IN-VITRO EVALUATION OF COMBINATION OF FLUCONAZOLE AND FLUCYTOSINE AGAINST CRYPTOCOCCUS-NEOFORMANS VAR NEOFORMANS

Amphotericin B and fluconazole are current acceptable therapies for cr yptococcal meningitis; however, their effect remains suboptimal. The c ombination of fluconazole and flucytosine has yielded encouraging clin ical results in human immunodeficiency virus patients,vith cryptococca l meningitis, To investigate the biological basis of this finding, we performed in vitro combination testing of fluconazole and flucytosine against 50 clinical strains of Cryptococcus neoformans var, neoformans , Synergy (fractional inhibitory concentration index of <1.0) was obse rved in 62% of cases, while antagonism (fractional inhibitory concentr ation index of >2.0) was not observed, For cases in which synergy was not achieved (autonomous or additive effects), the beneficial effect o f the combination was still seen (i.e,, there was still a decrease, al though not as dramatic, in the MIC of one or both drugs when used in c ombination), The in vitro inhibitory action of flucytosine was greatly enhanced by the addition of fluconazole; the flucytosine MICs for Cry ptococcus isolates were markedly decreased to concentrations which wer e severalfold lower than the achievable cerebrospinal fluid flucytosin e concentration, On the other hand, the addition of flucytosine did no t greatly enhance the in vitro activity of fluconazole if the initial fluconazole MIC for the isolate was greater than or equal to 8 mu g/ml . Controlled clinical studies are warranted to further elucidate the p otential utility of fluconazole-flucytosine combination therapy.