agent for PCP, but alternative prophylaxis may not provide desired clinical outcomes.
· PCP is most common in patients with systemic rheumatoid arthritis, and risk factors include age, use of glucocorticoids, and existing comorbidities.
· TMP-SMX decreased the incidence of PCP and associated mortality after 1 year, but there are no guidelines for PCP prophylaxis in patients with rheumatological and other autoimmune dysfunctions.
Limitations:
. The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
· Limited number of studies,
· Small sample size, resulting in false-negative or false-positive findings.
Conclusion
· Low dose of TMP-SMX reduces mortality and PCP-associated AEs.
· This strategy reduces the economic burden and improves adherence to the daily regimen plan.
· Prophylactic treatment for HIV patients with PCP may be necessary for some patient populations with large-scale, prospective RCTs and cohort studies to provide guidelines.
==================================== What is the level of evidence provided by this article?
Level III
Introduction:
Pneumocystis pneumonia causes significant morbidity and mortality in immunocompromised patients. The incidence in transplant patients is 5-15% and more than 50% in immunocompromised patients. TMP-SMX is the mainstay of treatment and prophylaxis for pneumocystis. TMP-SMX has got got serious side effects which can hamper compliance and completing therapy. In accordance with current dosing guidelines, treatment of PCP is high dose TMP-SMX (TMP 15-20 mg/kg/day and SMX 75-100 mg/Kg/day) for 2-3 weeks. There is a high incidence of A/E in patients receiving the recommended high dose of TMP-SMX. Due to insufficient data on the optimal dose of TMP-SMX, its use is limited. The AEs include:
Skin irritation
GI disturbances
Bone marrow suppression
Renal impairment
Hepatotoxicity
Electrolyte disorders
Therefore, to ensure the safety of of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
Materials and Methods:
This was a sytematic review carried out using PRISMA guidelines.
Based on the titles and abstracts, studies of all types with any data on clinical outcomes of TMP-SMX regimens were included in the screening. Studies before the year 2000 were excluded from the study.
Data extraction was performed using the predesigned data collection form for this review using Microsoft Word 2013.
The quality of each article was evaluated using the Newcastle-Ottawa Scale (NOS) for retrospective studies and Cochrane bias tool for RCTs
Two of the reviewers assessed the quality of each included study independently.
Results:
Out of the 857 related published studies, 163 were evaluated for eligibility criteria.From these, a total of 13 articles met the inclusion criteria for the final analysis. Out of the 13 studies, 9 were retrospective studies, 2 were case reports and 2 were RCTs. All the studies collected were published after the year 2000
Of the 13 studies, 5 compared the low dose of TMP-SMX regimen with a high dose regimen. These studies demonstrated that low dose TMP-SMX therapy must be considered as a first line therapy option to prevent occurrence and recurrence of PCP and PCP associated side effects
Low dose regimens usually reported fewer side effects compared to the conventional dosing regimens
In both RCTs, no cases of PCP were documented up to 24 and 52 weeks
Discussion:
This review revealed that low-dose TMP-SMX therapy should the first line treatment option, resulting in the reduction of mortality rate and PCP-associated adverse effects.
The Cochrane meta analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group. Although TMP-SMX has been regarded as the first line therapy, it is often switched to second line therapy due to TMP-SMX associated side effects.
A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia. Therefore, routine prophylaxis is only required in the early months post-transplant and after treatment of rejection.
Conclusion:
The standard doses result in an absolute increase of 18% in the incidence of grade 3 AEs. Step down therapy may be worthy in exploring approaches to improve clinical outcomes and will reduce overall economic burden and improve patient compliance
Study limitations:
Selected articles included patients from different countries, so the finding could have been affected by different sociodemographic characteristics like ethnicity, region, lifestyle
There were limited number of studies conducted after the year 2000
The sample sizes of most of the studies were small
Level of evidence:
This is a systematic review. Level I evidence
Introduction:
Pneumocystis jirovecii (PCP) pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases.
PCP is disease rising alarm of human immunodeficiency virus (HIV) infection.
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family, is the drug of choice for prophylaxis and treatment of PCP.
The recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks, associated with hepatorenal side effects as well as skin rash.
Materials and Methods Data Sources and Search Strategy– Articles in English from January 2000 to December 2021, search keywords were “dose optimization”, “Pneumocystis carinii pneumonia”, “Pneumocystis jirovecii pneumonia”, “HIV-patients”, “immune compromised patients” “Cotrimoxazole”, “trimethoprim/sulfamethoxazole”, and “TMP-SMX”.
INCLUSION CRITERIA:
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP. Data on clinical outcomes of TMP-SMX regimens.The retrospective studies, randomized controlled trials (RCTs), and case reports available in English.EXCLUSION CRITERIA:
The studies published before January 2000 or having inappropriate and incomplete information. Any article not met the inclusion criteria or not English.No full text, literature review, and inappropriate intervention.Article Quality Assessment- The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs). Aim of the study:
To assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.The impact of PCP on mortality and morbidity of the patients especially immunosuppressive patients. Results:
13 studies included, out of them 4 in AIDS patients received TMP-SMX for prophylaxis, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency.Five studies out of 13, compared the low-dose regimen of TMP-SMX with a high-dose regimen, documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated side effects.A study reported that a in a total of 438 patients, the dose of TMP-SMX was reduced in 84 kidney transplant recipients for hyperkalemia, and 102 for leukopenia, side effects were found in 58.3% in low dose group and in 72,4% in a high dose group.Another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%).A study documented that TMP-SMX was reported to cause hemolysis in patients with G6PD deficiency.In both RCTs, no cases of PCP were documented up to weeks 24 and 52.The low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.Switching to second-line treatment such as dapsone, atovaquone, and pentamidine nebulizers due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.The risk factors for PCP in patients with rheumatoid disorders include age group (elderly > 65 years), use of glucocorticoids, and existing comorbidities. Limitations:
Demographic variations of population.Limited studies number after the year 2000.All studies were of small sample size, resulting in false positive and false negative results. Conclusions:
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.Large sample randomized trials, and prospective cohort studies are needed to provide guidelines dosing strategy for the PCP. What is the level of evidence provided by this article?
The level of evidence is I – systematic review of randomized trials,cohort, and case reports, tests treatment.
# The objective:
*The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes
# Introduction:
*The rate of PCP was more than 50% in immunocompromised patients with incidence of (5–15%) in transplant recipients.
*PCP is associated with high morbidity and mortality rate in patient with KT
*The improved technology and diagnostic methods result in early diagnosis; newest management programs and advanced preventive measures.
*Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine
analog, and sulfamethoxazole (SMX), which is from the sulfonamide family.
*TMP-SMX prophylactic reduce the incidence of PCP in non-HIV patients.
*TMP-SMX should be taken in correct way to get sufficient antimicrobial activity and to prevent over dose mainly in resistant cases.
*The TMP-SMX dose recommendations, on the basis of TMP, is 320–640 mg/day, every 12 h, orally, for bacterial infections.
15–20 mg/kg every (6 – 8 h) I/V then orally for the treatment of PCP infections.
In current guidelines high dose is recommended for PCP (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks), but the risk of S/E is high such as skin irritation, GIT disturbances, BM suppression, renal impairment, hepatotoxicity and electrolyte disorder.
*The therapeutic option for treatment of PCP is 16 mg/kg of TMP-SMX with risk of
hepato-renal AEs so it need dose optimization strategies.
# Methods:
*The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines
*Various databases were searched from January 2000
to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
*The data were collected in a specific form with predefined inclusion and exclusion criteria.
*The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
*Studies of all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening.
*The studies published before January 2000 or having inappropriate and incomplete information were excluded from the study.
*Data extraction was performed using the predesigned data collection form for this review using Microsoft word 2013
# Results:
*Thirteen studies met the inclusion criteria for final analysis.
*Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
*Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
*The study found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
*This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan.
# Discussion
*The impact of PCP on mortality and morbidity of the patients especially
immunosuppressive patients is significant.
* This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
*The incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
*TMP-SMX is a first-line regimen for prophylaxis of PCP, but switch to second-line
treatment such as dapsone, atovaquone, and atomized pentamidine is recommended due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and (G6PD) deficiency.
* the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, ATG, or CNI
# The limitations of the study:
*The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
*It is include all studies that met inclusion criteria, due to limited number of studies that conducted after January 2000.
*Small sample size results in false-negative or false-positive findings.
# Conclusions
*The study provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
*The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
*Reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
* The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
What is the level of evidence provided by this article?
Please summarise this article.
-Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has incidence more than 50% in immunocompromised patients and 5–15% in transplant recipients . The clinical indications of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients measures .
-TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage .
-The TMP-SMX dosing recommendations, on the basis of TMP component, 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections .
-In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) . There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
– It is systematic review of different databases searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria.
-It revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
-The TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency .
-The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors .
-Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts .
-Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes, HIV-positive patients who have CD4+ counts less than 200 cells/mm3, rheumatological and other autoimmune dysfunctions .
-The low dose of TMP-SMX provides satisfactory outcomes while
reducing the mortality rate and PCP-associated AEs.
-Prospective RCTs and cohort studies are needed to provide guidelines regarding the dosing strategiesfor the PCP. What is the level of evidence provided by this article?
Level 3
Aim of this systematic review : To assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodefi-ciency syndromes.
Introduction :
PCP is a hallmark disorder indicating human immunodeficiency virus (HIV) infection, the incidence of PCP was more than 50% in immunocompromised patients,but has been reduced due to advanced technology in diagnosis ,treatment and preventive measures. High-dose TMP-SMX is recommended for PCP, but its use is limited due to insufficient data. To ensure safety, dose optimization strategies should be used.
Materials and Methods:
-Data Sources and Search Strategy: The systematic search assessed the dosing guidelines of TMP-SMX in patients using PRISMA guidelines and free-text web searches. Free-text web searchesexplorearticles in English from January 2000 to December 2021. Keywords used were “dose optimization”, “Pneumocystis carinii pneumonia”, “HIV-patients”, “immunocompromised patients”, “Co-trimoxazole”, “trimethoprim/sulfamethoxazole“
Selection Criteria and Procedure:Studies reporting the dosing strategy of TMP-SMX in patients for PCP were included in this review, with retrospective studies, randomized controlled trials (RCTs), and case reports available in English. Titles and abstracts of all included articles were screened independently by two reviewers, with uncertainty as to whether selected studies met inclusion criteria discussed with a third reviewer.
Data extraction : was performed by one of the reviewers and reviewed by another co-author, with any discrepancies resolved by a third reviewer.
Article Quality Assessment: Article quality was evaluated using the Newcastle–Ottawa Scale (NOS), Joanna Briggs Institute (JBI) critical checklist, and Cochrane bias tool. Two reviewers compared their results and disagreements were resolved by detailed discussion.
Results:
Study Characteristics : 857 related published studies were identified from grey literature and electronic databases, and 163 studies were evaluated for eligibility criteria. 25 articles were excluded due to no full-text, literature reviews, inappropriate intervention, no required data, and non-English. 13 articles met inclusion criteria for final analysis, nine of which were retrospective cohort studies.
Quality Assessment of Studies: Based on the NOS eight studies were rated as a total score of 7, one study scored 6, and the remaining four studies scored 8. The Cochrane bias tool assessed that almost all domains for RCT were at low risk of bias, and the quality of case reports in both reports was of good quality.
Dosing Strategy of TMP-SMX in Selected Studies: The dosing regimen of TMP-SMX and clinical outcomes of 13 studies was evaluated ,of which four studies reported that patients had AIDS, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency. Low-dose treatment regimens (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), were found to be as well-tolerated and effective as high-dose regimens ( (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), , but had fewer side effects compared to conventional dosing regimens. Nakashima et al. reported that the total AEs rate was 58.3% in the low-dose group.
Discussion:
The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group. Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immuno-compromised patients. PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3. The first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP160 mg/day). Alternative PCP strategies include administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays. The standard doses result in an absolute increase of 18% in the incidence of grade ≥3 AEs, but step-down therapy may be a worthy approach to improve clinical outcomes. The incidence of occurrence of PCP is the most frequent in patients with systemic rheumatoid arthritis disease taking steroids and immunosuppressive agents.
Conclusions:
TMP-SMX provides satisfactory outcomes while reducing mortality and AEs, and reduces economic burden and compliance.
Level of evidence :
This systematic review includes case reports, case control studies and observational cohort studies . The grade of recommendation is grade B and level of evidence in systematic review of cohort studies is level 2a while in systematic review of case-control studies is level 3a . I didn’t find information regarding the level of evidence in systematic review of mixed cohorts ,case control and case reports studies .
Introduction The most frequently fatal fungal infection for autoimmune people is Pneumocystis carinii pneumonia. Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%. Immunosuppressive patients die mostly from PCP critical symptoms as tachycardia, hypoxia, tachypnea, shortness of breath, etc. Hence, PCP is an HIV hallmark. Due to enhanced diagnostic technologies, early diagnosis, intensive care management strategies, and preventive measures, PCP in HIV-positive patients has decreased in recent years.
Materials and Methods PRISMA recommendations were used for the systematic search of TMP-SMX dosage guidelines in patients. This review covered studies on TMP-SMX dose for PCP incidence or recurrence. Based on titles and abstracts, all studies involving TMP-SMX clinical outcomes were screened. The selected studies provided author, year, design, sample size, patient characteristics, dosage approach, clinical outcomes, and findings.
Results Among a total of more than 857 papers screened, only 13 matched the inclusion criteria for evaluation. Of the 13 selected studies, nine were retrospective designs, two case reports, and two RCTs. Based on the NOS quality of studies evaluation, eight studies received a total score of 7, one study had a score of 6, and four studies received a score of 8. The average score for the included studies was 7. The Cochrane bias test determined that the majority of RCT domains posed a minimal risk of bias. According to the JBI critical checklist, the case report quality in both reports was high. Five out of thirteen studies compared the low-dose regimen of TMP-SMX to the high-dose regimen, and they recommended the low-dose regimen of TMP-SMT as first-line therapy for preventing the recurrence or development of PJP because it was much more tolerable. Ohmura and his colleagues reported in one more research that a low-dose treatment regimen of TMP-SMX with 10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy and was linked with fewer side effects and a lower death rate of 19% compared to >25% in conventional dose. Low-dose treatments had fewer side effects than conventional regimens. Among 84 kidney transplant recipients with hyperkalemia and 102 with leukopenia, TMP-SMX was reduced in 438 patients. TMP-SMX caused hyperkalemia in another research. Nakashima et al. found that 72.4% of patients in the conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day) and 58.3% in the low-dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day) had AEs. In G6PD-deficient patients, TMP-SMX caused hemolysis. Up to weeks 24 and 52, neither RCT reported PCP.
Discussion PCP has a significant impact on patient mortality and morbidity, especially in immunocompromised individuals. According to this analysis, low-dose TMP-SMX should be the first-line treatment because it reduces mortality and PCP-related side effects. Compared to the control group, there was a 91% reduction in the incidence of PCP and an 83% reduction in the mortality rate. Due to TMP-SMX-associated adverse effects and medication intolerance induced by neutropenia and G6PD deficiency, it is usually necessary to move to second-line therapies (dapsone, atovaquone, and pentamidine). Conclusion The low dose of TMP-SMX produces good results while decreasing mortality and PCP-associated adverse events. This approach decreases the overall economic load and increases patient adherence to their daily prescription.
Level of evidence In the current meta-analysis, the evidence of selected studies ranges between retrospective studies with level of evidence III, case reports/series-level IV and level I for RCTs. Hence, based on the majority of studies being Level of evidence III, I propose a III LOE, however the meta-analysis and systemic review implies LOE I.
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Introduction
Co-trimoxazole (TMP-SMX), is the drug of choice for prophylaxis and treatment of PCP.
We need to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities.
Adverse events (AEs) related to TMP-SMX , are skin rashes, gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity and electrolyte disorder.
The current dosing guidelines, recommend high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) for PCP.
This review included the studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP. Results
13 studies included in the study, with a total of 2663 patients.
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
One study, reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy.
In another study, in patients who received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day), 23% were switched to low-dose TMP-SMX due to various AEs. This regimen was deemed to be safe and effective in patients with various immune dysfunctions.
Nakashima et al. reported that the total AEs rate was 58.3% in the low dose group, and 72.4% in conventional-dose group.
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
In one study there was a decrease in mortality rate in the low dose group (19.5%) compared to the conventional-dose group (25.0%)
Discussion
This review has shown that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, but it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX associated AEs.
The study failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
Limitations of the study:
The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
The majority of included studies were had small sample size, this may result in false-negative or false-positive findings.
Conclusions
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Level of evidence:
Since this systemic review included retrospective cohorts and case studies in the analysis, the level is 3
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders .
The incidence of PCP was more than 50% in immunocompro- mised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases .
The clinical indica- tions of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients .
TMP-SMX has been observed to substantially minimize the incidence of PCP in patients .
The TMP-SMX dosing recommendations, on the basis of TMP compo- nent, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections .
In accordance with current dosing guidelines, the recommended therapy for PCP is high- dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) .
Although the TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency .
The current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs .
Summary : Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review Introduction
Pneumocystis jirovecii pneumonia (PJP) has an impact on mortality and morbidity in immunocompromised patient including kidney transplant one
Substantial evidence from multiple trials raises the benefit of antibiotic prophylaxis in reducing the incidence of PJP
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family, currently, it is used for prophylaxis of PJP but adverse events like neutropenia and hepatic toxicity has been observed that elaborate the need for formulating well-defined guide for its use
The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections [7]. In accordance with current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks)
Therefore, to ensure the safety of TMP-SMX, systematic review is needed to optimize the benefit and reduce the associated adverse events Materials and methods
Web based search done and 3 types of research work included (retrospective. randomized controlled and case studies) published from year 2000- 2021 where the data validation done using the following tools: a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
The web-based search resulted in 857 titles that reduced to 13 trials after application of exclusion and inclusion criteria Results
· five of thirteen included trials compared the low-dose regimen of TMP-SMX with a high-dose regimen they conclude that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
· Ohmura and his colleagues concluded that a low-dose treatment regimen (<10 mg/kg ) of TMP-SMX is effective in prevention of PJP in the target groups without adverse events.
· Schild et al. in their study they use an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, switched to low-dose TMP-SMX cause of 23% of patients showed various AEs
· Nakashima et al. reported that the total AEs rate in the low dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), to be 58.3% and 72.4% respectively
· As regard mortality due to TMP-SMX, Kosaka et al ; reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%) Discussion
low-dose TMP-SMX therapy should be the first-line treatment option as it is concluded that it reduces both the related mortality and adverse events
the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg every other day but, daily dose may be beneficial in prevention of other posttransplant infection like toxoplasmosis
second-line treatment such of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays can be used in case of TMP-SMX intolerance Routine PCP prophylaxis is recommended
· Upon hospital admission of immucompromized patient where the prevalence of PJP is > 3%
· 1-6 months after organ transplantation (high immunosuppressive burden)
· CMV infection
· Increase number of rejection episodes
· low CD4+ lymphocyte counts (less than 200 cells/mm3) limitations.
1- Small sample size in the included 13 studies
2- Differences in the demografic data included due to differences in the distribution countries where the studies have been done
Conclusion
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs without causing economic burden.
Further large-scale, prospective RCTs and cohort studies are needed to provide guidelines regarding the dosing strategies for the PCP
Introduction: Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders. The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases The clinical indications of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX). Therefore, to ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies. Objective :
To assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes. Methods:
Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data
were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
Selection Criteria and Procedure:
studies of all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening. The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study.
The studies published before January 2000 or having inappropriate and incomplete information were excluded. Data Extraction:
Data extraction was performed using Microsoft Word 2013 using a pre designed data collection form for this review. Results:
13 studies met the inclusion criteria for final analysis. Of the 13 studies selected, 9 were retrospective cohort studies, 2 case reports and 2 randomized controlled trials (RCTs).
Most studies compared high-dose TMP-SMX regimens to low-dose regimens in PCP. Low-dose TMP-SMX provides satisfactory results while reducing mortality and side effects associated with PCP.
This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan Recommendations:
Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
PCP prophylaxis is highly recommended in HIV-positive patients who have
CD4+ counts less than 200 cells/mm3
Study limitation:
This study does have several limitations. Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment. Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
Thirdly, although the quality of the majority of the included studies was
good, due to small sample size, this may result in false-negative or false-positive findings Conclusions:
The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
level 111: Evidence from evidence summaries developed from systematic review
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
This is a retrospective study, reviewing current evidence in PCP patients with a focus on dose optimization strategies, databases were searched from January 2000 to December 2021.
1. In accordance with current dosing guidelines, the recommended therapy for PCP is high- dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
2. High dose of TMP-SMX had higher rates of AEs such as skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs.
The TMP-SMX dosing recommendations
1. Recommendation on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections.
2. In accordance with current dosing guidelines, the recommended therapy for PCP is high- dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
3. The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of hepato-renal AEs.
Results of the study:
1. Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy.
2. Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions.
3. Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
4. AEs rate was 58.3% in the low- dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day) and72.4% in the conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day).
5. Mortality rates were reported lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%)..
Discussion
1. This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
2. It often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
3. Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
4. The first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day).
Limitations of the study:
1. The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
2. The limited number of studies conducted after January 2000 forced the authors to include all studies that met inclusion criteria.
3. The majority of the included studies, due to small sample size, may result in false-negative or false-positive findings.
Conclusions
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
The level of evidence provided by this article:
This is a retrospective study with level of evidence grade 3.
☆ Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review ______________________________
◇ Introduction ▪︎Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii has high incidence in immunocompromised patients, hematological malignancy, and transplant recipients. ▪︎The occurrence or recurrence of PCP in HIV-positive patients has been reduced due to advanced technology and tools in diagnostic process. ▪︎Co-trimoxazole is the combination of trimethoprim (TMP), and sulfamethoxazole (SMX). ▪︎ There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX such as skin irritation (e.g., rashes), GIT disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder. ▪︎The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of hepato-renal AEs.
¤ To ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
◇ Methods: ▪︎Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
▪︎The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each
article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
◇ Results: ▪︎Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected
studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
▪︎Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
▪︎ The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Limitations of the study: 1. The findings could have been affected by socio-demographic characteristics because the selected articles included patients from various countries. 2. The limited number of studies conducted after January 2000 forced the authors to include all studies that met inclusion criteria. 3. Small sample size.
◇ Conclusions ▪︎These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. ▪︎The low dose of TMP-SMX provides satisfactory outcomes while decreasing the mortality rate and PCP-associated AEs. It also reduces overall economic burden and enhances patients’ compliance. ▪︎For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. ▪︎The study findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Introduction Pneumocystis carinii pneumonia (PCP),is frequent and significant fungal infection for patients with autoimmune disorders. May present as tachycardia, hypoxia, tachypnea, shortness of breath The occurrence or recurrence of PCP in HIV-positive patients due to advanced diagnostic tools and new therapeutic strategies Co-trimoxazole is the combination of trimethoprim (TMP) and sulfamethoxazole (SMX) This review focused on the use of TMP-SMX in PCP patients with a focus on dose optimization strategies
Methodology · Various databases were searched from January 2000 to December 2021 · The focus was on the dose optimization of TMP-SMX. · Specific form with predefined inclusion and exclusion criteria was used · Quality of article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies. · Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs);
Results 13 Studies were analyzed – ( 9 Retropsective cohort, 2 case reports, 2 RCT) Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP It was found that low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and adverse events. This reduced the economic burden of illness and enhances patients’ compliance to daily regimen
Conclusion · The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events · This strategy also reduces economic implications · Large-scale, prospective RCTs and cohort studies are required to provide guidance for adequate dosing strategy What is the level of evidence provided by this article? Level 1
The level of evidence question highlighted the most important aspect of this study: It was a bad study.
Normally, if it was a meta-analysis of just the two RCTs, it would be a level one study. If it was a meta-analysis of just the 9 retrospective trials it would be a level 3 study. Meta-analysis are not done for case reports. They somehow managed to throw those in…
I would grade it as “ungradable” if such a category exists!
The level of evidence may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size. As always, a systematic review is generally better than an individual study.
● PCP is the most frequent and highly morbid fungal infection for patients with
autoimmune disorders
● The incidence of PCP
☆ > 50% in immunocompromised patients
☆ 50% of patients with hepatotoxicity
☆ 22–45% in hematological malignancy
☆ 5–15% in transplant recipients
☆ 2% in patients with rheumatoid diseases
● The symptoms of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients
● PCP indicates HIV infection
● TMP-SMX minimizes the incidence of PCP in patients.
● AEs such as skin irritation ( rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity and electrolyte disorder
● Treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX
Routine PCP prophylaxis is recommended for patients :
☆ Hospitalized patients
☆ Transplant recipients
☆ Concomitant CMV infections
☆ Graft rejection episodes
☆ Low CD4+ count lymphocyte
Materials and Methods
● Free-text web searches were explored for articles in English from 2000 to 2021.
● The study includes studies of all types with any data on clinical outcomes of TMP-SMX regimens
● The main goal of this systematic review is assessing the current dosing strategy of TMP-SMZ to reduce the risk of PCP especially in immunodeficiency syndromes.
Results
● Low-dose TMP-SMX therapy should be the first-line . it reduces mortality rate and PCP-associated AEs.
● It decreases PCP by 91% and mortality by 83% when compared to control group
● Though TMP-SMX is a first-line for prophylaxis of PCP, it often has to be switched to other treatment such as dapsone, atovaquone, and atomized pentamidine due to it’s AEs and drug intolerance ” neutropenia and (G6PD) deficiency
● The double-strength seems to be effective while taken daily or thrice in a week, though daily TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
● The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
limitations :
☆ Selected articles included patients from various countries, so it affected by socio-demographic such as ethnicity, region, lifestyle, and environment.
☆ Limited number of studies conducted after 2000
☆ Small sample size of studies
-Pneumocystis pneumonia PCP is highly prevalent fungal infection in immunocompromised individuals and carries significant morbidity and mortality. TMP-SMX decreases the incidence of PCP in patients.
-Data on the optimal dose of TMP-SMX is insufficient, the current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX, this regimen associated with high incidence of adverse events.
Aim of the study:
-Review current evidence in PCP patients with various immunodeficiency syndromes focusing on dose optimization strategies to ensure the safety of TMP-SMX.
Materials and Methods
-Search for articles in English only from January 2000 to December 2021 which focus on the dose optimization of TMP-SMX
– Systematic search in different databases.
– Included studies reporting the dosing strategy of TMP-SMX in PCP, any clinical outcomes of TMP-SMX regimens.
– Included; retrospective studies, RCTs, and case reports
-Exclusion: studies published before January 2000 or studies with incomplete information
– Collected data in a specific form were screened by two reviewers independently.
– The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for RCTs
Results:
– Initially, 163 studies were evaluated for eligibility criteria after screening only 13 studies met the inclusion criteria for final analysis.
– Of the 13 selected studies; 9 retrospective cohort studies, 2 case reports, and 2 RCT.
– A total of 2663 patients were recruited in the included studies.
– Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
– low-dose treatment regimen is well-tolerated, effective , and fewer side effects compared with high-dose therapy
– Low dose group has lower mortality rate and PCP-associated adverse events
Conclusion:
-low-dose TMP-SMX therapy resulting in the reduction of mortality rate and PCP-associated AEs and can be used as first strategy.
-No significant differences in the occurrence or recurrence of PCP between full-dose and low-dose TMP-SMX.
This strategy reduces economic burden of illness and enhances patients compliance to daily regimen plan.
Limitations:
– Small number of study included.
– Comparing studies with different designs.
– Socio-demographic data may affect the results of the selected articles as it included patients from various countries.
– The included studies with small sample size may result in in false-negative or false-positive findings.
Level of evidence: Level II: Systematic review with heterogenous studies and evidence obtained from at least one well designed RCT (eg large multi-site RCT).
Pneumocystis carinii pneuomonia PCPC known as pneumocystic jirovecii pneuomonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorder.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases.
PCP is considered a hallmark disorder indicating human immunodeficiency virus infection.
TMP-SMX has been observed to substantially minimize the incidence of PCP in patients.
A retrospective study reported that the incidence of PCP and PCP -associated mortality was lower in patients with rheumatoid arthritis who received high-dose of glucocorticoids.
The incidence of adverse events (AEs) was decreased in non-HIV patients who received TMP-SMX prophylactically.
Methods
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA).
Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, etc., were explored for articles in English from January 2000 to December 2021.
Reference lists of relevant studies were screened for additional titles for inclusion in the review.
The keywords used for the search were “dose optimization”,pneumocystics carinii pneumonia”,.
“pneumocystics pneumonia “HIV-patients”, “immune compromised patients” “Cotrimoxazole”, “trimethoprim/sulfamethoxazole”, and “TMP-SMX”.
Results
857 related published studies were identified from grey literature as well as electronic databases.
After the removal of the duplicate studies and other reasons, 163 studies were evaluated for eligibility criteria.
Based on inclusion and exclusion criteria, 125 studies were excluded after the screening of the titles and abstracts.
Full-text articles were screened for final analysis.
Twenty-five articles were excluded due to the following reasons: no full-text (N = 09), literature reviews (N = 04), inappropriate intervention (N = 03), no required data (N = 03), and non-English (N = 06).
A total of 13 articles met the inclusion criteria for final analysis.
Of the 13 selected studies, nine were retrospective cohort studies, two case reports and two RCT
Discussion
The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
The impact of PCP on mortality and morbidity of the patients especially immunosuppressive patients is significant [ 36 ].
TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP –associated AEs,. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to.
The TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX.
Public Health 2022, 19, 2833 8 of 11 associated AEs, and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency [9,10,36] Conclusion
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP -associated AEs, The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP -associated AEs.
This strategy reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV patients, it may still warrant to start prophylactic treatment regimen.
Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic ReviewIntroduction
· Advanced management strategies in intensive care settings and advanced in prevention measurement result in reducing the occurrence or recurrence of PCP in HIV patients.
· Co-trimoxazole is the combination of trimethoprim (TMP) which is a pyrimidine analog, and sulfamethoxazole.
· The TMP-SMX recommended dose to treat PCP is 15 to 20vmg /kg every 6-8 hours and orally for 2-3 weeks.
· High doses of TMP-SMX as a first-line treatment regimen had higher rates of S/E such as skin rash, GIT disturbance, M suppression .renal impairment, and hepatotoxicity. And electrolytes disturbance..
· This review ensures the safety of TMP-SMX there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
· Dose optimization is very effective to ensure the therapeutic outcome of antimicrobial therapy like the management of PCP.
· The retrospective studies, randomized, controlled trials, and case reports available in English were included in this study. Result
· related published studies were identified from grey literature as well as the data base .
· 25 articles were excluded due to :
· Full text, literature reviews, inappropriate intervention, no required data, and non-English.
· 13 articles met the inclusion criteria.
· Nine were retrospective cohort studies,
· Two cases of randomized controlled studies .
· These studies documented that low-dose TMP-SMX therapy must be considered as a first-line treatment option to prevent the occurrence and recurrence of PCP and the low-dose treatment regimen reported fewer side effects compared to the converting dosing regimen.
· Some of the studies report side effects such as hyperkalemia, leukopenia a, auto-hemolysis.in G6PD deficiency. Discussion
· The aim of systemic review was to assess the current dosing of TMP-SMX to reduce the risk of PCP in immunocompromized patients.so review conclude that low-dose TMP-SMX therapy should be the first line treatment option .in reducing mortality rate and PCP-associated AEs,
· Second-line treatment of PCP case of SE or intolerance of TMP-SMX such as dapsone, atovaquone and pentamidine.
· Study failed to identify significant differences between the full-dose and dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
· PCP prophylaxis rather than TMP-SMX is dapsone either alone or combined with pyrimethamine .atovaquone, or pentamidine sprays. Limitations of the study
1-Patients from different countries, so the social, ethnic region, lifestyle, and environmental affect of the findings.
2-limitation number of studies conducted from Jan 2000.
3- The sample size is small in the majority of the studies Conclusion
· This finding provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
· The low dosage TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
· Due to limited data available on the optimal dose of TMP-SMX these findings would support the conduct of large-scale prospective RCTs and cohort studies to provide guiding the dosing strategies for the PCP.
What is the level of evidence provided by this article?
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimisation in Pneumocystis jirovecii Pneumonia (PCP) Management:
A Systematic Review include of retrospective studies, randomized controlled trials (RCTs), and case reports which done between January/2000 to December/ 2021 Introduction:
This study is address role and target dose of TMP-SMZ in reducing risk of PCP in patients with immunocompromised such as HIV patients or lymphproliferative disease or patients with immunosuppressive therapy in solid organ transplant.
Targeting of TMP-SMZ dose and close adherence of TMP-SMZ at time is important to treatment patients with PCP for reduce incidence of mortality from PCP.
So TMP-SMZ is recommended as first line of treatment and patients shifted to second line of treatment as dapsone, atovaquone, and atomized pentamidine because of side effects of TMP-SMZ like neutropenia G6PD deficiency.
TMP-SMZ used as prophylaxis for prevent PCP infection and treatment of PCP infection in transplanted patients.
Risk factors for expose patients to PCP infection is early 6 months post transplant where patients on neutropenic phase, large dose of steroid and receive ATG and on calcinurine inhibitors
Other factors are previous history of graft rejection and history of CMV infection and low CD4+ count lymphocyte counts.
The recommended dose of TMP-SMX is TMP 80 mg/day; SMX 400 mg/day better than doubling the dose ( 160/ 800mg), to avoid side effects of drug.
The incidence of PCP infection is more common in patients with systemic rheumatoid arthritis on immunosuppressive agents or high dose of steroid or autoimmune disease on immunosuppressive agents. Limitations:
Limited of this study is heterogeneous sample and small size of sample lead to false positive and false negative results. also this study done in January which lead to force to include all studies met inclusion criteria. Conclusion:
Low dose of TMP-SMX is recommended to prevent and treat PCP infection in patients with immunosuppressive therapy or congenital and acquired immunodeficiency.
Low dose TMP-SMX carry low risk of mortality and less side effects.
What is the level of evidence provided by this article?
I- Summary: Aim of the study:
To review current evidence in PCP patients with a focus on dose optimization strategies. Material and methods:
Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP were included in this review.
Information retrieved from the selected articles included author and year, design, sample size, characteristics of patients, dosing strategy, clinical outcomes, and findings.
Results:
A total of 13 articles met the inclusion criteria for final analysis.
Nine were retrospective cohort studies , two case reports and two randomized controlled trial (RCT).
Four reported AIDS patients received TMP-SMX for prophylaxis, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency.
A low dose of TMP-SMX provides satisfactory outcomes in comparison to high dose while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Conclusion:
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
The following abbreviations are used throughout my reply below:
TMP-SMZ: trimethoprim-sulfamethoxazole
PCP: Pneumocystis jirovecii
In this review, published in the International Journal of Environmental Research and Public Health in 2022, the authors state their main aim is to “assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes”.
This statement in itself exposes many flaws of the paper. The intention to evaluate “dosing of TMP-SMZ in order to reduce the risk of PCP” implies a focus on prophylactic use of the drug rather than therapeutic use. However, only 6 of the included studies report on PCP prophylaxis (with 1 of these being a duplicate of the same RCT with different reporting times) whilst the remaining 7 papers focus on use of treatment dose TMP-SMZ for confirmed cases of infection. This amalgamation of prophylaxis vs. treatment papers results in very different study end-points making it hard for the reader to understand the focus of the paper, e.g. are the authors focussing on incidence of PCP with low versus high dose TMP-SMZ prophylaxis, incidence of adverse drug effects or efficacy of treatment with low versus higher dose TMP-SMZ? Furthermore, the use of the term “various immunodeficiency syndromes” highlights the heterogeneity of the populations studied across the included papers and indicates it may not be possible to draw useful conclusions that should influence clinical practice. This failure to demonstrate recognition of the potential differences between included patient populations is further exposed in the opening statement in the abstract when the authors comment on the particular impact of PCP in patients with autoimmune disorders, whereas their included studies have population groups ranging from transplant recipients, haemodialysis patients without HIV and patients receiving TMP-SMZ for various infections without detail on immunosuppression status.
Comments on the review methods of this paper
The authors’ intentions for this paper were to conduct a systematic review. Their search included papers published in English from January 2000-December 2021 and they accessed a broad range of databases in order to maximise chances of capturing relevant studies. The keywords they used for their search were: “dose optimisation” “Pneumocystis carinni pneumonia” “Pneumocystis jirovecii pneumonia” “HIV-patients” “immune-compromised patients” “Co-trimozaxole” “trimethoprim/sulfamethoxazole” and “TMP-SMX”. I would suggest that there may have been some limitations in using these search terms, e.g. “immune-compromised patients” is a very specific phrasing and may not capture different terms such as immunosuppressed. Similarly “HIV” rather than “HIV-patients” would probably have been less limiting as search terminology. The authors state that most of their included papers were actually found through reference snowballing and I would hypothesise that this was partially because their search terms were not effective enough and additionally their review question was not well structured with a clear aim and therefore led to a problematic search strategy.
The authors used a predesigned form to extract data from their included studies. A single reviewer is reported to have performed this data collection with the results reviewed by another author and any conflicts resolved by a third person. I would suggest this process was ineffective as there are some very misleading summaries of the included patient characteristics in Table 1 (see later comments).
The initial search process identified 857 papers but the use of automatic tools excluded 224 of these and of the 104 papers sought for retrieval 66 were not retrieved- this is a huge proportion of the papers and I could not see any comments about why these papers were not retrieved. In total, only 13 papers were included in the review. Comments on the included studies in this review
The authors state their systematic review includes 9 retrospective cohort studies, 2 randomised controlled trials (RCT) and 2 case reports. Of these trial types, RCTs should provide the highest-quality evidence. However, there is actually only 1 RCT used in this study as it is the same trial with 2 separate publications depending on outcome reporting (one at 24 weeks and one at 52 weeks). The authors state that 2663 patients were recruited from their included studies but this is untrue as the same 183 patients for the RCT have been counted twice. The included RCT (Utsunomiya et al.) was looking at PCP prophylaxis for patients with rheumatological conditions who were receiving concurrent steroid treatment greater than or equal to 0.6mg/kg/day. In one year there were no reported cases of PCP in either prophylaxis group: for a relatively low incidence disease it is unlikely a population size of 183 is large enough to draw significant conclusions.
The authors included 2 case reports in their systematic review. It is unusual practice to include case reports in systematic reviews as they frequently do not provide high-enough quality evidence. However, in cases of a rare incidence disease or where a case report shed light on an emerging or different treatment one might justify reference being made to them in order to provide the reader with a current overview of the topic. However, I feel the two case reports included in this review are irrelevant to the review aim and should not have been included at all. Rehman et al. 2021 describes a delayed diagnosis of PCP in an individual newly-identified as HIV-positive. The purpose of the case report is to highlight symptoms that should trigger clinical suspicion of PCP and the authors do not even give details on the dose of TMP-SMZ used. Lu et al. 2020 describes a patient with G6PD deficiency who received treatment with TMP-SMZ without developing haemolysis, despite the drug usually being contraindicated in such patients: I do not feel this case report should have been included.
The majority of papers included in this systematic review are therefore retrospective cohort studies which may be prone to bias. In table 1 the authors summarise the studies, including commenting on the characteristics of included patients and the findings of each study. There are some very significant errors here which significantly undermined my trust in the way the authors have interpreted the studies they included.
For example, the authors state Dao et al., 2014 is a retrospective cohort study with 305 patients and that these patients are “patients with PCP infection”. This study was actually investigating the difficulty of achieving TMP-SMX concentrations within target range and concluded that it was difficult to achieve the desired target, with no difference between groups receiving higher or low dose TMP-SMX. The patient population was those receiving TMP-SMX treatment for wide variety of clinical indications, with only 43 of the 305 patients being treated for PCP in contrast to the authors summary that these were 305 patients with PCP infection.
Secondly, the table indicates that Yamashita et al., 2021 is a retrospective study of 81 “patients with HIV” when in fact the population studied was 81 haemodialysis patients who were HIV-uninfected. The study was investigating PCP prophylaxis with low versus higher dose TMP-SMX but there were no reported cases of PCP in either group and the sample size of 81 is very small relative to the predicted incidence of the disease.
Thirdly, the authors describe Park et al., 2021 as being a retrospective cohort study of 1092 “patients with PCP and rheumatoid arthritis”; this is grossly misleading as the study was looking at prophylaxis in patients with rheumatic disease who were receiving non-high dose steroid treatment and the majority of patients did not have PCP. The authors of the systematic review summarised that the clinical outcomes were that “TMP-SMX reduced 1 year PCP incidence and related mortality” but the significant difference between the groups being investigated was the dose of steroids they were taking rather than TMP-SMX. The inclusion of a study with 1092 patients at first glance provides credibility to the sample size included in the systematic review but I feel on closer inspection the study is not as closely related to the review aim as would be expected. Comments on the analysis and conclusions in this paper
The analysis and conclusions in this systematic review are difficult to follow and I think this relates back to the poorly defined research question and the heterogeneity of the patient populations and study outcomes in the included studies. The authors state that they “failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP. This strategy reduces economic burden of illness and enhances patients’ compliance to daily regimen plan”. Considering that the studies which used varying doses of TMP-SMZ for PCP prophylaxis were small and did not report any cases of PCP in either group, it is not reliable to conclude that a lower dose regimen is effective in reducing the incidence of PCP. It is widely-recognised that the use of TMP-SMX may be limited by its side effects and for this reason many of the studies had included outcomes of dose changes or treatment switches. The commonly reported reasons for change were effects such as cytopenia or hyperkalaemia which would be detected by health professionals and the advice to change treatment would most likely be based on this rather than reported patient symptoms. I therefore cannot see the evidence justifying the authors’ conclusion that lower-dose TMP-SMX increases patient concordance with taking their medications. The economic impact equally cannot be evaluated without understanding the incidence of PCP illness in those taking varying doses of prophylaxis.
The authors state that the small number of studies identified through their search methods “forced us to include all studies that met inclusion criteria”. I would argue that their search did not perhaps identify all relevant papers, and that the inclusion of papers and in particular case reports which were not relevant to their question undermines the quality of the review they have published.
What level of evidence does this review provide?
On first glance, this paper is a systematic review which should provide level 1 evidence. However, this is not the case and the paper cannot be viewed as giving an overview of RCTs in this area. There are very significant flaws in the paper as I have explored above and I do not think the review provides any relevant conclusions which should influence clinical practice. It is a good example of the detrimental effect that a poorly-defined research question can have on subsequent search strategy and analysis. It is very difficult to assess incidence of rarer infections such as PCP but in order to provide transparent recommendations for clinical care authors must be clear about definitions of patient populations and the interventions/outcomes being studied: I do not think the authors have done this in this review paper and they have tried to synthesise highly heterogenous papers including those of low quality evidence.
No, I don’t believe it provides level 1 evidence. Instead I think it needs to be significantly downgraded on the basis of the errors in the interpretation of certain papers, inclusion of irrelevant case reports and counting the same RCT as 2 separate trials when it was the same patient cohort with different reporting times. My issue is I am not sure it can be accurately categorised to a level based on these mistakes- I would go as far as to say some of the very significant issues in the interpretations made in the paper should have been picked up at the editorial stage and the authors should have been asked to correct them as errors such as saying a trial has 305 patients with PCP when actually only 43 had PCP is very misleading.
This systemic analysis analyzing Trimethoprim-Sulfamethoxazole dose optimization.
InPCP management. A total of 13 articles met the inclusion criteria for final analysis.
Of the 13 selected studies:
nine were retrospective cohort studies
two case reports
two randomized controlled trial
A total of 2663 patients were recruited in the included studies.
Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
Risk of PCP among transplant recipients
is greater in 1–6 month post-transplantation period
during prolonged neutropenia
in patients receiving steroids,antilymphocyte antibodies, or calcineurin inhibitors
concomitant cytomegalovirus, infections,
number of graft rejection episodes
low CD4+ count lymphocyte counts
First-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
Double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
Standard doses result in an absolute increase of 18% in the incidence of grade>3 AEs
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs
Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
The study showed no significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
Low dose reduces the economic burden of illness and enhances patients’ compliance to daily regimens.
No guidelines are available for PCP prophylaxis in immune mediated dermatological conditions on high dose steroids.
Limitations:
Included studies from various countries hence the findings could be affected by social-demographic, ethnic, religion, lifestyle, and environment.
There was a limited number of studies conducted after January 2000.
Some studies included had small sample sizes leading to false negative and false positive findings.
Study provides current dosing regimen for treatment and prophylaxis of PCP.
Low dose TMP-SMZ provides satisfactory outcomes while reducing the mortality and P.CP associated adverse events.
Low dose reduces economic disease burden and enhance treatment compliance
This is a systematic review with low-quality studies, a level of evidence II
PCP has the most frequent and highly morbid fungal infection for patients with autoimmune disorders the incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid disease.
TMP-SMX dosing recommendation:
on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections [In accordance with current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) .
There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
Materials and Methods:
Data Sources and Search Strategy the systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.
Selection Criteria and Procedure:
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP were included in this review. Retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study.
Article Quality Assessment:
The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Results:
13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen.
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
Discussion:
The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndrome.
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
Although the TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as Dapsone, Atovaquone, and atomized pentamidine due to TMP-SMX AE.
STUDY failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
This strategy reduces economic burden of illness and enhances patients’ compliance to daily regimen plan.
Study limitations.
Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment. Secondly, the limited number of studies
Thirdly, small sample size, this may result in false-negative or false-positive finding.
Conclusions:
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immuno-compromised patients Moreover, the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors
Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts . A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia Therefore, routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes. PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3
AIM OF STUDY
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Limitations of The study
the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
TMP-SMX Dosing recommendations must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage
. The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infection
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks)
There is a high incidence of AEs in patients receiving recommended high doses of TMP-SMX.
2. Materials and Method
Based on the titles and abstracts, studies of all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening. The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study. The studies published before January 2000 or having inappropriate and incomplete information were excluded from the study.
Article Quality Assessment The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
In total, 857 related published studies were identified from grey literature as well as electronic databases
A total of 13 articles met the inclusion criteria for final analysis Of the 13 selected studies, nine were retrospective cohort studies two case reports and two randomized controlled trial (RCT)
**Prasad et al., 2019 Retrospective study
438 Kidney transplant recipients
SS dose of TMP-SMX OD, thrice daily and twice daily The dose was reduced in 84 patients who experienced hyperkalemia and 102 patients who experienced leukopenia
TMP-SMX dose reduction is frequent in the first post-transplant year, but PCP does not occur
Park et al., 2021 Retrospective cohort study
1092 Patients with PCP and rheumatoid arthritis one SS tablet of TMP-SMX (400/80 mg) per day for prophylaxis TMP-SMX reduced 1 year PCP incidence and related mortality TMP-SMX prophylaxis significantly decreased the incidence of the PCP with a favorable safety profile in a patient with RA taking steroids
Yamashita et al., 2021 Retrospective study 81 Patients with HIV Group A: standard-dose (≥6 SS (TMP-SMX 80 mg/400 mg tablets/week) Group B: low-dose groups (<6 SS tablets/week). PCP was not developed in any patients during study period Low-dose TMP-SMX is optimal treatment option to treat and prevent PCP
These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy . Similarly, Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions
What is the level of evidence provided by this article?
LEVEL 5
.
Pneumocystis carinii causes pneumonia (PCP), with increased incidence in immunocompromised patients (50%), hematological malignancies (22-45%), transplant recipients (5-15%) and among patients suffering from autoimmune disorders (2%). PCP is associated with increased morbidity and mortality. Trimethoprim-Sulfamethoxazole (TMP-SMX) has been used as treatment modality for PCP. TMP-SMX use is associated with adverse effects like hepatotoxicity, rash, nephrotoxicity, gastrointestinal disturbances, bone marrow suppression etc. The article deals with analysis of effect of dose of TMP-SMX on PCP patient outcomes.
It was a retrospective analysis of dose-optimization of TMP-SMX in PCP patients. A total of 13 studies (9 retrospective cohort studies, 2 case reports, and 2 randomized controlled trials, RCT) out of 163 shortlisted studies involving 2663 patients were included in the study. The studies compared effect of low-dose TMP-SMX (<15 mg/kg/ day of TMP) with high-dose TMP-SMX (15-20 mg/kg/day of TMP) in PCP patients.
Out of the 13 studies, 4 dealt with HIV positive patients, 4 dealt with rheumatoid arthritis patients, 2 involved transplant patients, 2 involved non-HIV patients, while one was with respect to patient with G6PD deficiency. 9 studies dealt with treatment of PCP and found that low dose TMP-SMX treatment was associated with lower mortality and lower adverse effects. The adverse event rate was 58% in the low-dose patients (versus 72% in high-dose patients), and mortality rates were 19.5% in low-dose patients (versus 25% in high-dose group). Low-dose regimen was found to be safe and effective, well-tolerated, increases compliance, reduces pill burden, as well costs. 4 studies dealt with PCP prophylaxis, and concluded that low dose TMP-SMX prophylaxis reduced the incidence of PCP with a favorable safety profile with effectiveness. The studies found that there was no significant difference in PCP occurrence or recurrence groups.
Limitations of the study include small sample size, retrospective nature, studies included from many countries providing with a heterogenous group, lack of recent studies (post-2000), absence of major RCT, and use of different definitions for low-dose in different studies.
To conclude, the study revealed that low dose TMP-SMX strategy for PCP treatment is advantageous over high-dose regimen with respect to lower mortality and adverse effects and providing satisfactory outcomes, and hence should be preferred. Larger prospective RCT and cohort studies are required for further recommendations.
2. What is the level of evidence provided by this article?
This articel, although is presented as a systematic review, but lacks any major RCT, includes studies which are retrospective in nature, hence I thought it to be as a narrative review.
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review Introduction
{PCP} is the common disease in the immunocompromised patient, with variable incidence;
50% in immunocompromised patients.
22-45% in hematological malignancy.
5-15% in transplant recipients.
2% in rheumatoid patients.
The outcome of treatment regiments according to studies
TMP-SMX has been reported to reduce the incidence of PCP.
The lower mortality rate with the use of high-dose glucocorticoids in rheumatoid arthritis by a retrospective study.
PCP developed in up to 40% of patients with LPD or ALL, and 50% develop hepatotoxicity, however, the incidence was decreased in patients who received TMP-SMX prophylaxis.
TMP-DMX
The appropriate dose for adequate antimicrobial activity.
Dose optomisation is required to ensure effectiveness, avoid resistance and to avoid side effects.
The recommended dose is 320-640 mg/day every 12 hrs PO for bacterial infection, and 15-20 mg/kg every 6-8 hrs IV then POfor PCP infection.
A high dose of TMP-DMX is recommended for PCP infection (TMP 15-20 mg/kg/D and SMXn75-100 mg/kg/D for 2-3 weeks), with high AEs.
In one randomized trial a high dose TMP-SMX associated with a higher rate of AEs (Rash, GI disturbance, bone marrow suppression,renal impairement, hepatotoxicity, and electrolyte disorders) which necesciate alternative regiment to avoid side effects.
Discussion
The aim of this study is to optime dose of TMP-SMX and to reduce the incidence as well as the mortality and morbidity of the PCP infection.
First line treatment should involve low dose TMP-SMX, which reduce the PCP infection rate, AEs, mortality and morbidity.
Second line treatment include Dapsone, Atovaquone and Pentamidine due to TMP-SMX AEs.
Routine PCP prophylaxis is recommended in hospitalized hospital PCP is prevalent.
Risk factors for PCP in transplant recipients;
Steroids.
ATG.
CNIs.
Concamitant CMV.
Concamitant infection.
Graft rejection.
Low CD4 count.
Routine prophylaxis is recommended maily for during the early post-transplant month and after therapy of rejection.
PCP prophylaxis is highly recommended in HIV-positive patients who have CD4 count less than 200 cells/mm3.
No proper guideline on PCP prophylaxis in patient taking immunosuppressat medication.
Alternative regiment for PCP prophylaxis include; Dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine spray.
Limitation of the study
The Articles include patients from various countries, so the finding may be affected by socio-demographic charecteristics (ethnicity, region, lifestyle, and environement).
The limited number of study conducted after January 2000 forced us to include all studies that met inclusion criteria.
Although good quality studies included, the small sample size may results in a false-negative or false-positive results.
Conclusion
The Article provide the common recommended dosage of TMP-SMX in prophylaxis and treatment of {PCP}.
Low dose of TMP-SMX provide a satisfactory result of treating PCP with less side effects, mortality and morbidity.
Limited data available for optimal dose of TMP-SMX, the finding supports towords conducting RCTs, and Cohort studies to establish guidelines regarding dosage strategies.
THE AIM OF THE STUDY ;
———————————-
was to assess the effect of low TMP-SMZ in reducing the risk of PCP in patients with various immunodeficiency syndromes.
THE TYPE OF THE STUDY ;
—————————————
systematic review.
THE METHOD :
———————–
1-Various databases were searched from January 2000to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
2-The data were collected in a specific form with predefined inclusion and exclusion criteria.
3-The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
THE POPULATION ;
——————————–
1-Thirteen studies met the inclusion criteria for final analysis.
2-Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
THE RESULT:
————————–
Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. The analysis found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
THE LIMITATIONS ;
————————–
1-The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
2-The limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
3- Small sample size .
THE CONCLUSION;
———————————
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
What is the level of evidence provided by this article?
————————————————————
Level III
Summary Introduction
Pneumocystis carinii pneumonia (PCP) or jirovecii (PJP) is one of the serious opportunistic I fungal infections which carry a high mortality rate in patients with autoimmune disease or intense immunosuppression like SOT including kidney transplantation, HIV patients, hematological malignancy with prevalence up to 50% .
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family, as per evidence from retrospective studies it is still the drug of choice for chemoprophylaxis and treatment of PJP with current dosing guidelines, the recommended therapy for PCP is high-
dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) (). The use of high-dose TMP-SMT is limited due to renal hepatotoxicity, bone marrow suppression risk, skin allergy, GI disturbance, and electrolyte imbalance. Method
This is a systematic review and meta-analysis of Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, all articles in English have been reviewed from 2000-2021. Selection criteria include
1. The studies reporting the dosing strategy of TMP-SMX in the patients for the occurring-or recurrence of PCP.
2. studies with any data on clinical outcomes of TMP-SMX regimens
3. different study designs included retrospective, RCT, C case reports
They exclude all studies before Jan 2000 or studies with incomplete data, all the studies are reviewed by two independent reviewers Data extraction
Data records by data collection form designed by the reviewer and collection of the information include author and year, design, sample size, characteristics of patients, dosing strategy, clinical outcomes, and findings. The data will be reviewed by another reviewer and any area of conflict can be solved with a third reviewer’s help. The quality assessment of each study was also performed according to the known standardized scales. Results
Only 13 articles met the inclusion criteria for evaluation from a total of more than 857 articles that have been reviewed from the 13 selected studies, 9 were retrospective design, two case reports and another two were RCT. Based on the NOS quality of studies assessment, eight studies were rated with a total
score of 7, one study scored 6, and the remaining four studies scored 8. Overall, the score of included studies was 7. The Cochrane bias tool assessed that almost all the domains for RCTs were at low risk of bias. As per the JBI critical checklist, the quality of case reports in both reports was of good quality. Out of 13 studies, five equated the low-dose regimen of TMP-SMX with a high-dose regimen and they preferred low dose regimen of TMP-SMT as first-line therapy for prevention of recurrence or occurrence of PJP and much more tolerated even one more study by Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy and associated with lower side effects and well tolerated and even lower mortality rate of 19% compared to > 25% in conventional dose in one report. Discussion
This review has confirmed that low-dose MP-SMX therapy should be the first-line therapy for PJP resulting in the reduction of
mortality rate and PCP-associated side effects despite MP-SMT being considered as first-line chemoprophylaxis. but in case of side effects or intolerance still, we can use second-line therapy like dapsone pentamidine, and atovaquone, different doses of MP-SMT like single strength vs double strength, second line chemoprophylaxis doses also summarized in table 3, PCP chemoprophylaxis should be considered in the first 1-6 months post-transplantation, also those with autoimmune disease high dose steroids ad impaired t cell immunity with low C4D count
Limitations of this study
Different populations with diverse ethnicity and socioeconomic backgrounds can affect the results (selection bias)
a limited number of the studies included small sample sizes the majority of the studies included. Conclusions
The low dose strategy of TMP-SMX for the prevention and treatment of PCP. Providing better outcomes less mortality, effective and better tolerated, with improved patient compliance with the regimens at less cost. however, still we don’t have standardized protocols for PCP chemoprophylaxis and treatment and we need more prospective RCT to address this limitation.
What is the level of evidence provided by this article?
LEVEL 2 A despite its systematic review and meta-analysis of retrospective cohorts with good quality a case controls only two RCTs. cant be level 1
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders.
Incidence: 5–15% in transplant recipients
Dosing of TMP-SMX therapy:
low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/ mm3.
The study failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
Limitation:
findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment
small sample size
Conclusion:
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan
PCP more frequently occur in immuno-compromised patients (> 50%), hematological malignancy patients (22–45%), transplant recipients (5–15%), & rheumatioid diseases (2%)
The clinical indications of PCP treatment, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients.
PCP significantly affects patients’ morbidity & mortality, particularly in those with autoimmune diseases, necessitating the use of TMP-SMX at the right doses.
As a result, there is a strong need to examine recent data in PCP patients with an emphasis on dose optimization techniques in order to ensure the safety of TMP-SMX.
Methodology:
From January 2000 to December 2021, a number of databases were searched with a focus on the dose optimization of TMP-SMX.
A predetermined inclusion & exclusion criteria were used to collect the data.
A Newcastle-Ottawa Scale (NOS) for retrospective research, a Joanna Briggs Institute (JBI) critical checklist for case reports, & a Cochrane bias tool for randomized clinical trials were used to assess the quality of each paper.
The main objective of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immuno-deficiency syndromes.
Using grey literature & internet databases, a total of 857 related published papers were identified. 163 studies were assessed for eligibility after the duplicate studies were eliminated. Following the screening of the titles & abstracts, 125 studies were eliminated based on inclusion & exclusion criteria.
Twenty-five articles were excluded due to various reasons.
A total of 13 articles met the inclusion criteria for final analysis.
Results:
The final analysis’s inclusion criteria were met by thirteen studies.
Of the 13 selected studies, 9 were retrospective cohort studies, 2 case reports, & 2 RCTs.
The majority of research compared PCP treatment using high-dose & low-dose TMP-SMX.
It was found that a low dose of TMP-SMX produces acceptable results while lowering mortality & PCP-related side effects. This tactic lowers the financial burden of disease & improves patients’ adherence to their daily regimen.
Comparing low-dose therapy regimens to standard dosage regimens, less adverse effects are typically noted.
Discussion
PCP has a major effect on patient mortality & morbidity, particularly in immuno-suppressive patients.
According to this review, low-dose TMP-SMX medication should be the 1stline of treatment because it will lower the mortality rate & PCP-related adverse events.
There was a decrease in the incidence of PCP up to 91% & decrease in mortality rate up to 83% when compared to the control group.
Although the TMP-SMX has been considered a 1st-line regimen for PCP prophylaxis, it frequently needs to be switched to 2nd-line treatments (dapsone, atovaquone, & pentamidine) because of TMP-SMX associated adverse events & drug intolerance caused by neutropenia & G6PD deficiency.
Limitations
Patients studied are from different geographical, ethnical, environmental, & socioeconomic backgrounds.
Limited number of studies conducted after January 2000 forced authors to include all studies that met inclusion criteria.
The quality of the majority of the included studies was good; however, the small sample size may result in false-negative or false-positive findings.
======================== 2. What is the level of evidence provided by this article?
Level IIa(Systematic review of cohort studies of “exposed” & “unexposed” subjects).
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: 1-Please summarise this article. Introduction; –The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid disease.
-The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
-Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts.
-Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family.
-TMP-SMX has been observed to substantially minimize the incidence of PCP in patients.
-The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections.
-In accordance with current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks). Methods;
-Various data bases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
-The data were collected in a specific form with predefined inclusion and exclusion criteria.
-The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs). Results;
-163 studies from total 857 studies After the removal of the duplicate studies and other reasons were evaluated for eligibility criteria.
-Based on inclusion and exclusion criteria, 125 studies were excluded after the screening of the titles and abstracts.
-Most of the studies were identified through reference snowballing. Full-text articles were then screened for final analysis.
-Twenty-five articles were excluded for different causes ; a total of 13 articles met the inclusion criteria for final analysis.
-Of the 13 selected studies, nine were retrospective cohort studies,two case reports and two randomized controlled trial (RCT).
-Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
-They found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
-The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group. Limitation;
-The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
-The limited number of studies conducted after January 2000 forced them to include all studies that met inclusion criteria.
-Although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings. Conclusions; –This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
-This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan.
-The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
2-What is the level of evidence provided by this article?
-This Systematic Reviews and Meta-analysis; level V evidence.
Pneumocystis carinii pneumonia (PCP) is the most common and deadly fungal infection in autoimmune individuals. Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%. Immunosuppressive patients die mostly from PCP symptoms such as tachycardia, hypoxia, tachypnea, shortness of breath, etc.
Aim:
The Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) criteria were used for doing the systematic search with the goal of evaluating the dose recommendations for TMP-SMX in patients.
Methods:
Gray and electronic literature yielded 857 relevant studies. 163 studies were assessed for eligibility after removing duplicates and other reasons. After reviewing titles and abstracts, 125 papers were removed.
Results:
Four trials reported TMP-SMX prophylaxis for AIDS, four for rheumatoid arthritis, two for non-HIV patients, two for kidney transplant recipients, and one for G6PD deficiency. Five studies compared low-dose TMP-SMX to high-dose.
These trials showed that low-dose TMP-SMX therapy should be used initially to avoid PCP and PCP-associated AEs. However, Ohmura and colleagues found that low-dose TMP-SMX with <10 mg/kg/day TMP was as well-tolerated and effective as high-dose therapy.
limitations:
1- the chosen publications included patients from diverse nations, therefore socio-demographic factors including ethnicity, geography, lifestyle, and environment may have impacted the results.
2- there was little research after January 2000, thus we included those that matched the inclusion criteria.
3- while most of the included studies were strong, small sample sizes may lead to false-negative or false-positive results.
Conclusions:
TMP-SMX dose for PCP prevention and therapy is based on these results. TMP-low SMX’s dosage improves outcomes and reduces mortality and PCP-associated AEs. This technique decreases economic stress and improves patients’ daily regimen compliance. PCP developing TMP-SMX prophylaxis in HIV patients may merit preventive therapy. These results recommend large-scale, prospective RCTs and cohort studies to establish PCP dosage guidelines due to the lack of TMP-SMX dose data.
This is a systematic review with low-quality studies, a level of evidence II
SUMMARY Introduction
PCP is highly frequent and morbid fungal infection in persons with autoimmune disorders. It has a high incidence in immunocompromised individuals at >50%, while haematological malignancy is at 22-45%, transplant recipients 5-15% and 2% in rheumatoid diseases.
Co-trimoxazole is the combination of trimethoprim (TMP) and sulfamethoxazole (SMX).
TMP-SMX minimizes the incidence of PCP in patients, however it must be administered in an appropriate dose to achieve antimicrobial activity while reducing concentration-dependent toxicities.
Recommended high doses have been associated with increased adverse effects.
Dose optimization is the key in antimicrobial stewardship programs and effective to ensure therapeutic outcome of antimicrobial therapy as like in management of PCP Methodology
This was a systematic review. Aim:
To asses the current dosing of TMP-SMZ to reduce the risk of PCP in persons with various immunodeficiencies. Exclusion:
Studies published before January 2000
Studies with inappropriate or incomplete data.
Thirteen studies were included- 9 were retrospective cohort studies, 2-case reports, 2-RCT.
Patients included were 2633.
Studies included: (2)kidney transplant recipients, (4)HIV patients with PCP, (2)PCP patients without HIV, (4)rheumatoid patients (1)G6PD and various immune dysfunctions.
Five studies compared the low-dose regimen of TMP-SMX with a high-dose regimen Results
Low dose TMP-SMX therapy should be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP associated adverse events.
Low-dose treatment regimens have fewer side effects compared to the conventional dosing regimens. Discussion
Low dose TMP-SMX should be the first line resulting in reducing mortality and PCP associated adverse events.
Incidence rate decreased up to 91% and mortality rate up to 83% compared to the control group.
Transplant recipients have a high risk of PCP first 6 months post-transplantation, or when receiving immunosuppressive agents like steroids, anti lymphocyte antibodies and CNI. Other factors that predispose them include concomitant infections like CMV and episodes of graft rejection. Therefore prophylaxis should be considered in the early post-transplant period and after treatment for rejection.
This study showed no significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP. This reduces the economic burden of illness and enhances patients’ compliance to daily regimens.
No guidelines are available for PCP prophylaxis in immune mediated dermatological conditions on high dose steroids. Limitations:
Included studies from various countries hence the findings could be affected by social-demographic, ethnic, religion, lifestyle and environment.
There was a limited number of studies conducted after January 2000.
Some studies included had small sample sizes leading to false negative and false positive findings.
Conclusion.
Study provides current dosing regimen for treatment and prophylaxis of PCP.
Low dose TMP-SMZ provides satisfactory outcomes while reducing the mortality and PCP associated adverse events.
Low dose reduces economic disease burden and enhance treatment compliance.
Large scale prospective RCT and cohort studies are recommended to guide the dosing strategies. Level of evidence
This was a systemic review of combined RCT, cohort and case reports studies making it a level V.
The level of evidence may be graded down depending on the study quality.
For instance this review combined case reports and observational cohorts reducing its study quality.
Introduction
Pneumocystosis has become the most prevalent fungal infection in patients with autoimmune disease, probably due to the high doses of corticosteroids required. The combination of sulfa drugs has been the drug of choice for its treatment.
High doses of sulfa are related to myelotoxicity and hepatotoxicity.
Materials and methods
Systematic review study, considered as level I of evidence, to define the appropriate dose of the TMP-SMX combination based on articles published between January 2000 and December 2021.
Retrospective studies, randomized controls, and reported cases were considered, which may have directly interfered with the quality of the study.
Results
Of the 857 studies evaluated, 163 were included in the initial eligibility criteria, with only 13 being included in this meta-analysis (9 retrospective cohort studies, two case reports and two randomized controlled trials). A total of 2663 patients were included, but quite heterogeneous depending on the study (HIV, rheumatological diseases, solid organ transplantation, immune dysfunction, G6PD deficiency).
The prophylaxis regimens were different, as were the loading and maintenance doses.
Something that disturbs in this study is the absence of the calculation of the heterogeneity of the studies, done by the X2 formula, making it very difficult to assess the real quality of this study. Different population groups, different countries, rheumatic diseases not separated by type or treatment, the existence of chemoprophylaxis, and use of corticosteroids, among other variables, were not evaluated.
Systematic review study, considered as level I of evidence, to define the appropriate dose of the TMP-SMX combination based on articles published between January 2000 and December 2021.
But the absence of the calculation of the heterogeneity of the studies, done by the X2 formula, making it very difficult to assess the real quality of this study
-Introduction
Pneumocystis carinii pneumonia (PCP) is a prevalent and highly morbid fungal infection in autoimmune diseases.
PCP incidence exceeded 50% in immunocompromised cases.
It is presented by tachycardia, hypoxia, tachypnea, dyspnea ,and other symptoms which are poor prognostic signs in immunocompromised cases as HIV patients.
Lately the development in diagnosis ,treatment and prophylaxis of PCP lowered it’s incidence and recurrence in HIV patients.
TMP-SMX use as prophylaxis decreased the incidence of adverse events in non-HIV patients .
Proper antibiotic dosing is essential to avoid antibiotic resistance.
The TMP-SMX dosing for TMP is 320–640 mg/day BID orally to treat bacterial infections, and
15–20 mg/kg every 6 to 8 h IV then orally for the treatment of PCP infections.
The recommended treatment for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SM X 75–100 mg/kg/day for 2–3 weeks which is associated with high rates of adverse effects.
Dose optimization is essential for favourable therapeutic outcome . Methods
Data within 21 years was collected for articles on the dose optimization of TMP-SMX with predefined inclusion and exclusion criteria. Each article value was accessed using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials(RCTs) Results
13 studies were included,9 were retrospective cohort studies, 2 case reports, and 2 RCT. The studies compared high-dose with low-dose TMP-SMX treatment for PCP.
It was noticed that low dose of TMP-SMX lead to acceptable outcomes and in the same time reducing mortality rate and PCP-associated adverse events.
This regimen lowers the economic load and improves patients’ compliance . Discussion
This systematic review evaluated the current dosing policy of TMP-SMZ to reduce the risk of PCP in immunosuppressed cases.
The studies concluded that the first-line of treatment can be low-doseTMP-SMX therapy to decrease mortality rate and adverse events.
Although TMP-SMX is the first option for prophylaxis it’s side effects lead to chosing second line drugs as dapsone , atovaquone, and atomized pentamidine.
The necessity of including prophylactic drugs in immunosuppressive regimens represent economic load for patients and health institutes.
PCP risk among transplant recipients is more in the first 6 month post-transplantation , during neutropenia, or with longstanding steroids, ATG , or CNI as well as CMV infection, multiple
graft rejection episodes, and low CD4+ counts.
Routine prophylaxis is needed in the early post-transplant month and after rejection treatment. PCP prophylaxis is highly recommended in HIV-positive patients with CD4+ counts less than 200 cells/mm3
The first-line prophylaxis is one single strengthTMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP160 mg/day; SMX 800 mg/day) .
Or using one double strength TMP-SMX tablet thrice per week, or intake of dapsone either alone or with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays.
Standard doses are associated with higher incidence of AE.
Step-down therapy need to be assessed to improve clinical outcomes.
Limitations are variable sociodemographic characters of involved studies,small number of studies done after Jan 2000 obliged them to involve all studies meeting their criteria and most studies had small ample size.
Conclusions
Low dose of TMP-SMX provides satisfactory outcomes and decreases mortality rate and PCP-associated AEs ,on the other side it reduces economic load and improves patients’ compliance .
The large-scale RCTs and cohort studies are needed to improve dosing regimens as prophylaxis for primary occurrence of PCP or recurrence of PCP in immunosuppressed cases
-level of evidence is 1 as it is a systematic review
This is a very fundamental issue: the level of evidence of a meta-analysis or a systematic review is as good as the studies included. There is an expression called GIGO. Apologies for using a swear word with all due respect to the authors of this wonderful article. GIGO= garbage in, garbage out.
PCP is an important cause of mortality among immunocompromised patients.
PCP occur in 50% of immunocompromised patients, 22%-45% of hematological malignancies, 5%-15% in SOT & 2% in rheumatoid diseases.
TMP-SMX due incidence of PCP.
Guidelines recommend high dose of TMP-SMX(15-20mg/kg/day+75-100mg/kg/day) for 2-3weeks, but this dose associated with side effects.
TMP-SMX side effects include: skin irritation, gastro-entistinal disturbance, bone marrow suppression, renal impairment, hepatotoxicity & electrolytes abnormalities.
Aim of the study:
Review of evidence about PCP effective treatment & best optimal dose optimized strategy.
Method:
Systemic review of studies published between 200-2021in English.
Included studies :
Report include TMP-SMX dose strategy in PCP treatment.
any data about clinical outcome of TMP-SMX.
retrospective, RCT & case report in English.
Only 13 studies included in analysis.
Result & discussion:
Low dose TMP-SMXis effective in PCP treatment & prophylaxis & reduce mortality with low incidence of adverse effects.
TMP-SMX is the first line prophylaxis used but commonly changed to second line drug( dapsone, atovaquone & atomized pentamidine) due to side effects.
Risk factors of PCP:
intensified immunosuppression in SOT (1-6 months post transplant).
concomitant CMV infection.
infection
number of acute rejection episodes.
low CD4 lymphocyte count.
No different between low dose & full dose of TMP-SMX in occurrence & recurrence of PCP.
First line prophylaxis is one single strength TMP-SMX(80mg/day+400mg/day) or one double strength TMP-SMX (160mg+800mg/day).
Alternative is double strength TMP-SMX as thrice weekly is effective in PCP prevention but daily use will prevent other post transplant infection e.g. toxoplasmosis.
Step down therapy may be worthy in improving clinical outcome.
Limitation of the study:
Heterogeneity of the sample ( different countries).
Number of studies conducted after 2000 forced to included all studies met inclusion criteria.
Small sample size may cause false negative or false positive results.
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence? Can you please reconsider in light of my objection?
Systemic review may assess health care intervention( efficacy, effectiveness & adverse events), & to accommodate evaluation of different research question inclusion of of more one study design in necessary.
introduction: TMP/SMX should be given in an appropriate dose for an adequate response. The recommended dose of TMP/SMX for PCP treatment is 15-20 mg/kg/day every 12 hours for 2-3 weeks. Side effects (myelosuppression, hepatotoxicity, hyperkalemia, nephritis, &rash) are common with high doses. There is insufficient data on the optimal dosage. This study is a systematic review to assess the current dosing strategy of TMP/SMX to reduce the risk of PCP in immunocompromised patients.
9 studies were retrospective cohorts, 2 were case reports, and 2 were randomized controlled trials (RCTs) of the 13 papers that met the inclusion criteria.
The low dose is 10 mg/kg/d in comparison to 15-20 mg/kg/d for the high dose.
Limitation of the study: – the selected articles comprised patients from different nations, thus ethnicity, geography, lifestyle, and environment may have affected the findings. – small sample sizes may lead to false-negative or false-positive results. Conclusion: – low dose TMP/SMX may be effective as the high dose in terms of reducing mortality & PCP-associated side effects, in addition, to reducing economic burden & improve compliance of the patients. – It is required to conduct large-scale, prospective RCTs and cohort studies in order to offer dose guidelines for PCP. level of evidence:
level III
Introduction
o TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity with avoidance of excessive dosage
o The recommended therapy for PCP may be a high dose with high incidence of AEs skin rashes, gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity and electrolyte disorder)
o There is no sufficient data on the optimal dose of TMP-SMX
Aim of the study: review current evidence in PCP patients with a focus on dose optimization strategies
Materials and Methods
Various databases were searched (2000-2021 for articles, focusing on the dose optimization of TMP-SMX
Inclusion criteria:
1. All types with any data on clinical outcomes of TMP-SMXregimens
2. Retrospective studies, randomized controlled trials (RCTs), and case reports
Exclusion criteria:
1. Studies published before January 2000
1. Studies with inappropriate and incomplete information
Results
Thirteen studies were included in this review:
1. Nine were retrospective cohort studies
2. Two case reports
3. Two randomized controlled trials (RCT)
Of 13 studies:
1. 4 reported patients having AIDS received TMP-SMX for prophylaxis
2. 4 reported patients with rheumatoid arthritis
3. 2 documented non-HIV patients
4. 2 reported kidney transplant recipients
5. 1 reported the patient with G6PDdeficiency
o Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP
o Low dose of TMP-SMX (<10 mg/kg/day) provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events
o This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Discussion
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs
In the Cochrane meta-analysis, there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
Limitations of the study:
1. The selected articles included patients from various countries (findings may be affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment)
2. Limited number of studies after January 2000 and inclusion of all studies that met inclusion criteria 3. The majority of studies were small sample size
Conclusions
o Low dose of TMP-SMX provides satisfactory outcomes, reducing the mortality rate and adverse effects
o Low dose strategy, reduces overall economic burden and enhances patients’ compliance to treatment
o Large-scale RCTs and cohort studies are required to improve dosing strategies
What is the level of evidence provided by this article?
Level III
This is a very fundamental issue: the level of evidence of a meta-analysis or a systematic review is as good as the studies included. There is an expression called GIGO. Apologies for using a swear word with all due respect to the authors of this wonderful article. GIGO= garbage in, garbage out.
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection that cause severe lung injury, and is associated with increased morbidity and mortalityThe incidence of PCP differ according to the underlying condition , it is highest in immunocompromised patients (50%), followed by patients with hematological malignancy (22-45%) then transplant recipients ( 5–15%) and is least in patients with rheumatoid diseases (2%).In transplant recipients PCP usually occurs in early transplant period ( in the first 1–6 month post-transplantation). Risk factors for PCP include prolonged neutropenia, CMV infection, the use of steroids, CNI and ATG and low CD4+ count lymphocyte counts.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.Regimens for prophylaxis include either 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) or one double-strength TMP-SMX tablet every other day. Daily administration of TMP-SMX may have the advantage of preventing toxoplasmosis as well.Optimization of the dose of TMP-SMX in the treatment of PCP is crucial to avoid long term adverse effect.Side effects of TMP-SMX include skin rashes, GIT toxicity, BM suppression, hepatotoxicity, renal impairment and electrolyte disturbance (hyperkalemia). And G6PD deficiency is a contraindication to the drug.In patients with either contraindications or intolerable side effects, alternative therapy can be used including dapsone, atovaquone, and atomized pentamidine.
This study is assessing the dose optimization of TMP-SMX using data from 13 previous studies (9 retrospective studies, 2 case reports, and 2 RCT) from January 2000 till December 2021.
Most of these studies were addressing the difference in outcome when using high (TMP dose is 15–20 mg/kg/day) versus low dose TMP-SMX therapy (TMP dose is 4–10 mg/kg/day) for PCP treatment. Results
Low dose TMP-SMX use in the treatment of PCP is associated with comparable outcome (mortality, PCP related morbidity) to high dose protocol with lower drug related side effects and more complianceConclusions:
Low dose TMP-SMX may replace high dose with comparable efficacy and lesser side effects, but larger RCT are needed to assess this dose in immunocompromied patientsWhat is the level of evidence provided by this article?
This is a meta-analysis of level III studies , so it is level III
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection that cause severe lung injury, and is associated with increased morbidity and mortality The incidence of PCP differ according to the underlying condition , it is highest in immunocompromised patients (50%), followed by patients with hematological malignancy (22-45%) then transplant recipients ( 5–15%) and is least in patients with rheumatoid diseases (2%)
In transplant recipients PCP usually occurs in early transplant period ( in the first 1–6 month post-transplantation). Risk factors for PCP includes prolonged neutropenia, CMV infection, the use of steroids, CNI and ATG and low CD4+ count lymphocyte counts 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 Regimens for prophylaxis include either 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) or one double-strength TMP-SMX tablet every other day. Daily administration of TMP-SMX may have the advantage of preventing toxoplasmosis as well. Side effects of TMP-SMX include skin rashes, GIT toxicity, BM suppression, hepatotoxicity, renal impairment and electrolyte disturbance (hyperkalemia). And G6PD deficiency is a contraindication to the drug
In patients with either contraindications or intolerable side effects, alternative therapy can be used including dapsone, atovaquone, and atomized pentamidine Optimization of the dose of TMP-SMX in the treatment of PCP is crucial to avoid long term adverse effect.
This study is assessing the dose optimization of TMP-SMX using data from 13 previous studies (9 retrospective studies, 2 case reports, and 2 RCT) from January 2000 till December 2021
Most of these studies were addressing the difference in outcome when using high (TMP dose is 15–20 mg/kg/day) versus low dose TMP-SMX therapy (TMP dose is 4–10 mg/kg/day) for PCP treatment.Results
Low dose TMP-SMX use in the treatment of PCP is associated with comparable outcome (mortality, PCP related morbidity) to high dose protocol with lower drug related side effects and more complianceConclusions:
Low dose TMP-SMX may replace high dose with comparable efficacy and lesser side effects, but larger RCT are needed to assess this dose in immunocompromied patients
PCP is the most frequent and highly morbid fungal infection for patients with autoimmune disorders, and is a hallmark disorder indicating human immunodeficiency virus (HIV) infection.
Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole that has been found to reduce the incidence of PCP in non-HIV patients.
TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration dependent tox-icities.
In the era of antimicrobial resistance, optimal antibiotics usage is essential. Current dosing guidelines recommend 320-640 mg/day, administered every 12 h, orally, to treat bacterial infections and 15-20 mg/kg every 6 to 8 h intravenously then orally for PCP infections.
However, there is a high incidence of AEs in patients receiving recommended high doses. To ensure safety, dose optimization strategies are needed.
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using PRISMA guidelines and free-text web searches using Google Scholar, PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews. Keywords used were “dose optimization”, “Pneumocystis carinii pneumonia”, “HIV-patients”, “immune compromised patients”, “Co-trimoxazole”, “trimethoprim/sulfamethoxazole”.
Selection Criteria and Procedure
Studies reporting the dosing strategy of TMP-SMX in PCP were included for further screening, with retrospective studies, randomized controlled trials, and case reports excluded.
2.3. Data Extraction
Data extraction was performed by one reviewer and coauthor, with any discrepancies resolved by a third reviewer.
2.4. Article Quality Assessment
Two reviewers assessed the quality of each included study independently, with disagreements resolved by detailed discussion.
857 related published studies were identified from grey literature and electronic databases, and 163 were evaluated for eligibility criteria.
25 articles were excluded due to no full-text, literature reviews, inappropriate intervention, no required data, and non-English.
13 articles met the inclusion criteria for final analysis, nine of which were retrospective cohort studies.
2663 patients were recruited in selected studies.
3.2. Quality Assessment of Studies
The NOS, Cochrane Bias tool, and JBI critical checklist assessed the quality of studies, with 8 studies rated as 7.2.
3.3. Dosing Strategy of TMP-SMX in Selected Studies
Low-dose TMP-SMX therapy must be considered as a first-line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Low-dose treatment regimens reported fewer side effects than conventional dosing regimens, but hyperkalemia, leukopenia, hemolysis, and PCP were reported.
Low-dose TMP-SMX therapy should be the first-line treatment option to reduce the risk of PCP in immunosuppressive patients, as a Cochrane meta-analysis reported a decrease in the incidence of PCP up to 91% and mortality rate up to 83%.
Routine PCP prophylaxis is recommended for immunocompromised and transplanted patients, as the risk of PCP is greater in 1-6 month post transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
This strategy reduces economic burden of illness and enhances compliance to daily regimen plan.
TMP-SMX is the first-line prophylactic agent for PCP, but alternative prophylaxis may not provide desired clinical outcomes.
PCP is the most frequent in patients with systemic rheumatoid arthritis, and risk factors include age, use of glucocorticoids, and existing comorbidities.
Guidelines for PCP prophylaxis for various cohorts are needed due to limited data on predictors and risk factors.
Small sample size and limited number of studies may lead to false-negative or false positive findings.
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence? Can you please reconsider in light of my objection?
This is a very fundamental issue: the level of evidence of a meta-analysis or a systematic review is as good as the studies included. There is an expression called GIGO. Apologies for using a swear word with all due respect to the authors of this wonderful article. GIGO= garbage in, garbage out.
PCP remained the most frequent & highly morbid fungal infection among immunocompromised patients such as autoimmune disease
the first line drug of co-trimoxazole (trimetheoprim(TMP)+ sulfamethoxazole (SMX) markedly decreases the incidence of PCP.
Different protocols available regarding dosage and duration , so the optimization of both afro mentioned issues are crucial for proper coverage and decreasing of adverse events (AE).
the lowwer doses effective and associated with lower AE
S.E of co-trimoxazole : rash , GIT disturbances, BM suppression, renal impairment, electrolyte disturbance and hepatotoxicity
think about alternatives/ second lines such as dapsone, atovaquone, pentamidine, in cases of not tolerate side effects, neutropenia, G6PD deficiency and resistance to first line
Pneumocystis jirovecii(PJP) pneumonia previously known as pneumocystis carinii(PCP) is leading cause of morbidity in those with autoimmune disease.
Incidence is > 50% in immune compromised hosts.
In setting of HIV,the incidence has reduced due use of prophylaxis and the use of HAART.
Co-trimoxazole is compose of trimethoprim(pyrimidine) and sulfamethazole(sulfonamide) and this drug has significantly reduced the incidence of PCP.
The antimicrobial resistance is a threat to the use of antibiotics and therefore optimal antibiotic usage is essential for effective treatment.
Due to limited data on the optimal dosage of TMP-SMX, there is a need to review the available literature in PCP regarding dose optimization strategies.
Methodology
The English guidelines and articles for dosing of TMP-SMX from January 2000 to December 2021 was reviewed using the steps for systematic review and meta-analysis(PRISMA).
Quality of the articles was evaluated as follows; retrospective studies by NOS(Newcastle-Ottawa Scale), case report by JBI(Joanna Briggs Institute), RCTs by Cocrhane tool.
Studies before January 2000 or those with inadequate data were ruled out.
Results
After the process of identification, screening, 13 articles made it and accepted for the final assessment.
Their design was retrospective( 9 studies), case reports (2 studies), and RCTs(2 studies).
The majority of the studies looked at the difference between high-dose and low dose TMP-SMX in treatment of PJP.
This systematic review showed that, low-dose TMP-SMX is effective and associated with decrease mortality, reduced treatment cost, and adherence to daily drug intake.
Conclusion
The use of low-dose TMP-SMX may result in favorable outcomes in PJP treatment
Further RCTs are badly needed to give better understanding on the optimal dosage of TMP-SMX in PJP treatment
What is the level of evidence provided by this article?
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence? Can you please reconsider in light of my objection?
I agree with you these study had 9 retrospectives ( level III), 2 case control (level IV) and 2 RCTs ( level I)
My thoughts he would reviewed either observational cohort alone, or RCTS alone to come out with systematic review but not mixing them because of different designs and level of evidence in each study
Why he did that, I am not sure
Yes, he used PRISMA protocol but he had only 2 RCTS, not powered
I would give him III or IV in the middle of these confusions
1- Pneumocystis jirovecii pneumonia PCP is one of the commonest and high mortality infection in SOT either in HIV or non-HIV patient.
2- Its treatment by trimethoprime-sulphmethoxazole TMP-SMZ should be adequate to ensure adequate antimicrobial activity and not inducing drug resistance and also try to minimize its adverse effects.
3- It was found that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs, with decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
4- TMP-SMX is considered as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX drug intolerance and side effects like neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
5- Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients.
6- the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
7- Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts.
8- routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
9- PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3.
10- the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day).
11- Alternative PCP prophylaxis includes one doublestrength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays.
12- The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis.
13- The risk factors for PCP in patients with rheumatoid disorders include age group (elderly > 65 years), use of glucocorticoids, and existing comorbidities.
14- Limitations of this study include the following:
a- patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
b- the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
c- the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence?
PCP is the most frequent and serious fungal infection for patients with autoimmune disorders. The incidence of PCP was about 50% in immunocompromised individuals, 20 to 40% in hematological malignancy patients, 5 to 15 % in transplant recipients and 2% in RA.
TMP-SMX has been observed to minimize the incidence of PCP in these patients.
As with other antibiotics,TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration dependent toxicity, necessitating the avoidance of excessive dosage.
In accordance with current dosing guidelines, the recommended therapy for PCP is high dose of TMP-SMX.
Patients receiving recommended high dose of TMP-SMX as first line treatment regimen had higher rates of adverse effects such as skin iirritation, GIT disturbances, bone marrow suppression, renal and hepatoxicity.
Thus requiring optimal dosing strategies of TMP-SMX, therefore to ensure drug safety and there is a high demand to review current evidence in patients with PCP with a focus on dose optimization strategies
Methods
Various databases were searched from Jan 2000 to Dec 2021 for articles in English, focusing on dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria .
Results
Thirteen articles from 857 met the Inclusion criteria for final analysis
Most of studies compared the high dose with the low dose TMP-SMX therapy for PCP
They found that a low dose of TMP-SMX provides satisfactory outcomes while reducing mortality rate and PCP associated adverse effects. This strategy reduces the economic burden of illness and enhances patients compliance .
Level of evidence III
This systematic review article
They analyzed 13 study (from (857 studies) that match the criteria of their main goal
Main goal of this study is to assess the current dosing strategy of
TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
the studies included PCP in HIV ,kidney transplant ,GCPD patients,rheumatoid arthritis
they recommended that low dose prophylaxis is the best option to avoid PCP infection and possible side effects from Sulfa-trimethoprime
but still need more RCTs for some patient populations like PCP emerging on TMP-SMX prophylaxis in HIV patients ,due to limited data available
This is a systematic search assessing the dosing guidelines of TMP-SMX in patients from 31 studies chosen out of 857 studies. The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group . Although the TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients. Moreover, the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors . Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts . A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia . Therefore, routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes. the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) . Alternative PCP prophylaxis includes one double strength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays . This practice may not provide desired clinical outcomes with the minimal risk of AEs. The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
level of evidence 3
Study backgroud
Databased from January 2000 to December 2021
Searched for PCP dose optimization of TMP-SMX – 13 studies meet the inclusion and exclusion (9 retrospectives, 2 RCT, 2 case reports)
Comparator: High vs Low dose TMP-SMX
Outcome: Low dose provide a satisfactory outcome – reducing mortality and PCP adverse outcome
Introduction:
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders. The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients
Methods:
Data Sources and Search Strategy The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, etc., were explored for articles in English from January 2000 to December 2021. Reference lists of relevant studies were screened for additional titles
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan. For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
level of evidenc:
Level 3
-The incidence of PCP was more than 50% in immunocompromised patients.
-The study aimed for dose optimization of TMP-SMX concluding that low dose of TMP-SMX provides satisfactory outcomes with low mortality rate and less side effects but large RCT are needed .
The article discusses the dosing strategy of trimethoprim-sulfamethoxazole (TMP-SMX) for the prevention and treatment of Pneumocystis carinii pneumonia (PCP) in patients with autoimmune disorders. PCP is a fungal infection that is common in immunocompromised patients, and it is a significant cause of morbidity and mortality. The incidence of PCP has been reduced in HIV-positive patients due to advances in diagnostic tools, management strategies, and preventive measures.
TMP-SMX, a combination of trimethoprim and sulfamethoxazole, has been shown to effectively reduce the incidence of PCP. However, the recommended high doses of TMP-SMX can lead to adverse events (AEs) such as skin irritation, gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity, and electrolyte disorders. Therefore, optimizing the dose of TMP-SMX is important to ensure its safety and effectiveness.
The study conducted a systematic search of relevant articles published from 2000 to 2021. A total of 13 studies were included in the analysis, including retrospective cohort studies, case reports, and randomized controlled trials. The studies evaluated the dosing strategy of TMP-SMX in various patient populations, including HIV-positive patients, patients with rheumatoid arthritis, non-HIV patients, kidney transplant recipients, and patients with G6PD deficiency.
Among the included studies, some compared low-dose regimens of TMP-SMX with high-dose regimens and found that low-dose therapy could be considered as a first-line treatment option for preventing PCP and its associated AEs. The low-dose regimen showed satisfactory outcomes in terms of reducing mortality rates and PCP-related AEs while also reducing the economic burden and improving patient compliance.
However, it is important to note that the study has limitations, such as the inclusion of studies from various countries with potential socio-demographic influences and a limited number of studies conducted after 2000. Therefore, further large-scale prospective studies are needed to provide more specific guidelines for dosing strategies in PCP prevention and treatment.
In conclusion, the study highlights the importance of optimizing the dose of TMP-SMX in the prevention and treatment of PCP. Low-dose regimens can be effective in reducing AEs and improving patient outcomes. However, more research is needed to establish clear dosing guidelines for different patient populations and to address the limitations of the current evidence.
level of evidence 3
Introduction
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX. In randomized trials where various treatment regimen was compared for virus-associated PCP, patients receiving recommended high dose of TMP-SMX as a first-line treatment regimen had higher rates of AEs such as skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs .
Materials and Methods
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines .In total, 857 related published studies were identified from grey literature as well as electronic databases.A total of 13 articles met the inclusion criteria for final analysis . Of the 13 selected studies, nine were retrospective cohort studies two case reports and two randomized controlled trial (RCT).
Dosing Strategy of TMP-SMX in Selected Studies
Of 13 studies, four reported that patients having AIDS received TMP-SMX for prophylaxis, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency. Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen option to prevent occurrence and recurrence of PCP and PCP-associated AEs. Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy Similarly, Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs. Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.In both RCTs, no cases of PCP were documented up to weeks 24 and 52 in low dose group.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
What is the level of evidence provided by this article?
Level 3
Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the morbidity and mortality of patients, especially those with autoimmune disorders, thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX). Therefore, to ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies; (2) Methods: Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs); (3) Results: Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan; (4) Conclusions: The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan. For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Level III
Pneumocystis pneumonia is a an opportunistic pathogen that affects immunocompromised patient. The incidence is 2-15% IN transplant recipients and about 40% in hematological malignancy cases. Co-trimoxazole is the treatment of choice and the optimum dosage & duration remain questionable .Co-trimoxazole if not given in the proper dose is not effective and may result in antibiotic resistance. High dose of TMP-SMX may cause rashes ;the most common side effect, followed by hepatotoxicity& bone marrow suppression.
TMP-SMX has 2 ingredients: Sulfamethoxazole 75-100 mg/kg/day + trimethoprim 15- 20mg/kg/day for 2 to 3 weeks….
Databases were studied from Jan 2000 to Dec 2021 for articles in English that focused on TMP SMX dose optimization.
13 studies met inclusion criteria for final analysis;9 retrospective studies, 2 case reports & 2 RCTs. Mainly, studies compared high dose with low dose TMP – SMX therapy for PCP. They concluded that low dose TMP-SMX therapy was equal with regard to outcomes in addition to reducing the mortality and reducing the adverse events.
The Cochrane meta analysis revealed a decrease in incidence of PCP up to 91% and mortality reduction up to 83% in comparison to the control group.
It was concluded that prophylactic treatment involved in the immunosuppression regimen, resulted in diminishing the economic burden.
Routine PCP prophylaxis is advised in 1-6 months following transplantation .The study highlighted predisposing factors for PCP eg CMV infections, repeated graft rejections.
Various socio economic categories were included in the study.5 out of 13 studies compared low dose with high dose TMP-SMX protocol with low dose protocol; with the final conclusion that low dose protocol is equally effective as high dose protocol.
(1) Introduction:
●This article is to ensure the safety of TMP-SMX
●there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies
(2) Methods:
■Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
■The data were collected in a specific form with predefined inclusion and exclusion criteria.
■ The quality of each article was evaluated using a (NOS) for retrospective studies, (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
(3) Results:
○Thirteen studies met the inclusion criteria for final analysis.
○Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
○Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
○We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
○This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan;
●The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91%and decrease in mortality rate up to 83%when compared to the control group
prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients.
■Routine PCP prophylaxis is recommended
the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period
■Other predisposing factors include
1- concomitant cytomegalovirus,
2- infections,
3- number of graft rejection episodes,
4- and low CD4+ count lymphocyte counts
5- PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3 [
● The first-line prophylactic agent is
1– one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day)
2– or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
● Alternative PCP prophylaxis includes one
1– double strength TMP-SMX tablet thrice per week
2– administration of dapsone either alone or in combination with leucovorin
3– and pyrimethamine, atovaquone, or pentamidine sprays].
♡The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
Nowadays, patients with PCP differ from the patients that were treated 30–40 years ago
♤The standard doses result in an absolute increase of 18% in the incidence of grade ≥3AEs
♡However, step-down therapy may be a worthy in exploring approaches to improve clinical outcomes
This study does have several limitations:
1– Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics
2– Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
3– Thirdly, due to small sample size, this may result in false-negative or false-positive findings.
●Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
● However, Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
● Similarly,Schildetal. Reported that the patients received an intermediate-dose TMP-SMX (TMP10–15mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AE sand this regimen was deemed to be safe and effective in patients with various immune dysfunctions
●Nakashima et al. reported that the total AEs rate was 58.3%in the low dose group and in conventional-dose group 72.4%of patients experienced AEs
●Similarly, another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group(25.0%)
● A study documented that tTMP-SMX was reported to cause hemolysis in patients with G6PD deficiency
In both RCTs, no cases of PCP were documented up to weeks 24and
4. Conclusions
□The low dose of TMP-SMX provides satisfactory outcomes .
□This strategy also reduces overall economic burden and enhances patients’ compliance.
□Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale,
□ prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%.Pneumocystis jirovecii has 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, primary infection occurs mostly in childhood – manifest with respiratory infection and infant death syndrome, due to its specific tropism for lung parenchyma and alveoli.
Life cycle of PCP is not completely understood
Mode of transmission – both sexual and asexual cycles proposed; sexual replication with in the lungs; environmental changes due to immunosuppression.
Drug treatment;
Pentamidine was the first drug to treat PCP
Anti-folate, diamines, atovaquone, and microlides. sulfadoxine and pyriamid, TMP-SMX dapsone, pentamidine, clindamycin plus pyrimethamine.
Prophylaxes;.
Chemoprophylaxis was initially used .
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
Introduction
The most frequently fatal fungal infection for autoimmune people is Pneumocystis carinii pneumonia. Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%. Immunosuppressive patients die mostly from PCP critical symptoms as tachycardia, hypoxia, tachypnea, shortness of breath, etc. Hence, PCP is an HIV hallmark. Due to enhanced diagnostic technologies, early diagnosis, intensive care management strategies, and preventive measures, PCP in HIV-positive patients has decreased in recent years.
Materials and Methods
PRISMA recommendations were used for the systematic search of TMP-SMX dosage guidelines in patients.
This review covered studies on TMP-SMX dose for PCP incidence or recurrence. Based on titles and abstracts, all studies involving TMP-SMX clinical outcomes were screened.
The selected studies provided author, year, design, sample size, patient characteristics, dosage approach, clinical outcomes, and findings.
Results
Among a total of more than 857 papers screened, only 13 matched the inclusion criteria for evaluation. Of the 13 selected studies, nine were retrospective designs, two case reports, and two RCTs. Based on the NOS quality of studies evaluation, eight studies received a total score of 7, one study had a score of 6, and four studies received a score of 8. The average score for the included studies was 7. The Cochrane bias test determined that the majority of RCT domains posed a minimal risk of bias. According to the JBI critical checklist, the case report quality in both reports was high. Five out of thirteen studies compared the low-dose regimen of TMP-SMX to the high-dose regimen, and they recommended the low-dose regimen of TMP-SMT as first-line therapy for preventing the recurrence or development of PJP because it was much more tolerable. Ohmura and his colleagues reported in one more research that a low-dose treatment regimen of TMP-SMX with 10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy and was linked with fewer side effects and a lower death rate of 19% compared to >25% in conventional dose.
Low-dose treatments had fewer side effects than conventional regimens. Among 84 kidney transplant recipients with hyperkalemia and 102 with leukopenia, TMP-SMX was reduced in 438 patients. TMP-SMX caused hyperkalemia in another research. Nakashima et al. found that 72.4% of patients in the conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day) and 58.3% in the low-dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day) had AEs. In G6PD-deficient patients, TMP-SMX caused hemolysis. Up to weeks 24 and 52, neither RCT reported PCP.
Discussion
PCP has a significant impact on patient mortality and morbidity, especially in immunocompromised individuals.
According to this analysis, low-dose TMP-SMX should be the first-line treatment because it reduces mortality and PCP-related side effects.
Compared to the control group, there was a 91% reduction in the incidence of PCP and an 83% reduction in the mortality rate.
Due to TMP-SMX-associated adverse effects and medication intolerance induced by neutropenia and G6PD deficiency, it is usually necessary to move to second-line therapies (dapsone, atovaquone, and pentamidine).
Conclusion
The low dose of TMP-SMX produces good results while decreasing mortality and PCP-associated adverse events.
This approach decreases the overall economic load and increases patient adherence to their daily prescription.
Level III
3. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Abdul Haseeb 1,* , Mohammed A. S. Abourehab 2 , Wesam Abdulghani Almalki 1
Int. J. Environ. Res. Public Health 2022, 19, 2833. https://doi.org/10.3390/ijerph19052833
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, primary infection occurs mostly in childhood – manifest with respiratory infection and infant death syndrome, due to its specific tropism for lung parenchyma and alveoli.
Life cycle of PCP is not completely understood
Mode of transmission – both sexual and asexual cycles proposed; sexual replication with in the lungs; environmental changes due to immunosuppression.
Drug treatment;
Pentamidine was the first drug used in 1958, to treat PCP successfully.
The major class 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 used are dapsone, aerosolized pentamidine, clindamycin plus pyrimethamine. The mortality has reduced from 70-90% to 10-15% in recent decades due to universal prophylaxes, better diagnostic tools, early effective treatment and use of corticosteroids use.
Prophylaxes;
Opportunistic infection has been the main cause of mortality in immune-compromised patients, with loss of graft function in renal transplantation.
Chemoprophylaxis was initially used by Dutz by 1950s in Iran. HIV patients and those with 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
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders [1,2]. The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases.
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family. TMP-SMX has been observed to substantially minimize the incidence of PCP in patients. As with other antibiotics, TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage.
The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections. In accordance with current dosing guidelines, the recommended therapy for PCP is high-dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks). There is a high incidence of adverse events (AE) in patients receiving recommended high doses of TMP-SMX.
Among the main results, we have:
– the meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
– the most common cause for second-line treatment are associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency
– The following are predisposing factors to PCP and therefore conditions that indicate prophylaxis:
· patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients
· transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors
· patients with concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts ( HIV-positive patients who have CD4+ counts less than 200 cells/mm3, because HIV-negative CD4+ count levels do not interfere)
· The incidence of occurrence of PCP is the most frequent in patients with systemic rheumatoid arthritis disease taking steroids and immunosuppressive agents. The risk factors for PCP in patients with rheumatoid disorders include age group (elderly > 65 years), use of glucocorticoids, and existing comorbidities
– the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
– Alternative PCP prophylaxis includes dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays
This is a systematic review – so its level is 01.
Pneumocystis pneumonia is a an opportunistic fungal pathogen which causes disease in immunocompromised patients… the incidence is 2-15% among transplant recipients… and around 40% in hematological malignancy patients…. Cotrimoxazole has been the treatment of choice in many individuals and the optimum dosage and duration remains a question… cotrimoxazole if not given in the proper dose may not be effective for the treatment of PCP and may pave way for antibiotic resistance also…. High dose of TMP-SMX may cause rashes (most common side effect) followed by hepatotoxicity, bone marrow suppression…
TMP-SMX has 2 components – Sulfamethoxazole 75-100 mg/kg/day + trimethoprim 15-20mg/kg/day for 2 to 3 weeks….
The various databases were searched from Jan 2000 to Dec 2021 for articles in English that focused on the optimization of the dose of TMP SMX… The data were collected in a proforma with inclusion and exclusion criteria….
13 studies were met inclusion criteria for final analysis… 9 were retrospective studies, 2 case reports and 2 RCT…. Most of the studies compared the high dose with low dose TMP – SMX therapy for PCP…. they analyzed and found out that low dose TMP-SMX therapy was equal with respect to outcomes while reducing the mortality and reducing the adverse events….
The Cochrane meta analysis reported a decrease in incidence of PCP unto 91% and mortality reduction upto 83% when compared to the control group…..
Based on the meta analysis they concluded that prophylactic drugs are included in the crucial immunosuppression regimen, resulting in reducing the economic burden of the patient…
The routine PCP prophylaxis is recommended in 1-6 months post transplantation…the study also defined other predisposing factors for PCP namely CMV, Infections, number of graft rejection episodes…..
The study included all patients from various socio economic categories…. 5 out of 13 studies compared low dose with high dose TMP-SMX regimen with low dose regimen…. they concluded that low dose regimen is as effective as high dose regimen..
(1) Introduction
●This article is to ensure the safety of TMP-SMX
●there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies
(2) Methods:
■Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
■The data were collected in a specific form with predefined inclusion and exclusion criteria.
■ The quality of each article was evaluated using a (NOS) for retrospective studies, (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
(3) Results:
○Thirteen studies met the inclusion criteria for final analysis.
○Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
○Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
○We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
○This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan;
●The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91%and decrease in mortality rate up to 83%when compared to the control group
prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients.
■Routine PCP prophylaxis is recommended
the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period
■Other predisposing factors include
1- concomitant cytomegalovirus,
2- infections,
3- number of graft rejection episodes,
4- and low CD4+ count lymphocyte counts
5- PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3 [
● The first-line prophylactic agent is
1– one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day)
2– or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
● Alternative PCP prophylaxis includes one
1– double strength TMP-SMX tablet thrice per week
2– administration of dapsone either alone or in combination with leucovorin
3– and pyrimethamine, atovaquone, or pentamidine sprays].
♡The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
Nowadays, patients with PCP differ from the patients that were treated 30–40 years ago
♤The standard doses result in an absolute increase of 18% in the incidence of grade ≥3AEs
♡However, step-down therapy may be a worthy in exploring approaches to improve clinical outcomes
This study does have several limitations.
1– Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics
2– Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
3– Thirdly, due to small sample size, this may result in false-negative or false-positive findings.
●Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
● However, Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
● Similarly,Schildetal. Reported that the patients received an intermediate-dose TMP-SMX (TMP10–15mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AE sand this regimen was deemed to be safe and effective in patients with various immune dysfunctions
●Nakashima et al. reported that the total AEs rate was 58.3%in the low dose group and in conventional-dose group 72.4%of patients experienced AEs
●Similarly, another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group(25.0%)
● A study documented that tTMP-SMX was reported to cause hemolysis in patients with G6PD deficiency
In both RCTs, no cases of PCP were documented up to weeks 24and
4. Conclusions
□The low dose of TMP-SMX provides satisfactory outcomes .
□This strategy also reduces overall economic burden and enhances patients’ compliance.
□Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale,
□ prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
1. Please summarise this article.
PCP is a opportunistic infection usually involves those patient immunocompromissed. The incidence of PCP was around 50% in immunocompromissed patients, and it has a substantial impact on the mortality and morbidity of patients.
Currently the most effective drugs for treatment and prophylaxes is TMP-SMX, so there is high demand to review regularly the dose optimization.
Co-trimoxazole is a combination of trimethoprim and sulfamthoxazole, it’s being used for PCP, and as antibiotic as single or as combination of other antibiotic.
Recommended dose in bacterial infection is 320-640mg/day bid, while its TMP 15-20mg/kg, SMX 75-100mg tds 6 to 8 hourly for PCP IV then orally.
Due to its safety issues there is high demands to review the current dose to prevent toxicity.
Material and methods;
This is randomize and retrospective studies and case reports were included.
1. Those studies were included done after 2000 to before 2021.
2. Assessing the dosing guidelines used were PRISMA.
3. Selection criteria were—- all those articles included with titles abstract containing TMP-SMX,
4. Article quality evaluated using different methods.
5. Data extraction was performed using Microsoft Word 2013, and information retrieved.
Result;
Total 857 related published studies were identified. On the bases of quality assessment of studies the outcomes based on the NOS, and scored accordingly out of 13, eight scored 7, one scored 6 and the remaining scored 8.
Overall the score included studies was 7.
Second, the dosing strategy regimen documented that low dose regimen of TMP-SMX must be considered as a first line treatment option prevent occurrence and recurrence of PCP and PCP associated AEs. The studies shows fewer side effects.
Discussion and conclusion;
This review has revealed the low dosing strategy regimen showed be first line treatment option. They documented that low dose regimen of TMP-SMX must be considered as a first line treatment option prevent occurrence and recurrence of PCP and PCP associated AEs.
The risk PCP is high at 1-6 month post-transplantation, other risk factors are CMV infection, number of rejections.
The low dose of drug provides satisfactory outcomes while reducing the mortality rate and PCP associated AEs.
However, they failed to identify significant differences b/w the full dose and low dose of TMP-SMX for the recurrence and prophylaxes of PCP.
level of evidence III
Introduction
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders . The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases
PCP is considered a hallmark disorder indicating human immunodeficiency virus (HIV) infection
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine
analog, and sulfamethoxazole (SMX), which is from the sulfonamide family . TMP-SMX has been observed to substantially minimize the incidence of PCP in patients. There have been some published data on this topic.
As with other antibiotics, TMP-SMX must be administered in an appropriate way
to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX. Due to insufficient data on the optimal dose of TMP-SMX, its use is limited. In randomized trials where various treatment regimen was compared for virus-associated PCP, patients receiving recommended high dose of TMP-SMX as a first-line treatment regimen had higher rates of AEs such as skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs
Materials and Methods
Data Sources and Search Strategy
The systematic search assessing the dosing guidelines of TMP-SMX in patients was
carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines . Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, etc., were explored for articles in English from January 2000 to December 2021.
Selection Criteria and Procedure
The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study. The studies published before January 2000 or having inappropriate and incomplete information were excluded from the study. Titles and abstracts of all included articles collected through the search were screened by two reviewers independently. In case of uncertainty as to whether selected studies met inclusion criteria, they discussed with a third reviewer.
Data Extraction
Data extraction was performed using the predesigned data collection form for this
review using MicrosoftWord 2013. Information retrieved from the selected articles included author and year, design, sample size, characteristics of patients, dosing strategy, clinical outcomes, and findings. Data extraction was performed by one of the reviewers and reviewed by another co-author. Any discrepancies were resolved by a third reviewer.
Article Quality Assessment
The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs) . Two of the reviewers assessed the quality of each included study independently. They compared their results and disagreements were resolved by detailed discussion.
Dosing Strategy ofTMP-SMX in Selected Studies
Low-dose treatment regimens usually reported fewer side effects compared to the
conventional dosing regimens. However, a study reported that a in a total of 438 patients, the dose of TMP-SMX was reduced in 84 kidney transplant recipients for hyperkalemia, and 102 for leukopenia Another study reported side effects, such as hyperkalemia, with the use of TMP-SMX. Nakashima et al. reported that the total AEs rate was 58.3% in the lowdose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), 72.4% of patients experienced AEs
Discussion
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
Over the past few years, various preventive treatment options are available for opportunistic infections in immunocompromised and transplanted patients . Although highly recommended by the healthcare community, prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients
Extrapolated from previous data, the first-line prophylactic agent is one single strength
TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) . Alternative PCP prophylaxis includes one doublestrength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays
Nowadays, patients with PCP differ from the patients that were treated 30–40 years
ago .The standard doses result in an absolute increase of 18% in the incidence of grade ≥3 AEs
However, step-down therapy may be a worthy in exploring approaches to improve clinical outcomes . The incidence of occurrence of PCP is the most frequent in patients with systemic rheumatoid arthritis disease taking steroids and immunosuppressive agents
This study does have several limitations. Firstly, the selected articles included patients
from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment. Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria. Thirdly, although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention
and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan. For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Level 3
Summary
Introduction
This article is focussed around the drug treatment of PCP, in particular, TMP SMX known popularly as Bactrim.
The importance of PCP and its effects on patients, especially auto immune and immunosuppressed patients. PCP was a rare infection in the past, and has now become more common. It causes significant damage to the allograft and mortality rate of patients even when treated aggressively with antibiotics.
TMP SMX is part of the first line therapy for PCP and can help to a great extent. However, dosage has to be decided carefully since it has to be balanced with the immunosuppressive regimen. This article is an attempt to look further into dose optimization to achieve maximum effect and good outcome.
Discussion
This article is a systematic review. The baseline of the study was to find out how to optimize dosage of TMP SMX in such a way as to give good outcome for the patient in terms of life span as well as quality of life.
The authors of the study found that low dose TMP SMX is better as first line management, since it reduced mortality rate and adverse events incidence associated with PCP. This reduction was found to be significant by the Cochrane meta analysis up-to 90%.
The side effects of TMP SMX such as neutropenia and G6PD deficiency made it difficult to use it as a first line drug despite its efficacy against PCP. However, with the use of lower dosage, we are able to prevent or reduce the intensity of these side effects and effectively treat or prevent PCP at the same time.
PCP prophylaxis so far includes TMP SMX and other drugs such as atovaquone, dapsone, etc being given in double or triple strength two or three times a week. In contrast to this, administration of single strength TMP SMX daily may help prevent not only PCP, but other post transplant infectious diseases such as toxoplasmosis.
Conclusion
The main theme of this article has been to assess what strategies would work best to optimize TMP SMX regimen so that it would yield the best results for the patient. This study concluded that low dose TMP SMX has the upper hand, in comparison with high dose. Low dosage of TMP SMX was able to achieve lower mortality rates along with reduced incidence of PCP associated adverse events. These benefits in turn lower the economic burden of the disease and allow the patients to adhere better to their daily drug regimen.
Further study is needed in this area to develop proper clinical practice and standardized dosing regimen for different patients. Large scale RCTs would help to prevent occurrence of PCP in itself in immunocompromised patients, in comparison with treating the disease once it has affected the patient.
Level of evidence
This article is a systematic review, and thus level of evidence is 1.
Q1- Summary
Abstract
Background : Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the
morbidity and mortality of patients, especially those with autoimmune disorders, thus requiring
optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX).
Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
We have found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the
mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of
illness and enhances patients’ compliance to daily regimen plan.
Conclusions: The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
1. Introduction
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia
has remained the most frequent and highly morbid fungal infection for patients with
autoimmune disorders .
The incidence was more than 50% in immunocompromised patients,
22–45% with hematological malignancy,
5–15% in transplant recipients
2% with rheumatoid diseases .
PCP is considered a hallmark disorder indicating (HIV) infection .
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family .
TMP-SMX has ability to substantially minimize the incidence of PCP in patients.
The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections .
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose
TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) .
There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
There is an insufficient data on the optimal dose of TMP-SMX .
In randomized trials where various treatment regimen was compared for virus-associated PCP, patients receiving recommended high dose had higher AEs such as skin irritation ( rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs . The therapeutic option for treatment of PCP requires a dose of more than 16 mg/kg of TMP-SMX with risk of hepato-renal AEs .
Materials and Methods
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.
Dosing Strategy of TMP-SMX in Selected Studies.
The included studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Ohmura and his colleagues reported that a low-dose treatment regimen of
TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose
Schild et al. reported that the patients received an intermediate-dose
TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose
TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in
patients with various immune dysfunctions .
Low-dose treatment regimens usually reported fewer side effects compared to the
conventional dosing regimens.
Nakashima et al. reported that the total AEs rate was 58.3% in the low dose
group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose
group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), 72.4% of patients experienced
AEs .
another study reported that the mortality rates were lower in the
low-dose group (19.5%) compared to the conventional-dose group (25.0%) .
Discussion:
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
second-line treatment include : such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency .
Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients . The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors, concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts.
PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3 . this failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP. This strategy reduces economic burden of illness and enhances patients’ compliance to daily regimen plan.
Extrapolated from previous data, the first-line prophylactic agent is one single strength
TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP
160 mg/day; SMX 800 mg/day) . Alternative PCP prophylaxis includes one doublestrength
TMP-SMX tablet thrice per week, administration of dapsone either alone or in
combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays .
The double-strength seems to be effective while taken daily or thrice in a week, but daily
administration of TMP-SMX prevents other post-transplant infectious diseases such as
toxoplasmosis .
This study does have several limitations.
Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics .
Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
Thirdly, although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions :
The low dose of TMP-SMX provides satisfactory outcomes while
reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall
economic burden and enhances patients’ compliance to daily regimen plan. For
Q 2 level of evidence 3
STUDY DESIGN
13 articles were reviewed, including 2 RCT
DOSE
LOW-TMP-SMX 10 MG/KG/DAY OF TMP
INTERMEDIATE – 10-15 MG/KG/DAY OF TMP
HIGH >15 MG/KG/DAY OF TMP
Out of 13 study , 2 had kidnet transplant recipients patients
Lod dose of TMP-SMX is associated with less AE and dose reduction in kidney transplants were done for hyperkalemia and leucopenia
Prophylaxis
1 SS or DS per day
1 DS 3 times a week
Duration 6-12 months
Prophyalaxis decrease the incidence of PCP up to 91% and decrease in mortality rate up to
83% when compared to the control group
Second line like dapsone and other durgs are chosen in case of AE due to TMP-SMX and in G6PD deff patients
Introduction
· Pneumocystis jirovecii pneumonia still a common cause of morbidity from fungal infections
In patients with autoimmune diseases.
· TMP-SMX reduce the incidence of PJP and may reduce mortality.
· High dose of TMP-SMX used in the treatment regimen associated with higher rates of adverse effects.
Materials and Methods
· Data used from Systematic Reviews and Meta-analysis guidelines and articles in English from January 2000 to December 2021.
· Inclusion criteria: studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP
· Exclusion criteria: The studies published before January 2000 or having inappropriate and incomplete information
Discussion
· The goal of this study is evaluation of dose of TMP-SMX to prevent PJP in immunocompromised patients.
· This study found that low-dose TMP-SMX therapy should be the first-line treatment option, as it reduced mortality and PCP-associated AEs.
· TMP-SMX can be switched to dapsone, atovaquone, or pentamidine in case of TMP-SMX associated AEs and drug intolerance caused by neutropenia and G6PD deficiency
· Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients
· the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, (neutropenia, steroids, ATG, or CNI)
· Other risk factors for PJP: concomitant CMV, infections, rejections, and low CD4+ count lymphocyte counts
· PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3
· There was no difference between the full-dose and low-dose PJP prophylaxis regimen of TMP-SMX.
· Nowadays the standard doses of TMP-SMX have increased risk of AEs.
· The incidence of PCP is the most frequent in patients with Rheumatoid arthritis on steroids and immunosuppressive agents
Limitations of the study
· Articles were selected from different countries with possible different socio-demographic characteristics
· limited number of studies after January 2000.
· small sample size may result in false-negative or false-positive findings.
Conclusions
· The low dose of TMP-SMX has accepted outcomes while reducing the mortality rate and PCP-associated AEs.
· prophylactic treatment regimen is warranted in HIV-patients
This is a Retrospective study with evidence 3
INTRODUCTION
PCP has become one of the most frequent opportunistic infections in immunocompromised patients. It accounts for about 50% of the total infections. It usually manifests with respiratory symptomatology like tachypnoea, shortness of breath, hypoxia with other symptoms including fever and tachycardia.
It significantly affects morbidity and mortality of patients . This is even more significant in post transplant patients. The usual drug of choice is cotrimoxazole (TMP-SMX).
Hence, there is need to ensure the safety of TMP-SMX. Dose optimization is the key methods in antimicrobial stewardship programs and very effective to ensure therapeutic outcome of antimicrobial therapy as like in management of PCP.
MATERIALS AND METHODS
Databases were searched from period of January 2000 to December 2021 to find the studies focusing on dose optimisation of TMP-SMX. A set of inclusion and exclusion criteria were applied and 13 articles were included in the study.
The main objective was to assess and analyse the dosing strategies of TMP-SMX followed by various centers to manage PCP.
RESULTS
A total of 13 articles met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective
cohort studies , two case reports and two randomized controlled trial (RCT).
The outcomes based on the NOS, eight studies were rated as a total score of 7, one study scored 6, and the remaining four studies scored 8. Overall, the score of included studies was 7. The Cochrane bias tool assessed that almost all the domains for RCT were at low risk of bias. As per the JBI critical checklist, the quality of case reports in
both reports were of good quality.
Of 13 studies, four reported that patients having AIDS received TMP-SMX for prophylaxis, four reported
patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency.
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
DISCUSSION
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Over the past few years, various preventive treatment options are available for opportunistic infections in immunocompromised and transplanted patients . Although highly recommended by the healthcare community, prophylactic drugs are included in the crucial immunosuppressive regimen, resulting in considerable economic burden for the immunocompromised patients.
CONCLUSION
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
LIMITATIONS
1. Socio-demographic characteristics of patients are different as studies are included from different countries.
2. Although the quality of the included studies is good, the sample sizes were small.
LEVEL OF EVIDENCE
Level 3
*Introduction
Pneumocystis jirovecii pneumonia is serious fungal infection in autoimmune disease patients causing significant
mortality.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in hematological malignancy, 5–15% in transplant recipients
and around 2% in patients with rheumatoid diseases .
Using TMP-SMX showed decrease in the incidence of PCP in patients.
appropriate dosing is important to achieve adequate effect with lowest toxicities.
The TMP-SMX dosing recommendations is oral 320–640 mg/day/12 h, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections.
current dosing guidelines, the recommended therapy for PCP is high-dose TMP-SMX (TMP 15–20
mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
AEs include skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow
suppression, renal impairment, hepatotoxicity and electrolyte disorder .
Therefore dose optimization is mandatory to achieve optimal therapeutic effects with minimal AEs.
*Materials and Methods
-All studies reporting the dosing and
outcomes of TMP-SMX in patients with PCP were included in this
review from January 2000 to December
2021.
-Of all studies, 13 articles including 2663 patients met the inclusion criteria for final analysis.
-5 studies compared the low-dose with high dose regimen of TMP-SMX and documented
that low-dose therapy should be used as a first-line treatment to prevent occurrence and recurrence of PCP and to minimize AEs.
-hyperkalemia and leukopenia occurred in some KTR even on low dose required
more dose reduction.
-Nakashima et al. Reported that the total AEs rate was 58.3% in the low-dose group (TMP,
4–10 mg/kg/day; SMX 20–50 mg/kg/day).and AEs rate was 72.4% in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day).
– mortality rate was lower in the low-dose group (19.5%) compared to the
conventional-dose group (25.0%) .
*Discussion
-PCP is a leading cause of mortality and
morbidity in immunocompromised patients
.
-this is a systematic review done to assess different dosing strategy of TMP-SMZ to
reduce the risk of PCP in immunocompromised patients.
-Thereview recommended low-dose TMP-SMX as the first-line treatment option, to reduce
AEs.
-The Cochrane meta-analysis reported that there was a decrease in the incidence of
PCP up to 91% and decrease in mortality rate up to 83% when compared to the
control group.
-second-line treatment such as dapsone, atovaquone, and atomized
pentamidine can be used in case of intolerance due AEs or resistance to drug.
-routine prophylaxis of PCP is required during the early post-transplant month
and after therapy of rejection episodes due to higher risk of PCP among transplant recipients
The risk is greater in 1–6 month
post-transplantation period, during prolonged neutropenia, or in patients
receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
– this review found no significant
differences between the full-dose and low-dose regimen of TMP-SMX for the
occurrence or recurrence of PCP.
– using TMP-SMX double-strength is effective either daily or 3/week , but
daily administration of TMP-SMX prevents other post-transplant infectious
diseases such as toxoplasmosis.
-there were no proper
guidelines on PCP prophylaxis in patients treated with immunosuppressive drugs,
and high-dose steroids for immune-mediated dermatologic conditions.
Level of evidence 1
BACTRIM DOSE OPTIMIZATION IN PCP MGT;A SYSTEMATIC REVIEW.
INTRODUCTION.
-Incidence of PCP ;50% in immunocompromised,22-455 in hematological malignancies,5-15% in KTR and 2% in RA pts.
-As per guidelines ,bactrim is dosed at 15-20mg/kg 6-8 hrly fpr PCP tx.Effective dose for PCP tx is >16 mg/kg of Bactrim which is associated with side effects which should be closely monitored.
MATERIALS AND METHODS.
RESULTS.
-13 Studies met inclusion criteria,9 were retrospective while 2 were RCTS.2663 pts were recruited.
-From studies comparing low vs high dose septrin recommended low dose for 1st line tx for PCP to prevent recurrence, occurrence of PCP and minimize SE.The low dose group had fewer side effects, less mortality in comparison to conventional group.(TMP – SMX 4-10mg/kg/day/20-50mg/kg/day vs 10-20mg/kg/day/20-50mg/kg/day)
DISCUSSION.
-Low dose septrin should be considered 1st line to achieve low SE and mortality rate. In the event of SE from septrin, we should switch to 2nd line ;dapsone, atovaquone and atomized pentamidine. Routine prophylaxis should be administered early post transplant due to high immunosuppressive medications used then.
-Options for 1st line prophylaxis ;x1 single strength septrin OD,x1 double strength septrin OD,X1 double strength septrin x3/week, Dapsone, dapsone +leucovorin+ pyrimethamine, atovaquone or pentamidine sprays.
-All pts with rheumatological conditions, autoimmune dysfunction, HIV and any immunosuppression need PCP prophylaxis.
STUDY LIMITATIONS.
-Varied sources of article and pts from different countries hence they might have been affected by sociodemographic xtics.
-Limited studies after jan 2000 thus some low quality studies were included.
-Small sample sizes thus some false +VEs and -VEs occurred.
LEVEL EVIDENCE – 1
III. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Summarise this article
Introduction
– Trimethoprim-Sulfamethoxazole (TMP-SMX) substantially reduces the incidence of Pneumocystis jirovecii pneumonia (PCP)
– optimal dosing of TMP-SMX is crucial since PCP has a significant impact on the morbidity and mortality of immunocompromised patients
– the recommended treatment for PCP is high-dose TMP-SMX i.e., TMP 15-20mg/kg/day and SMX 75-100mg/kg/day for 2-3weeks
– a higher incidence of adverse events has been reported among patients receiving the recommended high-dose TMP-SMX
Methods
– various databases were searched from January 2000 to December 2021 focusing on TMP-SMX dose optimization
– there was a predefined inclusion and exclusion criteria
– studies reporting the TMP-SMX dosing strategy in patients for PCP occurrence or recurrence were included
– studies looking at clinical outcomes of TMP-SMX regimens were included
– studies published before January 2000, studies with inappropriate and incomplete information were excluded
– a predesigned data collection form was used to extract data
– quality of each article was evaluated
Results
– 13 studies met the inclusion criteria for final analysis, 9 were retrospective cohort studies, 2 case reports and 2 RCTs
– a total of 2663 patients were recruited in the included studies
– most studies compared the high-dose with low-dose TMP-SMX treatment for PCP
– out of the 13 studies, 5 compared low-dose TMP-SMX with a high-dose regimen
– these studies documented that low-dose TMP-SMX therapy must be considered as the 1st line therapy to prevent the occurrence and recurrence of PCP as well as PCP-associated adverse events
– low-dose TMP-SMX was well-tolerated and effective as high-dose therapy
– low-dose TMP-SMX regimens were associated with fewer adverse events and lower mortality rates compared to the conventional dosing regimens
– this low-dose strategy enhances patients’ adherence to the daily regimen plan and reduces the economic burden of the illness
Discussion
– PCP has a significant impact on morbidity and mortality among immunocompromised patients
– low-dose TMP-SMX therapy should be considered s the 1st line treatment option resulting in a reduction in the mortality and adverse events associated with PCP
– 2nd line options in case of TMP-SMX intolerance and adverse events include dapsone, pentamidine and atovaquone
– risk factors for PCP include the first 6 months post-transplant, neutropenia, use of corticosteroids, antithymocyte antibodies, CNIs, CMV, infections, number of rejection episodes, low CD4 counts
– routine prophylaxis is recommended in the early post-transplant period and following treatment for graft rejection
– low-dose TMP-SMX therapy enhances patients’ compliance to daily regimen plan and reduces the economic burden of the illness
– one single strength or one double strength TMP-SMX tablet daily is considered as the first-line prophylactic agent
– alternative PCP prophylaxis includes: – one double strength TMP-SMX tablet given thrice weekly, dapsone monotherapy, dapsone combined with leucovorin and pyrimethamine, atovaquone or pentamidine
– daily administration of TMP-SMX prevents other post-transplant infections like toxoplasmosis
Study limitations
– patients included in the study were from different countries hence the findings could be affected by the different sociodemographic characteristics
– limited number of studies
– false positive or negative findings due to the small sample size of the studies included
Conclusion
– low-dose TMP-SMX therapy provides satisfactory outcomes while reducing the mortality and PCP-associated adverse events
– low-dose TMP-SMX dosing strategy also reduces the economic burden of PCP and enhances patients’ adherence to the daily regimen plan
– large-scale RCTs and cohort studies looking at TMP-SMX dosing strategies are required to improve the dosing strategies to prevent the initial occurrence of PCP and to prevent recurrence of PCP in immunocompromised patients
What is the level of evidence provided by this article?
– Level IIb
SUMMARY:
Introduction:
Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders. The incidence of PCP is high among immunocompromised patients and it is more than 50%. Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family . TMP-SMX has been observed to substantially minimize the incidence of PCP.
Method
Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Result:
Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. This study has found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan.
Conclusion:
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy also reduces economic burden. The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immunocompromised patient.
Level of evidence: level 1
Pneumocystis Jirovecii pneumonia PJP: Is the most common pathogen encountered in immune compromised patients causing pneumonia. It’s mainly targeted by cell mediated immunity, hence its prevalent in rheumatoid patients, HIV, particularly when C4D count is less than 200, and solid organ transplant recipients. It begets increased morbidity and mortality. Therefore, prophylaxis against PJP was an essential part of management of immune compromised patients. Risk factors for PJP infection include:
no. of rejections, use of ATG, prolonged lymphopenia, concomitant CMV infection, and use of CNi.
Trimethoprime- Sulphamethoxasol TMP-SMX: Is the drug of first choice for prophylaxis and treatment of PJP. Trimethoprim is a derivative of Pyrimethamine and sulphamethoxazol is sulfa antibiotic. It’s used in a single or double strengths.
single strength is 80/400 and double strength is 160/800 mg. In practice both of the strengths were in use. Nevertheless, double dose TMP-SMX was linked to several significant complications, reported in 27% of renal allograft recipients, these AEs including:
1] Bone marrow suppression.
2] Hepatotoxicity.
3] Renal toxicity.
4} Contraindicated in G6PD.
5] Electrolytes disturbance
6] Gastrointestinal disturbance.
Regular dose is 16 mg/kg body wt. PJP is higher between 1-6 months and after treatment of acute rejection episodes.
Proper dosing of antibiotic is crucial to prevent and treat the infection with PJP.
Nevertheless, due to the side effects and complications related to double dosing of antibiotics, many patients fall short of adequate medications. single strength TMP-SMX was advocated as safer alternative.
This meta-analysis study tested the hypothesis that low dose TMP-SMX is as efficient and effective with lesser side effects than double dose TMP-SMX. By screening all studies compared the two dosing strategies, conducted between 2000 through 2021.
13 studies were surveyed for the same reason.
Conclusively the study showcased non inferiority of low dose antibiotic in preventing PJP infection, featuring less economic burden, more compliance and lesser side effects.
Its a meta-analysis with level of evidnce 1.
PJP has significant impact on mortality and morbidity of immunocompromised patients.
What is the optimum dosing strategy for these patients is an unanswered question which has been explored in this review.
Methods:
Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen These studies documented that low-dose TMP-SMX therapy must be considered as a first- line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs. However, Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy. Similarly, Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions.
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
Level of evidence
II/III
Introduction
Pneumocystis jirovecii pneumonia (PCP) has a substantial impact on the morbidity and mortality of patients, thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX). TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage.
Method
This systemic review was done from various databases, from January 2000 to December 2021 with articles in English, the systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP were included in this review.
Result
-Thirteen studies met the inclusion criteria, nine were retrospective cohort studies two case reports [31] and two randomized controlled trial (RCT)
-In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of hepato-renal AEs
-Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
-Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen. These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs
-Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
-Nakashima et al. reported that the total AEs rate was 58.3% in the lowdose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), 72.4% of patients experienced AEs
-This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AE
The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Conclusion
The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immunocompromised patient.
Limitation
-Study failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP
-Mixed homogenous data
-small sample size
Level of evidence is -level 1- systemic review of RCT
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization
in Pneumocystis jirovecii Pneumonia (PCP) Management
Introduction
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia
has remained the most frequent and highly morbid fungal infection for patients with
autoimmune disorders.
The incidence of PCP classified as follow
* 50% in immunocompromised patients
* 22–45% in patients with hematological malignancy
* 5–15% in transplant recipients
* around 2% in patients with rheumatoid diseases
A retrospective study reported that the incidence
of PCP and PCP-associated mortality was lower in patients with rheumatoid arthritis who
received high-dose of glucocorticoids.
Another study reported that PCP developed
in up to 40% of patients with the lymphoproliferative disease or acute lymphoblastic
leukemia, and about 50% of patients experience hepatotoxicity .
Moreover, the incidence of adverse events (AEs) was decreased in non-HIV patients who
received TMP-SMX prophylactically
TMP-SMX must be administered in an appropriate way
to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities,
necessitating the avoidance of excessive dosage . Specifically, in the era of
antimicrobial resistance, optimal antibiotics usage is very crucial to ensure effectiveness
of therapy.
The TMP-SMX dosing recommendations 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections .
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX
(TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks)
the occurnace of AE is associated more with high doses .
The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of
hepato-renal AEs .
Therefore, to ensure the safety of TMP-SMX, there is a high demand
to review current evidence in PCP patients with a focus on dose optimization strategies.
Dose optimization is the key methods in antimicrobial stewardship programs and very
effective to ensure therapeutic outcome of antimicrobial therapy as like in management of
PCP
Dosing Strategy of TMP-SMX in Selected Studies
Of 13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen
These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option
to prevent occurrence and recurrence of PCP and PCP-associated AEs.
However, Ohmura and his colleagues reported that a low-dose treatment regimen of
TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose
therapy
Low-dose treatment regimens usually reported fewer side effects compared to the
conventional dosing regimens.
Discussion
The main goal of this systematic review was to assess the current dosing strategy of
TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
The impact of PCP on mortality and morbidity of the patients especially
immunosuppressive patients is significant
his review has revealed that low-dose
TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of
mortality rate and PCP-associated AEs
Routine PCP prophylaxis is recommended for patients
treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients
A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with
other medications experienced AEs such as cytopenia
Therefore, routine prophylaxis
is mainly required during the early post-transplant month and after therapy of rejection
episodes. PCP prophylaxis is highly recommended in HIV-positive patients who have
CD4+ counts less than 200 cells/mm3
However, we failed to identify significant
differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or
recurrence of PCP
extrapolated from previous data, the first-line prophylactic agent is one single strength
TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP
160 mg/day; SMX 800 mg/day) .
Alternative PCP prophylaxis includes one double strength TMP-SMX tablet thrice per week,
administration of dapsone either alone or in
combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays .
This practice may not provide desired clinical outcomes with the minimal risk of AEs
This study does have several limitations.
Firstly, the selected articles included patients
from various countries, so the findings could have been affected by socio-demographic
characteristics such as ethnicity, region, lifestyle, and environment.
Secondly, the limited number of studies conducted after January 2000
forced us to include all studies that met inclusion criteria.
Thirdly, although the quality of the majority of the included studies was
good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions
These findings provided the current dosing strategy of TMP-SMX for the prevention
and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while
reducing the mortality rate and PCP-associated AEs. This strategy also reduces overall
economic burden and enhances patients’ compliance to daily regimen plan. For some
patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it
may still warrant to start prophylactic treatment regimen. Due to limited data available on
the optimal dose of TMP-SMX, these findings would support the conduct of large-scale,
prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies
for the PCP.
Level I
Name of the study: Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization
in Pneumocystis jirovecii Pneumonia (PCP) Management:A Systematic Review
Year of the study: 2022
journal: Int. J. Environ. Res. Public Health, the journal has a 2020 impact factor of 3.390
Introduction:
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases
Study Aim:
dose optimization of TMP-SMX to provider satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
Material and methods:
Data Sources and Search Strategy Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines
Free-text web searches using Google Scholar, and databases such as
PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews,etc.
The keywords used for the search were “dose optimization”, “Pneumocystis carinii pneumonia”,“Pneumocystis jirovecii pneumonia”, “HIV-patients”, “immune compromised patients” “Co-trimoxazole”, “trimethoprim/sulfamethoxazole”, and “TMP-SMX”
Selection Criteria and Procedure all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening. The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study.
results as showen in figure 1
conclusion
The low dose of TMP-SMX provides satisfactory outcomes with low mortality rate and less side effects but large RCT still needed to clarify, confirm and provide guidelines regarding the dosing strategies for the PCP.
limitations
–diagnosis of PCP and difference between treatment and prophylactic unclear
–RCT are done in rheumatology patient which already have the lowest incidence
-mixed non homogeneous data
level of evidence
unclear and difficult to decide
figure 1
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review.
Introduction:
PJP is considered the most common fungal infection in immunocompromised patients such as HIV, post kidney transplant and other immunological diseases, the treatment of choice is Trimethoprim-Sulfamethoxazole, and as other antibiotics, TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage and when using The therapeutic option for treatment of PCP requires a dose of _16 mg/kg of TMP-SMX with risk of hepato-renal adverse effects and herein, this systematic review focus on dose optimization to ensure the safety of TMP-SMX.
Materials and Methods.
Various databases were searched from January 2000 to December 2021 for articles that focusing on the dose optimization of TMP-SMX, the retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included and others having inappropriate and incomplete information were excluded from the study, total included studies are 13 studies.
Results:
There are13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT). Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP or effect of early diagnosis and treatment in prognosis.
Most of these studies revealed that low dose of TMP-SMX provides satisfactory outcomes and reducing the mortality rate and PCP-associated adverse events.
Conclusion:
The low dose of TMP-SMX provides satisfactory outcomes with low mortality rate and less side effects and so this lead to reduces overall economic burden and helps in patients’ compliance to daily medications and large RCT still needed to clarify, confirm and provide guidelines regarding the dosing strategies for the PCP.
Level of evidence: I (Systematic review).
III. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Please summarise this article:
Introduction:
PJP is the most frequent and highly morbid fungal infection for patients with autoimmune disorders and is a hallmark disorder indicating human immunodeficiency virus (HIV) infection, Incidence is > 50% in immune compromised hosts.
Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole that has been found to reduce the incidence of PJP in non-HIV patients.
TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration dependent toxicities.
In the era of antimicrobial resistance, optimal antibiotics usage is essential. Current dosing guidelines recommend 320-640 mg/day, administered every 12 h, orally, to treat bacterial infections and 15-20 mg/kg every 6 to 8 h intravenously then orally for PCP infections.
However, there is a high incidence of AEs in patients receiving recommended high doses. To ensure safety, dose optimization strategies are needed.
Methods:
It is a systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using PRISMA guidelines and free-text web searches using Google Scholar, PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews.
Keywords used were “dose optimization”, “Pneumocystis carinii pneumonia”, “HIV-patients”, “immune compromised patients”, “Co-trimoxazole”, “trimethoprim/sulfamethoxazole”.
Selection Criteria and Procedure
Studies reporting the dosing strategy of TMP-SMX in PCP were included for further screening, with retrospective studies, randomized controlled trials, and case reports excluded.
Data extraction was performed by one reviewer and coauthor, with any discrepancies resolved by a third reviewer.
Two reviewers assessed the quality of each included study independently, with disagreements resolved by detailed discussion.
Study Characteristics:
857 related published studies were identified from grey literature and electronic databases, and 163 were evaluated for eligibility criteria.
25 articles were excluded due to no full-text, literature reviews, inappropriate intervention, no required data, and non-English.
13 articles met the inclusion criteria for final analysis, nine of which were retrospective cohort studies.
2663 patients were recruited in selected studies.
Quality Assessment of Studies:
The NOS, Cochrane Bias tool, and JBI critical checklist assessed the quality of studies, with 8 studies rated as 7.2.
Dosing Strategy of TMP-SMX in Selected Studies:
Low-dose TMP-SMX therapy must be considered as a first-line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Low-dose treatment regimens reported fewer side effects than conventional dosing regimens, but hyperkalemia, leukopenia, hemolysis, and PCP were reported.
Results:
After the process of identification, screening, 13 articles made it and accepted for the final assessment.
Their design was retrospective (9 studies), case reports (2 studies), and RCTs (2 studies).
Most of the studies looked at the difference between high-dose and low dose TMP-SMX in treatment of PJP.
This systematic review showed that, low-dose TMP-SMX is effective and associated with decrease mortality, reduced treatment cost, and adherence to daily drug intake.
Discussion:
Low-dose TMP-SMX therapy should be the first-line treatment option to reduce the risk of PCP in immunosuppressive patients, as a Cochrane meta-analysis reported a decrease in the incidence of PCP up to 91% and mortality rate up to 83%.
Routine PCP prophylaxis is recommended for immunocompromised and transplanted patients, as the risk of PCP is greater in 1–6-month post transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
This strategy reduces economic burden of illness and enhances compliance to daily regimen plan.
TMP-SMX is the first-line prophylactic agent for PCP, but alternative prophylaxis may not provide desired clinical outcomes.
PCP is the most frequent in patients with systemic rheumatoid arthritis, and risk factors include age, use of glucocorticoids, and existing comorbidities.
Guidelines for PCP prophylaxis for various cohorts are needed due to limited data on predictors and risk factors.
Small sample size and limited number of studies may lead to false-negative or false positive findings.
Conclusions:
Low-dose TMP-SMX may result in satisfactory outcomes in PJP treatment.
Further RCTs needed for better understanding on the optimal dosage of TMP-SMX in PJP treatment.
What is the level of evidence provided by this article?
The level of evidence provided by this article => level 1
Introduction
Pneumocystis jirovecii pneumonia (PCP) has significant cause of morbidity and mortality 50% in immunocompromised patient, and 22% to 45% in haematological malignancies and 5% to 15 %in post transplanted one ,and 2% in patients with rheumatoid disease.
For that number of mortality and morbidity ,antibiotics prophylaxis reduce the incidence of PCP.
TMP-SMX it is used for prophylaxis of PCP but adverse effects . like leukemia and hepatic toxicity has been observed that elaborate the need for formulating well-defined guide for its use .
TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage.
In high doses of TMP-SMX many adverse effects:
skin rash
gastrointestinal disturbances
bone marrow suppression
renal impairment
hepatotoxicity as well as electrolyte disorder
for which alternative treatment is required to avoid these adverse effects and optimize treatment.
Materials and method
data collected from from January 2000 to December 202 for dose optimization.
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP.
The quality of each article was evaluated using a Newcastle–Ottawa Scale for retrospective studies, Joanna Briggs Institute, The University of Adelaide critical checklist for case reports.
Results
13studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen.
Low dose treatment regimens is recommended for treatment and prophylaxis.
Low-dose treatment regimens is effective and less adverse effects.
Conclusion
Inspite of limited data available on the optimal dose of TMP-SMX ,the recommendation for treatment and prophylaxis is low dose of TMP-SMX.
Level of evidence .III
Please summarise this article.
Introduction
· PCP is the most frequent and highly morbid fungal infection for patients with autoimmune disorders, with an incidence of 50% in immunocompromised patients, 22-45% in hematological malignancy, 5-15% in transplant recipients, and 2% in rheumatoid diseases.
· PCP in HIV-positive patients has been reduced due to advanced technology and preventive measures.
· Co-trimoxazole is a combination of trimethoprim and sulfamethoxazole that has been found to reduce the incidence of PCP and associated mortality in non-HIV patients.
· PCP and hepatotoxicity were lower in non-HIV patients who received TMP-SMX prophylactically.
· TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities.
· Current dosing guidelines recommend 320-640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15-20 mg/kg every 6 to 8 h intravenously than orally for PCP infections. However, there is a high incidence of AEs in patients receiving recommended high doses.
· To ensure safety, dose optimization strategies are needed.
Method
· Database searches were conducted from 2000 to 2021. focusing on the dose optimization of TMP-SMX.
· The quality of articles was evaluated using a Newcastle-Ottawa Scale, JBI critical checklist, and Cochrane bias tool.
Discussion:
· Low-dose TMP-SMX therapy should be the first-line treatment option to reduce the risk of PCP in immunosuppressive patients, resulting in a decrease in mortality rate and PCP-associated AEs.
· Routine PCP prophylaxis is recommended for immunocompromised and transplanted patients, as the risk of PCP is greater in 1-6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, anti-lymphocyte antibodies, or calcineurin inhibitors.
· A study reported that 27% of kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia. This strategy reduces the economic burden of illness and enhances patients’ compliance with daily regimen plans.
· TMP-SMX is the first-line prophylactic agent for PCP, but alternative prophylaxis may not provide desired clinical outcomes.
· PCP is most common in patients with systemic rheumatoid arthritis, and risk factors include age, use of glucocorticoids, and existing comorbidities.
· TMP-SMX decreased the incidence of PCP and associated mortality after 1 year, but there are no guidelines for PCP prophylaxis in patients with rheumatological and other autoimmune dysfunctions.
Limitations:
. The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
· Limited number of studies,
· Small sample size, resulting in false-negative or false-positive findings.
Conclusion
· Low dose of TMP-SMX reduces mortality and PCP-associated AEs.
· This strategy reduces the economic burden and improves adherence to the daily regimen plan.
· Prophylactic treatment for HIV patients with PCP may be necessary for some patient populations with large-scale, prospective RCTs and cohort studies to provide guidelines.
====================================
What is the level of evidence provided by this article?
Level III
Introduction:
Pneumocystis pneumonia causes significant morbidity and mortality in immunocompromised patients. The incidence in transplant patients is 5-15% and more than 50% in immunocompromised patients. TMP-SMX is the mainstay of treatment and prophylaxis for pneumocystis. TMP-SMX has got got serious side effects which can hamper compliance and completing therapy. In accordance with current dosing guidelines, treatment of PCP is high dose TMP-SMX (TMP 15-20 mg/kg/day and SMX 75-100 mg/Kg/day) for 2-3 weeks. There is a high incidence of A/E in patients receiving the recommended high dose of TMP-SMX. Due to insufficient data on the optimal dose of TMP-SMX, its use is limited. The AEs include:
Therefore, to ensure the safety of of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
Materials and Methods:
This was a sytematic review carried out using PRISMA guidelines.
Based on the titles and abstracts, studies of all types with any data on clinical outcomes of TMP-SMX regimens were included in the screening. Studies before the year 2000 were excluded from the study.
Data extraction was performed using the predesigned data collection form for this review using Microsoft Word 2013.
The quality of each article was evaluated using the Newcastle-Ottawa Scale (NOS) for retrospective studies and Cochrane bias tool for RCTs
Two of the reviewers assessed the quality of each included study independently.
Results:
Out of the 857 related published studies, 163 were evaluated for eligibility criteria.From these, a total of 13 articles met the inclusion criteria for the final analysis. Out of the 13 studies, 9 were retrospective studies, 2 were case reports and 2 were RCTs. All the studies collected were published after the year 2000
Of the 13 studies, 5 compared the low dose of TMP-SMX regimen with a high dose regimen. These studies demonstrated that low dose TMP-SMX therapy must be considered as a first line therapy option to prevent occurrence and recurrence of PCP and PCP associated side effects
Low dose regimens usually reported fewer side effects compared to the conventional dosing regimens
In both RCTs, no cases of PCP were documented up to 24 and 52 weeks
Discussion:
This review revealed that low-dose TMP-SMX therapy should the first line treatment option, resulting in the reduction of mortality rate and PCP-associated adverse effects.
The Cochrane meta analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group. Although TMP-SMX has been regarded as the first line therapy, it is often switched to second line therapy due to TMP-SMX associated side effects.
A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia. Therefore, routine prophylaxis is only required in the early months post-transplant and after treatment of rejection.
Conclusion:
The standard doses result in an absolute increase of 18% in the incidence of grade 3 AEs. Step down therapy may be worthy in exploring approaches to improve clinical outcomes and will reduce overall economic burden and improve patient compliance
Study limitations:
Level of evidence:
This is a systematic review. Level I evidence
Thank you All
Many thanks for you Prof.Halawa
Please summarise this article.
Introduction:
Pneumocystis jirovecii (PCP) pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases.
PCP is disease rising alarm of human immunodeficiency virus (HIV) infection.
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family, is the drug of choice for prophylaxis and treatment of PCP.
The recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks, associated with hepatorenal side effects as well as skin rash.
Materials and Methods
Data Sources and Search Strategy– Articles in English from January 2000 to December 2021, search keywords were “dose optimization”, “Pneumocystis carinii pneumonia”, “Pneumocystis jirovecii pneumonia”, “HIV-patients”, “immune compromised patients” “Cotrimoxazole”, “trimethoprim/sulfamethoxazole”, and “TMP-SMX”.
INCLUSION CRITERIA:
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP. Data on clinical outcomes of TMP-SMX regimens.The retrospective studies, randomized controlled trials (RCTs), and case reports available in English.EXCLUSION CRITERIA:
The studies published before January 2000 or having inappropriate and incomplete information. Any article not met the inclusion criteria or not English.No full text, literature review, and inappropriate intervention.Article Quality Assessment- The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Aim of the study:
To assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.The impact of PCP on mortality and morbidity of the patients especially immunosuppressive patients.
Results:
13 studies included, out of them 4 in AIDS patients received TMP-SMX for prophylaxis, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency.Five studies out of 13, compared the low-dose regimen of TMP-SMX with a high-dose regimen, documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated side effects.A study reported that a in a total of 438 patients, the dose of TMP-SMX was reduced in 84 kidney transplant recipients for hyperkalemia, and 102 for leukopenia, side effects were found in 58.3% in low dose group and in 72,4% in a high dose group.Another study reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%).A study documented that TMP-SMX was reported to cause hemolysis in patients with G6PD deficiency.In both RCTs, no cases of PCP were documented up to weeks 24 and 52.The low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.Switching to second-line treatment such as dapsone, atovaquone, and pentamidine nebulizers due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.The risk factors for PCP in patients with rheumatoid disorders include age group (elderly > 65 years), use of glucocorticoids, and existing comorbidities.
Limitations:
Demographic variations of population.Limited studies number after the year 2000.All studies were of small sample size, resulting in false positive and false negative results.
Conclusions:
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.Large sample randomized trials, and prospective cohort studies are needed to provide guidelines dosing strategy for the PCP.
What is the level of evidence provided by this article?
The level of evidence is I – systematic review of randomized trials,cohort, and case reports, tests treatment.
Please summarise this article.
# The objective:
*The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes
# Introduction:
*The rate of PCP was more than 50% in immunocompromised patients with incidence of (5–15%) in transplant recipients.
*PCP is associated with high morbidity and mortality rate in patient with KT
*The improved technology and diagnostic methods result in early diagnosis; newest management programs and advanced preventive measures.
*Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine
analog, and sulfamethoxazole (SMX), which is from the sulfonamide family.
*TMP-SMX prophylactic reduce the incidence of PCP in non-HIV patients.
*TMP-SMX should be taken in correct way to get sufficient antimicrobial activity and to prevent over dose mainly in resistant cases.
*The TMP-SMX dose recommendations, on the basis of TMP, is 320–640 mg/day, every 12 h, orally, for bacterial infections.
15–20 mg/kg every (6 – 8 h) I/V then orally for the treatment of PCP infections.
In current guidelines high dose is recommended for PCP (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks), but the risk of S/E is high such as skin irritation, GIT disturbances, BM suppression, renal impairment, hepatotoxicity and electrolyte disorder.
*The therapeutic option for treatment of PCP is 16 mg/kg of TMP-SMX with risk of
hepato-renal AEs so it need dose optimization strategies.
# Methods:
*The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines
*Various databases were searched from January 2000
to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
*The data were collected in a specific form with predefined inclusion and exclusion criteria.
*The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
*Studies of all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening.
*The studies published before January 2000 or having inappropriate and incomplete information were excluded from the study.
*Data extraction was performed using the predesigned data collection form for this review using Microsoft word 2013
# Results:
*Thirteen studies met the inclusion criteria for final analysis.
*Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
*Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
*The study found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
*This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan.
# Discussion
*The impact of PCP on mortality and morbidity of the patients especially
immunosuppressive patients is significant.
* This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
*The incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
*TMP-SMX is a first-line regimen for prophylaxis of PCP, but switch to second-line
treatment such as dapsone, atovaquone, and atomized pentamidine is recommended due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and (G6PD) deficiency.
* the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, ATG, or CNI
# The limitations of the study:
*The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
*It is include all studies that met inclusion criteria, due to limited number of studies that conducted after January 2000.
*Small sample size results in false-negative or false-positive findings.
# Conclusions
*The study provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
*The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
*Reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
* The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
What is the level of evidence provided by this article?
Level 1
Please summarise this article.
-Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has incidence more than 50% in immunocompromised patients and 5–15% in transplant recipients . The clinical indications of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients measures .
-TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage .
-The TMP-SMX dosing recommendations, on the basis of TMP component, 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections .
-In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) . There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
– It is systematic review of different databases searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data were collected in a specific form with predefined inclusion and exclusion criteria.
-It revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
-The TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency .
-The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors .
-Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts .
-Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes, HIV-positive patients who have CD4+ counts less than 200 cells/mm3, rheumatological and other autoimmune dysfunctions .
-The low dose of TMP-SMX provides satisfactory outcomes while
reducing the mortality rate and PCP-associated AEs.
-Prospective RCTs and cohort studies are needed to provide guidelines regarding the dosing strategiesfor the PCP.
What is the level of evidence provided by this article?
Level 3
Please summarise this article
Thirteen studies on the dose optimization of Trimethoprim-Sulfamethoxazole (TMP-SMX) in patients with Pneumocystis jirovecii pneumonia were reviewed.
Studies included :
Patient groups are varied and included
Results:
Limitations
What is the level of evidence provided by this article?
Please summarise this article.
Aim of this systematic review : To assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodefi-ciency syndromes.
Introduction :
PCP is a hallmark disorder indicating human immunodeficiency virus (HIV) infection, the incidence of PCP was more than 50% in immunocompromised patients,but has been reduced due to advanced technology in diagnosis ,treatment and preventive measures. High-dose TMP-SMX is recommended for PCP, but its use is limited due to insufficient data. To ensure safety, dose optimization strategies should be used.
Materials and Methods:
-Data Sources and Search Strategy: The systematic search assessed the dosing guidelines of TMP-SMX in patients using PRISMA guidelines and free-text web searches. Free-text web searches explore articles in English from January 2000 to December 2021. Keywords used were “dose optimization”, “Pneumocystis carinii pneumonia”, “HIV-patients”, “immunocompromised patients”, “Co-trimoxazole”, “trimethoprim/sulfamethoxazole“
Selection Criteria and Procedure:Studies reporting the dosing strategy of TMP-SMX in patients for PCP were included in this review, with retrospective studies, randomized controlled trials (RCTs), and case reports available in English. Titles and abstracts of all included articles were screened independently by two reviewers, with uncertainty as to whether selected studies met inclusion criteria discussed with a third reviewer.
Data extraction : was performed by one of the reviewers and reviewed by another co-author, with any discrepancies resolved by a third reviewer.
Article Quality Assessment:
Article quality was evaluated using the Newcastle–Ottawa Scale (NOS), Joanna Briggs Institute (JBI) critical checklist, and Cochrane bias tool. Two reviewers compared their results and disagreements were resolved by detailed discussion.
Results:
Study Characteristics : 857 related published studies were identified from grey literature and electronic databases, and 163 studies were evaluated for eligibility criteria. 25 articles were excluded due to no full-text, literature reviews, inappropriate intervention, no required data, and non-English. 13 articles met inclusion criteria for final analysis, nine of which were retrospective cohort studies.
Quality Assessment of Studies: Based on the NOS eight studies were rated as a total score of 7, one study scored 6, and the remaining four studies scored 8. The Cochrane bias tool assessed that almost all domains for RCT were at low risk of bias, and the quality of case reports in both reports was of good quality.
Dosing Strategy of TMP-SMX in Selected Studies:
The dosing regimen of TMP-SMX and clinical outcomes of 13 studies was evaluated ,of which four studies reported that patients had AIDS, four reported patients with rheumatoid arthritis, two documented non-HIV patients, two reported kidney transplant recipients, and one reported the patient with G6PD deficiency. Low-dose treatment regimens (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), were found to be as well-tolerated and effective as high-dose regimens ( (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), , but had fewer side effects compared to conventional dosing regimens. Nakashima et al. reported that the total AEs rate was 58.3% in the low-dose group.
Discussion:
The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group. Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immuno-compromised patients. PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3. The first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP160 mg/day).
Alternative PCP strategies include administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays. The standard doses result in an absolute increase of 18% in the incidence of grade ≥3 AEs, but step-down therapy may be a worthy approach to improve clinical outcomes. The incidence of occurrence of PCP is the most frequent in patients with systemic rheumatoid arthritis disease taking steroids and immunosuppressive agents.
Conclusions:
TMP-SMX provides satisfactory outcomes while reducing mortality and AEs, and reduces economic burden and compliance.
Level of evidence :
This systematic review includes case reports, case control studies and observational cohort studies . The grade of recommendation is grade B and level of evidence in systematic review of cohort studies is level 2a while in systematic review of case-control studies is level 3a . I didn’t find information regarding the level of evidence in systematic review of mixed cohorts ,case control and case reports studies .
Introduction
The most frequently fatal fungal infection for autoimmune people is Pneumocystis carinii pneumonia. Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%. Immunosuppressive patients die mostly from PCP critical symptoms as tachycardia, hypoxia, tachypnea, shortness of breath, etc. Hence, PCP is an HIV hallmark. Due to enhanced diagnostic technologies, early diagnosis, intensive care management strategies, and preventive measures, PCP in HIV-positive patients has decreased in recent years.
Materials and Methods
PRISMA recommendations were used for the systematic search of TMP-SMX dosage guidelines in patients.
This review covered studies on TMP-SMX dose for PCP incidence or recurrence. Based on titles and abstracts, all studies involving TMP-SMX clinical outcomes were screened.
The selected studies provided author, year, design, sample size, patient characteristics, dosage approach, clinical outcomes, and findings.
Results
Among a total of more than 857 papers screened, only 13 matched the inclusion criteria for evaluation. Of the 13 selected studies, nine were retrospective designs, two case reports, and two RCTs. Based on the NOS quality of studies evaluation, eight studies received a total score of 7, one study had a score of 6, and four studies received a score of 8. The average score for the included studies was 7. The Cochrane bias test determined that the majority of RCT domains posed a minimal risk of bias. According to the JBI critical checklist, the case report quality in both reports was high. Five out of thirteen studies compared the low-dose regimen of TMP-SMX to the high-dose regimen, and they recommended the low-dose regimen of TMP-SMT as first-line therapy for preventing the recurrence or development of PJP because it was much more tolerable. Ohmura and his colleagues reported in one more research that a low-dose treatment regimen of TMP-SMX with 10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy and was linked with fewer side effects and a lower death rate of 19% compared to >25% in conventional dose.
Low-dose treatments had fewer side effects than conventional regimens. Among 84 kidney transplant recipients with hyperkalemia and 102 with leukopenia, TMP-SMX was reduced in 438 patients. TMP-SMX caused hyperkalemia in another research. Nakashima et al. found that 72.4% of patients in the conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day) and 58.3% in the low-dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day) had AEs. In G6PD-deficient patients, TMP-SMX caused hemolysis. Up to weeks 24 and 52, neither RCT reported PCP.
Discussion
PCP has a significant impact on patient mortality and morbidity, especially in immunocompromised individuals.
According to this analysis, low-dose TMP-SMX should be the first-line treatment because it reduces mortality and PCP-related side effects.
Compared to the control group, there was a 91% reduction in the incidence of PCP and an 83% reduction in the mortality rate.
Due to TMP-SMX-associated adverse effects and medication intolerance induced by neutropenia and G6PD deficiency, it is usually necessary to move to second-line therapies (dapsone, atovaquone, and pentamidine).
Conclusion
The low dose of TMP-SMX produces good results while decreasing mortality and PCP-associated adverse events.
This approach decreases the overall economic load and increases patient adherence to their daily prescription.
Level of evidence
In the current meta-analysis, the evidence of selected studies ranges between retrospective studies with level of evidence III, case reports/series-level IV and level I for RCTs. Hence, based on the majority of studies being Level of evidence III, I propose a III LOE, however the meta-analysis and systemic review implies LOE I.
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Introduction
This review included the studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP.
Results
Discussion
Limitations of the study:
Conclusions
Level of evidence:
Since this systemic review included retrospective cohorts and case studies in the analysis, the level is 3
Summary : Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Introduction
Pneumocystis jirovecii pneumonia (PJP) has an impact on mortality and morbidity in immunocompromised patient including kidney transplant one
Substantial evidence from multiple trials raises the benefit of antibiotic prophylaxis in reducing the incidence of PJP
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family, currently, it is used for prophylaxis of PJP but adverse events like neutropenia and hepatic toxicity has been observed that elaborate the need for formulating well-defined guide for its use
The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections [7]. In accordance with current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks)
Therefore, to ensure the safety of TMP-SMX, systematic review is needed to optimize the benefit and reduce the associated adverse events
Materials and methods
Web based search done and 3 types of research work included (retrospective. randomized controlled and case studies) published from year 2000- 2021 where the data validation done using the following tools: a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
The web-based search resulted in 857 titles that reduced to 13 trials after application of exclusion and inclusion criteria
Results
· five of thirteen included trials compared the low-dose regimen of TMP-SMX with a high-dose regimen they conclude that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
· Ohmura and his colleagues concluded that a low-dose treatment regimen (<10 mg/kg ) of TMP-SMX is effective in prevention of PJP in the target groups without adverse events.
· Schild et al. in their study they use an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, switched to low-dose TMP-SMX cause of 23% of patients showed various AEs
· Nakashima et al. reported that the total AEs rate in the low dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day), and in conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day), to be 58.3% and 72.4% respectively
· As regard mortality due to TMP-SMX, Kosaka et al ; reported that the mortality rates were lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%)
Discussion
low-dose TMP-SMX therapy should be the first-line treatment option as it is concluded that it reduces both the related mortality and adverse events
the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg every other day but, daily dose may be beneficial in prevention of other posttransplant infection like toxoplasmosis
second-line treatment such of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays can be used in case of TMP-SMX intolerance
Routine PCP prophylaxis is recommended
· Upon hospital admission of immucompromized patient where the prevalence of PJP is > 3%
· 1-6 months after organ transplantation (high immunosuppressive burden)
· CMV infection
· Increase number of rejection episodes
· low CD4+ lymphocyte counts (less than 200 cells/mm3)
limitations.
1- Small sample size in the included 13 studies
2- Differences in the demografic data included due to differences in the distribution countries where the studies have been done
Conclusion
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs without causing economic burden.
Further large-scale, prospective RCTs and cohort studies are needed to provide guidelines regarding the dosing strategies for the PCP
Introduction:
Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii pneumonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorders.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant
recipients and around 2% in patients with rheumatoid diseases
The clinical indications of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients thus requiring optimal dosing strategies of Trimethoprim–Sulfamethoxazole (TMP-SMX).
Therefore, to ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
Objective :
To assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
Methods:
Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX. The data
were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
Selection Criteria and Procedure:
studies of all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening. The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study.
The studies published before January 2000 or having inappropriate and incomplete information were excluded.
Data Extraction:
Data extraction was performed using Microsoft Word 2013 using a pre designed data collection form for this review.
Results:
13 studies met the inclusion criteria for final analysis. Of the 13 studies selected, 9 were retrospective cohort studies, 2 case reports and 2 randomized controlled trials (RCTs).
Most studies compared high-dose TMP-SMX regimens to low-dose regimens in PCP. Low-dose TMP-SMX provides satisfactory results while reducing mortality and side effects associated with PCP.
This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Recommendations:
Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
PCP prophylaxis is highly recommended in HIV-positive patients who have
CD4+ counts less than 200 cells/mm3
Study limitation:
This study does have several limitations. Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment. Secondly, the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
Thirdly, although the quality of the majority of the included studies was
good, due to small sample size, this may result in false-negative or false-positive findings
Conclusions:
The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
level 111: Evidence from evidence summaries developed from systematic review
Summary of the article
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
This is a retrospective study, reviewing current evidence in PCP patients with a focus on dose optimization strategies, databases were searched from January 2000 to December 2021.
1. In accordance with current dosing guidelines, the recommended therapy for PCP is high- dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
2. High dose of TMP-SMX had higher rates of AEs such as skin irritation (e.g., rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte disorder for which alternative treatment is required to avoid these AEs.
The TMP-SMX dosing recommendations
1. Recommendation on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections.
2. In accordance with current dosing guidelines, the recommended therapy for PCP is high- dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
3. The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of hepato-renal AEs.
Results of the study:
1. Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy.
2. Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions.
3. Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
4. AEs rate was 58.3% in the low- dose group (TMP, 4–10 mg/kg/day; SMX 20–50 mg/kg/day) and72.4% in the conventional-dose group (TMP, 10–20 mg/kg/day; SMX, 50–100 mg/kg/day).
5. Mortality rates were reported lower in the low-dose group (19.5%) compared to the conventional-dose group (25.0%)..
Discussion
1. This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
2. It often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX associated AEs and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
3. Routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
4. The first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day).
Limitations of the study:
1. The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
2. The limited number of studies conducted after January 2000 forced the authors to include all studies that met inclusion criteria.
3. The majority of the included studies, due to small sample size, may result in false-negative or false-positive findings.
Conclusions
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
The level of evidence provided by this article:
This is a retrospective study with level of evidence grade 3.
☆ Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
______________________________
◇ Introduction
▪︎Pneumocystis carinii pneumonia (PCP), also known as Pneumocystis jirovecii has high incidence in immunocompromised patients, hematological malignancy, and transplant recipients.
▪︎The occurrence or recurrence of PCP in HIV-positive patients has been reduced due to advanced technology and tools in diagnostic process.
▪︎Co-trimoxazole is the combination of trimethoprim (TMP), and sulfamethoxazole (SMX).
▪︎ There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX such as skin irritation (e.g., rashes), GIT disturbances, bone marrow suppression, renal impairment, hepatotoxicity as well as electrolyte
disorder.
▪︎The therapeutic option for treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX with risk of hepato-renal AEs.
¤ To ensure the safety of TMP-SMX, there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
◇ Methods:
▪︎Various databases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
▪︎The data were collected in a specific form with predefined inclusion and exclusion criteria. The quality of each
article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
◇ Results:
▪︎Thirteen studies met the inclusion criteria for final analysis. Of the 13 selected
studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
▪︎Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
▪︎ The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events. This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Limitations of the study:
1. The findings could have been affected by socio-demographic characteristics because the selected articles included patients from various countries.
2. The limited number of studies conducted after January 2000 forced the authors to include all studies that met inclusion criteria.
3. Small sample size.
◇ Conclusions
▪︎These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
▪︎The low dose of TMP-SMX provides satisfactory outcomes while decreasing the mortality rate and PCP-associated AEs. It also reduces overall economic burden and enhances patients’ compliance.
▪︎For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen.
▪︎The study findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies
for the PCP.
◇ Level of evidence: Level 1
Please summarise this article.
Introduction
Pneumocystis carinii pneumonia (PCP),is frequent and significant fungal infection for patients with autoimmune disorders.
May present as tachycardia, hypoxia, tachypnea, shortness of breath
The occurrence or recurrence of PCP in HIV-positive patients due to advanced diagnostic tools and new therapeutic strategies
Co-trimoxazole is the combination of trimethoprim (TMP) and sulfamethoxazole (SMX)
This review focused on the use of TMP-SMX in PCP patients with a focus on dose optimization strategies
Methodology
· Various databases were searched from January 2000 to December 2021
· The focus was on the dose optimization of TMP-SMX.
· Specific form with predefined inclusion and exclusion criteria was used
· Quality of article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies.
· Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs);
Results
13 Studies were analyzed – ( 9 Retropsective cohort, 2 case reports, 2 RCT)
Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP
It was found that low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and adverse events.
This reduced the economic burden of illness and enhances patients’ compliance to daily regimen
Conclusion
· The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events
· This strategy also reduces economic implications
· Large-scale, prospective RCTs and cohort studies are required to provide guidance for adequate dosing strategy
What is the level of evidence provided by this article?
Level 1
The level of evidence discussion has triggered very variable response on this thread.
At times my answer is too short such as, “Really? 5?”
I do not mean to be ridiculing, I mean to be precise. Brevity for the sake of clarity.
The level of evidence question highlighted the most important aspect of this study: It was a bad study.
Normally, if it was a meta-analysis of just the two RCTs, it would be a level one study. If it was a meta-analysis of just the 9 retrospective trials it would be a level 3 study. Meta-analysis are not done for case reports. They somehow managed to throw those in…
I would grade it as “ungradable” if such a category exists!
The level of evidence may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size. As always, a systematic review is generally better than an individual study.
I agree, Dr Saja.
Introduction
● PCP is the most frequent and highly morbid fungal infection for patients with
autoimmune disorders
● The incidence of PCP
☆ > 50% in immunocompromised patients
☆ 50% of patients with hepatotoxicity
☆ 22–45% in hematological malignancy
☆ 5–15% in transplant recipients
☆ 2% in patients with rheumatoid diseases
● The symptoms of PCP, such as tachycardia, hypoxia, tachypnea, shortness of breath, etc., are the major causes of death of immunosuppressive patients
● PCP indicates HIV infection
● TMP-SMX minimizes the incidence of PCP in patients.
● AEs such as skin irritation ( rashes), gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity and electrolyte disorder
● Treatment of PCP requires a dose of ≥16 mg/kg of TMP-SMX
Routine PCP prophylaxis is recommended for patients :
☆ Hospitalized patients
☆ Transplant recipients
☆ Concomitant CMV infections
☆ Graft rejection episodes
☆ Low CD4+ count lymphocyte
Materials and Methods
● Free-text web searches were explored for articles in English from 2000 to 2021.
● The study includes studies of all types with any data on clinical outcomes of TMP-SMX regimens
● The main goal of this systematic review is assessing the current dosing strategy of TMP-SMZ to reduce the risk of PCP especially in immunodeficiency syndromes.
Results
● Low-dose TMP-SMX therapy should be the first-line . it reduces mortality rate and PCP-associated AEs.
● It decreases PCP by 91% and mortality by 83% when compared to control group
● Though TMP-SMX is a first-line for prophylaxis of PCP, it often has to be switched to other treatment such as dapsone, atovaquone, and atomized pentamidine due to it’s AEs and drug intolerance ” neutropenia and (G6PD) deficiency
● The double-strength seems to be effective while taken daily or thrice in a week, though daily TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
● The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
limitations :
☆ Selected articles included patients from various countries, so it affected by socio-demographic such as ethnicity, region, lifestyle, and environment.
☆ Limited number of studies conducted after 2000
☆ Small sample size of studies
Level : 5
Really? 5?Please use bold or underline for headings or sub-headings to make it easier to read
Summary
· The current metanalysis involved many studies, but unfortunately retrospective cohort, case reports and only 2 RCT.
· It concluded that low dose SMX-TMP has good efficacy in prevention of PCP and less side effects.
· High dose SMX-TMP was associated with higher incidence of neutropenia, BM depression, hepatitis, pancreatitis and interstitial nephritis.
· Low dose was also associated with decreased economic burden and improve patient adherence to prophylaxis.
Level of evidence: III (as the included studies are retrospective)
Really? 3?Typing whole sentence in bold or capitals equals to shouting !
I don’t know the level of evidence , but may be level II AS being derived from retrospective cohort
-Pneumocystis pneumonia PCP is highly prevalent fungal infection in immunocompromised individuals and carries significant morbidity and mortality. TMP-SMX decreases the incidence of PCP in patients.
-Data on the optimal dose of TMP-SMX is insufficient, the current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX, this regimen associated with high incidence of adverse events.
Aim of the study:
-Review current evidence in PCP patients with various immunodeficiency syndromes focusing on dose optimization strategies to ensure the safety of TMP-SMX.
Materials and Methods
-Search for articles in English only from January 2000 to December 2021 which focus on the dose optimization of TMP-SMX
– Systematic search in different databases.
– Included studies reporting the dosing strategy of TMP-SMX in PCP, any clinical outcomes of TMP-SMX regimens.
– Included; retrospective studies, RCTs, and case reports
-Exclusion: studies published before January 2000 or studies with incomplete information
– Collected data in a specific form were screened by two reviewers independently.
– The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for RCTs
Results:
– Initially, 163 studies were evaluated for eligibility criteria after screening only 13 studies met the inclusion criteria for final analysis.
– Of the 13 selected studies; 9 retrospective cohort studies, 2 case reports, and 2 RCT.
– A total of 2663 patients were recruited in the included studies.
– Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
– low-dose treatment regimen is well-tolerated, effective , and fewer side effects compared with high-dose therapy
– Low dose group has lower mortality rate and PCP-associated adverse events
Conclusion:
-low-dose TMP-SMX therapy resulting in the reduction of mortality rate and PCP-associated AEs and can be used as first strategy.
-No significant differences in the occurrence or recurrence of PCP between full-dose and low-dose TMP-SMX.
This strategy reduces economic burden of illness and enhances patients compliance to daily regimen plan.
Limitations:
– Small number of study included.
– Comparing studies with different designs.
– Socio-demographic data may affect the results of the selected articles as it included patients from various countries.
– The included studies with small sample size may result in in false-negative or false-positive findings.
Level of evidence:
Level II: Systematic review with heterogenous studies and evidence obtained from at least one well designed RCT (eg large multi-site RCT).
evidence level is 3
Really? 3?
Introduction
Pneumocystis carinii pneuomonia PCPC known as pneumocystic jirovecii pneuomonia has remained the most frequent and highly morbid fungal infection for patients with autoimmune disorder.
The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid diseases.
PCP is considered a hallmark disorder indicating human immunodeficiency virus infection.
TMP-SMX has been observed to substantially minimize the incidence of PCP in patients.
A retrospective study reported that the incidence of PCP and PCP -associated mortality was lower in patients with rheumatoid arthritis who received high-dose of glucocorticoids.
The incidence of adverse events (AEs) was decreased in non-HIV patients who received TMP-SMX prophylactically.
Methods
The systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA).
Free-text web searches using Google Scholar, and databases such as PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, etc., were explored for articles in English from January 2000 to December 2021.
Reference lists of relevant studies were screened for additional titles for inclusion in the review.
The keywords used for the search were “dose optimization”,pneumocystics carinii pneumonia”,.
“pneumocystics pneumonia “HIV-patients”, “immune compromised patients” “Cotrimoxazole”, “trimethoprim/sulfamethoxazole”, and “TMP-SMX”.
Results
857 related published studies were identified from grey literature as well as electronic databases.
After the removal of the duplicate studies and other reasons, 163 studies were evaluated for eligibility criteria.
Based on inclusion and exclusion criteria, 125 studies were excluded after the screening of the titles and abstracts.
Full-text articles were screened for final analysis.
Twenty-five articles were excluded due to the following reasons: no full-text (N = 09), literature reviews (N = 04), inappropriate intervention (N = 03), no required data (N = 03), and non-English (N = 06).
A total of 13 articles met the inclusion criteria for final analysis.
Of the 13 selected studies, nine were retrospective cohort studies, two case reports and two RCT
Discussion
The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes.
The impact of PCP on mortality and morbidity of the patients especially immunosuppressive patients is significant [ 36 ].
TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP –associated AEs,. The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to.
The TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX.
Public Health 2022, 19, 2833 8 of 11 associated AEs, and drug intolerance caused by neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency [9,10,36]
Conclusion
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP -associated AEs, The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP -associated AEs.
This strategy reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV patients, it may still warrant to start prophylactic treatment regimen.
Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP
I like your analysis and summary. What is the level of evidence?
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic ReviewIntroduction
· Advanced management strategies in intensive care settings and advanced in prevention measurement result in reducing the occurrence or recurrence of PCP in HIV patients.
· Co-trimoxazole is the combination of trimethoprim (TMP) which is a pyrimidine analog, and sulfamethoxazole.
· The TMP-SMX recommended dose to treat PCP is 15 to 20vmg /kg every 6-8 hours and orally for 2-3 weeks.
· High doses of TMP-SMX as a first-line treatment regimen had higher rates of S/E such as skin rash, GIT disturbance, M suppression .renal impairment, and hepatotoxicity. And electrolytes disturbance..
· This review ensures the safety of TMP-SMX there is a high demand to review current evidence in PCP patients with a focus on dose optimization strategies.
· Dose optimization is very effective to ensure the therapeutic outcome of antimicrobial therapy like the management of PCP.
· The retrospective studies, randomized, controlled trials, and case reports available in English were included in this study.
Result
· related published studies were identified from grey literature as well as the data base .
· 25 articles were excluded due to :
· Full text, literature reviews, inappropriate intervention, no required data, and non-English.
· 13 articles met the inclusion criteria.
· Nine were retrospective cohort studies,
· Two cases of randomized controlled studies .
· These studies documented that low-dose TMP-SMX therapy must be considered as a first-line treatment option to prevent the occurrence and recurrence of PCP and the low-dose treatment regimen reported fewer side effects compared to the converting dosing regimen.
· Some of the studies report side effects such as hyperkalemia, leukopenia a, auto-hemolysis.in G6PD deficiency.
Discussion
· The aim of systemic review was to assess the current dosing of TMP-SMX to reduce the risk of PCP in immunocompromized patients.so review conclude that low-dose TMP-SMX therapy should be the first line treatment option .in reducing mortality rate and PCP-associated AEs,
· Second-line treatment of PCP case of SE or intolerance of TMP-SMX such as dapsone, atovaquone and pentamidine.
· Study failed to identify significant differences between the full-dose and dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
· PCP prophylaxis rather than TMP-SMX is dapsone either alone or combined with pyrimethamine .atovaquone, or pentamidine sprays.
Limitations of the study
1-Patients from different countries, so the social, ethnic region, lifestyle, and environmental affect of the findings.
2-limitation number of studies conducted from Jan 2000.
3- The sample size is small in the majority of the studies
Conclusion
· This finding provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP.
· The low dosage TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
· Due to limited data available on the optimal dose of TMP-SMX these findings would support the conduct of large-scale prospective RCTs and cohort studies to provide guiding the dosing strategies for the PCP.
LEVEL of evidence is 3
Really? 3?
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimisation in Pneumocystis jirovecii Pneumonia (PCP) Management:
A Systematic Review include of retrospective studies, randomized controlled trials (RCTs), and case reports which done between January/2000 to December/ 2021
Introduction:
This study is address role and target dose of TMP-SMZ in reducing risk of PCP in patients with immunocompromised such as HIV patients or lymphproliferative disease or patients with immunosuppressive therapy in solid organ transplant.
Targeting of TMP-SMZ dose and close adherence of TMP-SMZ at time is important to treatment patients with PCP for reduce incidence of mortality from PCP.
So TMP-SMZ is recommended as first line of treatment and patients shifted to second line of treatment as dapsone, atovaquone, and atomized pentamidine because of side effects of TMP-SMZ like neutropenia G6PD deficiency.
TMP-SMZ used as prophylaxis for prevent PCP infection and treatment of PCP infection in transplanted patients.
Risk factors for expose patients to PCP infection is early 6 months post transplant where patients on neutropenic phase, large dose of steroid and receive ATG and on calcinurine inhibitors
Other factors are previous history of graft rejection and history of CMV infection and low CD4+ count lymphocyte counts.
The recommended dose of TMP-SMX is TMP 80 mg/day; SMX 400 mg/day better than doubling the dose ( 160/ 800mg), to avoid side effects of drug.
The incidence of PCP infection is more common in patients with systemic rheumatoid arthritis on immunosuppressive agents or high dose of steroid or autoimmune disease on immunosuppressive agents.
Limitations:
Limited of this study is heterogeneous sample and small size of sample lead to false positive and false negative results. also this study done in January which lead to force to include all studies met inclusion criteria.
Conclusion:
Low dose of TMP-SMX is recommended to prevent and treat PCP infection in patients with immunosuppressive therapy or congenital and acquired immunodeficiency.
Low dose TMP-SMX carry low risk of mortality and less side effects.
Level of evidence 1
Really? 1?
I- Summary:
Aim of the study:
To review current evidence in PCP patients with a focus on dose optimization strategies.
Material and methods:
Results:
Conclusion:
II- level of evidence: IIIa
Really? IIIa?
The following abbreviations are used throughout my reply below:
TMP-SMZ: trimethoprim-sulfamethoxazole
PCP: Pneumocystis jirovecii
In this review, published in the International Journal of Environmental Research and Public Health in 2022, the authors state their main aim is to “assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndromes”.
This statement in itself exposes many flaws of the paper. The intention to evaluate “dosing of TMP-SMZ in order to reduce the risk of PCP” implies a focus on prophylactic use of the drug rather than therapeutic use. However, only 6 of the included studies report on PCP prophylaxis (with 1 of these being a duplicate of the same RCT with different reporting times) whilst the remaining 7 papers focus on use of treatment dose TMP-SMZ for confirmed cases of infection. This amalgamation of prophylaxis vs. treatment papers results in very different study end-points making it hard for the reader to understand the focus of the paper, e.g. are the authors focussing on incidence of PCP with low versus high dose TMP-SMZ prophylaxis, incidence of adverse drug effects or efficacy of treatment with low versus higher dose TMP-SMZ? Furthermore, the use of the term “various immunodeficiency syndromes” highlights the heterogeneity of the populations studied across the included papers and indicates it may not be possible to draw useful conclusions that should influence clinical practice. This failure to demonstrate recognition of the potential differences between included patient populations is further exposed in the opening statement in the abstract when the authors comment on the particular impact of PCP in patients with autoimmune disorders, whereas their included studies have population groups ranging from transplant recipients, haemodialysis patients without HIV and patients receiving TMP-SMZ for various infections without detail on immunosuppression status.
Comments on the review methods of this paper
The authors’ intentions for this paper were to conduct a systematic review. Their search included papers published in English from January 2000-December 2021 and they accessed a broad range of databases in order to maximise chances of capturing relevant studies. The keywords they used for their search were: “dose optimisation” “Pneumocystis carinni pneumonia” “Pneumocystis jirovecii pneumonia” “HIV-patients” “immune-compromised patients” “Co-trimozaxole” “trimethoprim/sulfamethoxazole” and “TMP-SMX”. I would suggest that there may have been some limitations in using these search terms, e.g. “immune-compromised patients” is a very specific phrasing and may not capture different terms such as immunosuppressed. Similarly “HIV” rather than “HIV-patients” would probably have been less limiting as search terminology. The authors state that most of their included papers were actually found through reference snowballing and I would hypothesise that this was partially because their search terms were not effective enough and additionally their review question was not well structured with a clear aim and therefore led to a problematic search strategy.
The authors used a predesigned form to extract data from their included studies. A single reviewer is reported to have performed this data collection with the results reviewed by another author and any conflicts resolved by a third person. I would suggest this process was ineffective as there are some very misleading summaries of the included patient characteristics in Table 1 (see later comments).
The initial search process identified 857 papers but the use of automatic tools excluded 224 of these and of the 104 papers sought for retrieval 66 were not retrieved- this is a huge proportion of the papers and I could not see any comments about why these papers were not retrieved. In total, only 13 papers were included in the review.
Comments on the included studies in this review
The authors state their systematic review includes 9 retrospective cohort studies, 2 randomised controlled trials (RCT) and 2 case reports. Of these trial types, RCTs should provide the highest-quality evidence. However, there is actually only 1 RCT used in this study as it is the same trial with 2 separate publications depending on outcome reporting (one at 24 weeks and one at 52 weeks). The authors state that 2663 patients were recruited from their included studies but this is untrue as the same 183 patients for the RCT have been counted twice. The included RCT (Utsunomiya et al.) was looking at PCP prophylaxis for patients with rheumatological conditions who were receiving concurrent steroid treatment greater than or equal to 0.6mg/kg/day. In one year there were no reported cases of PCP in either prophylaxis group: for a relatively low incidence disease it is unlikely a population size of 183 is large enough to draw significant conclusions.
The authors included 2 case reports in their systematic review. It is unusual practice to include case reports in systematic reviews as they frequently do not provide high-enough quality evidence. However, in cases of a rare incidence disease or where a case report shed light on an emerging or different treatment one might justify reference being made to them in order to provide the reader with a current overview of the topic. However, I feel the two case reports included in this review are irrelevant to the review aim and should not have been included at all. Rehman et al. 2021 describes a delayed diagnosis of PCP in an individual newly-identified as HIV-positive. The purpose of the case report is to highlight symptoms that should trigger clinical suspicion of PCP and the authors do not even give details on the dose of TMP-SMZ used. Lu et al. 2020 describes a patient with G6PD deficiency who received treatment with TMP-SMZ without developing haemolysis, despite the drug usually being contraindicated in such patients: I do not feel this case report should have been included.
The majority of papers included in this systematic review are therefore retrospective cohort studies which may be prone to bias. In table 1 the authors summarise the studies, including commenting on the characteristics of included patients and the findings of each study. There are some very significant errors here which significantly undermined my trust in the way the authors have interpreted the studies they included.
For example, the authors state Dao et al., 2014 is a retrospective cohort study with 305 patients and that these patients are “patients with PCP infection”. This study was actually investigating the difficulty of achieving TMP-SMX concentrations within target range and concluded that it was difficult to achieve the desired target, with no difference between groups receiving higher or low dose TMP-SMX. The patient population was those receiving TMP-SMX treatment for wide variety of clinical indications, with only 43 of the 305 patients being treated for PCP in contrast to the authors summary that these were 305 patients with PCP infection.
Secondly, the table indicates that Yamashita et al., 2021 is a retrospective study of 81 “patients with HIV” when in fact the population studied was 81 haemodialysis patients who were HIV-uninfected. The study was investigating PCP prophylaxis with low versus higher dose TMP-SMX but there were no reported cases of PCP in either group and the sample size of 81 is very small relative to the predicted incidence of the disease.
Thirdly, the authors describe Park et al., 2021 as being a retrospective cohort study of 1092 “patients with PCP and rheumatoid arthritis”; this is grossly misleading as the study was looking at prophylaxis in patients with rheumatic disease who were receiving non-high dose steroid treatment and the majority of patients did not have PCP. The authors of the systematic review summarised that the clinical outcomes were that “TMP-SMX reduced 1 year PCP incidence and related mortality” but the significant difference between the groups being investigated was the dose of steroids they were taking rather than TMP-SMX. The inclusion of a study with 1092 patients at first glance provides credibility to the sample size included in the systematic review but I feel on closer inspection the study is not as closely related to the review aim as would be expected.
Comments on the analysis and conclusions in this paper
The analysis and conclusions in this systematic review are difficult to follow and I think this relates back to the poorly defined research question and the heterogeneity of the patient populations and study outcomes in the included studies. The authors state that they “failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP. This strategy reduces economic burden of illness and enhances patients’ compliance to daily regimen plan”. Considering that the studies which used varying doses of TMP-SMZ for PCP prophylaxis were small and did not report any cases of PCP in either group, it is not reliable to conclude that a lower dose regimen is effective in reducing the incidence of PCP. It is widely-recognised that the use of TMP-SMX may be limited by its side effects and for this reason many of the studies had included outcomes of dose changes or treatment switches. The commonly reported reasons for change were effects such as cytopenia or hyperkalaemia which would be detected by health professionals and the advice to change treatment would most likely be based on this rather than reported patient symptoms. I therefore cannot see the evidence justifying the authors’ conclusion that lower-dose TMP-SMX increases patient concordance with taking their medications. The economic impact equally cannot be evaluated without understanding the incidence of PCP illness in those taking varying doses of prophylaxis.
The authors state that the small number of studies identified through their search methods “forced us to include all studies that met inclusion criteria”. I would argue that their search did not perhaps identify all relevant papers, and that the inclusion of papers and in particular case reports which were not relevant to their question undermines the quality of the review they have published.
What level of evidence does this review provide?
On first glance, this paper is a systematic review which should provide level 1 evidence. However, this is not the case and the paper cannot be viewed as giving an overview of RCTs in this area. There are very significant flaws in the paper as I have explored above and I do not think the review provides any relevant conclusions which should influence clinical practice. It is a good example of the detrimental effect that a poorly-defined research question can have on subsequent search strategy and analysis. It is very difficult to assess incidence of rarer infections such as PCP but in order to provide transparent recommendations for clinical care authors must be clear about definitions of patient populations and the interventions/outcomes being studied: I do not think the authors have done this in this review paper and they have tried to synthesise highly heterogenous papers including those of low quality evidence.
Really? I?
No, I don’t believe it provides level 1 evidence. Instead I think it needs to be significantly downgraded on the basis of the errors in the interpretation of certain papers, inclusion of irrelevant case reports and counting the same RCT as 2 separate trials when it was the same patient cohort with different reporting times. My issue is I am not sure it can be accurately categorised to a level based on these mistakes- I would go as far as to say some of the very significant issues in the interpretations made in the paper should have been picked up at the editorial stage and the authors should have been asked to correct them as errors such as saying a trial has 305 patients with PCP when actually only 43 had PCP is very misleading.
This systemic analysis analyzing Trimethoprim-Sulfamethoxazole dose optimization.
InPCP management. A total of 13 articles met the inclusion criteria for final analysis.
Of the 13 selected studies:
A total of 2663 patients were recruited in the included studies.
Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
Risk of PCP among transplant recipients
First-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day)
Double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis
Standard doses result in an absolute increase of 18% in the incidence of grade>3 AEs
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs
Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy
Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
The study showed no significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
Low dose reduces the economic burden of illness and enhances patients’ compliance to daily regimens.
No guidelines are available for PCP prophylaxis in immune mediated dermatological conditions on high dose steroids.
Limitations:
Study provides current dosing regimen for treatment and prophylaxis of PCP.
Low dose TMP-SMZ provides satisfactory outcomes while reducing the mortality and P.CP associated adverse events.
Low dose reduces economic disease burden and enhance treatment compliance
This is a systematic review with low-quality studies, a level of evidence II
Really? II?
Introduction:
PCP has the most frequent and highly morbid fungal infection for patients with autoimmune disorders the incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid disease.
TMP-SMX dosing recommendation:
on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections [In accordance with current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) .
There is a high incidence of AEs in patients receiving recommended high doses of TMPSMX.
Materials and Methods:
Data Sources and Search Strategy the systematic search assessing the dosing guidelines of TMP-SMX in patients was carried out using Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.
Selection Criteria and Procedure:
The studies reporting the dosing strategy of TMP-SMX in the patients for the occurrence or recurrence of PCP were included in this review. Retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study.
Article Quality Assessment:
The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Results:
13 studies, five compared the low-dose regimen of TMP-SMX with a high-dose regimen.
These studies documented that low-dose TMP-SMX therapy must be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Low-dose treatment regimens usually reported fewer side effects compared to the conventional dosing regimens.
Discussion:
The main goal of this systematic review was to assess the current dosing strategy of TMP-SMZ to reduce the risk of PCP in patients especially those with various immunodeficiency syndrome.
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
Although the TMP-SMX has been regarded as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as Dapsone, Atovaquone, and atomized pentamidine due to TMP-SMX AE.
STUDY failed to identify significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP.
This strategy reduces economic burden of illness and enhances patients’ compliance to daily regimen plan.
Study limitations.
Firstly, the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment. Secondly, the limited number of studies
Thirdly, small sample size, this may result in false-negative or false-positive finding.
Conclusions:
These findings provided the current dosing strategy of TMP-SMX for the prevention and treatment of PCP. The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
level of evidence 1V.
Really? What is 1 V?
Please summarise this article.
Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immuno-compromised patients Moreover, the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors
Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts
. A study reported that 27% of the kidney transplant recipients receiving TMP-SMX prophylactically with other medications experienced AEs such as cytopenia Therefore, routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes. PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3
AIM OF STUDY
The low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated AEs.
reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
For some patient populations, such as PCP emerging on TMP-SMX prophylaxis in HIV-patients, it may still warrant to start prophylactic treatment regimen. Due to limited data available on the optimal dose of TMP-SMX, these findings would support the conduct of large-scale, prospective RCTs and cohort studies to provide guidelines regarding the dosing strategies for the PCP.
Limitations of The study
the selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
TMP-SMX Dosing recommendations
must be administered in an appropriate way to achieve adequate antimicrobial activity while reducing concentration-dependent toxicities, necessitating the avoidance of excessive dosage
. The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infection
In accordance with current dosing guidelines, the recommended therapy for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks)
There is a high incidence of AEs in patients receiving recommended high doses of TMP-SMX.
2. Materials and Method
Based on the titles and abstracts, studies of all types with any data on clinical outcomes of TMP-SMX regimens were included for further screening. The retrospective studies, randomized controlled trials (RCTs), and case reports available in English were included in this study. The studies published before January 2000 or having inappropriate and incomplete information were excluded from the study.
Article Quality Assessment The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute, The University of Adelaide (JBI, Adelaide, South Australia) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs)
In total, 857 related published studies were identified from grey literature as well as electronic databases
A total of 13 articles met the inclusion criteria for final analysis Of the 13 selected studies, nine were retrospective cohort studies two case reports and two randomized controlled trial (RCT)
**Prasad et al., 2019 Retrospective study
438 Kidney transplant recipients
SS dose of TMP-SMX OD, thrice daily and twice daily The dose was reduced in 84 patients who experienced hyperkalemia and 102 patients who experienced leukopenia
TMP-SMX dose reduction is frequent in the first post-transplant year, but PCP does not occur
Park et al., 2021 Retrospective cohort study
1092 Patients with PCP and rheumatoid arthritis one SS tablet of TMP-SMX (400/80 mg) per day for prophylaxis TMP-SMX reduced 1 year PCP incidence and related mortality TMP-SMX prophylaxis significantly decreased the incidence of the PCP with a favorable safety profile in a patient with RA taking steroids
Yamashita et al., 2021 Retrospective study 81 Patients with HIV Group A: standard-dose (≥6 SS (TMP-SMX 80 mg/400 mg tablets/week) Group B: low-dose groups (<6 SS tablets/week). PCP was not developed in any patients during study period Low-dose TMP-SMX is optimal treatment option to treat and prevent PCP
These studies documented that low-dose TMP-SMX therapy must be considered as a firstline treatment option to prevent occurrence and recurrence of PCP and PCP-associated AEs.
Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy . Similarly, Schild et al. reported that the patients received an intermediate-dose TMP-SMX (TMP 10–15 mg/kg/day) but later on, 23% of patients switched to low-dose TMP-SMX due to various AEs and this regimen was deemed to be safe and effective in patients with various immune dysfunctions
What is the level of evidence provided by this article?
LEVEL 5
.
Really? V?
1. Please summarise this article.
Pneumocystis carinii causes pneumonia (PCP), with increased incidence in immunocompromised patients (50%), hematological malignancies (22-45%), transplant recipients (5-15%) and among patients suffering from autoimmune disorders (2%). PCP is associated with increased morbidity and mortality. Trimethoprim-Sulfamethoxazole (TMP-SMX) has been used as treatment modality for PCP. TMP-SMX use is associated with adverse effects like hepatotoxicity, rash, nephrotoxicity, gastrointestinal disturbances, bone marrow suppression etc. The article deals with analysis of effect of dose of TMP-SMX on PCP patient outcomes.
It was a retrospective analysis of dose-optimization of TMP-SMX in PCP patients. A total of 13 studies (9 retrospective cohort studies, 2 case reports, and 2 randomized controlled trials, RCT) out of 163 shortlisted studies involving 2663 patients were included in the study. The studies compared effect of low-dose TMP-SMX (<15 mg/kg/ day of TMP) with high-dose TMP-SMX (15-20 mg/kg/day of TMP) in PCP patients.
Out of the 13 studies, 4 dealt with HIV positive patients, 4 dealt with rheumatoid arthritis patients, 2 involved transplant patients, 2 involved non-HIV patients, while one was with respect to patient with G6PD deficiency. 9 studies dealt with treatment of PCP and found that low dose TMP-SMX treatment was associated with lower mortality and lower adverse effects. The adverse event rate was 58% in the low-dose patients (versus 72% in high-dose patients), and mortality rates were 19.5% in low-dose patients (versus 25% in high-dose group). Low-dose regimen was found to be safe and effective, well-tolerated, increases compliance, reduces pill burden, as well costs. 4 studies dealt with PCP prophylaxis, and concluded that low dose TMP-SMX prophylaxis reduced the incidence of PCP with a favorable safety profile with effectiveness. The studies found that there was no significant difference in PCP occurrence or recurrence groups.
Limitations of the study include small sample size, retrospective nature, studies included from many countries providing with a heterogenous group, lack of recent studies (post-2000), absence of major RCT, and use of different definitions for low-dose in different studies.
To conclude, the study revealed that low dose TMP-SMX strategy for PCP treatment is advantageous over high-dose regimen with respect to lower mortality and adverse effects and providing satisfactory outcomes, and hence should be preferred. Larger prospective RCT and cohort studies are required for further recommendations.
2. What is the level of evidence provided by this article?
Level of evidence: Level 5 – Narrative review
Really? V?
This articel, although is presented as a systematic review, but lacks any major RCT, includes studies which are retrospective in nature, hence I thought it to be as a narrative review.
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
Introduction
The outcome of treatment regiments according to studies
TMP-DMX
Discussion
Limitation of the study
Conclusion
Level of evidence
level ((II))
Systematic review
Really? IIa?
THE AIM OF THE STUDY ;
———————————-
was to assess the effect of low TMP-SMZ in reducing the risk of PCP in patients with various immunodeficiency syndromes.
THE TYPE OF THE STUDY ;
—————————————
systematic review.
THE METHOD :
———————–
1-Various databases were searched from January 2000to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
2-The data were collected in a specific form with predefined inclusion and exclusion criteria.
3-The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
THE POPULATION ;
——————————–
1-Thirteen studies met the inclusion criteria for final analysis.
2-Of the 13 selected studies, nine were retrospective cohort studies, two case reports, and two randomized controlled trials (RCT).
THE RESULT:
————————–
Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP. The analysis found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
THE LIMITATIONS ;
————————–
1-The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
2-The limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
3- Small sample size .
THE CONCLUSION;
———————————
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs. This strategy also reduces overall economic burden and enhances patients’ compliance to daily regimen plan.
What is the level of evidence provided by this article?
————————————————————
Level III
Really? III?
Summary
Introduction
Pneumocystis carinii pneumonia (PCP) or jirovecii (PJP) is one of the serious opportunistic I fungal infections which carry a high mortality rate in patients with autoimmune disease or intense immunosuppression like SOT including kidney transplantation, HIV patients, hematological malignancy with prevalence up to 50% .
Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family, as per evidence from retrospective studies it is still the drug of choice for chemoprophylaxis and treatment of PJP with current dosing guidelines, the recommended therapy for PCP is high-
dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks) (). The use of high-dose TMP-SMT is limited due to renal hepatotoxicity, bone marrow suppression risk, skin allergy, GI disturbance, and electrolyte imbalance.
Method
This is a systematic review and meta-analysis of Free-text web searches using Google Scholar, and databases such as
PubMed, ScienceDirect, EMBASE, Scopus, the Cochrane Database for Systematic Reviews, all articles in English have been reviewed from 2000-2021.
Selection criteria include
1. The studies reporting the dosing strategy of TMP-SMX in the patients for the occurring-or recurrence of PCP.
2. studies with any data on clinical outcomes of TMP-SMX regimens
3. different study designs included retrospective, RCT, C case reports
They exclude all studies before Jan 2000 or studies with incomplete data, all the studies are reviewed by two independent reviewers
Data extraction
Data records by data collection form designed by the reviewer and collection of the information include author and year, design, sample size, characteristics of patients, dosing strategy, clinical outcomes, and findings. The data will be reviewed by another reviewer and any area of conflict can be solved with a third reviewer’s help. The quality assessment of each study was also performed according to the known standardized scales.
Results
Only 13 articles met the inclusion criteria for evaluation from a total of more than 857 articles that have been reviewed from the 13 selected studies, 9 were retrospective design, two case reports and another two were RCT. Based on the NOS quality of studies assessment, eight studies were rated with a total
score of 7, one study scored 6, and the remaining four studies scored 8. Overall, the score of included studies was 7. The Cochrane bias tool assessed that almost all the domains for RCTs were at low risk of bias. As per the JBI critical checklist, the quality of case reports in both reports was of good quality. Out of 13 studies, five equated the low-dose regimen of TMP-SMX with a high-dose regimen and they preferred low dose regimen of TMP-SMT as first-line therapy for prevention of recurrence or occurrence of PJP and much more tolerated even one more study by Ohmura and his colleagues reported that a low-dose treatment regimen of TMP-SMX with <10 mg/kg/day for TMP was as well-tolerated and effective as high-dose therapy and associated with lower side effects and well tolerated and even lower mortality rate of 19% compared to > 25% in conventional dose in one report.
Discussion
This review has confirmed that low-dose MP-SMX therapy should be the first-line therapy for PJP resulting in the reduction of
mortality rate and PCP-associated side effects despite MP-SMT being considered as first-line chemoprophylaxis. but in case of side effects or intolerance still, we can use second-line therapy like dapsone pentamidine, and atovaquone, different doses of MP-SMT like single strength vs double strength, second line chemoprophylaxis doses also summarized in table 3, PCP chemoprophylaxis should be considered in the first 1-6 months post-transplantation, also those with autoimmune disease high dose steroids ad impaired t cell immunity with low C4D count
Limitations of this study
Different populations with diverse ethnicity and socioeconomic backgrounds can affect the results (selection bias)
a limited number of the studies included small sample sizes the majority of the studies included.
Conclusions
The low dose strategy of TMP-SMX for the prevention and treatment of PCP. Providing better outcomes less mortality, effective and better tolerated, with improved patient compliance with the regimens at less cost. however, still we don’t have standardized protocols for PCP chemoprophylaxis and treatment and we need more prospective RCT to address this limitation.
LEVEL 2 A despite its systematic review and meta-analysis of retrospective cohorts with good quality a case controls only two RCTs. cant be level 1
Really? IIa?
Introduction:
Dosing of TMP-SMX therapy:
Limitation:
Conclusion:
What is the level of this study?
Please summarise this article. Introduction
Methodology:
Results:
Discussion
Limitations
========================
2. What is the level of evidence provided by this article?
Really? IIa?
Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management:
1-Please summarise this article.
Introduction;
–The incidence of PCP was more than 50% in immunocompromised patients, 22–45% in patients with hematological malignancy, 5–15% in transplant recipients and around 2% in patients with rheumatoid disease.
-The risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
-Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts.
-Co-trimoxazole is the combination of trimethoprim (TMP), which is a pyrimidine analog, and sulfamethoxazole (SMX), which is from the sulfonamide family.
-TMP-SMX has been observed to substantially minimize the incidence of PCP in patients.
-The TMP-SMX dosing recommendations, on the basis of TMP component, is 320–640 mg/day, administered every 12 h, orally, to treat bacterial infections, and 15–20 mg/kg every 6 to 8 h intravenously then orally for the treatment of PCP infections.
-In accordance with current dosing guidelines, the recommended therapy for PCP is high dose TMP-SMX (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day for 2–3 weeks).
Methods;
-Various data bases were searched from January 2000 to December 2021 for articles in English, focusing on the dose optimization of TMP-SMX.
-The data were collected in a specific form with predefined inclusion and exclusion criteria.
-The quality of each article was evaluated using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials (RCTs).
Results;
-163 studies from total 857 studies After the removal of the duplicate studies and other reasons were evaluated for eligibility criteria.
-Based on inclusion and exclusion criteria, 125 studies were excluded after the screening of the titles and abstracts.
-Most of the studies were identified through reference snowballing. Full-text articles were then screened for final analysis.
-Twenty-five articles were excluded for different causes ; a total of 13 articles met the inclusion criteria for final analysis.
-Of the 13 selected studies, nine were retrospective cohort studies,two case reports and two randomized controlled trial (RCT).
-Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP.
-They found that a low dose of TMP-SMX provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events.
-The Cochrane meta-analysis reported that there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
Limitation;
-The selected articles included patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
-The limited number of studies conducted after January 2000 forced them to include all studies that met inclusion criteria.
-Although the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
Conclusions;
–This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs.
-This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan.
-The large-scale RCTs and cohort studies are required to improve dosing strategies to prevent initial occurrence of PCP or to prevent recurrence of PCP in immune compromised patients.
2-What is the level of evidence provided by this article?
-This Systematic Reviews and Meta-analysis; level V evidence.
Really? V?
Introduction:
Pneumocystis carinii pneumonia (PCP) is the most common and deadly fungal infection in autoimmune individuals. Immunocompromised patients had more than 50% PCP, hematological malignancy patients 22–45%, transplant recipients 5–15%, and rheumatoid arthritis patients 2%. Immunosuppressive patients die mostly from PCP symptoms such as tachycardia, hypoxia, tachypnea, shortness of breath, etc.
Aim:
The Preferred Items for Systematic Reviews and Meta-analysis (PRISMA) criteria were used for doing the systematic search with the goal of evaluating the dose recommendations for TMP-SMX in patients.
Methods:
Gray and electronic literature yielded 857 relevant studies. 163 studies were assessed for eligibility after removing duplicates and other reasons. After reviewing titles and abstracts, 125 papers were removed.
Results:
Four trials reported TMP-SMX prophylaxis for AIDS, four for rheumatoid arthritis, two for non-HIV patients, two for kidney transplant recipients, and one for G6PD deficiency. Five studies compared low-dose TMP-SMX to high-dose.
These trials showed that low-dose TMP-SMX therapy should be used initially to avoid PCP and PCP-associated AEs. However, Ohmura and colleagues found that low-dose TMP-SMX with <10 mg/kg/day TMP was as well-tolerated and effective as high-dose therapy.
limitations:
1- the chosen publications included patients from diverse nations, therefore socio-demographic factors including ethnicity, geography, lifestyle, and environment may have impacted the results.
2- there was little research after January 2000, thus we included those that matched the inclusion criteria.
3- while most of the included studies were strong, small sample sizes may lead to false-negative or false-positive results.
Conclusions:
TMP-SMX dose for PCP prevention and therapy is based on these results. TMP-low SMX’s dosage improves outcomes and reduces mortality and PCP-associated AEs. This technique decreases economic stress and improves patients’ daily regimen compliance. PCP developing TMP-SMX prophylaxis in HIV patients may merit preventive therapy. These results recommend large-scale, prospective RCTs and cohort studies to establish PCP dosage guidelines due to the lack of TMP-SMX dose data.
This is a systematic review with low-quality studies, a level of evidence II
Really? II?
SUMMARY
Introduction
PCP is highly frequent and morbid fungal infection in persons with autoimmune disorders. It has a high incidence in immunocompromised individuals at >50%, while haematological malignancy is at 22-45%, transplant recipients 5-15% and 2% in rheumatoid diseases.
Co-trimoxazole is the combination of trimethoprim (TMP) and sulfamethoxazole (SMX).
TMP-SMX minimizes the incidence of PCP in patients, however it must be administered in an appropriate dose to achieve antimicrobial activity while reducing concentration-dependent toxicities.
Recommended high doses have been associated with increased adverse effects.
Dose optimization is the key in antimicrobial stewardship programs and effective to ensure therapeutic outcome of antimicrobial therapy as like in management of PCP
Methodology
This was a systematic review.
Aim:
To asses the current dosing of TMP-SMZ to reduce the risk of PCP in persons with various immunodeficiencies.
Exclusion:
Thirteen studies were included- 9 were retrospective cohort studies, 2-case reports, 2-RCT.
Patients included were 2633.
Studies included: (2)kidney transplant recipients, (4)HIV patients with PCP, (2)PCP patients without HIV, (4)rheumatoid patients (1)G6PD and various immune dysfunctions.
Five studies compared the low-dose regimen of TMP-SMX with a high-dose regimen
Results
Low dose TMP-SMX therapy should be considered as a first line treatment option to prevent occurrence and recurrence of PCP and PCP associated adverse events.
Low-dose treatment regimens have fewer side effects compared to the conventional dosing regimens.
Discussion
Low dose TMP-SMX should be the first line resulting in reducing mortality and PCP associated adverse events.
Incidence rate decreased up to 91% and mortality rate up to 83% compared to the control group.
Transplant recipients have a high risk of PCP first 6 months post-transplantation, or when receiving immunosuppressive agents like steroids, anti lymphocyte antibodies and CNI. Other factors that predispose them include concomitant infections like CMV and episodes of graft rejection. Therefore prophylaxis should be considered in the early post-transplant period and after treatment for rejection.
This study showed no significant differences between the full-dose and low-dose regimen of TMP-SMX for the occurrence or recurrence of PCP. This reduces the economic burden of illness and enhances patients’ compliance to daily regimens.
No guidelines are available for PCP prophylaxis in immune mediated dermatological conditions on high dose steroids.
Limitations:
Conclusion.
Study provides current dosing regimen for treatment and prophylaxis of PCP.
Low dose TMP-SMZ provides satisfactory outcomes while reducing the mortality and PCP associated adverse events.
Low dose reduces economic disease burden and enhance treatment compliance.
Large scale prospective RCT and cohort studies are recommended to guide the dosing strategies.
Level of evidence
This was a systemic review of combined RCT, cohort and case reports studies making it a level V.
Really? V?
The level of evidence may be graded down depending on the study quality.
For instance this review combined case reports and observational cohorts reducing its study quality.
Introduction
Pneumocystosis has become the most prevalent fungal infection in patients with autoimmune disease, probably due to the high doses of corticosteroids required. The combination of sulfa drugs has been the drug of choice for its treatment.
High doses of sulfa are related to myelotoxicity and hepatotoxicity.
Materials and methods
Systematic review study, considered as level I of evidence, to define the appropriate dose of the TMP-SMX combination based on articles published between January 2000 and December 2021.
Retrospective studies, randomized controls, and reported cases were considered, which may have directly interfered with the quality of the study.
Results
Of the 857 studies evaluated, 163 were included in the initial eligibility criteria, with only 13 being included in this meta-analysis (9 retrospective cohort studies, two case reports and two randomized controlled trials). A total of 2663 patients were included, but quite heterogeneous depending on the study (HIV, rheumatological diseases, solid organ transplantation, immune dysfunction, G6PD deficiency).
The prophylaxis regimens were different, as were the loading and maintenance doses.
Something that disturbs in this study is the absence of the calculation of the heterogeneity of the studies, done by the X2 formula, making it very difficult to assess the real quality of this study. Different population groups, different countries, rheumatic diseases not separated by type or treatment, the existence of chemoprophylaxis, and use of corticosteroids, among other variables, were not evaluated.
What is the level of evidence?
Systematic review study, considered as level I of evidence, to define the appropriate dose of the TMP-SMX combination based on articles published between January 2000 and December 2021.
But the absence of the calculation of the heterogeneity of the studies, done by the X2 formula, making it very difficult to assess the real quality of this study
-Introduction
Pneumocystis carinii pneumonia (PCP) is a prevalent and highly morbid fungal infection in autoimmune diseases.
PCP incidence exceeded 50% in immunocompromised cases.
It is presented by tachycardia, hypoxia, tachypnea, dyspnea ,and other symptoms which are poor prognostic signs in immunocompromised cases as HIV patients.
Lately the development in diagnosis ,treatment and prophylaxis of PCP lowered it’s incidence and recurrence in HIV patients.
TMP-SMX use as prophylaxis decreased the incidence of adverse events in non-HIV patients .
Proper antibiotic dosing is essential to avoid antibiotic resistance.
The TMP-SMX dosing for TMP is 320–640 mg/day BID orally to treat bacterial infections, and
15–20 mg/kg every 6 to 8 h IV then orally for the treatment of PCP infections.
The recommended treatment for PCP is highdose TMP-SMX (TMP 15–20 mg/kg/day and SM X 75–100 mg/kg/day for 2–3 weeks which is associated with high rates of adverse effects.
Dose optimization is essential for favourable therapeutic outcome .
Methods
Data within 21 years was collected for articles on the dose optimization of TMP-SMX with predefined inclusion and exclusion criteria. Each article value was accessed using a Newcastle–Ottawa Scale (NOS) for retrospective studies, Joanna Briggs Institute (JBI) critical checklist for case reports, and Cochrane bias tool for randomized clinical trials(RCTs)
Results
13 studies were included,9 were retrospective cohort studies, 2 case reports, and 2 RCT. The studies compared high-dose with low-dose TMP-SMX treatment for PCP.
It was noticed that low dose of TMP-SMX lead to acceptable outcomes and in the same time reducing mortality rate and PCP-associated adverse events.
This regimen lowers the economic load and improves patients’ compliance .
Discussion
This systematic review evaluated the current dosing policy of TMP-SMZ to reduce the risk of PCP in immunosuppressed cases.
The studies concluded that the first-line of treatment can be low-doseTMP-SMX therapy to decrease mortality rate and adverse events.
Although TMP-SMX is the first option for prophylaxis it’s side effects lead to chosing second line drugs as dapsone , atovaquone, and atomized pentamidine.
The necessity of including prophylactic drugs in immunosuppressive regimens represent economic load for patients and health institutes.
PCP risk among transplant recipients is more in the first 6 month post-transplantation , during neutropenia, or with longstanding steroids, ATG , or CNI as well as CMV infection, multiple
graft rejection episodes, and low CD4+ counts.
Routine prophylaxis is needed in the early post-transplant month and after rejection treatment. PCP prophylaxis is highly recommended in HIV-positive patients with CD4+ counts less than 200 cells/mm3
The first-line prophylaxis is one single strengthTMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP160 mg/day; SMX 800 mg/day) .
Or using one double strength TMP-SMX tablet thrice per week, or intake of dapsone either alone or with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays.
Standard doses are associated with higher incidence of AE.
Step-down therapy need to be assessed to improve clinical outcomes.
Limitations are variable sociodemographic characters of involved studies,small number of studies done after Jan 2000 obliged them to involve all studies meeting their criteria and most studies had small ample size.
Conclusions
Low dose of TMP-SMX provides satisfactory outcomes and decreases mortality rate and PCP-associated AEs ,on the other side it reduces economic load and improves patients’ compliance .
The large-scale RCTs and cohort studies are needed to improve dosing regimens as prophylaxis for primary occurrence of PCP or recurrence of PCP in immunosuppressed cases
-level of evidence is 1 as it is a systematic review
Can you please reconsider in light of my objections mentioned below?
This is a very fundamental issue:
the level of evidence of a meta-analysis or a systematic review is as good as the studies included.
There is an expression called GIGO. Apologies
for using a swear word with all due respect to the authors of this wonderful
article. GIGO= garbage in, garbage out.
Introduction:
Aim of the study:
Method:
Result & discussion:
Level of evidence is 1(systemic review).
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence?
Can you please reconsider in light of my objection?
Systemic review may assess health care intervention( efficacy, effectiveness & adverse events), & to accommodate evaluation of different research question inclusion of of more one study design in necessary.
introduction:
TMP/SMX should be given in an appropriate dose for an adequate response. The recommended dose of TMP/SMX for PCP treatment is 15-20 mg/kg/day every 12 hours for 2-3 weeks. Side effects (myelosuppression, hepatotoxicity, hyperkalemia, nephritis, &rash) are common with high doses. There is insufficient data on the optimal dosage.
This study is a systematic review to assess the current dosing strategy of TMP/SMX to reduce the risk of PCP in immunocompromised patients.
Limitation of the study:
– the selected articles comprised patients from different nations, thus ethnicity, geography, lifestyle, and environment may have affected the findings.
– small sample sizes may lead to false-negative or false-positive results.
Conclusion:
– low dose TMP/SMX may be effective as the high dose in terms of reducing mortality & PCP-associated side effects, in addition, to reducing economic burden & improve compliance of the patients.
– It is required to conduct large-scale, prospective RCTs and cohort studies in order to offer dose guidelines for PCP.
level of evidence:
level III
Is it really level III evidence? Can you please reconsider?
Please summarise this article
Introduction
o TMP-SMX must be administered in an appropriate way to achieve adequate antimicrobial activity with avoidance of excessive dosage
o The recommended therapy for PCP may be a high dose with high incidence of AEs skin rashes, gastrointestinal disturbances, bone marrow suppression, renal impairment, hepatotoxicity and electrolyte disorder)
o There is no sufficient data on the optimal dose of TMP-SMX
Aim of the study: review current evidence in PCP patients with a focus on dose optimization strategies
Materials and Methods
Various databases were searched (2000-2021 for articles, focusing on the dose optimization of TMP-SMX
Inclusion criteria:
1. All types with any data on clinical outcomes of TMP-SMXregimens
2. Retrospective studies, randomized controlled trials (RCTs), and case reports
Exclusion criteria:
1. Studies published before January 2000
1. Studies with inappropriate and incomplete information
Results
Thirteen studies were included in this review:
1. Nine were retrospective cohort studies
2. Two case reports
3. Two randomized controlled trials (RCT)
Of 13 studies:
1. 4 reported patients having AIDS received TMP-SMX for prophylaxis
2. 4 reported patients with rheumatoid arthritis
3. 2 documented non-HIV patients
4. 2 reported kidney transplant recipients
5. 1 reported the patient with G6PDdeficiency
o Most of the studies compared the high-dose with low-dose TMP-SMX therapy for PCP
o Low dose of TMP-SMX (<10 mg/kg/day) provides satisfactory outcomes while reducing the mortality rate and PCP-associated adverse events
o This strategy reduces the economic burden of illness and enhances patients’ compliance to daily regimen plan
Discussion
This review has revealed that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs
In the Cochrane meta-analysis, there was a decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group
Limitations of the study:
1. The selected articles included patients from various countries (findings may be affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment)
2. Limited number of studies after January 2000 and inclusion of all studies that met inclusion criteria
3. The majority of studies were small sample size
Conclusions
o Low dose of TMP-SMX provides satisfactory outcomes, reducing the mortality rate and adverse effects
o Low dose strategy, reduces overall economic burden and enhances patients’ compliance to treatment
o Large-scale RCTs and cohort studies are required to improve dosing strategies
What is the level of evidence provided by this article?
Level III
Is it really level III evidence?
Thank you prof
It is a systemic review of retrospective cohort study, case reports, and randomized control trials, so it is level II
This is a very fundamental issue:
the level of evidence of a meta-analysis or a systematic review is as good as the studies included.
There is an expression called GIGO. Apologies
for using a swear word with all due respect to the authors of this wonderful
article. GIGO= garbage in, garbage out.
Please summarise this article.
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection that cause severe lung injury, and is associated with increased morbidity and mortalityThe incidence of PCP differ according to the underlying condition , it is highest in immunocompromised patients (50%), followed by patients with hematological malignancy (22-45%) then transplant recipients ( 5–15%) and is least in patients with rheumatoid diseases (2%).In transplant recipients PCP usually occurs in early transplant period ( in the first 1–6 month post-transplantation). Risk factors for PCP include prolonged neutropenia, CMV infection, the use of steroids, CNI and ATG and low CD4+ count lymphocyte counts.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.Regimens for prophylaxis include either 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) or one double-strength TMP-SMX tablet every other day. Daily administration of TMP-SMX may have the advantage of preventing toxoplasmosis as well.Optimization of the dose of TMP-SMX in the treatment of PCP is crucial to avoid long term adverse effect.Side effects of TMP-SMX include skin rashes, GIT toxicity, BM suppression, hepatotoxicity, renal impairment and electrolyte disturbance (hyperkalemia). And G6PD deficiency is a contraindication to the drug.In patients with either contraindications or intolerable side effects, alternative therapy can be used including dapsone, atovaquone, and atomized pentamidine.
This study is assessing the dose optimization of TMP-SMX using data from 13 previous studies (9 retrospective studies, 2 case reports, and 2 RCT) from January 2000 till December 2021.
Most of these studies were addressing the difference in outcome when using high (TMP dose is 15–20 mg/kg/day) versus low dose TMP-SMX therapy (TMP dose is 4–10 mg/kg/day) for PCP treatment.
Results
Low dose TMP-SMX use in the treatment of PCP is associated with comparable outcome (mortality, PCP related morbidity) to high dose protocol with lower drug related side effects and more complianceConclusions:
Low dose TMP-SMX may replace high dose with comparable efficacy and lesser side effects, but larger RCT are needed to assess this dose in immunocompromied patientsWhat is the level of evidence provided by this article?
This is a meta-analysis of level III studies , so it is level III
Please summarise this article.
Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection that cause severe lung injury, and is associated with increased morbidity and mortality
The incidence of PCP differ according to the underlying condition , it is highest in immunocompromised patients (50%), followed by patients with hematological malignancy (22-45%) then transplant recipients ( 5–15%) and is least in patients with rheumatoid diseases (2%)
In transplant recipients PCP usually occurs in early transplant period ( in the first 1–6 month post-transplantation).
Risk factors for PCP includes prolonged neutropenia, CMV infection, the use of steroids, CNI and ATG and low CD4+ count lymphocyte counts
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
Regimens for prophylaxis include either 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) or one double-strength TMP-SMX tablet every other day. Daily administration of TMP-SMX may have the advantage of preventing toxoplasmosis as well.
Side effects of TMP-SMX include skin rashes, GIT toxicity, BM suppression, hepatotoxicity, renal impairment and electrolyte disturbance (hyperkalemia). And G6PD deficiency is a contraindication to the drug
In patients with either contraindications or intolerable side effects, alternative therapy can be used including dapsone, atovaquone, and atomized pentamidine
Optimization of the dose of TMP-SMX in the treatment of PCP is crucial to avoid long term adverse effect.
This study is assessing the dose optimization of TMP-SMX using data from 13 previous studies (9 retrospective studies, 2 case reports, and 2 RCT) from January 2000 till December 2021
Most of these studies were addressing the difference in outcome when using high (TMP dose is 15–20 mg/kg/day) versus low dose TMP-SMX therapy (TMP dose is 4–10 mg/kg/day) for PCP treatment.Results
Low dose TMP-SMX use in the treatment of PCP is associated with comparable outcome (mortality, PCP related morbidity) to high dose protocol with lower drug related side effects and more complianceConclusions:
Low dose TMP-SMX may replace high dose with comparable efficacy and lesser side effects, but larger RCT are needed to assess this dose in immunocompromied patients
I like your summary.
What is you comment of the level of evidence?
Is it really level III evidence?
Case reports are included in this meta-analysis. Would change the level of study further?
III. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review
====================================================================
Please summarise this article.
1. Introduction
====================================================================
2. Materials and Methods
2.1. Data Sources and Search Strategy
2.3. Data Extraction
2.4. Article Quality Assessment
====================================================================
3. Results
3.1. Study Characteristics
3.2. Quality Assessment of Studies
3.3. Dosing Strategy of TMP-SMX in Selected Studies
====================================================================
4. Discussion
====================================================================
5. Conclusions
====================================================================
What is the level of evidence provided by this article?
The level of evidence provided by this article is 1
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence?
Can you please reconsider in light of my objection?
Many thanks Prof. Sharma
=============================================================
Objection is mine, dear Dr Wadi
This is a very fundamental issue:
the level of evidence of a meta-analysis or a systematic review is as good as the studies included.
There is an expression called GIGO. Apologies
for using a swear word with all due respect to the authors of this wonderful
article. GIGO= garbage in, garbage out.
Please use bold or underline for headings or sub-headings to make it easier to read.What is you comment of the level of evidence?
Please summarize this article.
Introduction
Methodology
Results
Conclusion
What is the level of evidence provided by this article?
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence?
Can you please reconsider in light of my objection?
Thank you prof for bring this up;
1- Pneumocystis jirovecii pneumonia PCP is one of the commonest and high mortality infection in SOT either in HIV or non-HIV patient.
2- Its treatment by trimethoprime-sulphmethoxazole TMP-SMZ should be adequate to ensure adequate antimicrobial activity and not inducing drug resistance and also try to minimize its adverse effects.
3- It was found that low-dose TMP-SMX therapy should be the first-line treatment option, resulting in the reduction of mortality rate and PCP-associated AEs, with decrease in the incidence of PCP up to 91% and decrease in mortality rate up to 83% when compared to the control group.
4- TMP-SMX is considered as a first-line regimen for prophylaxis of PCP, it often has to be switched to second-line treatment such as dapsone, atovaquone, and atomized pentamidine due to TMP-SMX drug intolerance and side effects like neutropenia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
5- Routine PCP prophylaxis is recommended for patients treated in hospitals where the prevalence of PCP is at least 3% to 5% among immunocompromised patients.
6- the risk of PCP among transplant recipients is greater in 1–6 month post-transplantation period, during prolonged neutropenia, or in patients receiving steroids, antilymphocyte antibodies, or calcineurin inhibitors.
7- Other predisposing factors include concomitant cytomegalovirus, infections, number of graft rejection episodes, and low CD4+ count lymphocyte counts.
8- routine prophylaxis is mainly required during the early post-transplant month and after therapy of rejection episodes.
9- PCP prophylaxis is highly recommended in HIV-positive patients who have CD4+ counts less than 200 cells/mm3.
10- the first-line prophylactic agent is one single strength TMP-SMX tablet (TMP 80 mg/day; SMX 400 mg/day) or one double-strength (TMP 160 mg/day; SMX 800 mg/day).
11- Alternative PCP prophylaxis includes one doublestrength TMP-SMX tablet thrice per week, administration of dapsone either alone or in combination with leucovorin and pyrimethamine, atovaquone, or pentamidine sprays.
12- The double-strength seems to be effective while taken daily or thrice in a week, but daily administration of TMP-SMX prevents other post-transplant infectious diseases such as toxoplasmosis.
13- The risk factors for PCP in patients with rheumatoid disorders include age group (elderly > 65 years), use of glucocorticoids, and existing comorbidities.
14- Limitations of this study include the following:
a- patients from various countries, so the findings could have been affected by socio-demographic characteristics such as ethnicity, region, lifestyle, and environment.
b- the limited number of studies conducted after January 2000 forced us to include all studies that met inclusion criteria.
c- the quality of the majority of the included studies was good, due to small sample size, this may result in false-negative or false-positive findings.
level of evidence 1
How can inclusion of case reports, possibly case control studies and observational cohort studies in this systematic review would make this publication a Ia level of evidence?
because it is systematic review which make it level 1