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. Jacobs & 3 others Mark E. Pulse, William J. Weiss, Robert A. Bonomo

Research output: Research - peer-reviewArticle

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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.

LanguageEnglish (US)
Article numbere02243-16
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

beta-Lactam Resistance
Aztreonam
Enterobacteriaceae
beta-Lactamases
ceftazidime drug combination avibactam
Infection
Thigh
In Vitro Techniques
Inosine Monophosphate
Carbapenems
Gram-Negative Bacteria
Agar
Therapeutics
Asp(5)-oxytocin

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

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? Antimicrobial Agents and Chemotherapy, 61(4), [e02243-16]. DOI: 10.1128/AAC.02243-16

Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? / Marshall, Steven; Hujer, Andrea M.; Rojas, Laura J.; Papp-Wallace, Krisztina M.; Humphries, Romney M.; Spellberg, Brad; Hujer, Kristine M.; Marshall, Emma K.; Rudin, Susan D.; Perez, Federico; Wilson, Brigid M.; Wasserman, Ronald B.; Chikowski, Linda; Paterson, David L.; Vila, Alejandro J.; Van Duin, David; Kreiswirth, Barry N.; Chambers, Henry F.; Fowler, Vance G.; Jacobs, Michael R.; Pulse, Mark E.; Weiss, William J.; Bonomo, Robert A.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 4, e02243-16, 01.04.2017.

Research output: Research - peer-reviewArticle

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 2017, 'Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?' Antimicrobial Agents and Chemotherapy, vol 61, no. 4, e02243-16. DOI: 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? Antimicrobial Agents and Chemotherapy. 2017 Apr 1;61(4). e02243-16. Available from, DOI: 10.1128/AAC.02243-16
Marshall, Steven ; Hujer, Andrea M. ; Rojas, Laura J. ; Papp-Wallace, Krisztina M. ; Humphries, Romney M. ; Spellberg, Brad ; Hujer, Kristine M. ; Marshall, Emma K. ; Rudin, Susan D. ; Perez, Federico ; Wilson, Brigid M. ; Wasserman, Ronald B. ; Chikowski, Linda ; Paterson, David L. ; Vila, Alejandro J. ; Van Duin, David ; Kreiswirth, Barry N. ; Chambers, Henry F. ; Fowler, Vance G. ; Jacobs, Michael R. ; Pulse, Mark E. ; Weiss, William J. ; Bonomo, Robert A./ Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 4.
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