Shi Xiaoping, Yang Wenyu, Zhao Fanyu, Lao Donghui, Xu Qing, Li Xiaoyu, Lv Qianzhou, He Qingfeng, Xiang Xiaoqiang, Wang Ting, Zhu Xiao
Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China.
J Antimicrob Chemother. 2025 Jul 1;80(7):1915-1925. doi: 10.1093/jac/dkaf147.
Linezolid is a commonly prescribed antibiotic for multidrug-resistant enterococcal infections in liver transplant recipients (LTRs). However, changes in pharmacokinetics due to fluctuations in liver and renal functions, combined with the increased risk of thrombocytopenia, complicate its clinical use. This study aimed to characterize the exposure-thrombocytopenia risk relationship of linezolid in LTRs, and to identify safe dosing thresholds to promote rational drug use.
A retrospective analysis was conducted on adult LTRs treated with linezolid at Zhongshan Hospital between January 2019 and May 2022. A population exposure-safety model was developed and used to establish a thrombocytopenia risk threshold and optimize initial dosing strategies through Monte Carlo simulations. An area under the concentration-time curve (AUC) calculator was developed to facilitate individualized dose adjustments.
Exposure-safety analysis revealed that an AUCss,24h threshold of 291.7 mg/L·h was associated with an increased risk of thrombocytopenia. Monte Carlo simulations showed that current covariate-based initial dosing recommendations were suboptimal, highlighting the necessity of therapeutic drug monitoring (TDM) to improve outcomes in LTRs. The online AUC calculator developed in this study offers a practical tool for clinicians to implement timely dose adjustments (https://optimaldose.shinyapps.io/LinezolidAUC/).
This study provides the first comprehensive analysis of linezolid exposure and its relationship to thrombocytopenia risk in LTRs. The findings underscore the importance of AUC-guided dosing and TDM in optimizing treatment outcomes.
利奈唑胺是肝移植受者（LTRs）多重耐药肠球菌感染常用的处方抗生素。然而，肝肾功能波动导致的药代动力学变化，加之血小板减少风险增加，使其临床应用变得复杂。本研究旨在描述利奈唑胺在LTRs中的暴露-血小板减少风险关系，并确定安全给药阈值以促进合理用药。
对2019年1月至2022年5月在中山医院接受利奈唑胺治疗的成年LTRs进行回顾性分析。建立了群体暴露-安全性模型，并通过蒙特卡洛模拟用于建立血小板减少风险阈值和优化初始给药策略。开发了浓度-时间曲线下面积（AUC）计算器以促进个体化剂量调整。
暴露-安全性分析显示，24小时稳态AUC阈值为291.7mg/L·h与血小板减少风险增加相关。蒙特卡洛模拟表明，当前基于协变量的初始给药建议并非最优，突出了治疗药物监测（TDM）对改善LTRs治疗效果的必要性。本研究开发的在线AUC计算器为临床医生及时进行剂量调整提供了实用工具（https://optimaldose.shinyapps.io/LinezolidAUC/）。
本研究首次全面分析了利奈唑胺暴露及其与LTRs血小板减少风险的关系。研究结果强调了AUC指导给药和TDM在优化治疗效果方面的重要性。
