Target-Controlled Continuous Infusion for Antibiotic Dosing: Proof-of-Principle in an In-silico Vancomycin Trial in...

In this in-silico study, we investigate the clinical utility of target-controlled infusion for antibiotic dosing in an intensive care unit setting using vancomycin as a model compound. We compared target-controlled infusion and adaptive target-controlled infusion, which combines target-controlled infusion with data from therapeutic drug monitoring, with conventional (therapeutic drug monitoring-based) vancomycin dosing strategies.

A clinical trial simulation was conducted. This simulation was based on a comprehensive database of clinical records of intensive care unit patients and a systematic review of currently available population-pharmacokinetic models for vancomycin in intensive care unit patients. Dosing strategies were compared in terms of the probability of achieving efficacious concentrations as well as the potential for inducing toxicity.

Adaptive target-controlled infusion outperforms rule-based dosing guidelines for vancomycin. In the first 48 h of treatment, the probability of target attainment is significantly higher for adaptive target-controlled infusion than for the second-best method (Cristallini). Probability of target attainments of 54 and 72% and 47 and 59% for both methods after 24 and 48 h, respectively. Compared to the Cristallini method, which is characterized by a probability of attaining concentrations above 30 mg.L^-1 > 65% in the first few hours of treatment, adaptive target-controlled infusion shows negligible time at risk and a probability of attaining concentrations above 30 mg.L^-1 not exceeding 25%. Finally, in contrast to the other methods, the performance of target-controlled infusion is consistent across subgroups within the population.

Our study shows that adaptive target-controlled infusion has the potential to become a practical tool for patient-tailored antibiotic dosing in the intensive care unit.