Comparative efficacy and safety of colistin-based and alternative antibiotic regimens for multidrug-resistant Gram-negative infections: A systematic review and network meta-analysis

OBJECTIVES: To evaluate the comparative efficacy and safety of colistin monotherapy, colistin-based combination regimens, and alternative antibiotic strategies within a unified analytical framework for multidrug-resistant (MDR) Gram-negative infections. METHODS: Systematic search of PubMed, the Cochrane Library, Embase, and Web of Science was conducted from inception to July 15, 2025. A network meta-analysis integrating direct and indirect evidence was performed to estimate risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: A total of 17 randomized controlled trials with 1760 patients were included. Beta-lactam (BL) therapy combined with a beta-lactamase inhibitor (BLI) was associated with a significant reduction in all-cause mortality compared with colistin monotherapy (RR 0.62, 95% CI 0.39-0.99; very low certainty evidence). Colistin-based combination therapies, particularly combinations of colistin with BL/BLIs, achieved higher clinical cure (RR 4.43, 95% CI 1.44-13.66; very low certainty evidence) and microbiological eradication rates (RR 9.50, 95% CI 1.34-67.27; very low certainty evidence) than colistin monotherapy. In terms of safety, BL/BLI-based regimens were associated with significantly lower risks of nephrotoxicity compared with colistin-based regimens. CONCLUSION: Beta-lactam therapy combined with a beta-lactamase inhibitor was associated with a significant reduction in all-cause mortality while colistin-based combination therapies particularly combinations of colistin with beta-lactam/beta-lactamase inhibitors were associated with improved clinical and microbiological outcomes compared with colistin monotherapy. However, the low to very low certainty evidence across most comparison-preclude a firm conclusion on the effects of colistin or other antibiotic therapy for MDR Gram-negative infections. Well-designed randomized controlled trials directly comparing colistin-based combinations with newer BL/BLI therapies are needed to better define the optimal treatment strategy for MDR Gram-negative infections.