title: Plasma and target-site subcutaneous tissue population pharmacokinetics and dosing simulations of cefazolin in post-trauma critically ill patients.
abstract: OBJECTIVE
  The objective of this study was to describe the population pharmacokinetics of cefazolin in plasma and the interstitial fluid of subcutaneous tissue of post-trauma critically ill patients and provide clinically relevant dosing recommendations that result in optimal concentrations at the target site.
  
  
  METHODS
  This was a pharmacokinetic study in a tertiary referral ICU. We recruited 30 post-trauma critically ill adult patients and collected serial total and unbound plasma cefazolin concentrations. Interstitial fluid concentrations were determined using in vivo microdialysis. Population pharmacokinetic analysis and Monte Carlo simulations were undertaken with Pmetrics(®). Fractional target attainment against an MIC distribution for Staphylococcus aureus isolates was calculated.
  
  
  RESULTS
  The mean (SD) age, weight, APACHE II score and CLCR were 37.0 (14.1) years, 86.8 (22.7) kg, 16.9 (5.3) and 163 (44) mL/min, respectively. A three-compartment linear population pharmacokinetic model was most appropriate. Covariates included in the model were CLCR on drug clearance and serum albumin concentration and body weight on the volume of the central compartment. The fractional target attainment for a 1 g intravenous 8-hourly dose for a CLCR of 50 mL/min was 88%, whereas for a patient with a CLCR of 215 mL/min, a dose of 2 g 6-hourly achieved 84% fractional target attainment.
  
  
  CONCLUSIONS
  Clinicians should be mindful of the effects of elevated CLCR and serum albumin concentrations on dosing requirements for post-trauma critically ill patients.
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Department of Intensive Care Medicine, Royal Brisbane and Womens' Hospital, Brisbane, Australia Pharmacy Department, Royal Brisbane and Womens' Hospital, Brisbane, Australia Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Udy
authors.affiliation: Pharmacy Department, Royal Brisbane and Womens' Hospital, Brisbane, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.affiliation: Liverpool School for Tropical Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Centre for Medicine Use and Safety, Monash University, Melbourne, Australia.
authors.forename: Carl M J
authors.initials: CM
authors.lastname: Kirkpatrick
authors.affiliation: Department of Intensive Care Medicine, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kruger
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Department of Intensive Care Medicine, Royal Brisbane and Womens' Hospital, Brisbane, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D056808:Biostatistics; D002437:Cefazolin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D010949:Plasma / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D040521:Subcutaneous Tissue / Q000737:chemistry*; D014947:Wounds and Injuries / Q000150:complications*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002437:Cefazolin
keywords: Monte Carlo simulations; PK; antibiotics; microdialysis; pharmacodynamics