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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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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.

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
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-13451DOI: 10.1111/j.1469-0691.2007.01710.xISI: 000246199300008PubMedID: 17378925OAI: oai:DiVA.org:uu-13451DiVA: diva2:41221
Available from: 2008-01-23 Created: 2008-01-23 Last updated: 2017-12-11Bibliographically approved
In thesis
1. In vitro Pharmacodynamics of Antifungal Agents in the Treatment of Candida Infections
Open this publication in new window or tab >>In vitro Pharmacodynamics of Antifungal Agents in the Treatment of Candida Infections
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacodynamic studies are important for the optimal use of antimicrobial agents. Combination antifungal therapy may be one method to improve outcome in invasive Candida infections. An in vitro kinetic model to study the pharmacodynamic effects of a combination of two antifungal agents with different elimination rates was developed and the pharmacodynamics of amphotericin B (AMB), voriconazole (VRC) or the combination was evaluated. Exposure to VRC inhibited the fungicidal activity of sequential doses of AMB against VRC-susceptible strains of C. albicans. The interaction was VRC dose-dependent. AMB activity was regained once VRC was removed or it increased gradually when the concentration of VRC had fallen below the minimum inhibitory concentration (MIC). The VRC-AMB interaction, however, was also present against strains of C. albicans, C. glabrata and C. krusei despite reduced VRC susceptibility. Against these strains the interaction was not predicted by the MIC value, suggesting that mechanisms of resistance may be of importance. Until more data are available, a reasonable recommendation is probably to avoid the sequential use of VRC followed by AMB and to use the combination of VRC and AMB for the treatment of Candida infections with caution.

Only the unbound fraction of a drug is generally accepted as pharmacologically active. The activity of posaconazole (POS) with a protein binding of 98-99% was tested in serum against Candida species and compared with the calculated unbound serum concentration in protein-free media. Significant differences emerged at clinically relevant POS serum concentrations of 1.0 and 0.10 mg/l compared with the serum control regimen against one strain of C. lusitaniae. In RPMI 1640 the corresponding calculated unbound concentrations resulted in no effect for the low dose regimen compared with the RPMI 1640 control regimen. Further, against seven additional Candida strains tested, the effect of POS was greater in serum than in RPMI 1640. A flux from serum protein bound to fungal lanosterol 14α-demethylase bound POS may be the explanatory mechanism.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 83 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 633
Keyword
amphotericin B, antagonism, Candida, human serum, inhibition, interaction, in vitro, kinetic model, pharmacodynamics, pharmacokinetics, posaconazole, protein binding, voriconazole
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-133781 (URN)978-91-554-7974-9 (ISBN)
Public defence
2011-01-29, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:15 (Swedish)
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Available from: 2011-01-05 Created: 2010-11-16 Last updated: 2011-03-11Bibliographically approved

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Lignell, AndersLöwdin, ElisabethCars, OttoSjölin, Jan

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