Abstract
BackgroundColistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined.MethodsA multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7–14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved.ResultsA total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of − 2.16 (− 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015).ConclusionsThis study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination.Trial registrationClinicalTrials.gov, NCT01292031. Registered 9 February 2011.
Highlights
Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB)
Based on the results from the interim analysis with half of the sample size achieved, the Data Safety Monitoring Board (DSMB) suggested stopping the clinical trial considering that continuation could be a risk for the safety of patients due to the high nephrotoxicity observed in the colistin group
The trial was stopped on October 13, 2015, and this decision was communicated to the ethics committees in the three countries participating in the study
Summary
Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). Colistin is the antimicrobial with the greatest in vitro activity against carbapenem-resistant (CR)-GNB, and recent guidelines from Infectious Disease Society of America [8] and European Respiratory Society [9] recommend colistin combined with other antipseudomonal agents as a therapeutic option for the empirical treatment of VAP in units with high rates of resistance to antimicrobial agents from other classes, especially if Acinetobacter is the likely pathogen. Both expert panels recognize that no previous randomized clinical trial assessing colistin as empirical therapy for VAP has been published, which is a major limitation
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