多黏菌素B联合美罗培南在产KPC酶肺炎克雷伯菌血流感染患者中的体内药代动力学/药效学及耐药机制研究

Polymyxin B combined meropenem is the main option for treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) caused infections and exhibits good in vitro activity, however, the clinical outcomes are poor. The reason is that the in vivo plasma concentrations of polymyxin B and meropenem have not been optimized, then KPC-Kp is not effectively cleared and resistance is induced. The dose of polymyxin B is restricted by it’s toxicity. The key scientific problem is to discover the in vivo characteristics of polymyxin B combined meropenem, and to achieve the maximum anti-bacterial effect of the limited dose of drugs under the guidance of PK/PD theory. Different maintenance doses of polymyxin B combined with maximum dose of meropenem will be administrated to KPC-Kp blood stream infection patients, and the PK profile of polymyxin B and meropenem will be investigated. The PK/PD quantitative-effective relationship of drug combination to KPC-Kp will be established. The in vivo expression and regulation of genes related to KPC-Kp resistance will also be studied using transcriptomics. The study will illustrate the in vivo PK and PK/PD profile of polymyxin B combined with meropenem in blood stream infection patients for the first time. An optimized dose regimen will be provided. The in vivo dynamic susceptibility and resistance mechanism will also be discovered. This study will improve clinical outcome and reduce resistance of KPC-Kp infection treatment using polymyxin B combined meropenem.

多黏菌素B联合美罗培南是治疗产KPC酶肺炎克雷伯菌(KPC-Kp)感染的主要选择，但临床效果欠佳。这与其体内药物浓度未达优化水平下细菌未被有效清除并产生耐药的有关。但多黏菌素B的剂量受其毒性限制。探究两药联用的体内作用规律，在药代动力学/药效学（PK/PD）理论指导下使限制剂量的药物达到最佳抗菌效果，是本课题拟解决的科学问题。本课题拟考察多黏菌素B不同维持剂量联合极量美罗培南连续给药在KPC-Kp血流感染患者中PK规律，研究两药联用对KPC-Kp的PK/PD量效关系，并通过转录组学等考察体内KPC-Kp耐药相关基因的表达和调控。本项目将首次明确多黏菌素B联合美罗培南在血流感染患者中的PK特性和PK/PD特点，提供基于PK/PD理论指导下的优化给药方案，揭示KPC-Kp在体内敏感性变化规律和耐药机制。本项目对提高多黏菌素B联合美罗培南的临床疗效，减少耐药的产生具有重要的意义。

多黏菌素B联合美罗培南是治疗产KPC酶肺炎克雷伯菌(KPC-Kp)等碳青霉烯耐药革兰阴性菌感染的重要选择，但是多黏菌素B药代动力学/药效学(PK/PD)性质的不明阻碍了其临床作用的发挥。本研究建立多黏菌素B和美罗培南有关生物样本的分析方法，进行多黏菌素B在健康受试者中的PK和安全性研究，开展多黏菌素B联合美罗培南在KPC-KP血流感染患者中的PK研究；发现神经毒性是多黏菌素B的剂量限制性因素，多黏菌素B在健康受试者中体内过程符合三室模型，中央室的清除率和分布容积为0.027 L/h/kg和0.071 L/kg，肾排泄率低于10%，非房室模型分析多黏菌素B在患者中的清除率和分布容积为0.028 L/h/kg和0.49 L/kg，美罗培南则为5.8 L/h 和22.3 L。开展多黏菌素B和美罗培南对KPC-KP的PK/PD研究，包括棋盘法测定联合药敏、体外杀菌曲线、群体动力学(PPK)模型建立和评价、PK/PD分析和模拟等，并对多黏菌素B的PK/PD靶值进行临床的验证，结果发现多黏菌素B和美罗培南具有较好的体外协同作用，但美罗培南的体内PK/PD达标率较低；多黏菌素B的AUC/MIC达到54.4以上可实现血流感染的微生物清除；PPK模拟提示多黏菌素B维持剂量以1mg/kg/12h为宜，临床验证确认多黏菌素B的稳态AUC 50-100 mg∙h/L与低死亡率有关。对KPC-KP出现多黏菌素B耐药的机制进行了研究，认为可能与phoP/phoQ系统有关。本项目较系统地研究了多黏菌素B的PK/PD性质，对于多黏菌素B的合理使用具有一定意义。