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Efficacy of Trimethoprim-Sulfamethoxazole in Combination with an Echinocandin as a First-Line Treatment Option for Pneumocystis Pneumonia: A Systematic Review and Meta-Analysis.

ABSTRACT: Although combination therapy using trimethoprim-sulfamethoxazole (TMP-SMX) plus echinocandins has been reported to reduce the mortality of patients with pneumocystis pneumonia (PCP), it remains unclear whether it is more effective than TMP-SMX monotherapy, the current first-line treatment for this disease. Hence, we performed a systematic review and meta-analysis to compare the efficacies of these treatment options for PCP. The Scopus, EMBASE, PubMed, CINAHL, and Ichushi databases were searched for studies (up to January 2022) reporting the mortality and positive response rates (fewer clinical symptoms, improved partial pressure of arterial oxygen, and resolution of pneumonitis on chest imaging) of PCP patients receiving monotherapy or combination therapy. Four studies met the inclusion criteria. All four presented mortality data and one had positive response rates. Compared with the monotherapy, the combination therapy resulted in significantly lower mortality and higher positive response rates (mortality: odds ratio (OR) 2.20, 95% confidence interval (CI) 1.46-3.31; positive response rate: OR 2.13, 95%CI 1.41-3.23), suggesting it to be an effective and promising first-line therapy for PCP. However, further safety evaluations are needed to establish this as a fact.

SUBMITTER: Kato H

PROVIDER: S-EPMC9220274 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Efficacy of Trimethoprim-Sulfamethoxazole in Combination with an Echinocandin as a First-Line Treatment Option for Pneumocystis Pneumonia: A Systematic Review and Meta-Analysis.

Kato Hideo H Hagihara Mao M Asai Nobuhiro N Umemura Takumi T Shibata Yuichi Y Hirai Jun J Yamagishi Yuka Y Iwamoto Takuya T Mikamo Hiroshige H

Antibiotics (Basel, Switzerland) 20220526 6

Although combination therapy using trimethoprim-sulfamethoxazole (TMP-SMX) plus echinocandins has been reported to reduce the mortality of patients with pneumocystis pneumonia (PCP), it remains unclear whether it is more effective than TMP-SMX monotherapy, the current first-line treatment for this disease. Hence, we performed a systematic review and meta-analysis to compare the efficacies of these treatment options for PCP. The Scopus, EMBASE, PubMed, CINAHL, and Ichushi databases were searched ...[more]

PMID: 35740126

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Project description:BackgroundPneumocystis pneumonia (PCP) has a significant impact on the mortality of immunocompromised patients. It is not known whether the prophylactic application of trimethoprim-sulfamethoxazole (TMP-SMZ) can reduce the incidence of PCP and mortality in the human immunodeficiency virus (HIV)-negative immunodeficient population. The safety profile is also unknown. There have been few reports on this topic. The aim of this study was to systematically evaluate the efficacy and safety of the use of TMP-SMZ for the prevention of PCP in this population of patients from the perspective of evidence-based medicine.MethodsA comprehensive search without restrictions on publication status or other parameters was conducted. Clinical randomized controlled trials (RCTs) or case-control trials (CCSs) of TMP-SMZ used for the prevention of PCP in HIV-negative immunocompromised populations were considered eligible. A meta-analysis was performed using the Mantel-Haenszel fixed-effects model or Mantel-Haenszel random-effects model, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and reported.ResultsOf the 2392 records identified, 19 studies (n = 4135 patients) were included. The efficacy analysis results indicated that the PCP incidence was lower in the TMP-SMZ group than in the control group (OR = 0.27, 95% CI (0.10, 0.77), p = 0.01); however, the rate of drug discontinuation was higher in the TMP-SMZ group than in the control group (OR = 14.31, 95% CI (4.78, 42.91), p<0.00001). In addition, there was no statistically significant difference in the rate of mortality between the two groups (OR = 0.54, 95% CI (0.21, 1.37), p = 0.19). The safety analysis results showed that the rate of adverse events (AEs) was higher in the TMP-SMZ group than in the control group (OR = 1.92, 95% CI (1.06, 3.47), p = 0.03).ConclusionsTMP-SMZ has a better effect than other drugs or the placebo with regard to preventing PCP in HIV-negative immunocompromised individuals, but it may not necessarily reduce the rate of mortality, the rate of drug discontinuation or AEs. Due to the limitations of the research methodologies used, additional large-scale clinical trials and well-designed research studies are needed to identify more effective therapies for the prevention of PCP.

Project description:The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145-0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV-infected Taiwanese patients who received TMP/SMX for pneumocystosis. Concomitant use of fluconazole was associated with decreased risk for TMP/SMX-related hepatotoxicity.

Project description:ObjectivesTo investigate the incidence of pneumocystis pneumonia (PCP) and its risk factors in patients with rheumatic disease receiving non-high-dose steroid treatment, along with the risks and benefits of PCP prophylaxis.MethodsThis study included 28,292 treatment episodes with prolonged (≥ 4 weeks), non-high-dose steroids (low dose [< 15 mg/day, n = 27,227] and medium dose [≥ 15 to < 30 mg/day, n = 1065], based on prednisone) over a 14-year period. Risk factors for PCP and prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) were investigated if the 1-year incidence rate (IR) of PCP in each dose group was > 0.1/100 person-years. Cox regression with LASSO was used for analysis.ResultsOne-year PCP IR in the low-dose group was 0.01 (95% CI 0.001-0.03)/100 person-years, and only the medium-dose group showed eligible PCP IR for further analysis. In the medium-dose group, prophylactic TMP-SMX was administered in 45 treatment episodes while other episodes involved no prophylaxis (prophylaxis group vs. control group). In 1018.0 person-years, 5 PCP cases occurred exclusively in the control group, yielding an IR of 0.5 (0.2-1.2)/100 person-years. Concomitant steroid-pulse treatment and baseline lymphopenia were the most significant risk factors for PCP. Treatment episodes with at least one of these factors (n = 173, high-risk subgroup) showed higher 1-year PCP IR (3.4 (1.1-8.0)/100 person-years), while no PCP occurred in other treatment episodes. TMP-SMX numerically reduced the risk (adjusted HR = 0.2 (0.001-2.3)) in the high-risk subgroup. The IR of adverse drug reactions (ADRs) related to TMP-SMX was 41.5 (22.3-71.6)/100 person-years, including one serious ADR. The number needed to treat with TMP-SMX to prevent one PCP in the high-risk subgroup (31 (17-226)) was lower than the number needed to harm by serious ADR (45 (15-∞)).ConclusionIncidence of PCP in patients with rheumatic diseases receiving prolonged, medium-dose steroids depends on the presence of risk factors. Prophylactic TMP-SMX may have greater benefit than potential risk in the high-risk subgroup.

Project description:IntroductionPneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP.MethodsOur study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period.ResultsThe probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP.ConclusionsOur results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings.Clinical trial registrationwww.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.

Project description:BackgroundPneumocystis jirovecii pneumonia (PJP) is an opportunistic infection caused by the yeast-like fungus P. jirovecii. As recommended by some guidelines, the first-line treatment for this infection is trimethoprim-sulfamethoxazole (TMP-SMX), and the second-line treatment includes drugs such as dapsone, pentamidine, primaquine, Atovaquone, clindamycin, and caspofungin. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked gene disorder in which treatment with oxidizing drugs, such as sulfonamides, dapsone, primaquine, can directly destroy hemoglobin present in red blood cells (RBCs), thereby inducing methemoglobin and hemolysis.Case presentationHere, we present the case of a lymphoma patient with previous G6PD deficiency who was admitted to ICU for the treatment of severe pneumonia combined with respiratory failure. PJP was detected by the next-generation sequencing of the bronchoalveolar lavage fluid. The patient was initially treated with the antifungal drug caspofungin; however, this treatment showed poor therapeutic effect. Based on the evaluation of G6PD enzyme activity and the patient's previous history of G6PD deficiency, we finally treated the patient with low-dose TMP-SMX combined with caspofungin and provided rigorous medical care to the patient. Following this treatment, the patient's clinical symptoms improved, lung computed tomography showed reduced pulmonary inflammation, and the fungal β-(1,3)-D-glucan test (G test) showed decreased levels of fungal D-glucan. After 57 days, the TMP-SMX treatment was discontinued. No symptoms related to G6PD deficiency, such as hemolysis, hematuria, and anemia, occurred during the treatment course.ConclusionThis is the first report mentioning the successful treatment of Pneumocystis jirovecii pneumonia with a double-drug regimen with low-dose TMP-SMX and caspofungin in a T-lymphoblastic leukemia/lymphoma patient with previous G6PD deficiency. Enzyme activity detection is the first step for anti-PJP treatment in patients with G6PD deficiency. Although patients with mild enzyme deficiency may not show any adverse reactions, we still recommend the regular monitoring of the levels of RBCs, hemoglobin, and hematocrit before and after the use of sulfonamides or sulfoxides and other oxidizing drugs in patients with G6PD deficiency. Among other things, early and correct diagnosis of Pneumocystis jirovecii pneumonia in hematological malignancies patients is very important. Relevant oncologists should be alert to the risk of Pneumocystis jirovecii pneumonia in these patients.

Dataset Information

Efficacy of Trimethoprim-Sulfamethoxazole in Combination with an Echinocandin as a First-Line Treatment Option for Pneumocystis Pneumonia: A Systematic Review and Meta-Analysis.

Publications

Efficacy of Trimethoprim-Sulfamethoxazole in Combination with an Echinocandin as a First-Line Treatment Option for Pneumocystis Pneumonia: A Systematic Review and Meta-Analysis.

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