Li Xingang, Wang Xiaoping, Wu Yuanxing, Sun Shusen, Chen Kai, Lu Yanxia, Wang Qiang, Zhao Zhigang
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China; Precision Medicine Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
Department of Pharmacy, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Xian, 710003, China.
Diagn Microbiol Infect Dis. 2019 Apr;93(4):386-392. doi: 10.1016/j.diagmicrobio.2018.08.003. Epub 2018 Aug 17.
Combined intravenous and local intrathecal administration of meropenem in patients after craniotomy is widely used to treat intracranial infections. However, the optimal dosing regimen of meropenem has not been investigated, posing a risk to treatment efficacy. We aimed to identify significant factors associated with inter-individual variability in cerebrospinal fluid (CSF) pharmacokinetics of meropenem and to evaluate potential intravenous and intrathecal meropenem dosing regimens for the treatment of patients with intracranial infections. After the diagnosis of intracranial infection, 15 patients with an indwelling drain tube received intravenous and intrathecal administration of meropenem. Blood and cerebrospinal fluid (CSF) samples were obtained at the scheduled time to measure meropenem concentration. Plasma and CSF concentration-time data were fit simultaneously using a nonlinear mixed-effects modeling approach. A 3-compartmental model was selected to characterize the in vivo behavior of meropenem. Through population modeling, multiple covariates were tested about their impact on the meropenem pharmacokinetics. Considering CSF outflow via drain tube leading to a drug loss, the drug clearance in CSF (CL) was added to describe this drug loss. The covariate selection indicated that the drainage volume (mL/d) had a significant positive correlation with CL. Bootstrap and visual predictive check suggested a robust and reliable pharmacokinetic model was structured. The established final population model was useful to apply with simulation to identify meropenem dosing regimens for the treatment of patients with intracranial infections. With the goal of CSF concentrations exceeding the minimum inhibitory concentration during the therapy, we created a simple to use dosage regimen table to guide clinicians with drug dosing.
开颅术后患者联合静脉及鞘内注射美罗培南广泛用于治疗颅内感染。然而，美罗培南的最佳给药方案尚未得到研究，这对治疗效果构成风险。我们旨在确定与美罗培南脑脊液（CSF）药代动力学个体间差异相关的显著因素，并评估治疗颅内感染患者的潜在静脉及鞘内美罗培南给药方案。颅内感染诊断后，15例留置引流管的患者接受了美罗培南的静脉及鞘内给药。在预定时间采集血液和脑脊液（CSF）样本以测定美罗培南浓度。采用非线性混合效应建模方法同时拟合血浆和CSF浓度-时间数据。选择三室模型来表征美罗培南的体内行为。通过群体建模，测试了多个协变量对美罗培南药代动力学的影响。考虑到CSF通过引流管流出导致药物损失，增加了CSF中的药物清除率（CL）来描述这种药物损失。协变量选择表明引流量（mL/d）与CL呈显著正相关。自举法和可视化预测检查表明构建了一个稳健可靠的药代动力学模型。所建立的最终群体模型可用于模拟，以确定治疗颅内感染患者的美罗培南给药方案。以治疗期间CSF浓度超过最低抑菌浓度为目标，我们创建了一个易于使用的给药方案表来指导临床医生给药。
