Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function

Objectives: (1) To determine the pharmacokinetics of sequential intravenous and enteral fluconazole in the serum of surgical intensive care unit (ICU) patients with deep mycoses. (2) To determine the concentrations of flucona zole reached at the site of infection. (3) To determine if enteral administ ration of fluconazole, which has an important pharmaco-economic advantage, is justified in this specific patient group. Design: Descriptive, sequential study as a part of a therapeutic drug monit oring programme. Setting: Eighteen-bed surgical ICU in a referral centre. Patients: Fourteen critically ill surgical patients with recent gastro-inte stinal (GI) surgery and deep mycosis caused by a fluconazole-susceptible fu ngus and a calculated creatinine clearance of more than 40 ml/min. Interventions: Fluconazole dosage regimen: 400 mg i.v. every 24 h with an e xtra dose of 400 mg i.v. after 12 h on day 1. If the clinical condition all owed enteral administration on day 4, the content of two capsules of 200 mg was given via the feeding tube with concomitant enteral feeds. Measurements and main results: Serum, exudate from the site of infection an d urine samples collected at assumed steady state (after greater than or eq ual to5 doses). Fluconazole concentrations were determined by high-performa nce liquid chromatography (HPLC). The mean area under the concentration cur ve (AUC(0-24 h)) in serum after enteral administration did not significantl y differ from the AUC(0-24 h) during intravenous treatment. The elimination half-life was longer compared to healthy volunteers. The mean (95% CI) est imated bioavailability was 124 (90-158)%. The mean (95% CI) area under the concentration time curves (AUCs) achieved in the exudate from the site of i nfection were 67 (55-79)% of the AUCs reached in serum for both regimens. Conclusions: In critically ill patients with recent GI surgery and/or perit onitis the bioavailability of enteral fluconazole was adequate. The concent rations of fluconazole reached in exudate were lower than those in serum fo r both regimens, but adequate to treat most cases of deep mycoses in this s pecific patient group.