LAUSR

Cefepime/zidebactam (WCK 5222), a β-lactam/β-lactam enhancer antibiotic under development, was designed to retain in vitro activity against Enterobacteriaceae that simultaneously produce metallo-β-lactamase (MBL) and serine-β-lactamase (SBL). Currently, aztreonam (ATM) plus ceftazidime/avibactam (CZA) or meropenem/vaborbactam (M/V) is an attractive option for coverage of such strains, but clinical laboratories are unequipped to distinguish the more potent regimen to inform treatment decisions. We evaluated Enterobacteriaceae that expressed MBL and ≥1 SBL (N=15) using gradient diffusion strip (GDS) methods to (1) determine the minimum inhibitory concentration (MIC) of WCK 5222 and (2) compare the in vitro potency of CZA+ATM versus M/V+ATM. All isolates were non-susceptible to ATM, CZA, and M/V and were inhibited by WCK 5222 at cefepime concentrations ≥2 log2 dilutions below the susceptible-dose dependent breakpoint of 8 mg/L (MIC50/90, 1/2 mg/L). Activity of CZA+ATM versus M/V+ATM was compared using the zone of hope (ZOH) product, quantitated by multiplying the length (in mm) of inhibited growth adjacent to each GDS from the point of intersection. The median (interquartile range) ZOH product for CZA+ATM and M/V+ATM was 75.4 (62.8-93.7) and 23.5 (14.1-60.4), respectively (p=0.002). In strains with one carbapenemase (the MBL), the median ZOH products were not statistically different, but in strains with an OXA-type carbapenemase (n=6), the median product for CZA+ATM and M/V+ATM was 78.1 and 20.7, respectively (p=0.004). Thus, CZA+ATM may offer enhanced coverage over M/V+ATM of Enterobacteriaceae co-expressing MBL and SBL. With potent in vitro activity alone, further preclinical in vivo evaluations of WCK 5222 monotherapy are warranted.