Colistin Mono vs Combination Therapy for Carbapenem-Resistant Organisms

Background: Background: Pneumonia and bloodstream infections (BSI) due to extensively drug resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. Methods: The OVERCOME trial was an international, randomized, doubleblind, placebo-controlled trial performed at 21 sites in 7 countries. Participants were randomly assigned to receive colistin (5 mg/kg x 1 followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI due to XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality and secondary outcomes included clinical failure and microbiological cure. Results: Between 2012 and 2020, 464 participants were randomized, and 423 eligible patients comprised the modified intent to treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43% vs. 37%; p = 0.17), clinical failure (65% vs 58%; difference 6.8% percentage points (95% Confidence Interval (CI) - 3.1, 16.6)), microbiological cure (65% vs 60% 4.8% percentage points (95% CI -5.6%, 15.2%)), or adverse events (acute kidney injury 52% vs 49%; p = 0.55; hypersensitivity reaction 1% vs 3%; p = 0.22; neurotoxicity 5% vs 2%; p = 0.29) between patients receiving monotherapy and combination therapy, respectively. Conclusions: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI due to these pathogens. NCT015979