Association between antimicrobial regimens and 28-day mortality in patients with Stenotrophomonas maltophilia infection: a propensity score-weighted analysis

Stenotrophomonas maltophilia (S. maltophilia ) infections carry a high mortality risk, and optimal therapy remains uncertain. We compared commonly used regimens for 28-day outcomes. We conducted a retrospective cohort study of adult inpatients with S. maltophilia infection between 2020 and 2023. Definitive regimens included fluoroquinolone (FQ) monotherapy, cefoperazone-sulbactam (CSL) monotherapy, CSL plus FQ, and CSL plus trimethoprim-sulfamethoxazole (TMP-SMX). Confounding was addressed using propensity score-based inverse probability of treatment weighting (IPTW). The primary outcome was 28-day all-cause mortality assessed with weighted Cox models and Kaplan-Meier analyses. Overall, 28-day mortality was 31% (81/261). In the IPTW-weighted analysis, shock and chronic respiratory failure were associated with higher 28-day mortality, whereas combination therapy, compared with monotherapy, was associated with lower mortality. In regimen-specific analyses, FQ monotherapy showed the highest mortality estimate. CSL monotherapy and CSL plus FQ were associated with lower mortality than FQ monotherapy, while CSL plus FQ did not differ significantly from CSL monotherapy. CSL plus TMP-SMX was associated with lower mortality than both monotherapy regimens and had numerically lower mortality than CSL plus FQ (7% vs 19%), although this difference was not statistically significant. In this IPTW-adjusted cohort, combination therapy, compared with monotherapy, was associated with better 28-day survival outcomes. CSL-based regimens were associated with more favorable outcomes than FQ monotherapy, with CSL plus TMP-SMX showing the highest observed survival, although its advantage over CSL plus FQ was not statistically significant. Prospective multicenter studies are warranted to confirm these observations. IMPORTANCE Stenotrophomonas maltophilia is a difficult-to-treat hospital pathogen that can cause severe infections with high mortality, yet the best antibiotic strategy remains uncertain. In this study, we compared commonly used treatment regimens in hospitalized adults and found that patients receiving combination therapy had better 28-day survival than those receiving monotherapy. Fluoroquinolone monotherapy was associated with the poorest outcomes, whereas cefoperazone-sulbactam-based regimens generally performed better. Among the regimens evaluated, cefoperazone-sulbactam plus trimethoprim-sulfamethoxazole showed the most favorable observed survival, although this advantage over cefoperazone-sulbactam plus fluoroquinolone was not statistically significant. These findings provide real-world evidence to help guide treatment decisions for S. maltophilia infections, especially in settings where access to newer antimicrobial agents is limited, and highlight the need for prospective multicenter studies.