Int J Antimicrob Agents. 2021 Sep 18:106439. doi: 10.1016/j.ijantimicag.2021.106439. Online ahead of print.
We investigated the prevalence, resistance mechanisms, and activity of ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and comparator agents against carbapenem-resistant Enterobacterales (CRE; 1.1% of the overall isolates) that did not carry carbapenemase genes. Among 304 CREs collected in US hospitals during 2016-2018 (1.1% of Enterobacterales), 45 (14.8%) isolates did not carry carbapenemases. These isolates were mainly Klebsiella aerogenes (11), Enterobacter cloacae (11), and Klebsiella pneumoniae (10). Isolates carried 1 to 6 β-lactam resistance mechanisms (median, 3). Acquired β-lactamase genes were detected among 21 isolates; blaCTX-M-15 was the most common acquired β-lactamase gene found (14 isolates). All 11 K. aerogenes and 6 E. cloacae overexpressed AmpC. Only 1 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 6 species. One E. coli isolate produced a CTX-M-15 variant that displayed an increased meropenem 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 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 bacterial species.