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Although antioxidants enhanced the antifungal properties of both amphotericin B and its methyl ester derivative, the effect was significantly more pronounced with amphotericin B. This disparity is explained on the basis of differences observed in the dynamics of drug action.

Four antioxidants, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, and d-alpha-tocopherol acid succinate were found to stabilize amphotericin B and to prolong its antifungal activity against Candida albicans. Although each of the antioxidants was effective in this respect, propyl gallate and butylated hydroxyanisole were better than butylated hydroxytoluene and d-alpha-tocopherol acid succinate. None of the antioxidants alone adversely affected normal cell growth. It is suggested that amphotericin B instability is due, at least in part, to lability of the carbon-carbon double bonds of the polyene moiety toward autoxidation. By protecting the drug molecule with an antioxidant, it is possible to significantly lower the quantity of AB necessary to obtain particular antifungal effects.

Results indicated that the antioxidant n-propyl gallate can enhance amphotericin B activity against Candida albicans by two different mechanisms. One involves drug stabilization. The second has not been characterized.

Results of earlier turbidimetric growth experiments showed that certain antioxidants prolonged the antifungal activity of amphotericin B (AB) against Candida albicans, presumably by retarding autoxidative destruction of the drug. Viability studies were designed to examine this in more detail. Subinhibitory concentrations of either butylated hydroxyanisole, n-propyl gallate, or nordihydroguaiaretic acid in combination with fungistatic levels of AB exerted synergistic fungicidal activity against two strains of C. albicans and one of C. parapsilosis. Although synergism was not seen in tests with a strain of Torulopsis glabrata, antioxidants prolonged the inhibitory action of AB against this organism. On the basis of these findings and other considerations that are discussed, it is suggested that stabilization of AB and the ability to act synergistically with AB represent two distinctly different effects of the antioxidants.

Amphotericin B (AMB)-5-fluorocytosine (5-FC) synergism has generally been observed in yeasts displaying 5-FC resistance. The present study was designed to assess activity of these drugs on yeasts showing susceptibility to 5-FC as well as AMB. Selected strains were incubated in a synthetic liquid medium with the test agents and viability or 14C-5-FC uptake was determined. Combinations of AMB and 5-FC continued to be inhibitory during the period that cultures treated with either drug alone were recovering from transient inhibition. In this sense, AMB + 5-FC exerted greater antifungal activity than either drug alone. However, combined activity did not involve AMB stimulation of 5-FC uptake by the organism. Results were indicative of sequential drug action.