Comparative Effectiveness and Safety of Monotherapy and Defined Combination Regimens for Stenotrophomonas maltophilia. Infections: A Network Meta-Analysis

Background: Stenotrophomonas maltophilia is a multidrug-resistant pathogen with limited therapeutic options that predominantly affects critically ill and immunocompromised patients. Trimethoprim–sulfamethoxazole (TMP/SMX) remains the conventional first-line therapy; however, emerging resistance and toxicity concerns necessitate alternative regimens. This study represents, to our knowledge, the first network meta-analysis (NMA) comparing the efficacy and safety of clearly defined monotherapy and combination antibiotic regimens for S. maltophilia infections. Materials and methods: A systematic search of PubMed, Cochrane Library, Web of Science, and ClinicalTrials.gov (inception to January 2026) identified eligible randomized-controlled studies and retrospective studies. Data were analyzed using a frequentist random-effects NMA with TMP/SMX as the reference. Evaluated regimens included TMP/SMX, fluoroquinolone (FQ), minocycline (MIN), TMP/SMX + FQ, TMP/SMX + MIN, FQ + MIN and FQ + other. Primary and secondary outcomes were all-cause mortality, clinical cure, and adverse effects. Results: Thirteen retrospective studies encompassing 2980 patients were included. Using TMP/SMX as the reference, network meta-analysis demonstrated heterogeneity in all-cause mortality across antimicrobial regimens. FQ and MIN monotherapies were associated with lower odds of mortality (effect sizes: 0.65, 95% CI: 0.49–0.85 and 0.50, 95% CI: 0.28–0.90), whereas combination therapy with TMP/SMX plus FQ was associated with higher mortality (effect size: 2.93, 95% CI: 1.18–7.31). Treatment ranking based on effect sizes suggested more favorable mortality profiles for MIN and FQ regimsens. No significant differences were observed in clinical cure, while FQ was associated with a lower incidence of adverse effects compared with TMP/SMX. Conclusions: This network meta-analysis suggests that FQ and MIN monotherapies may be associated with more favorable survival and tolerability compared with TMP/SMX monotherapy. No clear differences were observed for combination therapy relative to other active monotherapy options. Prospective randomized studies are required to validate these observations and to better inform the management of S. maltophilia infections.