Piperacillin dosing in pediatric patients and augmented renal clearance: are current guidelines sufficient to achieve therapeutic concentration coverage?

backgroundAppropriate dosing of piperacillin/tazobactam is crucial for hospitalized children and might be a challenge in case of augmented renal clearance. This study assessed the appropriateness of piperacillin dosing regimens recommended to attain pharmacokinetic/pharmacodynamic targets by pediatric guidelines using a population pharmacokinetic approach.

methodsA population pharmacokinetic model for piperacillin was developed using therapeutic drug monitoring observations collected in hospitalized children between 2012 and 2021. Subsequently, simulations were performed to evaluate whether dosing regimens recommended by various pediatric guidelines achieved the pharmacodynamic target [i.e. maintaining free piperacillin plasma concentrations above the minimum inhibitory concentration for 100% of the dosing interval (100% fT > MIC)] in case of augmented, normal and moderately impaired renal functions.

resultsThe model best describing our 386 concentration values in 104 patients was a two-compartment model with allometric scaling of pharmacokinetic parameters based on bodyweight. Renal function also influenced clearance. Simulations revealed a risk of underdosing in patients with a creatinine clearance above 50 mL/min/1.73 m2 when piperacillin was administered as intermittent infusions, according to most guidelines. In contrast, continuous infusions consistently achieved the pharmacodynamic target even for MIC close to the limit of susceptibility.

conclusionThis study highlights the critical impact of renal function on piperacillin pharmacokinetics in pediatric patients. Continuous infusion regimens are necessary to ensure optimal drug exposure and efficacy, particularly in patients with augmented creatinine clearance. These results emphasize the need to revise pediatric dosing strategies considering a broader range of renal function.