Closed-Loop Control for Precision Antimicrobial Delivery: An In Silico Proof-of-Concept.

Abstract

Inappropriate dosing of patients with antibiotics is a driver of antimicrobial resistance, toxicity, and poor outcomes of therapy. In this paper, we investigate, in silico, the hypothesis that the use of a closed-loop control system could improve the attainment of pharmacokinetic-pharmacodynamic targets for antimicrobial therapy, where wide variations in target attainment have been reported. This includes patients in critical care, patients with renal disease, and patients with obesity. The presented in silico study focuses on vancomycin delivery, a first line therapy for Methicillin-resistant Staphylococcus aureus (MRSA) that has serious side effects, including nephrotoxicity. For this purpose, an in silico platform for the simulation of pharmacokinetics of vancomycin agents was developed including 24 virtual noncritically ill-adult subjects obtained from routinely collected data from two prospective audits of vancomycin therapy. Intraday variability on renal clearance, sensor error, and infusion constraints were taken into account. Proportional integral derivative (PID) controller was chosen because of its simplicity of implementation and satisfactory performance. Even though significant intraday variability and sensor error were considered in the simulations, by assuming a minimum inhibitory concentration of 1 mg/l for MRSA, the proposed controller was able to reach the well-established therapeutic target of 24-h area under curve to minimum inhibitory concentration ratio equal to 400 $\text{mg} \cdot \text{h}\text{/}\text{l}$ for all the studied subjects, while staying significantly below toxic levels. A PID controller has the potential to precisely deliver a vancomycin therapy in a noncritically ill-adult population. Closed-loop control for precision Vancomycin delivery can potentially reduce toxicity and poor therapeutic outcomes, as well as reduce antimicrobial resistance.