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Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase (ESBL) inhibitor. The combination of enmetazobactam with cefepime has entered clinical trials to assess safety and efficacy in patients with complicated urinary tract infections. Here, the in vitro activity of cefepime-enmetazobactam was determined for 1,993 clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa collected in the United States and Europe during 2014 and 2015. Enmetazobactam at a fixed concentration of 8 μg/ml lowered the cefepime MIC 90 from 16 to 0.12 μg/ml for Escherichia coli , from >64 to 0.5 μg/ml for Klebsiella pneumoniae , from 16 to 1 μg/ml for Enterobacter cloacae , and from 0.5 to 0.25 μg/ml for Enterobacter aerogenes Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa Applying the Clinical and Laboratory Standards Institute susceptible-dose-dependent (SDD) breakpoint of 8 μg/ml to cefepime-enmetazobactam for comparative purposes resulted in cumulative inhibitions of 99.9% for E. coli , 96.4% for K. pneumoniae , 97.0% for E. cloacae , 100% for E. aerogenes , 98.1% for all Enterobacteriaceae assessed, and 82.8% for P. aeruginosa Comparator susceptibilities for all Enterobacteriaceae were 99.7% for ceftazidime-avibactam, 96.2% for meropenem, 90.7% for ceftolozane-tazobactam, 87% for cefepime (SDD breakpoint), 85.7% for piperacillin-tazobactam, and 81.2% for ceftazidime. For the subset of ESBL-producing K. pneumoniae isolates, the addition of 8 μg/ml enmetazobactam to cefepime lowered the MIC 90 from >64 to 1 μg/ml, whereas the shift for 8 μg/ml tazobactam was from >64 to 8 μg/ml. Cefepime-enmetazobactam may represent a novel carbapenem-sparing option for empirical treatment of serious Gram-negative infections in settings where ESBL-producing Enterobacteriaceae are expected., (Copyright © 2019 Morrissey et al.)