The Impact of Colistin MIC on Clinical Failure and Mortality: Insights from the OVERCOME Trial

OBJECTIVES: Colistin is an essential antibiotic against carbapenem-resistant (CR) Gram-negative bacilli (GNB). Pharmacokinetic and pharmacodynamic limitations impact its efficacy, and susceptibility breakpoints equivocate regarding interpretation of MIC values. This post-hoc analysis of the OVERCOME trial investigated the association between colistin MIC and outcomes. METHODS: OVERCOME, a randomized, double-blind, placebo-controlled trial, compared colistin monotherapy with colistin plus meropenem for treatment of CR GNB pneumonia and/or bloodstream infections. Outcomes were compared between participants whose infections were caused by pathogens with colistin MIC values ≤ 1 mg/L and those with MIC values of 2 mg/L. RESULTS: Among 369 included participants the mean age was 67.7 ± 15.9 years, 246 (67%) were in the intensive care unit, 251 (68%) had pneumonia, and 286 (78%) were infected with A. baumannii. Overall, no association between an infecting pathogen with an MIC of 2 mg/L and either clinical failure (adjusted Odds Ratio (aOR) 1.59 (95% CI 0.72 - 3.52) or 28-day mortality (aOR 1.62 (0.85 - 3.09)) was demonstrated. Among participants receiving monotherapy, an infecting pathogen with MIC of 2 mg/L was independently associated with both clinical failure (aOR 3.59 (1.10 - 11.77)) and 28-day mortality (aOR 3.22 (1.32 - 7.84)). Among participants receiving combination therapy, no association was demonstrated between MIC and outcomes. CONCLUSIONS: When using colistin-based therapy for pathogens with an MIC of 2 mg/L, these findings support colistin and meropenem combination therapy over colistin monotherapy, particularly for pneumonia due to A. baumannii.