title: Dose optimization of piperacillin/tazobactam in critically ill children.
abstract: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.forename: Pieter A J G
authors.initials: PAJG
authors.lastname: De Cock
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333?CC Leiden, the Netherlands.
authors.forename: Sven C
authors.initials: SC
authors.lastname: van Dijkman
authors.affiliation: Department of Paediatric Intensive Care, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: de Jaeger
authors.affiliation: Department of Paediatric Intensive Care, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Willems
authors.affiliation: Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Carlier
authors.affiliation: Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.|Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Alain G
authors.initials: AG
authors.lastname: Verstraete
authors.affiliation: Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.|Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Joris R
authors.initials: JR
authors.lastname: Delanghe
authors.affiliation: Department of Pharmacy, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Robays
authors.affiliation: Department of Paediatric Nephrology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vande Walle
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 CC Leiden, the Netherlands.|Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Stockley Park, Uxbridge, UK.|Clinical Pharmacology and Therapeutics, BMA House, Tavistock Square, London WC1H 9HX, UK.
authors.forename: Oscar E
authors.initials: OE
authors.lastname: Della Pasqua
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Paepe
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination; D011446:Prospective Studies; D000078142:Tazobactam
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin