Department of Pharmacy, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, PR China; Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA.
Division of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi, PR China.
Int J Antimicrob Agents. 2024 Nov;64(5):107346. doi: 10.1016/j.ijantimicag.2024.107346. Epub 2024 Sep 26.
Currently, there is a lack of information on the clinical pharmacokinetics (PK), effectiveness, and safety of colistin sulphate (CS) in lung transplant recipients. This study aims to improve CS dosing regimens and evaluate its population PK in lung transplant recipients.
This study evaluated the clinical efficacy, microbiological efficacy, and adverse events of CS in lung transplant recipients. The NONMEM program was employed to construct the population PK model, and Monte Carlo simulations were executed to establish dosing regimens according to the probability of target attainment (PTA).
The study included 146 CS concentrations, spanning from 0.05 to 4.18 mg/L from 39 lung transplant recipients with multidrug-resistant Gram-negative bacteria. 26 (66.67%) patients successfully eradicated bacteria, and 30 (76.92%) patients had clinical cure or improvement. Additionally, only 2 (5.13%) patients developed CS-related nephrotoxicity. The PK profile was effectively represented by a one-compartmental model with linear elimination. Creatinine clearance and concomitant furosemide use were recognized as covariates influencing the clearance of CS. Based on the PTA results, a daily dosage of 1.5 million IU, divided into 2-3 administrations, could attain a PTA exceeding 90% for MIC ≤ 1 µg/mL at creatinine clearance of about 110 mL/min. However, this regimen would lead to insufficient exposure for MIC ≥ 2 µg/mL.
The clearance of CS is significantly influenced by concomitant furosemide use and renal function. The currently recommended dosing regimens by label sheet may result in subtherapeutic exposure for MIC exceeding 1 mg/L in lung transplant recipients.
目前，有关硫酸粘菌素（CS）在肺移植受者中的临床药代动力学（PK）、疗效和安全性的信息有限。本研究旨在改进 CS 的给药方案，并评估其在肺移植受者中的群体 PK。
本研究评估了 CS 在肺移植受者中的临床疗效、微生物疗效和不良事件。采用 NONMEM 程序构建群体 PK 模型，并通过蒙特卡罗模拟根据目标浓度达标概率（PTA）来建立给药方案。
该研究纳入了 39 例多重耐药革兰氏阴性菌感染的肺移植受者的 146 个 CS 浓度，范围为 0.05 至 4.18mg/L。26（66.67%）例患者成功清除细菌，30（76.92%）例患者临床治愈或改善。此外，仅 2（5.13%）例患者发生 CS 相关肾毒性。PK 谱通过具有线性消除的单室模型得到有效描述。肌酐清除率和同时使用呋塞米被认为是影响 CS 清除率的协变量。根据 PTA 结果，每日剂量为 150 万 IU，分为 2-3 次给药，在肌酐清除率约为 110mL/min 时，对于 MIC≤1μg/mL，可达到 PTA 超过 90%。然而，该方案将导致 MIC≥2μg/mL 时的暴露不足。
CS 的清除率受同时使用呋塞米和肾功能的显著影响。目前标签说明书推荐的给药方案可能导致 MIC 超过 1mg/L 的肺移植受者治疗暴露不足。
