Population Pharmacokinetics (PK) and Pharmacodynamics (PD) of Extended-Infusion Piperacillin (PIP), Administered with Tazobactam (TAZ), in Critically Ill Children

Background: PIP/TAZ PK have been studied in pediatrics, but PK data for extended-infusion (EI) dosing regimens are limited. The objective of this study was to evaluate the population PK/PD of EI PIP, administered with TAZ, in critically ill children.

Methods: Children (1-9 years) hospitalized in an ICU with a suspected or documented bacterial infection were studied. Patients received PIP/TAZ 100/12.5 mg/kg q8h, infused over 4 h. Serial blood samples were collected at steady state, and serum PIP/TAZ concentrations were determined. Population PK analyses were performed using NONMEM. 5,000-patient Monte Carlo simulations were performed to estimate PIP PK profiles for 4 dosing regimens: 80 and 100 mg/kg q8h (4 h infusion); 80 and 100 mg/kg q6h (3 h infusion). PTA for ≥ 50% fT>MIC was calculated for PIP at MICs ranging from 1 to 64 mg/L.

Results: 72 PIP concentrations from 12 patients (6M/6F) were included. Patient demographics (mean ± SD) were: age 5 ± 3 years; weight 17.0 ± 6.2 kg; CLcr 142 ± 46 mL/min. A 1-compartment model with zero-order input and first-order elimination with proportional residual errors best fit the PIP PK data. Weight was significantly associated with PIP CL. PK parameters (mean ± SD) were: CL 0.22 ± 0.07 L/h/kg; V 0.43 ± 0.16 L/kg; half-life 1.4 ± 0.4 h; AUC0-8 487 ± 127 mg*h/L. At MICs ≤ 16 mg/L, all regimens achieved PTA > 99%. Doses infused over 3 h achieved PTA > 90% at an MIC of 32 mg/L, but no regimen achieved PTA > 90% at an MIC of 64 mg/L.

Conclusions: For susceptible bacterial pathogens, PIP/TAZ doses ≥ 80/10 mg/kg q8h, infused over 4 h, achieve adequate PD exposures in critically ill children. More frequent dosing should be considered for less susceptible pathogens.