Comparative effectiveness of trimethoprim-sulfamethoxazole dosing strategies for Pneumocystis jirovecii pneumonia: a target trial emulation.

Objectives

Trimethoprim-sulfamethoxazole (TMP-SMX) is considered first-line therapy for Pneumocystis pneumonia (PCP); however, dosing recommendations have remained largely unchanged since the 1970s. Current dosing may increase adverse effects without clear beneficial outcomes. This study evaluated the comparative effectiveness of high-, intermediate-, and low-dose TMP-SMX on short-term mortality.

Methods

We conducted a retrospective cohort study emulating a target trial using Epic Cosmos of adult patients with PCP who received initial TMP-SMX treatment from January 1, 2020, to December 31, 2025. Patients were categorized into high (≥15 mg/kg/day), intermediate (10-15 mg/kg/day), or low dose (≤10 mg/kg/day) groups. Outcomes including 30-day mortality, 90-day mortality, and hyperkalemia (serum potassium ≥5.5 mmol/L) were assessed using propensity score overlap-weighted Cox models with multiple imputation to estimate missing variables.

Results

Among 4,572 patients, 2,348 (51.3%) received high-, 1,466 (32.1%) intermediate-, and 758 (16.6%) low-dose TMP-SMX. Thirty-day mortality occurred in 791 (17.3%) patients. After overlap weighting, low-dose (HR 0.79, 95% CI 0.57-1.08; p=0.135) and intermediate-dose TMP-SMX (HR 0.93, 95% CI 0.74-1.16; p=0.503) were not associated with mortality compared to high-dose TMP-SMX. Hyperkalemia occurred in 27.4% and was less frequent with low- (HR 0.60, 95% CI 0.46-0.78; p<0.001) but not intermediate-dose therapy (HR 0.86, 95% CI 0.72-1.02; p=0.085).

Conclusions

TMP-SMX dose for PCP treatment was not associated with 30-day mortality after accounting for relevant clinical factors. Lower dosed TMP-SMX may be effective for PCP therapy with less hyperkalemia. Randomized trials are needed to confirm optimal PCP dosing strategies.