Activity of MK-7655 combined with imipenem against enterobacteriaceae and Pseudomonas aeruginosa

David Livermore*, Marina Warner, Shazad Mushtaq

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

165 Citations (Scopus)

Abstract

Objectives:MK-7655 is a novel inhibitor of class A and C β-lactamases.We investigated its potential to protect imipenem.Methods: Chequerboard MICs were determined by CLSI agar dilution: (i) for Enterobacteriaceae with carbapenemases; (ii) for Enterobacteriaceae with carbapenem resistance contingent on combinations of impermeability together with an extended-spectrum b-lactamase or AmpC enzyme; and (iii) for Pseudomonas aeruginosa and other non-fermenters.Results: At a concentration of 4 mg/L, MK-7655 reduced imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16-64 mg/L to 0.12-1 mg/L. Synergy also was seen for Enterobacteriaceae with impermeability- mediated carbapenem resistance, withweaker synergyseen for isolates with the OXA-48 enzyme.Onthe other hand, MK-7655 failed to potentiate imipenem against Enterobacteriaceae with metallo-carbapenemases. In the case of P. aeruginosa, where endogenous AmpC confers slight protection versus imipenem, 4 mg/L MK-7655 reduced the MIC of imipenem for all isolates, except those with metallo-carbapenemases: the MICs of imipenem fell from 1-2 mg/L to 0.25-0.5 mg/L for imipenem-susceptible P. aeruginosa and from 16-64 mg/L to 1-4 mg/L for OprD-deficient strains. No potentiation was seen for chryseobacteria or for Stenotrophomonas maltophilia.Conclusions: MK-7655 potentiated imipenem against Enterobacteriaceae with KPC carbapenemases or combinations of β-lactamase and impermeability, but not those with metallo-carbapenemases. It augmented the activity of imipenem against P. aeruginosa in general and OprD mutants in particular.

Original languageEnglish
Article numberdkt178
Pages (from-to)2286-2290
Number of pages5
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number10
DOIs
Publication statusPublished - Oct 2013

Bibliographical note

Funding Information:
This work was sponsored by Merck & Co., to whom we are grateful.

Keywords

  • Carbapenemases
  • KPC
  • Metallo-Β-lactamases
  • OXA-48
  • OprD porin

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