Advances in combination therapies for serious infections due to Multidrug-resistant gram negative bacilli

Serious infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) remain a major global challenge, with high morbidity, mortality, and limited therapeutic options. Combination antibiotic therapy has long been proposed as a strategy to improve clinical outcomes, enhance bacterial killing, and prevent antimicrobial resistance, yet its clinical value across key pathogen groups remains uncertain.

This review summarizes current evidence on combination therapy for major MDR-GNB, including third-generation cephalosporin-resistant Enterobacterales, carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and other non-fermenters. We examine both clinical and preclinical data, reviewing in vitro synergy studies (checkerboard assays, time-kill experiments, and E-tests), randomized controlled trials, major observational studies, and treatment recommendations from international guidelines.

Robust clinical evidence supporting combination therapy is limited. Synergy observed in vitro does not reliably translate into improved patient outcomes, and toxicity risks remain important. For most MDR-GNB infections, current data support targeted monotherapy with newer β-lactam/β-lactam-inhibitors agents when active. Combination therapy may retain a role in selected scenarios, including salvage treatment, infections due to metallo-β-lactamase producers, A. baumannii and S. maltophilia, or in settings with limited access to newer agents.