Herrero Pau, Wilson Richard C, Armiger Ryan, Roberts Jason A, Holmes Alison, Georgiou Pantelis, Rawson Timothy M
Centre for Bio-Inspired Technology, Department of Electrical and Electronic Engineering, Imperial College London, London, United Kingdom.
Centre for Antimicrobial Optimisation, Imperial College London, London, United Kingdom.
Front Bioeng Biotechnol. 2022 Oct 20;10:1015389. doi: 10.3389/fbioe.2022.1015389. eCollection 2022.
Sub-therapeutic dosing of piperacillin-tazobactam in critically-ill patients is associated with poor clinical outcomes and may promote the emergence of drug-resistant infections. In this paper, an investigation of whether closed-loop control can improve pharmacokinetic-pharmacodynamic (PK-PD) target attainment is described. An platform was developed using PK data from 20 critically-ill patients receiving piperacillin-tazobactam where serum and tissue interstitial fluid (ISF) PK were defined. Intra-day variability on renal clearance, ISF sensor error, and infusion constraints were taken into account. Proportional-integral-derivative (PID) control was selected for drug delivery modulation. Dose adjustment was made based on ISF sensor data with a 30-min sampling period, targeting a serum piperacillin concentration between 32 and 64 mg/L. A single tuning parameter set was employed across the virtual population. The PID controller was compared to standard therapy, including bolus and continuous infusion of piperacillin-tazobactam. Despite significant inter-subject and simulated intra-day PK variability and sensor error, PID demonstrated a significant improvement in target attainment compared to traditional bolus and continuous infusion approaches. A PID controller driven by ISF drug concentration measurements has the potential to precisely deliver piperacillin-tazobactam in critically-ill patients undergoing treatment for sepsis.
在重症患者中，哌拉西林-他唑巴坦的亚治疗剂量与不良临床结局相关，且可能促进耐药感染的出现。本文描述了一项关于闭环控制是否能改善药代动力学-药效学（PK-PD）目标达成情况的研究。利用20例接受哌拉西林-他唑巴坦治疗的重症患者的PK数据开发了一个平台，其中定义了血清和组织间质液（ISF）的PK。考虑了肾清除率的日内变异性、ISF传感器误差和输注限制。选择比例积分微分（PID）控制进行药物输送调节。根据ISF传感器数据进行剂量调整，采样周期为30分钟，目标血清哌拉西林浓度在32至64mg/L之间。在虚拟人群中采用单一的调谐参数集。将PID控制器与标准治疗方法进行比较，标准治疗方法包括哌拉西林-他唑巴坦的推注和持续输注。尽管受试者间和模拟的日内PK变异性以及传感器误差很大，但与传统的推注和持续输注方法相比，PID在目标达成方面有显著改善。由ISF药物浓度测量驱动的PID控制器有可能在接受脓毒症治疗的重症患者中精确输送哌拉西林-他唑巴坦。
