title: Fluconazole loading dose pharmacokinetics and safety in infants.
abstract: BACKGROUND
  Invasive candidiasis is a leading cause of morbidity and mortality in critically ill infants. Prompt administration of fluconazole and achievement of the therapeutic target (area under the curve 0 to 24 hours >400 mg*h/L) improve outcomes in candidemic patients. A loading dose of fluconazole is advised for older patients but has not been evaluated in infants. We sought to determine the pharmacokinetics and safety of a fluconazole loading dose in infants at risk for invasive fungal infection.
  
  
  METHODS
  We enrolled 10 hospitalized infants <60 days old with suspected systemic fungal infection in this open-label study; 9 received a 25-mg/kg fluconazole loading dose followed by a maintenance dose of 12 mg/kg every 24 hours for 4 additional days. Plasma samples were obtained following the loading and steady-state doses (doses 3-5). We used a 1-compartment model to fit the data to estimate pharmacokinetic indices.
  
  
  RESULTS
  Data from 57 drug concentrations obtained from 8 infants (median postnatal age, 16 days [interquartile range, 13-32] and median gestational age, 37 weeks [35-38]) showed that the median fluconazole area under the curve 0 to 24 hours (mg*h/L) in this population was 479 (347-496). Of the 8 infants who received the loading dose, 5 (63%) achieved the therapeutic target on the first day of dosing, and all infants achieved a fluconazole 24-hour trough concentration >8 μg/mL. No adverse events were thought to be related to fluconazole therapy.
  
  
  CONCLUSIONS
  A loading dose of fluconazole (25 mg/kg) was safe in this small cohort of young infants and achieved the therapeutic target more rapidly than traditional dosing.
authors.affiliation: Department of Pediatrics and Duke Clinical Research Institute, Duke University, Durham, NC, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Piper
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Hornik
authors.forename: Ira M
authors.initials: IM
authors.lastname: Cheifetz
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Ganesh
authors.initials: G
authors.lastname: Moorthy
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.forename: Kelly C
authors.initials: KC
authors.lastname: Wade
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002177:Candidiasis / Q000188:drug therapy*; D002853:Chromatography, Liquid; D015725:Fluconazole / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D010949:Plasma / Q000737:chemistry; D053719:Tandem Mass Spectrometry
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole