Hayashi Yukitaka, Takahashi Mishu, Sasaki Moe, Suzuki Kenta, Mizukami Yuki, Liu Xiaoxi, Enoki Yuki, Taguchi Kazuaki, Yamaguchi Tetsuo, Tateda Kazuhiro, Matsumoto Kazuaki
Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Department of Microbiology and Infectious Diseases, Toho University School of Medicine, Tokyo, Japan.
J Antimicrob Chemother. 2025 Aug 1;80(8):2092-2099. doi: 10.1093/jac/dkaf175.
This study clarified the target values of VAN against Enterococcus faecium using pharmacokinetics/pharmacodynamics (PK/PD) analysis and compared a downsized hollow fibre infection model (HFIM) with a conventional HFIM.
VAN was administered subcutaneously and blood concentrations were measured to calculate the PK parameters. PD studies were performed in an infected mouse model by administering VAN at doses ranging from 25 to 400 mg/kg based on PK parameters. PK/PD parameters correlated with antimicrobial efficacy were determined, and a target value of 2 log10 kills was calculated. The efficacy of VAN against E. faecium was evaluated by reproducing the VAN PK in the plasma at doses that achieved the target value using conventional and novel downsized HFIMs.
PK/PD analysis showed that fAUC/minimum inhibitory concentration (MIC) demonstrated the most relevant index, with a target value of 249 to achieve a 2 log10 kill. Blood concentrations of 750 mg VAN every 12 h (equivalent to 260 fAUC/MIC) were simulated well with both HFIMs. Changes in E. faecium caused by continuous exposure to VAN resulted in a reduction in bacterial counts by ∼6.0 log10 kill 168 h after the start of treatment in both models. Downsizing reduced the extracapillary space volume, circulating medium, amount of drugs used and infectious waste. The total cost of the downsized cartridge system was approximately half that of the conventional model system.
We established a downsized HFIM and demonstrated its viability as a cost-effective and environmentally sustainable in vitro PK/PD. The findings highlighted its potential as a future PK/PD analysis standard.
本研究通过药代动力学/药效学（PK/PD）分析阐明了万古霉素（VAN）针对屎肠球菌的目标值，并将小型化中空纤维感染模型（HFIM）与传统HFIM进行了比较。
皮下注射VAN并测量血药浓度以计算PK参数。根据PK参数，在感染小鼠模型中以25至400mg/kg的剂量给予VAN进行PD研究。确定与抗菌疗效相关的PK/PD参数，并计算出2 log10杀灭的目标值。通过使用传统和新型小型化HFIMs在达到目标值的剂量下重现血浆中VAN的PK，评估VAN对屎肠球菌的疗效。
PK/PD分析表明，fAUC/最低抑菌浓度（MIC）显示出最相关的指标，目标值为249以实现2 log10杀灭。两种HFIMs均能很好地模拟每12小时给予750mg VAN的血药浓度（相当于260 fAUC/MIC）。在两个模型中，持续暴露于VAN导致的屎肠球菌变化在治疗开始后168小时细菌计数减少约6.0 log10杀灭。小型化减少了毛细血管外空间体积、循环介质、药物使用量和感染性废物。小型化盒式系统的总成本约为传统模型系统的一半。
我们建立了一种小型化HFIM，并证明了其作为一种具有成本效益和环境可持续性的体外PK/PD的可行性。研究结果突出了其作为未来PK/PD分析标准的潜力。
