The Impact of Synergistic Therapy Between Colistin and Meropenem on Outcomes of People With Pneumonia or Bloodstream Infection Due to Carbapenem-Resistant Gram-Negative Pathogens

Background. Colistin, a last-line treatment for carbapenem-resistant Gram-negative bacilli (CRGNB), is frequently used in combination with meropenem because these agents often demonstrate in vitro synergy. Using data from the OVERCOME trial comparing colistin + meropenem to colistin + placebo for treatment of pneumonia or bloodstream infection due to CRGNB, we evaluated the impact of synergistic therapy on outcomes. Methods. In vitro synergy testing between colistin and meropenem was conducted using 24-hour time-kill analysis; synergy was defined as >2-log reduction in colony-forming units/mL compared to the most active single agent. Patients receiving synergistic combination therapy were compared to patients receiving functional colistin monotherapy (colistin alone or combination therapy without synergy). Outcomes included mortality, clinical failure, and microbiologic cure. Adjusted analyses controlled for variables on which randomization was stratified and confounders. Results. A total of 146 subjects receiving synergistic combination therapy and 261 subjects receiving functional monotherapy were included. Most had pneumonia (70%), CR Acinetobacter baumannii infection (79%) and were in intensive care (69%). Acinetobacter baumannii was more common in those receiving synergistic combination therapy than functional monotherapy (P <.001). Mortality rates were similar (38.3% and 41.4%, respectively). In adjusted analyses, synergistic combination therapy was associated with significantly lower clinical failure rates (55.3%, 64.3%, adjusted odds ratio [aOR] 0.62, P =.049), with consistent findings in pneumonia (62.6%, 71.8%, aOR 0.55, P =.04) and A. baumannii subgroups (57.4%, 69.4%, aOR 0.60, P =.06). Microbiologic cure rates were similar. Conclusions. Colistin-based, synergistic combination treatment with meropenem (compared to nonsynergistic colistin-based therapy) was associated with decreased clinical failure, particularly in people with pneumonia and A. baumannii.