Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant enterobacteriaceae

Ghady Haidar, Cornelius J. Clancy, Liang Chen, Palash Samanta, Ryan K. Shields, Barry N. Kreiswirth, M. Hong Nguyen

Research output: Contribution to journalArticle

48 Scopus citations

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 -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--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.

Original languageEnglish (US)
Article numbere00642-17
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number9
DOIs
StatePublished - Sep 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Keywords

  • CRE
  • Ceftazidime-avibactam
  • Drug resistance mechanisms
  • Enterobacteriaceae
  • Imipenem-relabactam
  • KPC
  • Mechanisms of resistance
  • Porins

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