Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/99236
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Type: Journal article
Title: In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis
Author: Sinnollareddy, M.
Roberts, M.
Lipman, J.
Lassig-Smith, M.
Starr, T.
Robertson, T.
Peake, S.
Roberts, J.
Citation: Antimicrobial Agents and Chemotherapy, 2016; 60(2):827-832
Publisher: American Society for Microbiology
Issue Date: 2016
ISSN: 0066-4804
1098-6596
Statement of
Responsibility: 
Mahipal G. Sinnollareddy, Michael S. Roberts, Jeffrey Lipman, Melissa Lassig-Smith, Therese Starr, Thomas Robertson, Sandra L. Peake, Jason A. Roberts
Abstract: The 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.
Keywords: Extracellular Fluid; Humans; Candida; Candidiasis; Fluconazole; Antifungal Agents; Critical Care; Chromatography, High Pressure Liquid; Microdialysis; Spectrometry, Mass, Electrospray Ionization; Prospective Studies; Adult; Aged; Middle Aged; Intensive Care Units; Australia; Female; Male; Candidemia; Tertiary Care Centers
Rights: Copyright © 2016, American Society for Microbiology. All Rights Reserved.
RMID: 0030041826
DOI: 10.1128/AAC.02461-15
Grant ID: http://purl.org/au-research/grants/nhmrc/1048652
Appears in Collections:Anaesthesia and Intensive Care publications

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