Mode of Action of Itraconazole: Morphological Aspects

Abstract

The broad spectrum of antifungal activity of itraconazole is verified by morphologic criteria at the light and electron microscopical level. Yeast and fungal species examined are Candida albicans, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Pityrosporum ovale, Trichophyton rubrum and Aspergillus fumigatus. Exposures of cultures of these yeasts and fungi to itraconazole results in dose- and time-dependent alterations which vary in nature and intensity from one species to another. The most striking gross morphological change is seen in the biphasic species and consists of the abolishment of morphogenic development of the blastospore into the hyphal forms (C. albicans and P. ovale) and of the hyphal into the yeast forms (P. brasiliensis). Furthermore, the outgrowth and development of inoculated A. fumigatus hyphae into sporulating vesicles is almost completely abolished. The above mentioned effects on morphogenesis are achieved in the 10(-10)-10(-7) M range. Except for P. ovale, the earliest ultrastructural changes after itraconazole consist of abnormalities at the plasma membrane, the cell wall and cytoplasmic vacuoles. They precede a marked increase in cell volume, defective cell division, abortive hyphal outgrowth and loss of cell viability. These changes are identical to those previously described after miconazole and ketoconazole treatment. However, when compared to the other available azole-derivatives sharing the same basic mechanisms of action, itraconazole displays an exceptionally strong activity against A. fumigatus which can be morphologically translated by a potent necrotizing action on hyphae and inhibition of vesicle formation and sporulation. The in vitro effects of itraconazole are supported by data obtained from microscopic examinations of samples derived from patients with experimental animals infected with various fungal organisms.