Population Pharmacokinetics of Piperacillin/Tazobactam in Critically Ill Young Children

Introduction: Piperacillin/tazobactam is a frequently prescribed antibiotic in pediatric intensive care units, but pharmacokinetic data to justify the optimal piperacillin/tazobactam dosing regimen are sparse in critically ill children. Methods: Blood samples (2-4 per child) were collected from 13 children ages 9 months to 6 years admitted to the pediatric intensive care unit who were receiving standard piperacillin/tazobactam dosing regimens to treat infections. Piperacillin concentrations were measured by a bioassay, and the population pharmacokinetics of the piperacillin component was conducted using nonparametric adaptive grid (BigNPAG) with adaptive . Multiple models were tested to determine the best fit of the data. A 5000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for piperacillin/tazobactam 50mg/kg (of the piperacillin component) every 4 hours, 80mg/kg every 8 hours and 100mg/kg every 6 hours as 0.5-, 3- or 4-hour infusions in a population of 1- to 6-year-old male children. Centers for Disease Control and Prevention weight for age charts were used as weight distributions. The percent of the dosing interval of the free drug is above the minimum inhibitory concentration (MIC) (fT>MIC) was calculated over a range of MICs from 0.03 to 128 g/mL. The bactericidal target attainment was defined as 50% fT>MIC for piperacillin/tazobactam. PTA 90% at each MIC was defined as optimal. Results: A 2 compartment model fitted piperacillin concentration data the best. Mean (standard deviation) population estimates for clearance, volume of the central compartment (Vc) and intercompartment transfer constants were 0.299 (0.128) L/hr/kg, 0.249 (0.211) L/kg, 6.663 (6.871) hours(-1) and 8.48 (7.74) hours(-1), respectively. This resulted in a mean (standard deviation) elimination half-life of 1.39 (0.62) hours. The bias, precision and r(2) for the individual predicted versus observed concentrations were -0.055, 0.96 g/mL and 0.999, respectively. The only dosing regimens that achieved optimal PTA at the Clinical Laboratory Standards Institute susceptibility breakpoint of 16 g/mL against Psuedomonas aeruginosa were 100mg/kg every 6 hours administered as a 3-hour prolonged infusion and 400mg/kg administered as a 24-hour continuous infusion. These dosing regimens also achieved 77.7% and 74.8% PTA, respectively, at a MIC of 32 g/mL. Conclusion: These are the first pharmacokinetic data of piperacillin/tazobactam (piperacillin component) in critically ill pediatric patients (1-6 years of age). Based on these data, 100mg/kg q6h as a 3-hour infusion and 400mg/kg continuous infusion were the only regimens to provide optimal PTA at the Clinical Laboratory Standards Institute breakpoint of 16 mu g/mL.