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

Sinnollareddy, Mahipal G., Roberts, Michael S., Lipman, Jeffrey, Lassig-Smith, Melissa, Starr, Therese, Robertson, Thomas, Peake, Sandra L. and Roberts, Jason A. (2016) In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis. Antimicrobial Agents and Chemotherapy, 60 2: 827-832. doi:10.1128/AAC.02461-15

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Author Sinnollareddy, Mahipal G.
Roberts, Michael S.
Lipman, Jeffrey
Lassig-Smith, Melissa
Starr, Therese
Robertson, Thomas
Peake, Sandra L.
Roberts, Jason A.
Title In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis
Formatted title
In vivo microdialysis to determine subcutaneous interstitial fluid penetration and pharmacokinetics of fluconazole in intensive care unit patients with sepsis
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
1098-6596
Publication date 2016-02
Sub-type Article (original research)
DOI 10.1128/AAC.02461-15
Open Access Status File (Publisher version)
Volume 60
Issue 2
Start page 827
End page 832
Total pages 6
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2017
Language eng
Formatted 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, R2 = 0.86, P < 0.0001; Cmin, R2 = 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.
Keyword Critically-Ill Patients
Blood-Stream Infections
Septic Shock
Tissue Distribution
Dosing Simulations
Candida
Pharmacodynamics
Mortality
Healthy
Plasma
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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