Combined Activity of Minocycline and Amphotericin B In Vitro Against Medically Important Yeasts

Thecapacity ofminocycline toenhance theactivity ofamphotericin B against Candidaalbicans, Torulopsis glabrata, Cryptococcus neoformans, andnonalbicans Candida was examined invitro utilizing atime-killing curvetechnique. Synergism was apparent at4hwith5of5strains ofC.albicans, 8of8strains of C.neoformans, and1of12strains ofnon-albicans Candida. Synergism was apparent at24hwiththeremaining 11strains ofnon-albicans Candida andall 5strains ofT.glabrata. C.neoformans was themostsusceptible oftheyeasts to theminocycline-amphotericin combination; seven strains showed a 3-log or greater reduction incolony countin4handallstrains showedthis reduction in 24h atamphotericin B concentrations of0.4,tg/ml or less inthepresence of minocycline. Tetracycline hasnouseful activity against intact yeastcells, although itinhibits protein synthesis bycell-free yeast ribosomes (2). Kwan andco-workers noted thattetracycline, ataconcentration of100,tg/ml, actedsynergistically withamphotericin B (AmB)against astrain of Saccharomyces cerevisiae invitro (6), andtetracycline subsequently wasshowntopotentiate theeffect ofAmB intreating experimental coccidioidomycosis inmice(5). Thesefindings prompted ustoexplore thepossibility that other analogs oftetracycline wouldpossess greater antifungal activity whencombined withAmB. Initially, wetested fourtetracycline analogs individually andincombination withAmBinvitro against 20strains ofCandida albicans (7). Minocycline, arelatively lipid-soluble analog, potentiated theactivity ofAmB against all strains atmuchlower concentrations thandidtheother analogs tested. Killing-curve studies withtwo Candida isolates indicated thatminocycline, in thepresence ofsubinhibitory levels ofAmB, exerted fungicidal effects atconcentrations that areattainable inhumanserumwithoral therapy.Wenowdescribe theactivity ofminocycline andAmB invitro against other species ofmedically important yeasts andagainst additional strains ofC.albicans. (This workwaspresented inpartatthe17th Interscience Conference on Antimicrobial Agents andChemotherapy, October, 1977.)