基于PK/PD模型的碳青霉烯类抗生素在CRRT脓毒症患者中的合理化给药研究

脓毒症患者常并发急性肾损伤，需及时给予连续性肾脏替代治疗（CRRT）净化血液和抗生素治疗控制感染。碳青霉烯类抗生素是CRRT脓毒症患者的优选抗生素，但其合理给药方案的制定面临挑战。第一，CRRT会显著改变碳青霉烯类抗生素的药物动力学（PK）特征，而目前尚无CRRT患者的可靠PK数据和研究模型。第二，碳青霉烯类抗生素在脓毒症患者中的PK/PD靶标存在争议。第三，CRRT患者残余肾功能个体差异大，PK变异显著，毒性风险大，评估给药方案的临床效益/毒性风险比存在困难。本项目拟在实验动物水平上明确碳青霉烯类抗生素在脓毒症患者中的最佳PK/PD靶标；构建整合患者残余肾功能和CRRT因素的“人机一体”群体PK模型，结合PK/PD靶标确定患者群体的标准给药方案；开发基于群体PK模型的给药辅助系统，精准评估患者个体的临床效益/毒性风险比。本研究将为碳青霉烯类抗生素在CRRT患者中的合理化给药提供科学指导。

Patients with sepsis often suffer from acute kidney injury, and continuous renal replacement therapy (CRRT) and antibiotic treatment are required to purify the blood and to control infections, respectively. Carbapenems are the preferred antibiotics for sepsis patients undergoing CRRT, but the rational use of carbapenems is challenge. First, CRRT can significantly alter the pharmacokinetic (PK) characteristics of carbapenems, and there are no reliable PK data and mathematical models for CRRT patients. Second, the pharmacokinetic/pharmacodynamic (PK/PD) target for carbapenems in sepsis patients remains controversial. Third, CRRT patients show large individual differences in residual renal function, markable PK variation, and high risk of toxicity, thus it is very difficult to evaluate the clinical benefit/toxicity risk ratio for the treatment regimen. In this project, the best PK/PD target of carbapenems in sepsis patients will be determined through animal experiments; An "integrated human-machine" population PK model incorporating residual renal function and CRRT factors will be constructed and be combined with defined PK/PD target to determine the standard dosing regimen; Based on the population PK model, a dosing-decision system will be developed to precisely determine the clinical benefit/toxicity risk ratio of the treatment regimen. Through this project, we will provide solid scientific guidance for the rational administration of carbapenem antibiotics in CRRT patients.