Low-Dose TMP-SMX in the Treatment of Pneumocystis jirovecii Pneumonia: A Systematic Review and Meta-analysis

Abstract

Background: Pneumocystis jirovecii pneumonia (PJP) remains a common and highly morbid infection for immunocompromised patients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the antimicrobial treatment of choice. However, treatment with TMP-SMX can lead to significant dose-dependent renal and hematologic adverse events. Although TMP-SMX is conventionally dosed at 15-20 mg/kg/d of trimethoprim for the treatment of PJP, reduced doses may be effective and carry an improved safety profile.

Methods: We conducted a systematic search in the Medline, Embase, and Cochrane Library databases from inception through March 2019 for peer-reviewed studies reporting on reduced doses of TMP-SMX (15 mg/kg/d of trimethoprim or less) for the treatment of PJP. PRISMA, MOOSE, and Cochrane guidelines were followed. Gray literature was excluded.

Results: Ten studies were identified, and 6 were included in the meta-analysis. When comparing standard doses with reduced doses of TMP-SMX, there was no statistically significant difference in mortality (absolute risk difference, -9% in favor of reduced dose; 95% confidence interval [CI], -27% to 8%). When compared with standard doses, reduced doses of TMP-SMX were associated with an 18% (95% CI, -31% to -5%) absolute risk reduction of grade ≥3 adverse events.

Conclusions: In this systematic review, treatment of PJP with doses of ≤10 mg/kg/d of trimethoprim was associated with similar rates of mortality when compared with standard doses and with significantly fewer treatment-emergent severe adverse events. Although limited by the observational nature of the studies included, this review provides the most current available evidence for the optimal dosing of TMP-SMX in the treatment of PJP.

Keywords: HIV; Pneumocystis jirovecii; TMP-SMX; transplantation.

Figure 1.

Prisma flow diagram. Abbreviations: RCT, randomized controlled trial; TMP-SMX, trimethoprim-sulfamethoxazole.

Figure 2.

Standard-dose vs reduced-dose trimethoprim-sulfamethoxazole mortality meta-analysis. Results are reported as relative risk difference. Abbreviations: CI, confidence interval; RD, risk difference.

Figure 3.

Standard-dose vs reduced-dose trimethoprim-sulfamethoxazole adverse events meta-analysis. Results are reported as relative risk difference. Abbreviations: CI, confidence interval; RD, risk difference.

Figure 4.

Reduced-dose mortality Pneumocystis carinii pneumonia mortality rates with reduced doses of trimethoprim-sulfamethoxazole, including single-arm cohorts with HIV patients. Results are reported in relative risk. Abbreviation: CI, confidence interval.

Figure 5.

Mortality rate from historical control cohort of standard dose trimethoprim-sulfamethoxazole, as extracted from eligible randomized controlled trials on Pneumocystis carinii pneumonia therapy. Abbreviation: CI, confidence interval.