Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?
Steven H. Marshall,Andrea M. Hujer,Andrea M. Hujer,Laura J. Rojas,Laura J. Rojas,Krisztina M. Papp-Wallace,Romney M. Humphries,Brad Spellberg,Kristine M. Hujer,Kristine M. Hujer,Emma K. Marshall,Susan D. Rudin,Susan D. Rudin,Federico Perez,Federico Perez,Brigid Wilson,Ronald B. Wasserman,Linda Chikowski,David L. Paterson,Alejandro J. Vila,David van Duin,Barry N. Kreiswirth,Henry F. Chambers,Vance G. Fowler,Michael R. Jacobs,Mark Pulse,William J. Weiss,Robert A. Bonomo +27 more
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TLDR
In vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated, and the data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteria.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.read more
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Clinical features and outcomes of bloodstream infections caused by New Delhi Metallo-β-lactamase-producing Enterobacterales during a regional outbreak
Marco Falcone,Giusy Tiseo,Alberto Antonelli,Cesira Giordano,Vincenzo Di Pilato,Pietro Bertolucci,Eva Maria Parisio,Alessandro Leonildi,Noemi Aiezza,Ilaria Baccani,Enrico Tagliaferri,Lorenzo Righi,Silvia Forni,S. Sani,Maria Teresa Mechi,Filippo Pieralli,Simona Barnini,Gian Maria Rossolini,Fsrancesco Menichetti +18 more
TL;DR: Ceftazidime-avibactam plus aztreonam may represent a feasible therapeutic option for New Delhi metallo-β-lactamase bacteremia.
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TL;DR: Overall, the new β-lactamase inhibitor combinations have infused new life into the search for new antibacterial agents to treat multidrug-resistant bacteria.
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Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Children.
TL;DR: A framework for antibiotic treatment of CRE infections in children is provided, highlighting relevant microbiologic considerations and summarizing available data related to the evaluation of FDA-approved antibiotics (as of September 2019) with CRE activity, including carbapenems, ceftazidime-avibactam, meropenem-vaborbactam and plazomicin.
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Mechanisms of antimicrobial resistance among hospital-associated pathogens
TL;DR: Clinicians making treatment decisions based on the molecular basis of resistance may design therapeutic strategies that include de-escalation of broad spectrum antimicrobial usage, more focused therapies or combination therapies, likely to improve patient outcomes and decrease the risk of resistance in hospital settings.
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Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review.
TL;DR: Ceftazidime–avibactam has a favorable pharmacokinetic profile for severe infections and highly active against carbapenemases of KPC-2 type and the best pharmacodynamic profile is ƒT > MIC, validated in an animal model of soft tissue infection.
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Journal ArticleDOI
New Delhi Metallo-β-Lactamase-Producing Carbapenem-Resistant Escherichia coli Associated With Exposure to Duodenoscopes
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