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Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00642-17. doi: 10.1128/AAC.00642-17. Print 2017 Sep.

Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae.

Author information

1
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
2
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA cjc76@pitt.edu.
3
VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.
4
XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
5
Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
6
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Abstract

We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidime-avibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum β-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo-β-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (P < 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P = 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P < 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.

KEYWORDS:

CRE; Enterobacteriaceae; KPC; ceftazidime-avibactam; drug resistance mechanisms; imipenem-relabactam; mechanisms of resistance; porins

PMID:
28630202
PMCID:
PMC5571343
DOI:
10.1128/AAC.00642-17
[Indexed for MEDLINE]
Free PMC Article

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