title: Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children.
abstract: BACKGROUND
  Fluconazole is recommended as first-line treatment in invasive candidiasis in children and infants. Although timely achievement of adequate exposure of fluconazole improves outcome, therapeutic drug monitoring is currently not recommended.
  
  
  METHODS
  We conducted a retrospective study of critically ill children treated with fluconazole from January 2007 to October 2013 and for whom fluconazole concentrations were available. We collected demographic, clinical, and treatment data through review of the medical records and determined the correlation of clinical variables with the fluconazole concentration. Additionally, we assessed the relation between the fluconazole concentration and the time to culture conversion in patients with proven invasive candidiasis.
  
  
  RESULTS
  In total, 99 pediatric patients met the inclusion criteria. The fluconazole concentration was considered subtherapeutic in 40% of the patients. Multiple linear regression analysis showed a significant, independent, and positive association of the fluconazole trough concentration with the fluconazole dose (P <.001), weight (P = .009), and the serum urea concentration (P = .003), and a significant, independent, and negative association with age (P = .004) and cancer as an underlying condition (P = .003). A higher fluconazole concentration was associated with a shorter time to culture conversion (hazard ratio = 1.076 [95% confidence interval, 1.017-1.138]; P = .011).
  
  
  CONCLUSIONS
  The fluconazole concentration is not sufficient in pediatric cancer patients with the currently recommended dose regimen, and a higher fluconazole dose is required to achieve adequate drug exposure. Therapeutic drug monitoring of fluconazole can be a valuable tool to detect possible underexposure in critically ill children.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology.
authors.forename: Kim C M
authors.initials: KC
authors.lastname: van der Elst
authors.affiliation: Department of Clinical Pharmacy and Pharmacology.
authors.forename: Marieke
authors.initials: M
authors.lastname: Pereboom
authors.affiliation: Department of Epidemiology.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: van den Heuvel
authors.affiliation: Department of Clinical Pharmacy and Pharmacology Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care.
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: Department of Pediatrics (Infection/Immunology), University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Elisabeth H
authors.initials: EH
authors.lastname: Schölvinck
authors.affiliation: Department of Clinical Pharmacy and Pharmacology.
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000293:Adolescent; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D002177:Candidiasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D009369:Neoplasms / Q000378:metabolism / Q000382:microbiology*; D009426:Netherlands; D012189:Retrospective Studies
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole
keywords: fluconazole; pediatric patients; pharmacokinetics; therapeutic drug monitoring