Introduction

Enmetazobactam (a novel penicillanic acid sulfone extended-spectrum β-lactamase [ESBL] inhibitor) and cefepime combination has been shown to be comparable to that of meropenem against cefepime-nonsusceptible Enterobacteriaceae and Pseudomonas aeruginosa. This combination may provide an empirical treatment option in settings with a high incidence of ESBL-producing Enterobacteriaceae that pursue carbapenem-sparing strategies.

Aim

• To assess the in vitro activities of cefepime-enmetazobactam and comparator agents against a collection of clinical isolates (Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and Pseudomonas aeruginosa)
• To compare enmetazobactam with tazobactam when combined with cefepime against a subset of ESBL-producing isolates of K. pneumoniae

Patient Profile

• 1,993 clinical isolates of Gram-negative bacteria from hospitalized patients with complicated urinary tract infections or acute pyelonephritis, pneumonia, and intraabdominal infections

Method

Study Design

• Surveillance study

Results

Efficacy

• The addition of enmetazobactam 8 μg/ml to cefepime lowered the minimum inhibitory concentration at which 90% of isolates were inhibited (MIC₉₀) from 16 to 0.12 μg/ml for Escherichia coli, by at least eight doubling dilutions from >64 to 0.5 μg/ml for Klebsiella pneumoniae, by four doubling dilutions from 16 to 1 μg/ml for Enterobacter cloacae, and by one doubling dilution from 0.5 to 0.25 μg/ml for Enterobacter aerogenes
• Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa
• Enmetazobactam restored the activity of cefepime against ESBL-producing E. coli isolates (lowered MIC₉₀ by at least ten doubling dilutions from >64 to 0.12 μg/ml) 
• On applying the susceptible-dose-dependent (SDD) breakpoint of 8 μg/ml to cefepime, addition of enmetazobactam made ESBL-producing isolates more susceptible: cumulative inhibitions of 99.9% for E. coli, 96.4% for K. pneumoniae, 97.0% for Enterobacter cloacae, 100% for Enterobacter 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 and gentamicin but was below 80% for ciprofloxacin
• Enmetazobactam-cefepime combination was more potent than tazobactam-cefepime against ESBL-producing isolates of K. pneumoniae (lowered MIC90 from >64 to 1 μg/ml vs. >64 to 8 μg/ml, respectively)
• For E. coli, >90% of isolates were in the CLSI susceptible category for piperacillin-tazobactam, meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam.
• Between 50 and 85% susceptible isolates were observed for piperacillin-tazobactam and gentamicin for E. coli, and for ceftolozane-tazobactam for K. pneumoniae with an ESBL genotype
• For P. aeruginosa ceftolozane-tazobactam and ceftazidime-avibactam each had >90% of isolates in the CLSI susceptible category, and between 65 and 85% for the remaining comparators.
• Applying a breakpoint of 1 μg/ml to cefepime-enmetazobactam inhibited 99.7% of all E. coli isolates
• Applying breakpoints of 1 to 8 μg/ml to cefepime-enmetazobactam resulted in cumulative inhibitions of 93.2 to 96.4% for all K. pneumoniae isolates, 99.0 to 100% for E. aerogenes, 92.0 to 97.0% for E. cloacae isolates, 99.1% for E. coli with an ESBL genotype, 92.2 to 100% for K. pneumoniae with an ESBL genotype and 6.7 to 42.2% for K. pneumoniae isolates with a KPC genotype isolates susceptible to cefepime-enmetazobactam

Conclusion

• Cefepime-enmetazobactam was an effective carbapenem-sparing option for empirical treatment of serious Gram-negative infections, especially in Enterobacteriaceae expressing diverse ESBLs
• Cefepime-enmetazobactam combination outperformed piperacillin-tazobactam and was as potent as meropenem against Enterobacteriaceae and toward the subset of ESBL-producing E. coli and K. pneumoniae isolates, with limited effect against KPC-producing Enterobacteriaceae
• This combination was also more effective in vitro against E. cloacae compared to either piperacillin-tazobactam or ceftolozane-tazobactam and comparable to ceftazidime-avibactam

Antimicrob Agents Chemother 63: e00514-19