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. (28th May 2020)

• Record Type: Journal Article
• Authors: Lodise, Thomas P; Smith, Nicolas M; O'Donnell, Nick; Eakin, Ann E; Holden, Patricia N; Boissonneault, Katie Rose; Zhou, Jieqiang; Tao, Xun; Bulitta, Jürgen B; Fowler, Vance G; Chambers, Henry F; Bonomo, Robert A; Tsuji, Brian T
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 75:Number 9(2020)
• Page Start: 2622
• Page End: 2632
• Publication Date: 2020-05-28
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkaa197
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: 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 ( bla NDM-1, bla CTX-M, bla CMY, bla TEM ) and K. pneumoniae ARLG-1002 ( bla NDM-1, bla CTXM-15, bla DHA, bla SHV, bla TEM ) 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.