Combination and sequential antifungal therapy for invasive aspergillosis: review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001.

The development of newer antifungal drugs is creating new potential combination therapies to combat the dismal mortality rate associated with invasive aspergillosis (IA). The efficacy of combination therapy for IA has not been established; sparse data on combination or sequential antifungal therapy depict interactions ranging from synergy to antagonism. We reviewed data from all published in vitro studies, animal model studies, and clinical reports and recent abstracts on combination and sequential antifungal therapy for IA from 1966-2001. Among cases of IA during 1966-2001, 249 were treated with 23 different antifungal combinations. Amphotericin B plus 5-fluorocytosine was the most commonly used (49% of cases), followed by amphotericin B plus itraconazole (16%) or plus rifampin (11%). Combination therapy resulted in improvement in 63% of patients, generally with amphotericin B plus 5-fluorocytosine or rifampin and indifference with amphotericin B plus itraconazole. In 27 in vitro reports, we found synergy (in 36% of reports), additivity (in 24%), indifference (in 28%), and antagonism (in 11%). Amphotericin B plus 5-fluorocytosine and amphotericin B plus rifampin showed generally positive interactions and amphotericin B plus itraconazole showed results that were largely indifferent. Eighteen animal model reports demonstrated synergy (in 14% of reports), additivity (in 20%), indifference (in 51%), and antagonism (in 14%). In general, amphotericin B plus 5-fluorocytosine, amphotericin B plus rifampin, and amphotericin B plus itraconazole showed indifferent results, whereas amphotericin B plus micafungin showed positive interactions. Thirty-four cases treated during 1990-2001 with sequential therapy, excluding amphotericin B followed by itraconazole, showed improvement in 68% of cases. Improvement was noted with amphotericin B or itraconazole followed by voriconazole but not with itraconazole followed by amphotericin B.