Prevalence of carbapenemase genes among carbapenem-nonsusceptible Enterobacterales collected in US hospitals in a five-year period and activity of ceftazidime/avibactam and comparator agents

Objectives To evaluate the prevalence of acquired beta-lactamase genes and susceptibility profiles of carbapenem-nonsusceptible Enterobacterales (CNSE) clinical isolates collected in US hospitals during a 5-year period. Methods Isolates were susceptibility tested by reference broth microdilution methods. Results were interpreted using CLSI breakpoints. Isolates displaying nonsusceptible MICs for imipenem or meropenem were categorized as CNSE. CNSE isolates were screened for beta-lactamase-encoding genes using whole-genome sequencing. New genes were cloned, expressed in an Escherichia coli background and susceptibility tested. Results A total of 450 (1.3%) isolates were CNSE. Klebsiella pneumoniae serine carbapenemase (KPC) production was the most common resistance mechanism among CNSE isolates: 281/450 (62.4%) carried bla(KPC), including three new variants. OXA-48-like and metallo-beta-lactamase (MBL) encoding genes were detected among seven and 12 isolates, respectively. Among MBL genes, bla(NDM-1) was the most common, but bla(NDM-5), bla(VIM-1) and bla(IMP-27) were also identified. 169 (37.6% of the CNSE) isolates did not produce carbapenemases. Ceftazidime/avibactam was the most active agent (95.0% to 100.0% susceptible) against CNSE isolates from all carbapenemase groups except MBL-producing isolates. Ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam inhibited 100.0%, 97.6% and 92.3% of the non-carbapenemase CNSE isolates, respectively. Among the three new bla(KPC) variants, one conferred resistance to ceftazidime/avibactam and low meropenem MIC results while the other two had profiles similar to bla(KPC-2) or bla(KPC-3). Conclusions A decline in carbapenemase production was noticed in US hospitals in the 5-year period analysed in this study. New beta-lactam/beta-lactamase inhibitor combinations tested had good activity against CNSE isolates.