@article{4243c08eabf74a19995897c2edbb3c96,
title = "Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?",
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.",
keywords = "Avibactam, Aztreonam, Ceftazidime, Disk diffusion, Metallo-β-lactamases",
author = "Steven Marshall and Hujer, {Andrea M.} and Rojas, {Laura J.} and Papp-Wallace, {Krisztina M.} and Humphries, {Romney M.} and Brad Spellberg and Hujer, {Kristine M.} and Marshall, {Emma K.} and Rudin, {Susan D.} and Federico Perez and Wilson, {Brigid M.} and Wasserman, {Ronald B.} and Linda Chikowski and Paterson, {David L.} and Vila, {Alejandro J.} and {Van Duin}, David and Kreiswirth, {Barry N.} and Chambers, {Henry F.} and Fowler, {Vance G.} and Jacobs, {Michael R.} and Pulse, {Mark E.} and Weiss, {William J.} and Bonomo, {Robert A.}",
note = "Funding Information: We thank C. Lascols and the SMART study for sharing isolates with R.A.B. This study was supported in part by funds and facilities provided by the Cleveland Department of Veterans Affairs, Veterans Affairs Merit Review Program award no.1I01BX001974, from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center VISN 10 to R.A.B. This work was also supported by funds from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award no. UM1AI104681, R01AI063517, R01AI072219, and R01AI100560 to R.A.B. The efficacy study in mice was supported by NIAID's Animal Models of Infectious Diseases program under contract HHSN272201500007C awarded to the University of North Texas. Funding organizations were not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, and preparation, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. Publisher Copyright: Copyright {\textcopyright} 2017 American Society for Microbiology. All Rights Reserved.",
year = "2017",
month = apr,
doi = "10.1128/AAC.02243-16",
language = "English",
volume = "61",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "4",
}