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

• Autores: 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 Jose; Van Duin, David; Kreiswirth, Barry N.; Chambers, Henry F.; Fowler Jr., Vance G.; Jacobs, Michael R.; Pulse, Mark E.; Weiss, William J.; Bonomo, Robert A.
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: AVIBACTAM; AZTREONAM; CEFTAZIDIME; DISK DIFFUSION; METALLO-β-LACTAMASES
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Marshall, Steven. Veterans Affairs Medical Center; Estados Unidos
Fil: Hujer, Andrea M.. Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos
Fil: Rojas, Laura J.. Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos
Fil: Papp Wallace, Krisztina M.. Veterans Affairs Medical Center; Estados Unidos
Fil: Humphries, Romney M.. University of California at Los Angeles. School of Medicine; Estados Unidos
Fil: Spellberg, Brad. University of Southern California; Estados Unidos
Fil: Hujer, Kristine M.. Case Western Reserve University; Estados Unidos. Veterans Affairs Medical Center; Estados Unidos
Fil: Marshall, Emma K.. Veterans Affairs Medical Center; Estados Unidos
Fil: Rudin, Susan D.. Case Western Reserve University; Estados Unidos. Veterans Affairs Medical Center; Estados Unidos
Fil: Perez, Federico. Case Western Reserve University; Estados Unidos. Veterans Affairs Medical Center; Estados Unidos
Fil: Wilson, Brigid M.. Veterans Affairs Medical Center; Estados Unidos
Fil: Wasserman, Ronald B.. Infectious Disease Doctors Medical Group; Estados Unidos
Fil: Chikowski, Linda. John Muir Health; Estados Unidos
Fil: Paterson, David L.. University of Queensland; Australia
Fil: Vila, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Van Duin, David. University of North Carolina; Estados Unidos
Fil: Kreiswirth, Barry N.. Rutgers University. New Jersey Medical School; Estados Unidos
Fil: Chambers, Henry F.. University of California; Estados Unidos. San Francisco General Hospital; Estados Unidos
Fil: Fowler Jr., Vance G.. University of Duke; Estados Unidos
Fil: Jacobs, Michael R.. Case Western Reserve University; Estados Unidos
Fil: Pulse, Mark E.. University of North Texas; Estados Unidos
Fil: Weiss, William J.. University of North Texas; Estados Unidos
Fil: Bonomo, Robert A.. Case Western Reserve University; Estados Unidos. Veterans Affairs Medical Center; Estados Unidos