Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance

Clin Pharmacokinet. 2019 Feb;58(2):223-233. doi: 10.1007/s40262-018-0682-1.


Background: Critically ill children frequently display observed alterations of pharmacokinetic (PK) parameters, leading to a reduction in β-lactam concentrations. This study aimed to develop a PK population model for piperacillin in order to optimize individual dosing regimens.

Methods: All children aged ≤ 18 years, weighing more than 2.5 kg, and receiving piperacillin infusions were included in this study. Piperacillin was quantified by high-performance liquid chromatography, and PK were described using the non-linear mixed-effect modeling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimens in order to attain two PK targets: 50% fT>MIC and 100% fT>MIC.

Results: We included 50 children with a median (range) postnatal age of 2.3 years (0.1-18), body weight (BW) of 11.9 kg (2.7-50), Pediatric Logistic Organ Dysfunction-2 (PELOD-2) severity score of 4 (0-16), and estimated glomerular filtration rate (eGFR) of 142 mL.min-1.1.73 m-2 (29-675). A one-compartment model with first-order elimination adequately described the data. Median (range) values for piperacillin clearance (CL) and volume of distribution were 3 L.h-1 (0.71-10) and 0.33 L.kg-1 (0.21-0.86), respectively. BW was integrated with the allometric relationship. eGFR and PELOD-2 severity score were the covariates explaining between-subject variability in CL and volume, respectively. According to the simulations, extended and continuous infusion provided the highest probability of reaching the target of 50% fT>MIC and 100% fT>MIC for normal and augmented renal clearance, respectively.

Conclusions: Unlike standard intermittent piperacillin dosing regimens, extended and continuous infusion allows the PK targets to be reached, for children with normal or augmented renal clearance.

Trial registration number: Registered at http://www.clinicaltrials.gov (NCT02539407).

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology
  • Bacteria / drug effects
  • Bacteria / growth & development
  • Child
  • Child, Preschool
  • Critical Illness
  • Female
  • Humans
  • Infant
  • Kidney / metabolism*
  • Male
  • Microbial Sensitivity Tests
  • Models, Biological
  • Piperacillin / pharmacokinetics*
  • Piperacillin / pharmacology
  • Tazobactam / pharmacokinetics


  • Anti-Bacterial Agents
  • Tazobactam
  • Piperacillin

Associated data

  • ClinicalTrials.gov/NCT02539407