Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms

Abstract Background We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms. Methods This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E). Results Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475–10.184; P = .006). Conclusions Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention. In a randomized, controlled trial, we evaluated whether colistin-meropenem combination therapy, compared to colistin monotherapy, for infections due to carbapenem-resistant Gram-negative bacteria reduces the emergence of colistin resistance. No evidence to support a reduction with combination therapy was found.