title: Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children.
abstract: The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.
authors.affiliation: Butler University College of Pharmacy and Health Sciences, Indianapolis, Indiana, USA Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, USA knichols@butler.edu.
authors.forename: Kristen
authors.initials: K
authors.lastname: Nichols
authors.affiliation: Purdue University College of Pharmacy, West Lafayette and Indianapolis, Indiana, USA.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Chung
authors.affiliation: Butler University College of Pharmacy and Health Sciences, Indianapolis, Indiana, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Knoderer
authors.affiliation: Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Buenger
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Healy
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dees
authors.affiliation: Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, USA Purdue University College of Pharmacy, West Lafayette and Indianapolis, Indiana, USA.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Crumby
authors.affiliation: Purdue University College of Pharmacy, West Lafayette and Indianapolis, Indiana, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kays
mesh_terms: D000367:Age Factors; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D016638:Critical Illness; D004334:Drug Administration Schedule; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007223:Infant; D007362:Intensive Care Units; 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; D012737:Sex Factors
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin