Table1_Relationship Between Linezolid Exposure and the Typical Clinical Laboratory Safety and Bacterial Clearance in Chinese Pediatric Patients.docx

Objectives: There have been limited studies concerning the safety and efficacy of linezolid (LZD) in children. This study aimed to evaluate the association between LZD exposure and clinical safety and efficacy in Chinese pediatric patients.Methods: This retrospective cross-sectional study included patients ≤18 years of age who received ≥3 days of LZD treatment between 31 January 2015, and 31 December 2020. Demographic characteristics, medication information, laboratory test information, and bacterial culture results were collected from the Hospital Information System (HIS). Exposure was defined as AUC24 and calculated by the non-linear mixed-effects modeling program (NONMEM), version 7.2, based on two validated population pharmacokinetic models. Binary logistic regression analyses were performed to analyze the associations between AUC24 and laboratory adverse events, and receiver operating characteristic curves were used to calculate the cut-off values. Efficacy was evaluated by bacterial clearance.Results: A total of 413 paediatric patients were included, with an LZD median (interquartile range) dose, duration, clearance and AUC24 of 30.0 (28.1-31.6) mg/kg/day, 8 (4‒15) days,1.31 (1.29-1.32) L/h and 81.1 (60.6-108.7) mg/L·h, respectively. Adverse events associated with TBil, AST, ALT, PLT, hemoglobin, WBC, and neutrophil count increased during and after LZD treatment when compared with before medication (p < 0.05), and the most common adverse events were thrombocytopaenia (71/399, 17.8%) and low hemoglobin (61/401, 15.2%) during the LZD treatment. Patients with AUC24 higher than 120.69 mg/L h might be associated with low hemoglobin 1–7 days after the end of the LZD treatment, and those with an AUC24 higher than 92.88 mg/L∙h might be associated with thrombocytopaenia 8–15 days after the end of the LZD treatment. A total of 136 patients underwent bacterial culture both before and after LZD treatment, and the infection was cleared in 92.6% (126/136) of the patients, of whom 69.8% (88/126) had AUC24/MIC values greater than 80.Conclusion: Hematological indicators should be carefully monitored during LZD treatment, especially thrombocytopaenia and low hemoglobin, and a continuous period of monitoring after LZD withdrawal is also necessary. Since the AUC24 cut-off values for laboratory adverse events were relatively low, a trade-off is necessary between the level of drug exposure required for treatment and safety, and the exposure target (AUC24/MIC) in pediatric patients should be further studied, especially for patients with complications and concomitant medications.

研究目标：关于利奈唑胺（LZD）在儿童中的安全性和有效性的研究尚显不足。本研究旨在评估LZD暴露与中国儿科患者临床安全性与有效性的关联。研究方法：本研究为回顾性横断面研究，纳入了自2015年1月31日至2020年12月31日期间接受≥3天LZD治疗的≤18岁患者。从医院信息系统（HIS）中收集了人口统计学特征、药物信息、实验室检验信息和细菌培养结果。暴露定义为AUC24，通过基于两个经过验证的群体药代动力学模型的非线性混合效应模型程序（NONMEM），版本7.2进行计算。采用二元逻辑回归分析AUC24与实验室不良事件之间的关联，并使用接受者操作特征曲线计算截断值。疗效通过细菌清除率进行评估。研究结果：共纳入413名儿科患者，LZD的中位数（四分位数范围）剂量、持续时间、清除率和AUC24分别为30.0（28.1-31.6）mg/kg/天、8（4-15）天、1.31（1.29-1.32）L/h和81.1（60.6-108.7）mg/L·h。与用药前相比，在LZD治疗期间及治疗后，与TBil、AST、ALT、PLT、血红蛋白、WBC和中性粒细胞计数相关的不良事件增加（p < 0.05），最常见的不良事件为血小板减少症（71/399，17.8%）和低血红蛋白（61/401，15.2%）。AUC24高于120.69 mg/L·h的患者可能在LZD治疗结束后的1-7天内出现低血红蛋白，而AUC24高于92.88 mg/L∙h的患者可能在LZD治疗结束后的8-15天内出现血小板减少症。共136名患者在LZD治疗前后均进行了细菌培养，其中92.6%（126/136）的患者感染得到清除，其中69.8%（88/126）的患者AUC24/MIC值大于80。结论：在LZD治疗期间，应仔细监测血液学指标，特别是血小板减少症和低血红蛋白，LZD停药后的持续监测也是必要的。鉴于实验室不良事件的AUC24截断值相对较低，治疗所需的药物暴露水平与安全性之间需要权衡，特别是对于并发症和合并用药的患者，儿科患者的暴露目标（AUC24/MIC）应进一步研究。