Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?

Steven Marshall, Andrea M. Hujer, Laura J. Rojas, Krisztina M. Papp-Wallace, Romney M. Humphries, Brad Spellberg, Kristine M. Hujer, Emma K. Marshall, Susan D. Rudin, Federico Perez, Brigid M. Wilson, Ronald B. Wasserman, Linda Chikowski, David L. Paterson, Alejandro J. Vila, David Van Duin, Barry N. Kreiswirth, Henry F. Chambers, Vance G. Fowler, Michael R. JacobsMark E. Pulse, William J. Weiss, Robert A. Bonomo

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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 agarbased 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.

Original languageEnglish
Article numbere02243-16
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number4
DOIs
StatePublished - Apr 2017

Keywords

  • Avibactam
  • Aztreonam
  • Ceftazidime
  • Disk diffusion
  • Metallo-β-lactamases

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