Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety
Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety
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DOI：
10.1128/aac.00605-19
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Pea, Federico
中科院分区：
文献类型：
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作者：
Crass, Ryan L.;Cojutti, Pier Giorgio;Pea, Federico
尽管有证据表明肾损害患者暴露量增加和骨髓抑制，但所有患者均接受固定剂量的利奈唑胺给药。这些研究的目的是评估标准剂量利奈唑胺治疗肾损害患者的血小板减少症风险，并确定替代给药策略。在研究1中，回顾性审查了接受利奈唑胺≥ 10天的成人患者的数据，以确定伴和不伴肾损害患者中血小板减少症的频率。使用考克斯比例风险模型进行至事件发生时间分析。在研究2中，使用常规治疗药物监测（TDM）期间获得的利奈唑胺浓度独立数据集，采用群体药代动力学建模构建协变量结构模型。进行Monte Carlo模拟，以确定在不同肾功能组中最大限度达到治疗谷浓度（2 - 8 mg/L）的利奈唑胺给药方案。毒性分析（研究1）包括341例患者，其中133例（39.0%）有肾损害。血小板减少在肾损害患者中发生率更高（42.9%对16.8%; P < 0.001），在多变量分析中，肾损害与这种毒性独立相关（校正风险比[aHR]，2.37; 95%置信区间[Cl]，1.52 - 3.68）。药代动力学分析（研究2）包括来自603例成人患者的1，309个利奈唑胺浓度。将年龄、体表面积和估计的肾小球滤过率（eGFR）确定为利奈唑胺清除率的协变量。利奈唑胺剂量降低提高了模拟患者达到最佳暴露量的概率，eGFR值为
Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for >= 10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P < 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [Cl], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of