Using a Validated Population Pharmacokinetic Model for Dosing Recommendations of Continuous Infusion Piperacillin for Critically Ill Adult Patients.

Abstract

Six models were evaluated with a dataset consisting of 30 critically ill patients (35 samples) receiving piperacillin by continuous infusion. Models were subject to prediction-based (bias and imprecision) and simulation-based evaluations. When a model had an acceptable evaluation, it was used for dosing simulations to evaluate the probability of target attainment. Bias and imprecision ranged from -35.7 to 295% and from 22.7 to 295%, respectively. The models of Klastrup et al. and of Udy et al. were acceptable according to our criteria and were used for dosing simulations. Simulations showed that a loading dose of 4 g followed by a maintenance dose of 16g/24h of piperacillin infused continuously was necessary to remain above a pharmacokinetic-pharmacodynamic target set as a minimal inhibitory concentration of 16mg/L in 90% of patients, for a median patient with a creatinine clearance of 76mL/min. Despite the considerable variation in the predictive performance of the models with the external validation dataset, this study was able to validate two of these models and led to the elaboration of a dosing nomogram for piperacillin by continuous infusion that can be used by clinicians in intensive care units.