Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02243-16. doi: 10.1128/AAC.02243-16. Print 2017 Apr.


Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

Keywords: avibactam; aztreonam; ceftazidime; disk diffusion; metallo-β-lactamases.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / pharmacology*
  • Aztreonam / pharmacology*
  • Ceftazidime / pharmacology*
  • Colony Count, Microbial
  • Cyclophosphamide
  • Drug Administration Schedule
  • Drug Combinations
  • Drug Therapy, Combination
  • Enterobacteriaceae / drug effects*
  • Enterobacteriaceae / enzymology
  • Enterobacteriaceae / genetics
  • Enterobacteriaceae / growth & development
  • Enterobacteriaceae Infections / drug therapy*
  • Enterobacteriaceae Infections / microbiology
  • Female
  • Gene Expression
  • Humans
  • Klebsiella Infections / complications
  • Klebsiella Infections / drug therapy
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / enzymology
  • Klebsiella pneumoniae / genetics
  • Klebsiella pneumoniae / growth & development
  • Mice
  • Microbial Sensitivity Tests
  • Neutropenia / chemically induced
  • Neutropenia / complications
  • Neutropenia / drug therapy
  • Neutropenia / microbiology
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Soft Tissue Infections / complications
  • Soft Tissue Infections / drug therapy
  • Soft Tissue Infections / microbiology
  • Thigh
  • beta-Lactam Resistance / drug effects
  • beta-Lactam Resistance / genetics
  • beta-Lactamases / genetics
  • beta-Lactamases / metabolism


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