Infections caused by multidrug resistant Klebsiella pneumoniae that produce K. pneumoniae carbapenemase (KPC) typically require treatment with two or more antimicrobial agents.1, 2 Although carbapenems are hydrolyzed by KPCs, combined therapy with a carbapenem and a polymyxin (colistin or polymyxin B) significantly lowers mortality in critically ill patients infected with polymyxin-susceptible K. pneumoniae that produce KPC.3, 4 However, KPC-producing Enterobacteriaceae often exhibit a range of carbapenem MICs.5 Mortality rates are higher in patients with isolates displaying higher levels of carbapenem resistance suggesting that carbapenem and polymyxin combinations may require modification based on the level of carbapenem resistance to improve outcomes.4 To better understand the pharmacodynamics and clinical utility of carbapenem and polymyxin combinations, we evaluated the time-kill activity and the emergence of polymyxin resistance of meropenem and polymyxin B alone and in combination against KPC-producing K. pneumoniae with varying MICs of meropenem.

We evaluated four clinical isolates of K. pneumoniae producing KPC-3, previously identified by PCR. Isolates were obtained from the University of Kentucky HealthCare System and designated KP 22, KP 24, KP 34 and KP 44. Of those, KP 22, KP 24 and KP 44 underwent whole-genome sequencing by the University of Kentucky Genomics Core Laboratory. IRB approval was obtained and the requirement for informed consent was waived. MIC testing for meropenem, polymyxin B and colistin were performed using broth microdilution in accordance with CLSI guidelines, whereas MIC testing of other beta-lactam antimicrobials were determined by the BD Phoenix Automated Microbiology System as part of routine clinical testing.6 Antimicrobial agents were obtained from Sigma-Aldrich (St Louis, MO, USA). Since Enterobacteriaceae are without CLSI-approved breakpoints for polymyxin B, isolates were considered ‘susceptible’ based upon CLSI-approved interpretive criteria for Pseudomonas aeruginosa and Acinetobacter baumannii.6 Polymyxin B susceptible strains representing a wide range of meropenem MICs were selected for time-kill studies. Those isolates, in order of ascending meropenem MIC, were KP 34 (MIC 4 mg l−1), KP 22 (MIC 16 mg l−1), KP 24 (MIC 32 mg l−1) and KP 44 (MIC 128 mg l−1).

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