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

United States

2017-03-01T18:44:01Z

2017-03-01T18:44:01Z

2017-02-06

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram negative bacteria, we tested the effectiveness 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 plus ATM (8 μg/ml) added, compared to the CAZ/AVI alone group. In the murine neutropenic thigh infection model, an almost 4 log10 reduction in CFUs was noted at 24 h for CAZ/AVI (32 mg/kg q8h) plus ATM (32 mg/kg q8h) vs. CAZ/AVI (32 mg/kg q8h) alone. The data presented herein, requires us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

https://www.ncbi.nlm.nih.gov/pubmed/28167541

AAC.02243-16

1098-6596

https://hdl.handle.net/10161/13737

eng

American Society for Microbiology

Antimicrob Agents Chemother

10.1128/AAC.02243-16

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

Journal article

Fowler, Vance G|0000-0002-8048-0897

https://www.ncbi.nlm.nih.gov/pubmed/28167541

Basic Science Departments

Clinical Science Departments

Duke

Duke Clinical Research Institute

Institutes and Centers

Medicine

Medicine, Infectious Diseases

Molecular Genetics and Microbiology

School of Medicine

Published online