Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation.

Published

Journal Article

Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics; thus, standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the pharmacokinetics of fluconazole in infants on ECMO.Infants <120 days of age received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected preoxygenator and postoxygenator around doses 1 and 2 to calculate pharmacokinetic indices and describe oxygenator extraction. A 1-compartment model was fit to the data using nonlinear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.Ten infants were enrolled. After dose 1 (n = 9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg and the median exposure in the first 24 hours (area under the curve from 0 to 24 hours) was 322 h × mg/L. After multiple doses (n = 7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg and the area under the curve from 0 to 24 hours was 352 h × mg/L. After dose 1, 78% of infants achieved the prophylaxis target, whereas only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (-2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (ρ= -0.05). There were no adverse events related to fluconazole.Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.

Full Text

Duke Authors

Cited Authors

  • Watt, KM; Benjamin, DK; Cheifetz, IM; Moorthy, G; Wade, KC; Smith, PB; Brouwer, KLR; Capparelli, EV; Cohen-Wolkowiez, M

Published Date

  • October 2012

Published In

Volume / Issue

  • 31 / 10

Start / End Page

  • 1042 - 1047

PubMed ID

  • 22627870

Pubmed Central ID

  • 22627870

Electronic International Standard Serial Number (EISSN)

  • 1532-0987

International Standard Serial Number (ISSN)

  • 0891-3668

Digital Object Identifier (DOI)

  • 10.1097/INF.0b013e31825d3091

Language

  • eng