Diversity of resistance mechanisms in carbapenem-resistant Enterobacteriaceae at a health care system in Northern California, from 2013 to 2016

Abstract

The mechanism of resistance in carbapenem-resistant Enterobacteriaceae (CRE) has therapeutic implications. We comprehensively characterized emerging mechanisms of resistance in CRE between 2013 and 2016 at a health system in Northern California. A total of 38.7% (24/62) of CRE isolates were carbapenemase gene-positive, comprising 25.0% (6/24) bla_{OXA-48 like}, 20.8% (5/24) bla_KPC, 20.8% (5/24) bla_NDM, 20.8% (5/24) bla_SME, 8.3% (2/24) bla_IMP, and 4.2% (1/24) bla_VIM. Between carbapenemases and porin loss, the resistance mechanism was identified in 95.2% (59/62) of CRE isolates. Isolates expressing bla_KPC were 100% susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam; bla_{OXA-48 like}-positive isolates were 100% susceptible to ceftazidime-avibactam; and metallo β-lactamase-positive isolates were nearly all nonsusceptible to above antibiotics. Carbapenemase gene-negative CRE were 100% (38/38), 92.1% (35/38), 89.5% (34/38), and 31.6% (12/38) susceptible to ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and ceftolozane-tazobactam, respectively. None of the CRE strains were identical by whole genome sequencing. At this health system, CRE were mediated by diverse mechanisms with predictable susceptibility to newer β-lactamase inhibitors.

Keywords: Avibactam; Carbapenem-resistant Enterobacteriaceae; Carbapenemase; Porin; Relebactam; Vaborbactam.

Fig. 1.

Carbapenemase genes detected in CRE isolates annually from 2013 to 2016. Carbapenemase genes tested include bla_KPC, bla_NDM, bla_IMP, bla_VIM, bla_{OXA-48 like}, bla_SME, bla_SIM, bla_SPM, bla_GES, bla_IMI, bla_NMC-A, and bla_GIM.

Fig. 2.

Porin protein and mRNA levels in CRE isolates with and without a carbapenemase gene. Bars show percentage of carbapenemase gene-positive (CARBase gene +) and gene-negative (CARBase gene−) CRE isolates with relative protein (A) and porin mRNA (B) down 2-fold or more compared with susceptible isolates.

Fig. 3.

Susceptibility of CRE isolates to imipenem–relebactam, meropenem–vaborbactam, ceftazidime–avibactam, and ceftolozane–tazobactam. Bars show percent susceptibility of carbapenemase gene-positive (CARBase gene +) and gene-negative (CARBase gene−) CRE to (A) imipenem–relebactam, (C) meropenem–vaborbactam, (E) ceftazidime–avibactam, and (G) ceftolozane–tazobactam. Graphs on the right (B, D, F, H) show fraction of carbapenemase genes detected in carbapenemase gene-positive isolates that are susceptible, intermediate, or resistant to the respective antibiotic combination.