Characterization of β-lactamase and porin mutants of Enterobacteriaceae selected with ceftaroline + avibactam (NXL104)

Livermore, David M. ORCID: https://orcid.org/0000-0002-9856-3703, Mushtaq, Shazad, Barker, Kevin, Hope, Russell, Warner, Marina and Woodford, Neil (2012) Characterization of β-lactamase and porin mutants of Enterobacteriaceae selected with ceftaroline + avibactam (NXL104). Journal of Antimicrobial Chemotherapy, 67 (6). pp. 1354-1358. ISSN 0305-7453

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Abstract

Objectives: Ceftaroline + avibactam (NXL104) is a novel inhibitor combination active against Enterobacteriaceae with class A and C β-lactamases. We investigated its risk of mutational resistance. Methods: Single- and multi-step mutants were sought and characterized from Enterobacteriaceae with extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases and KPC β-lactamases. Results: Overgrowth occurred on agar with low MIC multiples of ceftaroline + avibactam, but frequencies for single-step mutants were <10−9. Most mutants were unstable, with only three remaining resistant on subculture. For one, from an CTX-M-15-positive Escherichia coli, the ceftaroline + avibactam MIC was raised, but the organism had reduced resistance to ceftaroline and lost resistance to other oxyimino-cephalosporins, with this profile retained when the mutant blaCTX-M-15 was cloned into E. coli DH5α. Sequencing identified a Lys237Gln substitution in the CTX-M-15 variant. The other two stable single-step mutants were from an AmpC-derepressed Enterobacter cloacae strain; these had unaltered or slightly reduced resistance to other β-lactams. Both had amino acids 213–226 deleted from the Ω loop of AmpC. Further stable mutants were obtained from AmpC-inducible and -derepressed E. cloacae in multi-step selection, and these variously had reduced expression of OmpC and OmpF, and/or Asn366His/Ile substitutions in AmpC. Conclusions: Stable resistant mutants were difficult to select. Those from AmpC-derepressed E. cloacae had porin loss or AmpC changes, including Ω loop deletions. A Lys237Gln substitution in CTX-M-15 conferred resistance, but largely abolished ESBL activity.

Item Type: Article
Uncontrolled Keywords: anti-bacterial agents,azabicyclo compounds,cephalosporins,drug resistance, bacterial,enterobacteriaceae,genomic instability,microbial sensitivity tests,mutant proteins,phenotype,porins,selection, genetic,beta-lactamases
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Sophie Buckingham
Date Deposited: 05 Mar 2013 10:55
Last Modified: 08 Nov 2022 12:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/41712
DOI: 10.1093/jac/dks079

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