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: | Nicolas M Smith, Nick O'Donnell, Jürgen B. Bulitta, Katie Rose Boissonneault, Ann E. Eakin, Thomas P. Lodise, Xun Tao, Henry F. Chambers, Patricia N. Holden, Robert A. Bonomo, Jieqiang Zhou, Brian T. Tsuji, Vance G. Fowler |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Microbiology (medical)
Klebsiella pneumoniae Avibactam Ceftazidime Phases of clinical research Aztreonam Microbial Sensitivity Tests Pharmacology beta-Lactamases chemistry.chemical_compound Enterobacteriaceae medicine Escherichia coli Humans Pharmacology (medical) Dosing Prospective Studies Original Research biology business.industry Reproducibility of Results biochemical phenomena metabolism and nutrition biology.organism_classification Ceftazidime/avibactam bacterial infections and mycoses Anti-Bacterial Agents Regimen Drug Combinations Infectious Diseases chemistry business Azabicyclo Compounds medicine.drug |
| Zdroj: | J Antimicrob Chemother |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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