The antifungal activities of four tetracycline analogues in combination with amphotericin B (AmB) were determined against 20 strains of Candida albicans. When a microtiter checkerboard technique was used, minocycline (less than or equal to 10 microgram/ml) acted synergistically with AmB against all strains, whereas doxycycline had a reduced effect, and demeclocycline and tetracycline had no potentiating effect at this concentration. Killing-curve experiments with two strains of C. albicans demonstrated that the combination of minocycline and AmB produced a decrease in number of colony-forming units (cfu) of greater than 2 logs in 4 hr and a 4-log decrease in cfu in 24 hr at concentrations (minocycline, 0.64 microgram/ml; AmB, 0.1 microgram/ml) that were subinhibitory when each agent was used alone and that are readily achieved in human serum and body fluids with conventional doses. The killing-curve technique indicated that doxycycline had an intermediate degree of synergistic activity, whereas tetracycline had no synergistic activity at clinically relevant concentrations.

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The capacity of minocycline to enhance the activity of amphotericin B against Candida albicans, Torulopsis glabrata, Cryptococcus neoformans , and non- albicans Candida was examined in vitro utilizing a time-killing curve technique. Synergism was apparent at 4 h with 5 of 5 strains of C. albicans , 8 of 8 strains of C. neoformans , and 1 of 12 strains of non- albicans Candida . Synergism was apparent at 24 h with the remaining 11 strains of non- albicans Candida and all 5 strains of T. glabrata. C. neoformans was the most susceptible of the yeasts to the minocycline-amphotericin B combination; seven strains showed a 3-log or greater reduction in colony count in 4 h and all strains showed this reduction in 24 h at amphotericin B concentrations of 0.4 μg/ml or less in the presence of minocycline.

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