In Vivo Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis

Mahipal G. Sinnollareddy, Michael S. Roberts, Jeffrey Lipman, Melissa Lassig-Smith, Therese Starr, Thomas Robertson, Sandra L. Peake, Jason A. Roberts

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 steady state concentrations were measured over 24 hours in plasma and subcutaneous ISF using microdialysis. Plasma and microdialysis concentrations were measured using a validated High Performance Liquid Chromatography system with Electrospray Mass Spectrometer detector method. Non-compartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean ± standard deviation (SD) in vivo fluconazole recovery rates for microdialysis were 51.4 ± 16.1% with mean ± SD fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation 58%). The median free plasma AUC0-24 was significantly higher than the median ISF AUC0-24 (340.4 vs. 141.1 mg.h/L; p = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median 0.28 vs. 0.78; p = 0.106). Both 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 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 to recognize patients with reduced distribution/exposures, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.