Fundamental Studies on Combined Effect of Antifungal Agents

Visceral mycosis has become a worldwide problem recently, and many important problems in it's diagnosis, treatment and control are towering before us. Several strains of Candida albicans and Aspergillus fumigatus kuboyama strain were examined for their susceptibility to five antifungal agents separately and in combination using an in vitro agar dilution or microdilution assay. Media were Sabouraud dextrose agar and yeast nitrogen base supplemented with 1% glucose and 0.25% K₂HPO₄. The antifungal agents were amphotericin B (AMPH), 5-fluorocytosine (5-FC), miconazole, fluconazole and itraconazole. The cumulative mortality rate and histopathological findings in experimental candidiasis and the experimental pulmonary aspergillosis using a newly devised aerosol exposure apparatus treated with each of the five drugs were studied. Determinations were made of intracellular concentrations of 5-FC of C. albicans in yeast nitrogen base with or without AMPH. The levels of the antifungal agents in serum of human and mouse were also calculated. Synergistic effect of 5-FC and AMPH was found not only in vitro but in vivo. No significant difference in pharmacokinetics of 5-FC by single or combined administration was observed and Candida intracellular levels of 5-FC increased in parallel with the concentration of AMPH. No significant effects were noted in combinations with other drugs, but we must be very much aware that a precise method for evaluation of susceptibility in vitro has not yet been developed and the pharmacokinetics differ between human and animals. Detailed analysis of this point would be matter for further research.