title: Population pharmacokinetics and dosing simulations of cefuroxime in critically ill patients: non-standard dosing approaches are required to achieve therapeutic exposures.
abstract: OBJECTIVE
  To investigate the population pharmacokinetics of cefuroxime in critically ill patients.
  
  
  METHODS
  In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling.
  
  
  RESULTS
  One hundred and sixty blood samples were collected from 20 patients. CL(CR) ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CL(CR) was supported as a descriptor of drug CL. The population model for CL was CL = θ(1) × CL(CR)/100, where θ(1) is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT(>MIC) for an MIC of 8 mg/L with standard dosing regimens for patients with CL(CR) ≥50 mL/min.
  
  
  CONCLUSIONS
  Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CL(CR) of ≥300 mL/min if the MIC is 8 mg/L.
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium mieke.carlier@ugent.be.
authors.forename: Mieke
authors.initials: M
authors.lastname: Carlier
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Noë
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Stove
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Alain G
authors.initials: AG
authors.lastname: Verstraete
authors.affiliation: Burns, Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: De Waele
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D002444:Cefuroxime / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D016638:Critical Illness; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D011446:Prospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D002444:Cefuroxime
keywords: ICUs; PK/PD; antibiotics; cephalosporins; critical care medicine; β-lactams