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. and Bonomo, Robert A. (2017) Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?. Antimicrobial Agents and Chemotherapy, 61 4: . doi:10.1128/AAC.02243-16

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Author 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.
Title Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?
Formatted title
Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
0066-4804
Publication date 2017-04-01
Sub-type Article (original research)
DOI 10.1128/AAC.02243-16
Open Access Status File (Publisher version)
Volume 61
Issue 4
Total pages 9
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
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 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.
Formatted 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.
Keyword Avibactam
Aztreonam
Ceftazidime
Disk diffusion
Metallo-β-lactamases
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 AI100560
HHSN272201500007C
UM1 AI104681
R01 AI072219
R01 AI063517
I01 BX001974
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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