Effects of KPC Variant and Porin Genotype on the In Vitro Activity of Meropenem-Vaborbactam against Carbapenem-Resistant Enterobacteriaceae

Antimicrob Agents Chemother. 2019 Feb 26;63(3):e02048-18. doi: 10.1128/AAC.02048-18. Print 2019 Mar.

Abstract

Meropenem-vaborbactam is a new agent with the potential to treat carbapenem-resistant Enterobacteriaceae (CRE) infections. We describe the in vitro activity of meropenem-vaborbactam against representative CRE genotypes and laboratory-engineered Escherichia coli isolates harboring mutant blaKPC genes associated with ceftazidime-avibactam resistance. We also compared disk diffusion and gradient strip testing methods to standard broth microdilution methods. Against 120 CRE isolates, median ceftazidime-avibactam and meropenem-vaborbactam MICs were 1 and 0.03 µg/ml, respectively. Ninety-eight percent (117/120) of isolates were susceptible to meropenem-vaborbactam (MICs ≤ 4 µg/ml). Against Klebsiella pneumoniae isolates harboring mutant blaKPC, the addition of vaborbactam lowered the meropenem MICs in 78% of isolates (14/18); 100% were susceptible to meropenem-vaborbactam. Median meropenem-vaborbactam MICs were higher against K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae isolates with mutant ompK36 porin genes (n = 26) than against those with wild-type ompK36 porin genes (n = 54) (0.25 versus 0.03 µg/ml; P < 0.0001). Against E. coli TOP10 isolates with plasmid constructs containing wild-type blaKPC or mutant blaKPC, the addition of vaborbactam at 8 µg/ml lowered the meropenem MICs 2- to 512-fold, resulting in meropenem-vaborbactam MICs of 0.03 µg/ml. The rates of categorical agreement with broth microdilution for disk diffusion or gradient strips ranged from 90 to 95%. Essential agreement rates were higher for research-use-only (RUO) gradient strips manufactured by bioMérieux (82%) than for those manufactured by Liofilchem (48%) (P < 0.0001). Taken together, our data highlight the potent in vitro activity of meropenem-vaborbactam against CRE, including isolates resistant to ceftazidime-avibactam. Vaborbactam inhibited both wild-type and variant KPC enzymes. On the other hand, KPC-producing K. pneumoniae isolates with ompK36 mutations displayed higher meropenem-vaborbactam MICs than isolates with wild-type ompK36 The results of susceptibility testing with RUO bioMérieux gradient strips most closely aligned with those of broth microdilution methods.

Keywords: CRE; KPC; ceftazidime-avibactam; disk diffusion; gradient strip; meropenem-vaborbactam; porin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / pharmacology*
  • Bacterial Proteins / genetics
  • Boronic Acids / pharmacology*
  • Carbapenem-Resistant Enterobacteriaceae / drug effects*
  • Carbapenem-Resistant Enterobacteriaceae / genetics
  • Carbapenem-Resistant Enterobacteriaceae / isolation & purification
  • Ceftazidime / pharmacology*
  • Disk Diffusion Antimicrobial Tests
  • Drug Combinations
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics
  • Heterocyclic Compounds, 1-Ring / pharmacology*
  • Humans
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / genetics
  • Meropenem / pharmacology*
  • Porins / genetics
  • beta-Lactamases / genetics

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Bacterial Proteins
  • Boronic Acids
  • Drug Combinations
  • Heterocyclic Compounds, 1-Ring
  • OmpK36 protein, Klebsiella pneumoniae
  • Porins
  • avibactam, ceftazidime drug combination
  • meropenem and vaborbactam
  • Ceftazidime
  • beta-lactamase KPC-1
  • beta-Lactamases
  • Meropenem