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

Publication ,  Journal Article
Marshall, S; Hujer, AM; Rojas, LJ; Papp-Wallace, KM; Humphries, RM; Spellberg, B; Hujer, KM; Marshall, EK; Rudin, SD; Perez, F; Wilson, BM ...
Published in: Antimicrob Agents Chemother
April 2017

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.

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Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 2017

Volume

61

Issue

4

Location

United States

Related Subject Headings

  • beta-Lactamases
  • beta-Lactam Resistance
  • Thigh
  • Soft Tissue Infections
  • Plasmids
  • Neutropenia
  • Microbiology
  • Microbial Sensitivity Tests
  • Mice
  • Klebsiella pneumoniae
 

Citation

APA
Chicago
ICMJE
MLA
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Marshall, S., Hujer, A. M., Rojas, L. J., Papp-Wallace, K. M., Humphries, R. M., Spellberg, B., … Bonomo, R. A. (2017). Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? Antimicrob Agents Chemother, 61(4). https://doi.org/10.1128/AAC.02243-16
Marshall, Steven, Andrea M. Hujer, Laura J. Rojas, Krisztina M. Papp-Wallace, Romney M. Humphries, Brad Spellberg, Kristine M. Hujer, et al. “Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?Antimicrob Agents Chemother 61, no. 4 (April 2017). https://doi.org/10.1128/AAC.02243-16.
Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, et al. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017 Apr;61(4).
Marshall, Steven, et al. “Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?Antimicrob Agents Chemother, vol. 61, no. 4, Apr. 2017. Pubmed, doi:10.1128/AAC.02243-16.
Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman RB, Chikowski L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Chambers HF, Fowler VG, Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017 Apr;61(4).

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 2017

Volume

61

Issue

4

Location

United States

Related Subject Headings

  • beta-Lactamases
  • beta-Lactam Resistance
  • Thigh
  • Soft Tissue Infections
  • Plasmids
  • Neutropenia
  • Microbiology
  • Microbial Sensitivity Tests
  • Mice
  • Klebsiella pneumoniae