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Dose optimization of piperacillin/tazobactam in critically ill children
Pieter A J G De Cock, Sven C van Dijkman1, Annick de Jaeger2
1Division of Pharmacology, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333?CC Leiden, the Netherlands.
Insights
Standard piperacillin/tazobactam dosing may fail critically ill children. Continuous infusions or loading doses are recommended for optimal antibiotic exposure and to prevent treatment failure in pediatric intensive care unit patients.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Infectious Diseases
Background:
- Optimizing antibiotic dosing in critically ill children is crucial for effective treatment.
- Piperacillin/tazobactam is frequently used in pediatric intensive care units (PICUs).
- Standard dosing regimens may not achieve therapeutic targets in this vulnerable population.
Purpose of the Study:
- To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children.
- To develop an evidence-based, optimized dosing regimen for piperacillin/tazobactam in pediatric patients.
Main Methods:
- A pharmacokinetic study involving 47 critically ill children (2 months to 15 years) receiving intravenous piperacillin/tazobactam.
- Blood samples analyzed using LC-MS/MS for drug concentrations.
- Non-linear mixed-effects modeling incorporating allometric scaling and a maturation function.
Main Results:
- Piperacillin and tazobactam disposition was best described by a two-compartment model.
- Mean clearance estimates were provided for a reference child weight.
- Monte Carlo simulations identified specific dosing regimens (intermittent and continuous infusions) to achieve therapeutic targets for piperacillin.
Conclusions:
- Standard intermittent dosing of piperacillin/tazobactam may lead to suboptimal drug exposure in critically ill children.
- A loading dose followed by continuous infusion is recommended for treating severe infections in children over 2 months of age.
- Optimized dosing strategies are essential to improve treatment outcomes and reduce the risk of failure.
Objectives:
To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.
Patients And Methods:
This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling.
Results:
Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L).
Conclusions:
Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age.