Low Frequency of Ceftazidime-Avibactam Resistance among Enterobacteriaceae Isolates Carrying blaKPC Collected in U.S. Hospitals from 2012 to 2015

Antimicrob Agents Chemother. 2017 Feb 23;61(3):e02369-16. doi: 10.1128/AAC.02369-16. Print 2017 Mar.

Abstract

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying blaKPC collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 μg/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 μg/ml; 98.9% susceptible at ≤2 μg/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (K. pneumoniae; MICs, ≥16 μg/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-β-lactamase genes, blaNDM-1 or blaVIM-4, among other β-lactam resistance mechanisms, and one displayed a premature stop codon in ompK35 and decreased expression of ompK36 Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carrying blaKPC-3 (n = 221) and blaKPC-2 (n = 145), respectively. Isolates carrying blaKPC were more commonly recovered from pneumonia (n = 155), urinary tract (n = 93), and skin/soft tissue (n = 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites. K. pneumoniae (83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidime-avibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidime-avibactam was active against this large collection of isolates carrying blaKPC and represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producing Enterobacteriaceae.

Keywords: KPC; ceftazidime-avibactam; permeability.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / pharmacology*
  • Ceftazidime / pharmacology*
  • Colistin / pharmacology
  • Drug Combinations
  • Enterobacteriaceae / drug effects*
  • Enterobacteriaceae / genetics
  • Enterobacteriaceae / growth & development
  • Enterobacteriaceae Infections / drug therapy
  • Enterobacteriaceae Infections / epidemiology*
  • Enterobacteriaceae Infections / microbiology
  • Gene Expression
  • Hospitals
  • Humans
  • Microbial Sensitivity Tests
  • Minocycline / analogs & derivatives
  • Minocycline / pharmacology
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Pneumonia, Bacterial / drug therapy
  • Pneumonia, Bacterial / epidemiology
  • Pneumonia, Bacterial / microbiology
  • Soft Tissue Infections / drug therapy
  • Soft Tissue Infections / epidemiology
  • Soft Tissue Infections / microbiology
  • Tigecycline
  • United States / epidemiology
  • Urinary Tract Infections / drug therapy
  • Urinary Tract Infections / epidemiology
  • Urinary Tract Infections / microbiology
  • beta-Lactam Resistance / genetics*
  • beta-Lactamases / genetics*
  • beta-Lactamases / metabolism

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Drug Combinations
  • avibactam, ceftazidime drug combination
  • Tigecycline
  • Ceftazidime
  • beta-Lactamases
  • Minocycline
  • Colistin