Objective:

To compare and rank the clinical efficacy and overall survival associated with trimethoprim-sulfamethoxazole (TMP-SMX), levofloxacin, minocycline, and tigecycline for severe *Stenotrophomonas maltophilia* infections.

Approach:

• Protocol and Search Strategy: The systematic review and network meta-analysis followed the PRISMA extension for network meta-analyses and was registered with PROSPERO. PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception through April 3, 2026.
• Eligibility Criteria: Studies included patients with laboratory-confirmed *S maltophilia* infection, compared at least 2 eligible regimens, and reported clinical response or all-cause mortality or survival. Pediatric studies, case reports, editorials, animal studies, and studies lacking sufficient quantitative data were excluded.
• Data Extraction and Quality Assessment: Two reviewers independently extracted study, patient, treatment, and outcome data. Disagreements were resolved through discussion or consultation with a third reviewer. Study quality was assessed using the Newcastle-Ottawa Scale.
• Statistical Analysis: A frequentist random-effects network meta-analysis compared TMP-SMX, levofloxacin, minocycline, and tigecycline. Effects were expressed as odds ratios (ORs) with 95% confidence intervals, and treatments were ranked using surface under the cumulative ranking curve (SUCRA) values.

Key Findings:

• Fifteen retrospective cohort studies were included; all received moderate- to high-quality Newcastle-Ottawa Scale scores.
• Tigecycline produced a significantly higher clinical response than TMP-SMX (OR, 4.97; 95% CI, 1.69–14.61) and ranked first for clinical efficacy (SUCRA, 91.3%).
• Levofloxacin produced a clinical response comparable to TMP-SMX (OR, 1.50; 95% CI, 0.97–2.33) but was associated with significantly higher overall survival (OR, 2.01; 95% CI, 1.16–3.47).
• Levofloxacin ranked first for overall survival (SUCRA, 91.3%), followed by minocycline (75.8%), tigecycline (40.2%), and TMP-SMX (2.4%).
• Minocycline showed a nonsignificant trend toward improved survival compared with TMP-SMX (OR, 1.51; 95% CI, 0.90–2.54) and performed relatively consistently across the evaluated outcomes.
• Tigecycline did not demonstrate a statistically significant survival advantage over TMP-SMX despite its superior clinical-response ranking.
• Safety findings were summarized descriptively because adverse-event definitions and reporting varied across studies. TMP-SMX was associated with concerns including acute kidney injury, hyperkalemia, and treatment discontinuation.

Interpretation:

The findings suggest a divergence between initial clinical response and survival: tigecycline ranked highest for clinical efficacy without demonstrating a survival benefit, whereas levofloxacin produced the strongest survival result. Minocycline showed comparatively consistent performance across outcomes. However, these rankings were derived entirely from retrospective cohorts, and the limited direct comparisons among alternative agents mean that the findings warrant cautious interpretation.

Limitations:

• All included studies were retrospective cohorts, creating risks of selection bias, residual confounding, and other limitations inherent to nonrandomized evidence.
• The evidence network was largely star-shaped around TMP-SMX, with few direct comparisons among levofloxacin, minocycline, and tigecycline.
• The analysis primarily evaluated monotherapy because comparative data on combination regimens were limited.
• Regional differences in antimicrobial-resistance patterns could not be fully adjusted for.
• Most studies combined different infection sites rather than reporting outcomes separately for pneumonia, bloodstream infection, and other sources.
• Safety outcomes could not be quantitatively pooled because adverse-event definitions and reporting were heterogeneous.

Conclusion:

In this network meta-analysis of retrospective cohorts, levofloxacin was associated with significantly higher overall survival than TMP-SMX and ranked highest for survival, whereas tigecycline ranked highest for clinical response without a corresponding survival advantage. Minocycline performed consistently across outcomes. These findings support further reassessment of treatment selection for severe *S maltophilia* infection, but well-designed prospective head-to-head trials are needed, and treatment decisions should account for local susceptibility patterns, patient characteristics, toxicity, and antimicrobial-stewardship considerations.