Antimicrob Agents Chemother. 2020 Sep 14:AAC.01432-20. doi: 10.1128/AAC.01432-20. Online ahead of print.
WCK 5222 (cefepime-zidebactam, 2g + 1g, q8h) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined in vitro susceptibility of 1,385 clinical isolates of carbapenem not susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also carbapenem not susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) during 2014-2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using CLSI broth microdilution method. Cefepime-zidebactam inhibited 98.5% of carbapenem not susceptible Enterobacterales (n=1,018) at ≤8 μg/ml (provisional cefepime-zidebactam-susceptible MIC breakpoint). Against the subset of metallo-β-lactamase (MBL)-positive Enterobacterales (n=214), cefepime-zidebactam inhibited 94.9% of isolates at ≤8 μg/ml. Further, it inhibited 99.6% of MDR P. aeruginosa (n=262) isolates at ≤32 μg/ml (proposed cefepime-zidebactam-susceptible pharmacokinetic/pharmacodynamic MIC breakpoint), including all MBL-positive isolates (n=94). Moreover, cefepime-zidebactam was active against the majority of isolates of Enterobacterales (≥95%) and P. aeruginosa (99%) that were not susceptible to ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam and colistin. Most isolates (99%) of S. maltophilia (n=101; MIC50, 8 μg/ml; MIC90, 32 μg/ml) and Burkholderia spp. (n=4; MIC range, 16-32 μg/ml) were also inhibited by cefepime-zidebactam at ≤32 μg/ml. The activity of cefepime-zidebactam against carbapenem-resistant Gram-negatives is ascribed to its β-lactam enhancer mechanism of action (i.e., zidebactam binding to PBP2 and its universal stability to both serine β-lactamases and MBLs). The results from this study support the continued development of cefepime-zidebactam as a potential therapy for infections caused by Enterobacterales, P. aeruginosa, and other non-fermentative Gram-negative bacilli where resistance to marketed antimicrobial agents is a limiting factor.