Igarashi Yuki, Taguchi Kazuaki, Enoki Yuki, Chuang Victor Tuan Giam, Matsumoto Kazuaki
Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Discipline of Pharmacy, Curtin Medical School, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, WA 6845, Australia.
J Antimicrob Chemother. 2025 Feb 3;80(2):547-553. doi: 10.1093/jac/dkae443.
Nacubactam (NAC), a new diazabicyclooctane β-lactamase inhibitor, is being developed for use together with aztreonam (AZT) and cefepime (CFPM). However, the effective clinical dosages of AZT/NAC and CFPM/NAC have not yet been established. We have previously shown that free time above instantaneous MIC (fT > MICi) is a valuable pharmacokinetic (PK)/pharmacodynamic parameter for β-lactam (BL)/NAC in a mouse thigh infection model.
This study simulated the fT > MICi (%) for AZT/NAC and CFPM/NAC against carbapenemase-producing Enterobacterales (CPE) with different MIC in humans to estimate the clinical efficacy at practically achievable combination doses of AZT/NAC and CFPM/NAC.
Using previously reported PK parameters of each drug in humans and chequerboard MIC data, we calculated the fT > MICi (%) for AZT/NAC and CFPM/NAC in 10 000 simulated patients to predict the percentages of target attainment of bacteriostatic and bactericidal efficacies at various combined doses.
The results predicted that both BL/NAC combinations could achieve 100% 2 log10-kill against CPE strains at the lowest combination dose (0.5 g/0.5 g q8h). Additionally, in MIC studies examining BLs/NAC at a 1:1 ratio, the dosage regimen for strains with MICcomb ≤ 1 mg/L was expected to offer 100% bactericidal efficacy (2 log10-kill) at 0.5 g/0.5 g q8h or higher doses. For strains with 1 mg/L < MICcomb ≤ 16 mg/L, BLs/NAC at a 2 g/2 g q8h was predicted to produce bactericidal efficacy (1 log10-kill). At MICcomb = 32 mg/L, some bacteriostatic effect was expected at high BL doses.
AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages.
那西巴坦（NAC）是一种新型二氮杂双环辛烷β-内酰胺酶抑制剂，正与氨曲南（AZT）和头孢吡肟（CFPM）联合开发使用。然而，AZT/NAC和CFPM/NAC的有效临床剂量尚未确定。我们之前已经表明，在小鼠大腿感染模型中，高于瞬时最低抑菌浓度的自由时间（fT＞MICi）是β-内酰胺（BL）/NAC的一个有价值的药代动力学（PK）/药效学参数。
本研究模拟了AZT/NAC和CFPM/NAC对人类中不同最低抑菌浓度（MIC）的产碳青霉烯酶肠杆菌科细菌（CPE）的fT＞MICi（%），以评估AZT/NAC和CFPM/NAC在实际可达到的联合剂量下的临床疗效。
利用先前报道的每种药物在人体中的PK参数和棋盘法MIC数据，我们计算了10000名模拟患者中AZT/NAC和CFPM/NAC的fT＞MICi（%），以预测不同联合剂量下抑菌和杀菌疗效的达标百分比。
结果预测，两种BL/NAC联合用药在最低联合剂量（0.5g/0.5g q8h）时对CPE菌株均可实现100%的2 log10杀灭率。此外，在以1:1比例研究BLs/NAC的MIC研究中，对于MICcomb≤1mg/L的菌株，预计在0.5g/0.5g q8h或更高剂量时可提供100%的杀菌疗效（2 log10杀灭率）。对于1mg/L＜MICcomb≤16mg/L的菌株，预计2g/2g q8h的BLs/NAC可产生杀菌疗效（1 log10杀灭率）。在MICcomb = 32mg/L时，高BL剂量下预计会有一些抑菌作用。
AZT/NAC和CFPM/NAC在实际可达到的剂量下对CPE具有杀菌作用。
