Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model
| Autor: | Otto Cars, Elisabeth Löwdin, Anders Lignell, Jan Sjölin |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Microbiology (medical)
Posaconazole Antifungal Agents Time Factors medicine.drug_class Antibiotics Microbial Sensitivity Tests Pharmacology Biology Models Biological Microbiology Minimum inhibitory concentration Amphotericin B Candida albicans medicine Humans Pharmacology (medical) Voriconazole Microbial Viability Dose-Response Relationship Drug Triazoles biology.organism_classification Antimicrobial Corpus albicans Infectious Diseases Pyrimidines Drug Antagonism medicine.drug |
| Zdroj: | The Journal of antimicrobial chemotherapy. 62(1) |
| ISSN: | 1460-2091 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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