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

Abstract

This study aimed to investigate third-generation cephalosporin (3GC) resistance determinants [extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases and OXA-type β-lactamases] in contemporary clinical Enterobacterales isolates and to determine the in vitro activity of β-lactams and β-lactam/β-lactamase inhibitor combinations, including the investigational combination of cefepime and the novel β-lactamase inhibitor enmetazobactam. 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 µg/mL) and/or ceftriaxone (MIC ≥ 4 µg/mL) but retaining susceptibility to meropenem (MIC ≤ 1 µg/mL) was determined. β-Lactamase genotyping was performed on clinical isolates with ceftazidime, ceftriaxone, cefepime or meropenem MIC ≥ 1 µg/mL. 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 β-lactamase and 0.9% (n=11) encoded an OXA-type β-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 µg/mL. Against ESBL-producing isolates (n=801) confirmed by genotyping, only susceptibility to meropenem (96.0%) and cefepime/enmetazobactam (99.9%) exceeded 90%. This study describes the antibacterial activity of important therapies against contemporary 3GC-resistant clinical Enterobacterales isolates and supports the development of cefepime/enmetazobactam as a carbapenem-sparing option for ESBL-producing pathogens.