Amphotericin B combined with itraconazole or fluconazole for treatment of histoplasmosis

To investigate the efficacy of combined treatment with fluconazole (Flu) an d amphotericin B (AmB) for Histoplasma capsulatum meningitis, MICs were det ermined for 10 clinical isolates, following National Committee for Clinical Laboratory Standards guidelines. Weak synergy was observed for 6 of the 10 isolates. For the in vivo models, mice either were sham treated or were gi ven Flu (75 mg/kg/day), AmB (2 mg/kg every other day), itraconazole (Itra; 75 mg/kg/day), AmB + Flu, or AmB + Itra. Following infection with 5 x 10(5) yeasts, Flu antagonized AmB's reduction of fungal burden without reducing its effect on survival, When in vivo antagonism was reproduced following in fection with 1 x 10(4) yeasts, a higher fungal burden was observed in the l ungs. Itra had no effect on AmB's activity and was more effective than Flu for clearance of fungal burden. These findings caution against use of AmB Flu for treatment of histoplasmosis, but studies of the effect of treatmen t on the fungal burden in the brain are needed to assess combination therap y for meningitis.