Third-generation cephalosporin resistance in clinical isolates of Enterobacterales collected between 2016-2018 from USA and Europe: genotypic analysis of β-lactamases and comparative in vitro activity of cefepime/enmetazobactam

Objectives: This study aimed to investigate third-generation cephalosporin (3GC) resistance determinants [extended-spectrum beta-lactamases (ESBLs), AmpC beta-lactamases and OXA-type beta-lactamases] in contemporary clinical Enterobacterales isolates and to determine the in vitro activity of beta-lactams and beta-lactam/beta-lactamase inhibitor combinations, including the investigational combination of cefepime and the novel beta-lactamase inhibitor enmetazobactam. Methods: Antibacterial susceptibility of 7168 clinical Enterobacterales isolates obtained between 2016-2018 from North America and Europe was determined according to CLSI guidelines. Phenotypic resistance to the 3GC ceftazidime (MIC >= 16 mu g/mL) and/or ceftriaxone (MIC >= 4 mu g/mL) but retaining susceptibility to meropenem (MIC <= 1 mu g/mL) was determined. beta-Lactamase genotyping was performed on clinical isolates with ceftazidime, ceftriaxone, cefepime or meropenem MIC >= 1 mu g/mL. Results: Phenotypic resistance to 3GCs occurred in 17.5% of tested isolates, whereas 2.1% of isolates were resistant to the carbapenem meropenem. Within the 3GC-resistant subgroup, 60.1% (n = 752) of isolates encoded an ESBL, 25.6% (n = 321) encoded an AmpC-type beta-lactamase and 0.9% (n = 11) encoded an OXA-type beta-lactamase. Susceptibility of the subgroup to piperacillin/tazobactam (57.5%) and ceftolozane/tazobactam (71.3%) was <90% based on breakpoints established by the CLSI. Projected susceptibility to cefepime/enmetazobactam was 99.6% when applying the cefepime susceptible, dose-dependent breakpoint of 8 mu g/mL. Against ESBL-producing isolates (n = 801) confirmed by genotyping, only susceptibility to meropenem (96.0%) and cefepime/enmetazobactam (99.9%) exceeded 90%. Conclusion: This study describes the antibacterial activity of important therapies against con- temporary 3GC-resistant clinical Enterobacterales isolates and supports the development of cefepime/enmetazobactam as a carbapenem-sparing option for ESBL-producing pathogens. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

Automated summary

This study investigated resistance determinants in contemporary clinical Enterobacterales isolates, finding that a significant proportion encoded ESBLs, AmpC beta-lactamases, and OXA-type beta-lactamases. Susceptibility to different antibiotics varied among the isolates, with promising results for the combination of cefepime and enmetazobactam against ESBL-producing pathogens.