Objectives

The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death.

Methods

Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis.

Results

Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14–1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03–1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19–1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen.

Discussion

The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

中文翻译：

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大肠菌素的群体药代动力学及其与易感大肠菌素和碳青霉烯耐药菌感染的危重患者的生存率的关系。

目标

目的是分析粘菌素的总体药代动力学，并探讨粘菌素暴露与死亡时间之间的关系。

方法

AIDA随机对照试验中包含的患者接受了大肠粘菌素治疗，这些细菌是由对碳青霉烯耐药的革兰氏阴性菌引起的严重感染。所有受试者均接受900万单位（MU）的负荷剂量，然后接受4.5 MU的每日两次维持剂量，如果肌酐清除率（CrCL）<50 mL / min，则应降低剂量。从已开发的人群药代动力学模型和每位患者采样设计优化的两个样本中估算个体粘菌素暴露量。在参数生存分析中评估死亡时间。

结果

在406位随机分组的患者中，有349位提供了药代动力学数据。首次输注结束后15分钟，大肠菌素血浆中值浓度（90％范围）为0.44（0.14–1.59）mg / L。在维持剂量后10小时抽取的样品中，CrCL≤120mL / min和> 120 mL / min的患者中94％（195/208）和44％（38/87）的患者中浓度> 2 mg / L，分别。Colistin甲磺酸钠（CMS）和粘菌素的清除率强烈依赖于CrCL。在多因素分析中，高粘菌素暴露于MIC的比例与死亡风险增加相关（调整后的危险比（95％CI）：1.07（1.03-1.12））。其他重要的预测指标包括基线时的SOFA评分（每评分增加HR 1.24（1.19-1.30）），年龄和不动杆菌或假单胞菌作为指标病原体。

讨论区

群体药代动力学模型预测，稳定状态中> 90％的患者大肠菌素浓度> 2 mg / L，但开始治疗后4小时仅66％。高粘菌素暴露与肾功能差有关，与延长生存期无关。