Mode of action of clotrimazole: implications for therapy.

Ergosterol is an essential constituent of the fungal cytoplasmic membrane. Clotrimazole and other azoles interfere with the ergosterol biosynthesis in a concentration-dependent fashion. Although low concentrations exhibit only a partially inhibitory effect, high concentrations may completely block ergosterol synthesis. Reduction of fungal growth and inhibition of growth and fungicidal action during prolonged incubation are the corresponding effects at the cellular level that are a consequence of ergosterol depletion. The inoculum effect, the influence of the incubation period, and the influence of nutrient media, three factors that often complicate susceptibility testing in vitro, can also be explained by the mode of action of azole compounds. Another interesting characteristic of azole antifungals was revealed by the observation that hyphae and pseudomycelia of Candida albicans are much more susceptible to azoles than are yeast cells. Even 1% of the minimum inhibitory concentration of clotrimazole may totally inhibit mycelial growth in vitro. This may be of clinical importance, since germination was reported to enhance adherence of C. albicans to buccal and vaginal epithelial cells.

The combined action of azlocillin and sisomicin in a model simulating the in vivo serum kinetics.

The in vivo serum kinetics of azlocillin and sisomicin were simulated in a new in vitro test model. A strong synergistic effect against Pseudomonas aeruginosa resulted when both compounds were administered simultaneously and eliminated according to their individual half-life values, even when the decreasing drug concentrations exceeded the MICs for only a short period of time. When applied at intervals, neither pretreatment with azlocillin nor with sisomicin blocked the antibacterial activity of the combination partner.

[Experimental aspergillosis in mice]. / L'aspergillose expérimentale de la souris.

The experimentally induced aspergillosis of mice is discussed as a useful parameter for the screening of new antimycotics. There are important differences between this test model and aspergillus infections in humans. Mice must be infected intravenously with more than 10(6) spores of Aspergillus fumigatus to provoke multiple abscess formation in the kidneys which induces an acute, lethal course of infection. Intratracheal administration of 2 x 10(6) spores did not evoke any symptoms. The therapeutic efficacy of several antimycotics was examined; amphotericin B, 5-fluorocytosine and BAY h 4364--as the only imidazole-derivative--proved to be effective.

Experimental in vitro and in vivo comparison of modern antimycotics.

Studies were carried out with the current leading antimycotic agents, using identical test methods, to compare their activity in vitro and in animal in vivo experiments. In the broth dilution test, the minimum inhibitory concentrations against approximately 50 strains of the most important species of yeasts, dermatophytes and moulds were determined using different culture media. Efficacy against yeasts was examined in experimentally-induced candidosis in mice treated orally, and against dermatophytes in experimentally-induced trichophytia in guinea pigs receiving topical treatment. The results showed that the imidazole derivatives studied can be regarded as true broad-spectrum antimycotics, and clotrimazole, in particular, had a well-balanced overall effect. The significance of the experimental data with respect to therapeutic efficacy in man in various indications is discussed.