Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
Department of General Surgery, Heidenheim Hospital, Heidenheim, Germany.
Int J Antimicrob Agents. 2022 May;59(5):106572. doi: 10.1016/j.ijantimicag.2022.106572. Epub 2022 Mar 18.
Linezolid is a treatment option against multi-drug-resistant Gram-positive pathogens. Continuous infusion of linezolid has been proposed to optimize antimicrobial exposure, although pharmacokinetic data from large patient cohorts are lacking.
Population pharmacokinetics and the time-dependent association between linezolid exposure and the occurrence of thrombocytopenia in 120 critically ill patients were described. Monte Carlo simulations evaluated pharmacokinetic/pharmacodynamic/toxicodynamic target attainment in relation to body weight and creatinine clearance for continuously infused doses of 300-2400 mg/day.
Linezolid pharmacokinetics were highly variable (interindividual variability of clearance: 52.8% coefficient of variation). Non-linear clearance was quantified, which decreased from 6.82 to 3.82 L/h within 3-6 days in the population. A relationship between linezolid exposure and platelet count over time was established. For standard dosing (1200 mg/day), the model predicted Grade 2, 3 or 4 thrombocytopenia (<75 × 10/µL, <50 × 10/µL and <25 × 10/µL) in 21.7%, 10.4% and 2.5% of patients at day 14, respectively. Patients with impaired renal function displayed higher risk. The overall probability of Grade 3 thrombocytopenia could be reduced from 10.4% using standard dosing to 6.3% if a linezolid steady state plasma concentration of 7 mg/L is targeted, suggesting a value of therapeutic drug monitoring (TDM).
Dosing linezolid by continuous infusion should include considerations of creatinine clearance and body weight to maximize the achievement of therapeutic exposures. However, due to the high variability in individual dose, optimization using TDM seems necessary to optimize linezolid dosing under continuous infusion to avoid toxicity, particularly if longer treatment courses are expected.
利奈唑胺是一种治疗多重耐药革兰阳性病原体的选择药物。连续输注利奈唑胺被认为可以优化抗菌药物暴露，尽管缺乏来自大型患者队列的药代动力学数据。
描述了 120 名危重症患者的群体药代动力学和利奈唑胺暴露与血小板减少症发生之间的时间依赖性关系。蒙特卡罗模拟评估了连续输注剂量为 300-2400mg/天时与体重和肌酐清除率相关的药代动力学/药效学/毒性动力学目标的实现情况。
利奈唑胺的药代动力学具有高度变异性（清除率的个体间变异性：52.8%变异系数）。定量了非线性清除，在人群中，3-6 天内从 6.82 降至 3.82 L/h。建立了利奈唑胺暴露与血小板计数随时间的关系。对于标准剂量（1200mg/天），模型预测第 14 天分别有 21.7%、10.4%和 2.5%的患者出现 2 级、3 级或 4 级血小板减少症（<75×10/µL、<50×10/µL 和 <25×10/µL）。肾功能受损的患者风险更高。如果以 7mg/L 的利奈唑胺稳态血浆浓度为目标，使用标准剂量可将 3 级血小板减少症的总体发生率从 10.4%降低至 6.3%，这表明治疗药物监测（TDM）具有一定价值。
连续输注利奈唑胺时，应考虑肌酐清除率和体重，以最大限度地实现治疗性暴露。然而，由于个体剂量的高度变异性，使用 TDM 进行优化似乎是必要的，以优化连续输注下的利奈唑胺剂量，避免毒性，特别是如果预期治疗时间较长。
