Boonyasiri Adhiratha, Fuhs Dominika T, Naorungroj Thummaporn, Wang Lu, Wang Jiping, Ratanarat Ranistha, Li Jian, Nation Roger L, Thamlikitkul Visanu, Landersdorfer Cornelia B
Division of Clinical Epidemiology, Department of Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, Department of Infectious Disease, Imperial College London, London, United Kingdom.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Clin Microbiol Infect. 2025 Sep;31(9):1526-1531. doi: 10.1016/j.cmi.2025.05.021. Epub 2025 May 29.
Although colistin (administered as colistin methanesulphonate [CMS]) is used to treat infections in critically-ill patients undergoing sustained low-efficiency dialysis (SLED), there is a paucity of information on appropriate dosing regimens. This study aimed to characterize the population pharmacokinetics (popPK) of colistin during SLED and evaluate the likelihood of antibacterial benefit and colistin nephrotoxicity for different regimens.
A prospective popPK study included 13 critically-ill patients (six females) treated with CMS and receiving SLED (6-8 hours). For each subject, the PK of formed colistin was studied on a non-SLED day and a SLED day (n = 8 studied during SLED day first). A single intravenous daily dose (150 mg colistin base activity) was administered on a non-SLED day. On a SLED day, patients received 150 mg colistin base activity 12-hourly. Serial blood, urine and dialysate samples were collected over 24 hours on both days. Colistin plasma concentrations were measured by high-performance liquid chromatography. PopPK modelling and Monte Carlo simulations were performed.
A linear one-compartment disposition model well-described the data. The population mean apparent colistin body clearance, excluding SLED clearance, was 1.69 L/h (20.6% inter-individual variability [IIV], 42.1% inter-occasion variability). The apparent colistin SLED clearance was 3.49 L/h (41.7% IIV), i.e. 67.4% of total colistin clearance on a SLED day. The apparent volume of distribution was 50.2 L (23.0% IIV).
Colistin clearance was substantially higher during SLED; therefore, SLED should be accounted for in CMS dosing regimens. This project generated clinically applicable regimens, such as loading doses, to achieve required probabilities of target attainment in patients undergoing SLED.
尽管多粘菌素（以多粘菌素甲磺酸盐[CMS]形式给药）用于治疗接受持续低效透析（SLED）的重症患者的感染，但关于合适给药方案的信息却很少。本研究旨在描述SLED期间多粘菌素的群体药代动力学（popPK），并评估不同方案实现抗菌益处和多粘菌素肾毒性的可能性。
一项前瞻性popPK研究纳入了13例接受CMS治疗并接受SLED（6 - 8小时）的重症患者（6名女性）。对于每个受试者，在非SLED日和SLED日研究形成的多粘菌素的药代动力学（首先在SLED日研究8例）。在非SLED日给予单次静脉每日剂量（150mg多粘菌素碱活性）。在SLED日，患者每12小时接受150mg多粘菌素碱活性。在这两天的24小时内收集系列血液、尿液和透析液样本。通过高效液相色谱法测量多粘菌素血浆浓度。进行了popPK建模和蒙特卡洛模拟。
线性一室处置模型很好地描述了数据。排除SLED清除率后，群体平均表观多粘菌素体内清除率为1.69L/h（个体间变异性[IIV]为20.6%，个体间变异性为42.1%）。表观多粘菌素SLED清除率为3.49L/h（IIV为41.7%），即SLED日多粘菌素总清除率的67.4%。表观分布容积为50.2L（IIV为23.0%）。
SLED期间多粘菌素清除率显著更高；因此，在CMS给药方案中应考虑SLED因素。该项目产生了临床适用的方案，如负荷剂量，以在接受SLED的患者中实现达到目标的所需概率。
