Activity of ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam against carbapenemase-negative carbapenem-resistant Enterobacterales isolates from US hospitals

We investigated the prevalence, resistance mechanisms and activity of ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam and comparator agents against carbapenem-resistant Enterobacterales (CRE) that did not carry carbapenemase genes. Among 304 CRE isolates collected in US hospitals during 2016-2018 (1.1% of the overall Enterobacterales), 45 (14.8%) isolates did not carry carbapenemases. These isolates were mainly Klebsiella aerogenes (n = 11), Enterobacter cloacae (n = 11) and Klebsiella pneumoniae (n = 10). Isolates harboured one to six β-lactam resistance mechanisms (median, three mechanisms). Acquired β-lactamase genes were detected in 21 isolates; bla_CTX-M-15 was the most common acquired β-lactamase gene found (14 isolates). All 11 K. aerogenes and 6 E. cloacae isolates overexpressed AmpC. Only one isolate belonging to these species carried acquired β-lactamase genes. Disruptions or reduced expression of both outer membrane proteins (ompC/ompK36 and ompF/ompK35) were detected among 20 isolates. AcrAB-TolC was modestly expressed or overexpressed among 19 isolates from six species. One E. coli isolate produced a CTX-M-15 variant that displayed an increased meropenem minimum inhibitory concentration (MIC) when expressed in a clean background. Most β-lactam agents had limited activity against CRE isolates that did not carry carbapenemases. Ceftazidime/avibactam inhibited all isolates, while imipenem/relebactam and meropenem/vaborbactam inhibited 93.0% (88.9% if Proteus mirabilis is included) and 93.3% of tested isolates at current breakpoints. The resistance mechanisms among CRE isolates that did not produce carbapenemases are complex; β-lactam/β-lactamase inhibitor combinations might have different activity against these isolates depending on their resistance mechanisms and the Bacterial species.