Thomas P Lodise1, Nicolas M Smith2, Nick O'Donnell1, Ann E Eakin3, Patricia N Holden2, Katie Rose Boissonneault2, Jieqiang Zhou4, Xun Tao4, Jürgen B Bulitta4, Vance G Fowler5,6, Henry F Chambers7, Robert A Bonomo8,9, Brian T Tsuji2. 1. Albany College of Pharmacy and Health Sciences, Albany, NY, USA. 2. Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA. 3. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. 4. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, FL, USA. 5. Division of Infectious Diseases, Duke University, Durham, NC, USA. 6. Duke Clinical Research Institute, Duke University, Durham, NC, USA. 7. University of California, San Francisco, and San Francisco General Hospital, San Francisco, CA, USA. 8. 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. 9. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, USA.
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 (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.
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.
Authors: Nicholas M Smith; Katie Rose Boissonneault; Liang Chen; Vidmantas Petraitis; Ruta Petraitiene; Xun Tao; Jieqiang Zhou; Yinzhi Lang; Povilas Kavaliauskas; Zackery P Bulman; Patricia N Holden; Raymond Cha; Jürgen B Bulitta; Barry N Kreiswirth; Thomas J Walsh; Brian T Tsuji Journal: Antimicrob Agents Chemother Date: 2022-08-04 Impact factor: 5.938
Authors: Kamrul Islam; Fekade B Sime; Steven C Wallis; Michelle J Bauer; Saiyuri Naicker; Hayoung Won; Hosam M Zowawi; Md Abu Choudhury; Tahmina Shirin; Zakir H Habib; Patrick N A Harris; Meerjady S Flora; Jason A Roberts Journal: Antimicrob Agents Chemother Date: 2022-08-04 Impact factor: 5.938