In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

Antimicrob Agents Chemother. 2017 Jun 27;61(7):e00486-17. doi: 10.1128/AAC.00486-17. Print 2017 Jul.

Abstract

The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

Keywords: Klebsiella pneumoniae; New Delhi metallo-β-lactamase; ceftazidime-avibactam; resistance.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Azabicyclo Compounds / pharmacology*
  • Azabicyclo Compounds / therapeutic use
  • Aztreonam / pharmacology*
  • Aztreonam / therapeutic use
  • Ceftazidime / pharmacology*
  • Ceftazidime / therapeutic use
  • Drug Combinations
  • Enterobacteriaceae / drug effects
  • Female
  • Klebsiella Infections / drug therapy
  • Klebsiella pneumoniae / drug effects
  • Mice
  • Microbial Sensitivity Tests
  • beta-Lactamase Inhibitors / pharmacology
  • beta-Lactamase Inhibitors / therapeutic use

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Drug Combinations
  • avibactam, ceftazidime drug combination
  • beta-Lactamase Inhibitors
  • Ceftazidime
  • Aztreonam