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

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.