Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children
Céline Thibault1,2, Nastya Kassir3, Yves Théorêt1,2,3,4
1Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, QC, Canada.
Insights
Extended piperacillin-tazobactam infusions show promise, but pediatric dosing needs refinement. New strategies ensure optimal piperacillin-tazobactam (TZP) dosing in children, achieving high target attainment for various infections.
Area of Science:
- Pediatric Pharmacology
- Antimicrobial Dosing Strategies
- Pharmacokinetics and Pharmacodynamics
Background:
- Extended piperacillin-tazobactam (TZP) infusions are linked to favorable clinical outcomes.
- Current pediatric dosing guidelines for TZP are lacking.
Purpose of the Study:
- To establish optimal TZP dosing regimens for children aged 2 months to 6 years.
- To consider age and varying minimum inhibitory concentrations (MICs) in dosing recommendations.
Main Methods:
- Simulated pharmacokinetic parameters for 1000 children based on age and weight.
- Calculated probability of target attainment (PTA) for various TZP dosing strategies and MICs (4-128 mg/L).
- Defined pharmacodynamic target as 50% of the dosing interval with free drug concentration above MIC; optimal PTA set at ≥90%.
Main Results:
- PTA decreased with increasing MIC and age.
- Standard TZP infusions (0.5h) failed to achieve ≥90% PTA at MICs ≥16 mg/L across all age groups.
- Specific extended infusion regimens achieved ≥90% PTA up to MICs of 32 mg/L in infants and 16 mg/L in older children.
Conclusions:
- Recommended TZP dosing: 90 mg/kg/dose (2h infusion) every 8h for infants (2-6m) and 100 mg/kg/dose (4h infusion) every 8h for children (>6m-6y) up to MICs of 16 mg/L.
- These extended infusion strategies improve TZP efficacy in pediatric populations.
- Further research may be needed for higher MICs.
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%.
More Related Videos
Related Concept Videos
01:21Factors Affecting Drug Response: Overview
01:29Drug Dosing: Infants and Children
01:23Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption
01:17Pharmacokinetics in Pediatric Patients: Drug Distribution
01:24Pharmacokinetics in Pediatric Patients: Drug Metabolism
01:26Pharmacokinetics in Pediatric Patients: Drug Excretion