Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Laboratory for Antimicrobial Pharmacodynamics, University at Buffalo, Buffalo, NY, USA.
J Antimicrob Chemother. 2020 Sep 1;75(9):2622-2632. doi: 10.1093/jac/dkaa197.
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.
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.
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.
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.
产金属β-内酰胺酶（MBL）的肠杆菌科细菌是一个主要的公共卫生关注点。我们试图在产金属β-内酰胺酶的大肠埃希菌和肺炎克雷伯菌的中空纤维感染模型（HFIM）中确定头孢他啶/阿维巴坦与氨曲南的最佳联合治疗方案。
使用模拟人体给药方案的头孢他啶/阿维巴坦和氨曲南，在 HFIM 中研究大肠埃希菌 ARLG-1013（blaNDM-1、blaCTX-M、blaCMY、blaTEM）和肺炎克雷伯菌 ARLG-1002（blaNDM-1、blaCTXM-15、blaDHA、blaSHV、blaTEM）。实验设计旨在评估错开与同时给药、输注持续时间和氨曲南日剂量（6 g/天与 8 g/天）对细菌杀伤和耐药抑制的影响。对最有效的联合治疗方案进行了前瞻性验证实验，以确保可重复性。
错开给药（头孢他啶/阿维巴坦后给予氨曲南）的效果不如同时给药。与 30 分钟输注相比，较长的输注时间（2 小时和连续输注）也导致了更强的细菌杀伤。对于两种测试菌株，8 g/天与 6 g/天氨曲南联合方案的杀菌率更高。在前瞻性验证实验中，头孢他啶/阿维巴坦分别每 8 和 6 小时给药一次（头孢他啶/阿维巴坦 2/0.5 g 每 8 小时+氨曲南 2 g 每 6 小时），或头孢他啶/阿维巴坦与氨曲南作为连续输注，在 7 天内实现了最大的细菌杀伤和耐药抑制。
同时给予 8 g/天的氨曲南，以连续或 2 小时输注与头孢他啶/阿维巴坦联合使用，可导致完全的细菌清除和耐药抑制。需要对其他产 MBL 的革兰氏阴性病原体进一步研究这种联合治疗。这种双β-内酰胺策略的安全性也需要在 1 期临床试验中进一步研究。
