Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 64, Issue 12, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01432-20
Keywords
WCK 5222; cefepime; Zidebactam; bicycloacyl hydrazide; PBP2; enhancer; beta-lactamase inhibitors
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Funding
- Wockhardt Bio AG, Switzerland
- Wockhardt Bio AG
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WCK 5222 (cefepime-zidebactam, 2 g + 1g, every 8 h [q8h]) is in clinical development for the treatment of infections caused by carbapenem-resistant and multidrug-resistant (MDR) Gram-negative bacilli. We determined the in vitro susceptibility of 1,385 clinical isolates of non-carbapenem-susceptible Enterobacterales, MDR Pseudomonas aeruginosa (also non-carbapenem susceptible), Stenotrophomonas maltophilia, and Burkholderia spp. collected worldwide (49 countries) from 2014 to 2016 to cefepime-zidebactam (1:1 ratio), ceftazidime-avibactam, imipenem-relebactam, ceftolozane-tazobactam, and colistin using the CLSI broth microdilution method. Cefepime-zidebactam inhibited 98.5% of non-carbapenemsusceptible Enterobacterales (n = 1,018) at <= 8 mu g/ml (provisional cefepime-zidebactamsusceptible MIC breakpoint). Against the subset of metallo-lactamase (MBL)-positive Enterobacterales (n = 214), cefepime-zidebactam inhibited 94.9% of isolates at <= 8 mu g/ml. Further, it inhibited 99.6% of MDR P. aeruginosa (n = 262) isolates at <= 32 mu g/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 mu g/ml; MIC90, 32 mu g/ml) and Burkholderia spp. (n = 4; MIC range, 16 to 32 mu g/ml) were also inhibited by cefepime-zidebactam at <= 32 mu g/ml. The activity of cefepime-zidebactam against carbapenem-resistant Gram-negative bacteria is ascribed to its -lactam enhancer mechanism of action (i.e., zidebactam binding to penicillin binding protein 2 [PBP2] and its universal stability to both serine-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 nonfermentative Gram-negative bacilli where resistance to marketed antimicrobial agents is a limiting factor.
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