Determining the optimal dosing of a novel combination regimen of ceftazidime/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model.

Autor:	Lodise TP; Albany College of Pharmacy and Health Sciences, Albany, NY, USA., Smith NM; Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA., O'Donnell N; Albany College of Pharmacy and Health Sciences, Albany, NY, USA., Eakin AE; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA., Holden PN; Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA., Boissonneault KR; Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA., Zhou J; Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL, USA., Tao X; Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL, USA., Bulitta JB; Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL, USA., Fowler VG; Division of Infectious Diseases, Duke University, Durham, NC, USA.; Duke Clinical Research Institute, Duke University, Durham, NC, USA., Chambers HF; University of California, San Francisco, and San Francisco General Hospital, San Francisco, CA, USA., Bonomo RA; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA; Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, USA., Tsuji BT; Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2020 Sep 01; Vol. 75 (9), pp. 2622-2632.
DOI:	10.1093/jac/dkaa197
Abstrakt:	Background: MBL-producing strains of Enterobacteriaceae are a major public health concern. We sought to define optimal combination regimens of ceftazidime/avibactam with aztreonam in a hollow-fibre infection model (HFIM) of MBL-producing strains of Escherichia coli and Klebsiella pneumoniae. Methods: E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied in the HFIM using simulated human dosing regimens of ceftazidime/avibactam and aztreonam. Experiments were designed to evaluate the effect of staggered versus simultaneous administration, infusion duration and aztreonam daily dose (6 g/day versus 8 g/day) on bacterial killing and resistance suppression. Prospective validation experiments for the most active combination regimens were performed in triplicate to ensure reproducibility. Results: Staggered administration of the combination (ceftazidime/avibactam followed by aztreonam) was found to be inferior to simultaneous administration. Longer infusion durations (2 h and continuous infusion) also resulted in enhanced bacterial killing relative to 30 min infusions. The rate of killing was more pronounced with 8 g/day versus 6 g/day aztreonam combination regimens for both tested strains. In the prospective validation experiments, ceftazidime/avibactam with aztreonam dosed every 8 and 6 h, respectively (ceftazidime/avibactam 2/0.5 g every 8 h + aztreonam 2 g every 6 h), or ceftazidime/avibactam with aztreonam as continuous infusions resulted in maximal bacterial killing and resistance suppression over 7 days. Conclusions: Simultaneous administration of aztreonam 8 g/day given as a continuous or 2 h infusion with ceftazidime/avibactam resulted in complete bacterial eradication and resistance suppression. Further study of this combination is needed with additional MBL-producing Gram-negative pathogens. The safety of this double β-lactam strategy also warrants further study in Phase 1 clinical trials. (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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