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

Int J Antimicrob Agents. 2021 Nov;58(5):106439. doi: 10.1016/j.ijantimicag.2021.106439. Epub 2021 Sep 20.


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; blaCTX-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.

Keywords: CRE; Carbapenem-resistant Enterobacterales; Non-carbapenemase-producing; β-Lactam resistance mechanisms; β-Lactam/β-lactamase inhibitor combinations.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / pharmacology*
  • Bacterial Proteins / metabolism
  • Boronic Acids / pharmacology*
  • Carbapenem-Resistant Enterobacteriaceae / drug effects*
  • Carbapenem-Resistant Enterobacteriaceae / genetics
  • Carbapenem-Resistant Enterobacteriaceae / isolation & purification
  • Ceftazidime / pharmacology*
  • Drug Combinations
  • Drug Resistance, Multiple, Bacterial / genetics
  • Enterobacter aerogenes / drug effects
  • Enterobacter aerogenes / isolation & purification
  • Enterobacter cloacae / drug effects
  • Enterobacter cloacae / isolation & purification
  • Escherichia coli / drug effects
  • Escherichia coli / isolation & purification
  • Heterocyclic Compounds, 1-Ring / pharmacology*
  • Humans
  • Imipenem / pharmacology*
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / isolation & purification
  • Meropenem / pharmacology*
  • Microbial Sensitivity Tests
  • United States
  • beta-Lactamase Inhibitors / pharmacology*
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism


  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Bacterial Proteins
  • Boronic Acids
  • Drug Combinations
  • Heterocyclic Compounds, 1-Ring
  • avibactam, ceftazidime drug combination
  • beta-Lactamase Inhibitors
  • meropenem and vaborbactam
  • Imipenem
  • Ceftazidime
  • beta-Lactamases
  • carbapenemase
  • Meropenem
  • relebactam