Abstract
Cryptococcus neoformans is the leading cause of fungal meningitis, a life-threatening infection that occurs predominately in immuocompromised patients. Current drug therapies are limited to amphotericin B, flucytosine and the azoles since the echinocandins have no demonstrated activity against yeast like pathogens. Fluconazole, a drug belonging to the azole class and often the only available antifungal in the developing world, is fungistatic and therefore not effective in clearing cryptococcal infections in immunosuppressed individuals. Here we report that astemizole and a closely related analog (A2) promoted in vitro fungicidal activity of fluconazole against Cryptococcus neoformans var. grubii and Cryptococcus gattii. Astemizole, a second-generation antihistamine drug used as an H1 antagonist, has also been found to have antimalarial activity. Disk diffusion assays and MIC and MFC analysis confirmed that the inhibitory concentrations of these drug combinations were fungicidal. When tested in vivo, astemizole or A2 in combination with fluconazole significantly improved the survival of Galleria mellonella (wax moth caterpillar) that had been previously challenged with C. neoformans but not when caterpillars were challenged with a fluconazole-resistant strain. The findings reported here suggest that fungicidal combinations between azoles and other existing drugs may represent an alternative strategy for improving treatments for fungal infections.
Acknowledgements
We thank E. Mylonakis for technical help with the experiments using Galleria mellonella. We are especially grateful to J. Heitman and his group for hosting and training K. Vu in G. mellonella techniques. We are also indebted to E. Blumwald for discussions and critical reading of the manuscript. Financial support was provided by a NIHAID grant to A.G. and a NIHAID training grant to K.V.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
This paper was first published online on Early Online on 01 February 2010.