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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Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplantation: Management Principles
TL;DR: The epidemiology of CRE in SOT is reviewed and in vitro activity data are supportive for several agents providing hope for improved outcomes with these typically difficult-to-treat and highly morbid infections in transplant recipients.
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Safety and Efficacy of a Phage, kpssk3, in an in vivo Model of Carbapenem-Resistant Hypermucoviscous Klebsiella pneumoniae Bacteremia
Yunlong Shi,Yuan Peng,Yixin Zhang,Yu Chen,Cheng Zhang,Xiaoqiang Luo,Yajie Chen,Zhiqiang Yuan,Jing Chen,Yali Gong +9 more
TL;DR: In this article, the authors evaluated the therapeutic effects and safety of kpssk3, a previously isolated phage infecting carbapenem-resistant hypermucoviscous Klebsiella pneumoniae (CR-HMKP), were evaluated in a mouse model of systemic HMKP infection.
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Review of Clinical Pharmacokinetics of Avibactam, A Newly Approved non-β lactam β-lactamase Inhibitor Drug, In Combination Use With Ceftazidime
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The threat of multidrug-resistant/extensively drug-resistant Gram-negative respiratory infections: another pandemic
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Investigation of mechanisms responsible for decreased susceptibility of aztreonam/avibactam activity in clinical isolates of Enterobacterales collected in Europe, Asia and Latin America in 2019.
Rodrigo E. Mendes,Timothy B Doyle,Jennifer M. Streit,Francis F. Arhin,Helio S. Sader,Mariana Castanheira +5 more
TL;DR: The combination aztreonam/avibactam is currently under Phase 3 trials for the treatment of serious infections caused by Gram-negative bacteria including those with MBLs.
References
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Journal Article
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Jesse T. Jacob,Eili Y. Klein,Ramanan Laxminarayan,Zintars G. Beldavs,Ruth Lynfield,Alexander J. Kallen,Philip Ricks,Jonathan R. Edwards,Arjun Srinivasan,Scott K. Fridkin,J. Kamile Rasheed,David Lonsway,Sandie Bulens,Rosa Herrera,L. Clifford McDonald,Jean B. Patel,Brandi Limbago,Michael Bell,Denise M. Cardo +18 more
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Journal ArticleDOI
Ceftazidime/Avibactam and Ceftolozane/Tazobactam: Second-generation β-Lactam/β-Lactamase Inhibitor Combinations.
David van Duin,Robert A. Bonomo +1 more
TL;DR: Ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations and may prove useful in the treatment of MDR GNB infections.
Journal ArticleDOI
New Delhi Metallo-β-Lactamase-Producing Carbapenem-Resistant Escherichia coli Associated With Exposure to Duodenoscopes
Lauren Epstein,Jennifer C. Hunter,M. Allison Arwady,M. Allison Arwady,Victoria Tsai,Linda Stein,Marguerite Gribogiannis,Mabel Frias,Alice Guh,Alison S. Laufer,Stephanie R. Black,Massimo Pacilli,Heather Moulton-Meissner,J. Kamile Rasheed,Johannetsy J. Avillan,Brandon Kitchel,Brandi Limbago,Duncan MacCannell,David Lonsway,Judith Noble-Wang,Judith Conway,Craig Conover,Michael O. Vernon,Alexander J. Kallen +23 more
TL;DR: Exposure to duodenoscopes with bacterial contamination was associated with apparent transmission of NDM-producing E coli among patients at 1 hospital and facilities should be aware of the potential for transmission of bacteria including antimicrobial-resistant organisms via this route.
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New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World
TL;DR: This “renaissance” of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.
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