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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Journal ArticleDOI
Bacteraemia with an MBL-producing Klebsiella pneumoniae: treatment and the potential role of cefiderocol heteroresistance.
Lucy S. Witt,Danielle Barrios Steed,Eileen M. Burd,Tugba Ozturk,Michelle H Davis,Sarah W. Satola,David S. Weiss,Jesse T. Jacob +7 more
TL;DR: In this article , the authors describe a patient with Klebsiella pneumoniae bloodstream infection where heteroresistance to cefiderocol may have contributed to clinical failure despite seemingly appropriate antimicrobial therapy.
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Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults
Thomas P. Lodise,J. Nicholas O'Donnell,Stephen J. Balevic,Xing Liu,Kenan Gu,Jomy M. George,Shruti M. Raja,Jeffrey T. Guptill,Smitha Zaharoff,Nyssa Schwager,Vance G. Fowler,Alison Wall,Katherine Wiegand,Henry F. Chambers +13 more
TL;DR: In this paper , the authors describe the pharmacokinetic data of CZA-avibactam and assess the associations between ATM exposures and ALT/AST elevations, and they find that ATM-CZA-ATM administration reduced total ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone.
Journal ArticleDOI
Ceftazidime-avibactam: are we safe from class A carbapenemase producers' infections?
TL;DR: In this article, a detailed review data on global ceftazidime-avibactam susceptibility, the mechanisms involved in resistance, and the molecular epidemiology of resistant isolates is presented.
Journal ArticleDOI
In-vitro susceptibility testing methods for the combination of ceftazidime-avibactam with aztreonam in metallobeta-lactamase producing organisms: Role of combination drugs in antibiotic resistance era
Priya Sreenivasan,Bhawna Sharma,Satinder Kaur,Sudesh Rana,Manisha Biswal,Pallab Ray,Archana Angrup +6 more
TL;DR: The current study depicted the usefulness of combining ceftazidime-avibactam with aztreonam against organisms producing metallo-beta-lactamases and that disk diffusion methods can be used as a method for performing in-vitro antibiotic susceptibility testing of this combination.
Journal ArticleDOI
Success of ceftazidime–avibactam and aztreonam in combination for a refractory biliary infection with recurrent bacteraemia due to blaIMP-4 carbapenemase-producing Enterobacter hormaechei subsp. oharae
Genevieve McKew,Genevieve McKew,John Merlino,John Merlino,Alicia G. Beukers,Alicia G. Beukers,Sebastian van Hal,Sebastian van Hal,Thomas Gottlieb,Thomas Gottlieb +9 more
TL;DR: This case demonstrates that phenotypic antimicrobial susceptibility testing (layered Etests for synergy), backed up by WGS, can produce results that allow tailored antimicrobial therapy in difficult infections.
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