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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, Jr, Vance G ; Jacobs, Michael R ; Pulse, Mark E ; Weiss, William J ; Bonomo, Robert A

Antimicrobial agents and chemotherapy, 2017-04, Vol.61 (4) [Periódico revisado por pares]

United States: American Society for Microbiology

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Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?
Autor: 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, Jr, Vance G ; Jacobs, Michael R ; Pulse, Mark E ; Weiss, William J ; Bonomo, Robert A
Assuntos: Animals ; Anti-Bacterial Agents ; Anti-Bacterial Agents - pharmacology ; Azabicyclo Compounds ; Azabicyclo Compounds - pharmacology ; Aztreonam ; Aztreonam - pharmacology ; beta-Lactam Resistance - drug effects ; beta-Lactam Resistance - genetics ; beta-Lactamases - genetics ; beta-Lactamases - metabolism ; Ceftazidime ; Ceftazidime - pharmacology ; Colony Count, Microbial ; Cyclophosphamide ; Drug Administration Schedule ; Drug Therapy, Combination ; Enterobacteriaceae ; Enterobacteriaceae - drug effects ; Enterobacteriaceae - enzymology ; Enterobacteriaceae - genetics ; Enterobacteriaceae - growth & development ; Enterobacteriaceae Infections ; Enterobacteriaceae Infections - drug therapy ; Enterobacteriaceae Infections - microbiology ; Female ; Gene Expression ; Humans ; Klebsiella Infections - complications ; Klebsiella Infections - drug therapy ; Klebsiella Infections - microbiology ; Klebsiella pneumoniae - drug effects ; Klebsiella pneumoniae - enzymology ; Klebsiella pneumoniae - genetics ; Klebsiella pneumoniae - growth & development ; Mice ; Microbial Sensitivity Tests ; Neutropenia - chemically induced ; Neutropenia - complications ; Neutropenia - drug therapy ; Neutropenia - microbiology ; Plasmids - chemistry ; Plasmids - metabolism ; Soft Tissue Infections - complications ; Soft Tissue Infections - drug therapy ; Soft Tissue Infections - microbiology ; Susceptibility ; Thigh
É parte de: Antimicrobial agents and chemotherapy, 2017-04, Vol.61 (4)
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Citation Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman RB, Chikowski L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Chambers HF, Fowler VG, Jr, Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA. 2017. Can ceftazidime-avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae? Antimicrob Agents Chemother 61:e02243-16. https://doi.org/10.1128/AAC.02243-16.
S.M. and A.M.H. contributed equally to this article.
Descrição: 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 efficacy of a unique combination of CAZ-AVI and ATM against 21 representative isolates with a complex molecular background that included , , , , , and combinations thereof. Time-kill assays were conducted, and the 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 activity of CAZ-AVI in combination with ATM against diverse 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-log -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-log -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 .
Editor: United States: American Society for Microbiology
Idioma: Inglês

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Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

United States: American Society for Microbiology

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