title: Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa.
abstract: OBJECTIVE
  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 β-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, with weaker synergy seen for isolates with the OXA-48 enzyme. On the 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.
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D004338:Drug Combinations; D004755:Enterobacteriaceae / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015378:Imipenem / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D015378:Imipenem; C568736:relebactam
keywords: KPC; OXA-48; OprD porin; carbapenemases; metallo-β-lactamases