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Model-informed precision dosing (MIPD) might be used to optimize antibiotic treatment. Procalcitonin (PCT) is a biomarker for severity of infection and response to antibiotic treatment. The aim of this study was to assess the impact of MIPD on the course of PCT and to investigate the association of PCT with pharmacodynamic target (PDT) attainment in critically ill patients. This is a secondary analysis of the DOLPHIN trial, a multicentre, open-label, randomised controlled trial. Patients with a PCT value available at day 1 (T1), day 3 (T3), or day 5 (T5) after randomisation were included. The primary outcome was the absolute difference in PCT concentration at T1, T3, and T5 between the MIPD and the standard dosing group. In total, 662 PCT concentrations from 351 critically ill patients were analysed. There was no statistically significant difference in PCT concentration between the trial arms at T1, T3, or T5. The median PCT concentration was highest in patients who exceeded 10× PDT at T1 [13.15 ng/mL (IQR 5.43–22.75)]. In 28-day non-survivors and in patients that exceeded PDT at T1, PCT decreased significantly between T1 and T3, but plateaued between T3 and T5. PCT concentrations were not significantly different between patients receiving antibiotic treatment with or without MIPD guidance. The potential of PCT to guide antibiotic dosing merits further investigation. [ABSTRACT FROM AUTHOR]

Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated. [ABSTRACT FROM AUTHOR]