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Livermore, David M. 
ORCID: https://orcid.org/0000-0002-9856-3703, Mushtaq, Shazad, Doumith, Michel, Jamrozy, Dorota, Nichols, Wright W. and Woodford, Neil
(2018)
Selection of mutants with resistance or diminished susceptibility to ceftazidime/avibactam from ESBL- and AmpC- producing Enterobacteriaceae.
Journal of Antimicrobial Chemotherapy, 73 (12).
3336–3345.
ISSN 0305-7453
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Abstract
Introduction: Difficult Gram-negative infections are increasingly treated with new β-lactamase inhibitor combinations, e.g. ceftazidime/avibactam. Disturbingly, mutations in KPC carbapenemases can confer ceftazidime/avibactam resistance, which is sometimes selected during therapy. We explored whether this risk extended to AmpC and ESBL enzymes. Methods: Mutants were selected by plating AmpC-derepressed strains, ESBL producers and ceftazidime-susceptible controls on agar containing ceftazidime + avibactam (1 or 4 mg/L). MICs were determined by CLSI agar dilution; WGS was by Illumina methodology. Results: Using 2× MIC of ceftazidime + 1 mg/L avibactam, mutants were selected from all strain types at frequencies of 10−7–10−9. Rates diminished to <10−9 with 4 mg/L avibactam or higher MIC multiples, except with AmpC-derepressed Enterobacteriaceae. Characterized mutants (n = 10; MICs 4–64 mg/L) of AmpC-derepressed strains had modifications in ampC, variously giving Arg168Pro/His, Gly176Arg/Asp, Asn366Tyr or small deletions around positions 309–314. Mutants of ESBL producers (n = 19; MICs 0.5–16 mg/L) mostly had changes affecting permeability, efflux or β-lactamase quantity; only one had an altered β-lactamase, with an Asp182Tyr substitution in CTX-M-15, raising the ceftazidime/avibactam MIC, but abrogating other cephalosporin resistance. Mutants of ceftazidime-susceptible strains were not sequenced, but phenotypes suggested altered drug accumulation or, for Enterobacter cloacae only, AmpC derepression. In further experiments, avibactam reduced, but did not abolish, selection of AmpC-derepressed Enterobacteriaceae by ceftazidime. Conclusions: Most mutants of AmpC-derepressed Enterobacteriaceae had structural mutations in ampC; those of ESBL producers mostly had genetic modifications outside β-lactamase genes, commonly affecting uptake, efflux, or β-lactamase quantity. The clinical significance of these observations remains to be determined.
| Item Type: | Article |
|---|---|
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research (former - to 2023) Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health |
| Depositing User: | LivePure Connector |
| Date Deposited: | 23 Aug 2018 14:32 |
| Last Modified: | 22 Oct 2022 04:05 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/68118 |
| DOI: | 10.1093/jac/dky363 |
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