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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 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.

Authors+Show Affiliations

Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.Division of Infectious Diseases, Keck School of Medicine at USC and the Los Angeles County-USC Medical Center, Los Angeles, California, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA.Infectious Disease Doctors Medical Group, Walnut Creek, California, USA.John Muir Health, Walnut Creek, California, USA.The University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia.Instituto de Biología Molecular y Celular de Rosario Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Nacional de Rosario, Rosario, Argentina.Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina, USA.Public Health Research Institute Center, New Jersey Medical School-Rutgers University, Newark, New Jersey, USA.University of California, San Francisco, and San Francisco General Hospital, San Francisco, California, USA.Division of Infectious Diseases, Department of Medicine, and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA.Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.University of North Texas Health Science Center, Fort Worth, Texas, USA.University of North Texas Health Science Center, Fort Worth, Texas, USA.Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA robert.bonomo@va.gov. Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. Departments of Pharmacology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28167541

Citation

Marshall, Steven, et al. "Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred By Metallo-β-Lactamases in Enterobacteriaceae?" Antimicrobial Agents and Chemotherapy, vol. 61, no. 4, 2017.
Marshall S, Hujer AM, Rojas LJ, et al. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017;61(4).
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), doi:10.1128/AAC.02243-16.
Marshall S, et al. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred By Metallo-β-Lactamases in Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61(4) PubMed PMID: 28167541.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? AU - Marshall,Steven, AU - Hujer,Andrea M, AU - Rojas,Laura J, AU - Papp-Wallace,Krisztina M, AU - Humphries,Romney M, AU - Spellberg,Brad, AU - Hujer,Kristine M, AU - Marshall,Emma K, AU - Rudin,Susan D, AU - Perez,Federico, AU - Wilson,Brigid M, AU - Wasserman,Ronald B, AU - Chikowski,Linda, AU - Paterson,David L, AU - Vila,Alejandro J, AU - van Duin,David, AU - Kreiswirth,Barry N, AU - Chambers,Henry F, AU - Fowler,Vance G,Jr AU - Jacobs,Michael R, AU - Pulse,Mark E, AU - Weiss,William J, AU - Bonomo,Robert A, Y1 - 2017/03/24/ PY - 2016/10/19/received PY - 2017/01/22/accepted PY - 2017/2/9/pubmed PY - 2017/10/11/medline PY - 2017/2/8/entrez KW - avibactam KW - aztreonam KW - ceftazidime KW - disk diffusion KW - metallo-β-lactamases JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 61 IS - 4 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/28167541/Can_Ceftazidime_Avibactam_and_Aztreonam_Overcome_β_Lactam_Resistance_Conferred_by_Metallo_β_Lactamases_in_Enterobacteriaceae L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=28167541 DB - PRIME DP - Unbound Medicine ER -