The three imidazole antimycotics clotrimazole, miconazole, and ketoconazole all inhibit the demethylation of lanosterol to ergosterol, resulting in inhibition of growth of Saccharomyces cerevisiae; this is a fungistatic action. At higher concentrations clotrimazole and miconazole are fungicidal, whereas ketoconazole is not. The fungicidal action reflects direct membrane damage by the imidazoles. Evidence for this is that ketoconazole is markedly less active than the other imidazoles in its ability to allow methylene blue entry into cells and to disrupt liposome model membranes. The possible clinical significance of these findings is discussed.

The mechanism of the antifungal action of the imidazole antimycotics, miconazole ano clotrimazole, on Saccharomyces cerevisiae was explored. When grown aerobically both drugs were fungistatic at low concentrations and fungicidal at high concentrations. When grown anaerobically the fungistatic effect was not seen, but killing still occurred at high concentrations. The fungistatic effect correlated with inhibition of ergosterol synthesis and elevated lanosterol/ergosterol ratios in the organisms. The fungicidal effect involved rapid membrane damage and was unrelated to the imidazole-induced block in ergosterol synthesis. These agents each have 2 distinct antifungal actions.

In Staphylococcus aureus, using the imidazoles miconazole and ketoconazole, detailed studies of minimal inhibitory concentrations, kinetics of growth, viability, and release of intracellular K+ confirm that the two imidazoles work differently in this bacterium. Miconazole is bactericidal at low concentrations and causes release of cellular K+. Ketoconazole has no bactericidal effect at any tested concentration and has little effect on K+ permeability of S. aureus; it slows growth at high concentration. This is reflected in a low minimal inhibitory concentration for miconazole and a high one for ketoconazole. The probable mechanisms of the bacteriostatic and bactericidal effects of the imidazoles are discussed in light of these results and the previously described antifungal mechanisms of the drugs. alpha-Tocopherol blocks the action of both imidazoles.

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