In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis

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dc.contributor.authorSinnollareddy, M.G.
dc.contributor.authorRoberts, M.S.
dc.contributor.authorLipman, J.
dc.contributor.authorLassig-Smith, M.
dc.contributor.authorStarr, T.
dc.contributor.authorRobertson, T.
dc.contributor.authorPeake, S.L.
dc.contributor.authorRoberts, J.A.
dc.date.issued2016
dc.description.abstractThe objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) was significantly higher than the median ISF AUC0-24 (340.4 versus 141.1 mg · h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (Cmax and Cmin) showed a significant correlation with the fluconazole plasma exposure (Cmax, R(2) = 0.86, P < 0.0001; Cmin, R(2) = 0.75, P < 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.
dc.description.statementofresponsibilityMahipal G. Sinnollareddy, Michael S. Roberts, Jeffrey Lipman, Melissa Lassig-Smith, Therese Starr, Thomas Robertson, Sandra L. Peake, Jason A. Roberts
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 2016; 60(2):827-832
dc.identifier.doi10.1128/AAC.02461-15
dc.identifier.issn0066-4804
dc.identifier.issn1098-6596
dc.identifier.orcidPeake, S.L. [0000-0001-6682-7973]
dc.identifier.urihttp://hdl.handle.net/2440/99236
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1048652
dc.rightsCopyright © 2016, American Society for Microbiology. All Rights Reserved.
dc.source.urihttps://doi.org/10.1128/aac.02461-15
dc.subjectExtracellular Fluid
dc.subjectHumans
dc.subjectCandida
dc.subjectCandidiasis
dc.subjectFluconazole
dc.subjectAntifungal Agents
dc.subjectCritical Care
dc.subjectChromatography, High Pressure Liquid
dc.subjectMicrodialysis
dc.subjectSpectrometry, Mass, Electrospray Ionization
dc.subjectProspective Studies
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectIntensive Care Units
dc.subjectAustralia
dc.subjectFemale
dc.subjectMale
dc.subjectCandidemia
dc.subjectTertiary Care Centers
dc.titleIn vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis
dc.typeJournal article
pubs.publication-statusPublished

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