Closed-loop control of continuous piperacillin delivery: An in silico study

Area of Science:

• Pharmacology
• Critical Care Medicine
• Computational Biology

Background:

• Sub-therapeutic dosing of piperacillin-tazobactam in critically-ill patients is linked to adverse outcomes and antimicrobial resistance.
• Optimizing drug delivery is crucial for effective sepsis treatment in intensive care settings.

Purpose of the Study:

• To investigate the potential of closed-loop control systems to improve pharmacokinetic-pharmacodynamic (PK-PD) target attainment for piperacillin-tazobactam.
• To evaluate the efficacy of a proportional-integral-derivative (PID) controller in managing drug concentrations.

Main Methods:

• Developed an in silico platform using PK data from 20 critically-ill patients.
• Incorporated intra-day variability in renal clearance, interstitial fluid (ISF) sensor error, and infusion constraints.
• Utilized a PID controller adjusting piperacillin-tazobactam delivery based on ISF sensor data to maintain serum concentrations between 32-64 mg/L.

Main Results:

• The PID controller significantly improved PK-PD target attainment compared to standard bolus and continuous infusion methods.
• The system demonstrated robustness despite inter-subject PK variability, intra-day fluctuations, and simulated sensor errors.

Conclusions:

• A PID controller guided by ISF drug concentration measurements offers precise piperacillin-tazobactam delivery in critically-ill sepsis patients.
• This closed-loop system shows promise for optimizing antimicrobial therapy and potentially mitigating resistance development.