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Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e02534-16. doi: 10.1128/AAC.02534-16. Print 2017 May.

Mutations in blaKPC-3 That Confer Ceftazidime-Avibactam Resistance Encode Novel KPC-3 Variants That Function as Extended-Spectrum β-Lactamases.

Author information

1
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
2
University of Pittsburgh, Pittsburgh, Pennsylvania, USA cjc76@pitt.edu.
3
XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
4
VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.
5
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Abstract

We identified four blaKPC-3 mutations in ceftazidime-avibactam-resistant clinical Klebsiella pneumoniae isolates, corresponding to D179Y, T243M, D179Y/T243M, and EL165-166 KPC-3 variants. Using site-directed mutagenesis and transforming vectors into Escherichia coli, we conclusively demonstrated that mutant blaKPC-3 encoded enzymes that functioned as extended-spectrum β-lactamases; mutations directly conferred higher MICs of ceftazidime-avibactam and decreased the MICs of carbapenems and other β-lactams. Impact was strongest for the D179Y mutant, highlighting the importance of the KPC Ω-loop.

KEYWORDS:

KPC; ceftazidime-avibactam; drug resistance mechanisms; site-directed mutagenesis

PMID:
28223379
PMCID:
PMC5404534
DOI:
10.1128/AAC.02534-16
[Indexed for MEDLINE]
Free PMC Article

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