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A new in-vitro kinetic model to study the pharmacodynamics of antifungal agents: Inhibition of the fungicidal activity of amphotericin B against Candida albicans by voriconazole
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
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2007 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 13, no 6, 613-619 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to develop and validate a new in-vitro kinetic model for the combination of two drugs with different half-lives, and to use this model for the study of the pharmacodynamic effects of amphotericin B and voriconazole, alone or in combination, against a strain of Candida albicans. Bolus doses of voriconazole and amphotericin B were administered to a starting inoculum of C. albicans. Antifungal-containing medium was eliminated and replaced by fresh medium using a peristaltic pump, with the flow-rate adjusted to obtain the desired half-life of the drug with the shorter half-life. A computer-controlled dosing pump compensated for the agent with the longer half-life. Voriconazole and amphotericin B half-lives were set to 6 and 24 h, respectively. Pharmacokinetic parameters were close to target values when both single doses and sequential doses were simulated. Voriconazole and amphotericin B administered alone demonstrated fungistatic and fungicidal activity, respectively. Simultaneous administration resulted in fungicidal activity, whereas pre-exposure of C. albicans to voriconazole, followed by amphotericin at 8 and 32 h, resulted in fungistatic activity similar to that observed with voriconazole alone. Using this model, which allowed a combination of antifungal agents with different half-lives, it was possible to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of amphotericin B. The characteristics and clinical relevance of this interaction require further investigation. © 2007 European Society of Clinical Microbiology and Infectious Diseases.

Place, publisher, year, edition, pages
2007. Vol. 13, no 6, 613-619 p.
Keyword [en]
Amphotericin B, Antagonism, Candida albicans, Kinetic model, Pharmacodynamics, Voriconazole
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-49632DOI: 10.1111/j.1469-0691.2007.01710.xOAI: oai:DiVA.org:liu-49632DiVA: diva2:270528
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-12

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