Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function.
OBJECTIVE
(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 fluconazole reached at the site of infection. (3) To determine if enteral administration of fluconazole, which has an important pharmaco-economic advantage, is justified in this specific patient group.


METHODS
Descriptive, sequential study as a part of a therapeutic drug monitoring programme.


METHODS
Eighteen-bed surgical ICU in a referral centre.


METHODS
Fourteen critically ill surgical patients with recent gastro-intestinal (GI) surgery and deep mycosis caused by a fluconazole-susceptible fungus and a calculated creatinine clearance of more than 40 ml/min.


METHODS
Fluconazole dosage regimen: 400 mg i. v. every 24 h with an extra dose of 400 mg i.v. after 12 h on day 1. If the clinical condition allowed enteral administration on day 4, the content of two capsules of 200 mg was given via the feeding tube with concomitant enteral feeds.


RESULTS
Serum, exudate from the site of infection and urine samples collected at assumed steady state ( after > or = 5 doses). Fluconazole concentrations were determined by high-performance liquid chromatography (HPLC). The mean area under the concentration curve (AUC0-24 h) in serum after enteral administration did not significantly differ from the AUC0-24 h during intravenous treatment. The elimination half-life was longer compared to healthy volunteers. The mean (95% CI) estimated bioavailability was 124 (90-158)%. The mean (95% CI) area under the concentration time curves (AUCs) achieved in the exudate from the site of infection were 67 (55-79)% of the AUCs reached in serum for both regimens.


CONCLUSIONS
In critically ill patients with recent GI surgery and/or peritonitis the bioavailability of enteral fluconazole was adequate. The concentrations of fluconazole reached in exudate were lower than those in serum for both regimens, but adequate to treat most cases of deep mycoses in this specific patient group.
Department of Surgical Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands. buijk@rdgg.nl
S L
SL
Buijk
I C
IC
Gyssens
J W
JW
Mouton
H A
HA
Verbrugh
D J
DJ
Touw
H A
HA
Bruining
D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D013505:Digestive System Surgical Procedures; D004750:Enteral Nutrition; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016469:Fungemia / Q000188:drug therapy / Q000382:microbiology; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007362:Intensive Care Units; D008297:Male; D008480:Mediastinitis / Q000188:drug therapy / Q000382:microbiology; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology*; D011183:Postoperative Complications / Q000188:drug therapy / Q000382:microbiology*; D018709:Statistics, Nonparametric
D000935:Antifungal Agents; D015725:Fluconazole