Population pharmacokinetics and dose optimization of piperacillin-tazobactam in premature and term neonates with severe infections

Piperacillin-tazobactam is widely used off-label in neonates for the empirical treatment of severe infections, resulting in diverse dosing regimens across clinical settings. This variability, combined with high interindividual differences in renal maturation that impact drug disposition, complicates standardized dosing and emphasizes the need for individualized, evidence-based strategies. This study aimed to develop and evaluate a population pharmacokinetic model of piperacillin in neonates to support optimized initial dosing recommendations. Neonatal patients (postnatal age ≤28 days) admitted to an intensive care unit who received piperacillin-tazobactam (8:1 ratio) at Neofax-recommended doses were included. Plasma concentrations were measured using an ultra-high-performance liquid chromatography with tandem mass spectrometry method. Population pharmacokinetic analysis for piperacillin was performed using nonlinear mixed-effects modeling. A total of 65 blood samples were collected from 25 neonates, both preterm (56%) and full-term. Piperacillin pharmacokinetics was best described by a one-compartment model incorporating body weight-based allometric scaling, postmenstrual age, and serum creatinine as covariates influencing clearance. For a typical neonate in the study (1.76 kg), the estimated clearance was 0.748 L/h (coefficient of variation, 38.3%), and the volume of distribution was 0.866 L (37.7%). Simulations indicated adequate probability of target attainment with current recommendations, but a high proportion of preterm neonates (>75%) were at risk of overexposure (trough piperacillin plasma concentration >50 mg/L). Additional simulations supported individualized initial regimens based on renal maturation and suggested that extended infusions (1-4 h) may improve target attainment for stricter targets and less-susceptible pathogens. This study provides a validated pharmacokinetic model for piperacillin in neonates with severe infections, offering a framework to optimize empiric dosing based on renal function and developmental stage.