Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children.

BACKGROUND: Extended piperacillin-tazobactam (TZP) infusions have been associated with favourable outcomes. There are currently no pediatric dosing recommendations.

OBJECTIVES: To determine appropriate TZP dosing strategies in children 2 months - 6 years according to age and different minimal inhibitory concentrations (MICs).

METHODS: Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal.

RESULTS: PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m.

CONCLUSIONS: Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ≥ 90%.