验证一种新型每周三次的血液透析后头孢曲松方案在感染的澳大利亚原住民患者中的应用：一项群体药代动力学研究。
Validating a novel three-times-weekly post-hemodialysis ceftriaxone regimen in infected Indigenous Australian patients-a population pharmacokinetic study.
机构信息
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.
出版信息
J Antimicrob Chemother. 2023 Aug 2;78(8):1963-1973. doi: 10.1093/jac/dkad190.
OBJECTIVES
To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis.
METHODS
A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma samples were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic/pharmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total) ≥100 mg/L] were simulated for various dosing strategies.
RESULTS
Total and unbound concentrations were measured in 122 plasma samples collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations >5 µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by >10-fold during dialysis.
CONCLUSIONS
A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended.
目的
描述需要血液透析的澳大利亚原住民患者中，每周三次透析后给予 2g 头孢曲松的总人群和游离人群药代动力学。
方法
在澳大利亚一家偏远医院的透析单元进行了一项药代动力学研究。纳入了接受每周三次 2g 头孢曲松治疗的间歇性血液透析（使用高通量透析器）的成年原住民患者。在两个给药间隔期间连续采集血浆样本，并使用经过验证的方法进行检测。使用 R 中的 Pmetrics 进行群体药代动力学分析和蒙特卡罗模拟。模拟了各种给药方案下的药代动力学/药效学目标达标率（游离谷浓度≥1mg/L）和毒性[总浓度（总）≥100mg/L]。
结果
从 16 名患者（13 名女性）的 122 个血浆样本中测量了总浓度和游离浓度，患者的中位年龄为 57 岁。包括蛋白结合的两室模型能够很好地描述数据，血清胆红素浓度与头孢曲松清除率呈负相关。每周三次 2g 方案在血清胆红素为 5μmol/L 时，维持游离头孢曲松浓度≥1mg/L 的概率为 98%。在胆红素浓度>5μmol/L 的患者中观察到头孢曲松的蓄积增加。与每日一次方案相比，每周三次方案达到毒性暴露的可能性较小。透析期间头孢曲松清除率增加了 10 倍以上。
结论
对于 MIC≤1mg/L 的细菌感染，可推荐每周三次透析后给予 2g 头孢曲松的新方案。对于血清胆红素≥10μmol/L 的患者，建议给予每周三次 1g 头孢曲松的方案。不建议在透析期间给予头孢曲松。
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