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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.

Publication ,  Journal Article
Lodise, TP; Smith, NM; O'Donnell, N; Eakin, AE; Holden, PN; Boissonneault, KR; Zhou, J; Tao, X; Bulitta, JB; Fowler, VG; Chambers, HF ...
Published in: J Antimicrob Chemother
September 1, 2020

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.

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Published In

J Antimicrob Chemother

DOI

EISSN

1460-2091

Publication Date

September 1, 2020

Volume

75

Issue

9

Start / End Page

2622 / 2632

Location

England

Related Subject Headings

  • beta-Lactamases
  • Reproducibility of Results
  • Prospective Studies
  • Microbiology
  • Microbial Sensitivity Tests
  • Humans
  • Escherichia coli
  • Enterobacteriaceae
  • Drug Combinations
  • Ceftazidime
 

Citation

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Lodise, T. P., Smith, N. M., O’Donnell, N., Eakin, A. E., Holden, P. N., Boissonneault, K. R., … Tsuji, B. T. (2020). 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. J Antimicrob Chemother, 75(9), 2622–2632. https://doi.org/10.1093/jac/dkaa197
Lodise, Thomas P., Nicolas M. Smith, Nick O’Donnell, Ann E. Eakin, Patricia N. Holden, Katie Rose Boissonneault, Jieqiang Zhou, et al. “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.J Antimicrob Chemother 75, no. 9 (September 1, 2020): 2622–32. https://doi.org/10.1093/jac/dkaa197.
Lodise TP, Smith NM, O’Donnell N, Eakin AE, Holden PN, Boissonneault KR, et al. 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. J Antimicrob Chemother. 2020 Sep 1;75(9):2622–32.
Lodise, Thomas P., et al. “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.J Antimicrob Chemother, vol. 75, no. 9, Sept. 2020, pp. 2622–32. Pubmed, doi:10.1093/jac/dkaa197.
Lodise TP, Smith NM, O’Donnell N, Eakin AE, Holden PN, Boissonneault KR, Zhou J, Tao X, Bulitta JB, Fowler VG, Chambers HF, Bonomo RA, Tsuji BT. 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. J Antimicrob Chemother. 2020 Sep 1;75(9):2622–2632.
Journal cover image

Published In

J Antimicrob Chemother

DOI

EISSN

1460-2091

Publication Date

September 1, 2020

Volume

75

Issue

9

Start / End Page

2622 / 2632

Location

England

Related Subject Headings

  • beta-Lactamases
  • Reproducibility of Results
  • Prospective Studies
  • Microbiology
  • Microbial Sensitivity Tests
  • Humans
  • Escherichia coli
  • Enterobacteriaceae
  • Drug Combinations
  • Ceftazidime