title: Biliary amphotericin B pharmacokinetics and pharmacodynamics in critically ill liver transplant recipients receiving treatment with amphotericin B lipid formulations.
abstract: Fungal cholangitis is a potentially life-threatening condition. As amphotericin B (AmB) has a broad antimycotic spectrum, in this study its biliary penetration and activity was determined in two patients treated with liposomal AmB (L-AmB) and in one patient receiving AmB colloidal dispersion (ABCD). Biliary and plasma AmB levels were quantified by high-performance liquid chromatography after purification by solid-phase extraction. For assessment of biliary AmB activity, isolates of Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei were incubated in porcine bile at AmB concentrations of 0.025-5.00 mg/L. In addition, patient bile samples retrieved for AmB quantification were inoculated with the same Candida strains. Biliary AmB concentrations were lower and displayed a slower rise and decline than plasma levels. The highest penetration ratio, as expressed by the ratio between the area under the AmB concentration-time curve in bile and plasma (liberated AmB) over the sampling period (AUC0-n bile/AUC0-n LI plasma), was 0.28. Proliferation of C. albicans and C. tropicalis in bile was similar to that in culture medium, whereas growth of C. glabrata was diminished and proliferation of C. krusei was absent in bile. In comparison with culture medium, AmB activity decreased in spiked porcine bile. In all but one patient bile sample, fungal growth was delayed or lacking even when AmB was not detectable. However, no fungicidal effect was observed in patient bile at AmB concentrations up to 1.28 mg/L. Thus, a reliable response of fungal cholangitis to treatment with L-AmB or ABCD cannot be anticipated.
authors.affiliation: Clinical Pharmacokinetics Unit, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: René
authors.initials: R
authors.lastname: Welte
authors.affiliation: Transplant Intensive Care Unit, Department of Anaesthesia and Critical Care, Centre of Operative Medicine, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Eschertzhuber
authors.affiliation: Clinical Pharmacokinetics Unit, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Weiler
authors.affiliation: Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Leitner-Rupprich
authors.affiliation: Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Aigner
authors.affiliation: Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.affiliation: Clinical Pharmacokinetics Unit, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Stienecke
authors.affiliation: Department of Internal Medicine VI, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bellmann-Weiler
authors.affiliation: Division of Intensive Care and Emergency Medicine, Department Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Joannidis
authors.affiliation: Clinical Pharmacokinetics Unit, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. Electronic address: romuald.bellmann@i-med.ac.at.
authors.forename: Romuald
authors.initials: R
authors.lastname: Bellmann
mesh_terms: D000368:Aged; D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001659:Biliary Tract / Q000737:chemistry*; D002175:Candida / Q000187:drug effects*; D016638:Critical Illness; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D050296:Microbial Viability / Q000187:drug effects; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D066027:Transplant Recipients
chemical_list: D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B
keywords: Ex vivo simulation; Fungal cholangitis; In vitro simulation; Liver transplantation; Polyene antifungals; Target-site pharmacokinetics