Sun Qiang, Li Xiaojing, Wang Genzhu, Wang Xiaoying, Xing Baiqian, Xun Zhikun, Lu Nianfang, Li Zhongdong
Department of Pharmacy, Beijing Electric Power Hospital of State Grid Co. of China, Capital Medical University Electric Teaching Hospital, Beijing, China.
ICU, Beijing Electric Power Hospital of State Grid Co. of China, Capital Medical University Electric Teaching Hospital, Beijing, China.
Sci Rep. 2025 May 26;15(1):18295. doi: 10.1038/s41598-025-03503-9.
As the last defense against multidrug-resistant gram-negative bacteria, colistin sulfate's clinical use, which is often empirical, risks resistance and adverse reactions. This study aimed to develop a population pharmacokinetic (PPK) model of colistin sulfate for critically ill patients and determine the optimal dosing regimen. This retrospective study included 204 critically ill patients. We used a validated LC-MS/MS method to measure its plasma concentrations and RIFLE criteria for nephrotoxicity evaluation. NONMEM developed PPK models. Monte Carlo simulations set dosing regimens based on the probability of target attainment (PTA). A two-compartment model adequately described the data, creatinine clearance and weight were covariates for elimination rate and central volume, respectively. Only 11.8% had nephrotoxicity. With Monte Carlo simulations, all regimens except the maintenance dose of 0.5 MU administered every 12 h achieved > 90% PTA at the minimum inhibitory concentration (MIC) ≤ 0.5 mg/L. However, at MIC > 0.5 mg/L, the routine regimen resulted in insufficient exposure. Based on our PPK model, the dose of intravenous colistin sulfate should be adjusted according to creatinine clearance (CrCL) and weight. For critically ill patients with infections, under the conventional treatment regimens, when the MIC is ≥ 1 mg/L, it is difficult for patients to achieve the ideal therapeutic effect in terms of exposure dose. When CrCL is below 10 ml/min, the regimen of 1 MU every 8 h used could cause the potential for increasing nephrotoxicity risk, which is significantly concerned.
作为对抗多重耐药革兰氏阴性菌的最后一道防线，硫酸黏菌素的临床使用通常是经验性的，存在耐药和不良反应的风险。本研究旨在建立危重症患者硫酸黏菌素的群体药代动力学（PPK）模型，并确定最佳给药方案。这项回顾性研究纳入了204例危重症患者。我们使用经过验证的液相色谱-串联质谱法（LC-MS/MS）测量其血浆浓度，并采用RIFLE标准进行肾毒性评估。NONMEM软件用于建立PPK模型。蒙特卡洛模拟根据目标达成概率（PTA）设定给药方案。二室模型能充分描述数据，肌酐清除率和体重分别是消除率和中央室容积的协变量。只有11.8%的患者出现肾毒性。通过蒙特卡洛模拟，除了每12小时给予0.5 MU维持剂量外，所有给药方案在最低抑菌浓度（MIC）≤0.5 mg/L时的PTA均>90%。然而，当MIC>0.5 mg/L时，常规给药方案导致暴露不足。基于我们的PPK模型，静脉注射硫酸黏菌素的剂量应根据肌酐清除率（CrCL）和体重进行调整。对于感染的危重症患者，在传统治疗方案下，当MIC≥1 mg/L时，患者在暴露剂量方面难以达到理想的治疗效果。当CrCL低于10 ml/min时，每8小时使用1 MU的给药方案可能会增加肾毒性风险，这一点值得高度关注。
