Enhanced activity of cefepime-tazobactam (WCK 4282) against KPC-producing Enterobacteriaceae when tested in media supplemented with human serum or sodium chloride

Abstract

The aim of this study was to evaluate the in vitro activity of cefepime-tazobactam cation-adjusted Mueller-Hinton broth (CA-MHB) supplemented with 0.85% sodium chloride (NaCl) or 50% human serum in comparison to standard CA-MHB when testing KPC-producing isolates. A total of 209 contemporary Enterobacteriaceae clinical isolates carrying bla_KPC were tested, and cefepime-tazobactam (tazobactam at fixed 8mg/L) activity was enhanced 2-fold when tested in CA-MHB supplemented with 0.85% NaCl or 50% human serum (MIC_50/90, 8/32mg/L for both media) compared to standard CA-MHB (MIC_50/90, 16/64mg/L). Cefepime-tazobactam at a concentration of ≤16mg/L, which is the pharmacokinetics/pharmacodynamics tentative susceptibility breakpoint based on a high dosing regimen of cefepime-tazobactam (2g-2g q8h 90-minute infusion), inhibited 79.4-80.4% of Enterobacteriaceae isolates carrying bla_KPC in MHB supplemented with 0.85% NaCl or 50% human serum. A similar decrease in MIC values was observed when cefepime alone was tested against a subset of the isolates (n=54) in CA-MHB supplemented with 50% human serum or 0.85% NaCl; however, imipenem activity against these 54 organisms was similar or 2-fold higher in CA-MHB supplemented with 0.85% of NaCl (MIC_50/90, 8/16mg/L) or with 50% human serum (MIC₅₀ and MIC₉₀, 16mg/L) compared standard CA-MHB (MIC_50/90, 8/16mg/L). In summary, cefepime-tazobactam MIC values against Enterobacteriaceae isolates carrying bla_KPC were consistently lower in media supplemented with human serum or NaCl, which better mimics physiological conditions. These results suggest that this carbapenem-sparing candidate agent has potential to be used to treat infections caused by KPC-producing Enterobacteriaceae.

Keywords: Beta-lactamase inhibitor combination; Cefepime; Enterobacteriaceae; KPC; Susceptibility testing; Tazobactam.