Antifungal combination therapy: where we stand

Amphotericin B has been used in combination, simultaneously or sequentially, with fluconazole and itraconazole. However, there are no data from clinical trials to suggest the most appropriate use of these drug combinations. In vitro work has consistently described antagonism of polyenes and azoles, but new work suggests that hydrophilic azoles (e.g. fluconazole) with amphotericin B may not result in antagonistic effects, whereas lipophilic azoles (e.g. ketoconazole, itraconazole) antagonize the antifungal effects of amphotericin B. Experimental studies in animals with invasive candidiasis show that fluconazole and amphotericin B are not antagonistic and may be additive in their effects. In contrast, itraconazole and amphotericin B are antagonistic in this same murine candidiasis model. In animals infected with Aspergillus, itraconazole plus amphotericin B seem to be antagonistic when used simultaneously and possibly when used sequentially. Nevertheless, initial therapy with amphotericin B followed by itraconazole in patients with aspergillosis is a common clinical strategy. Recent data and concepts concerning the combined use of available antifungal drugs are discussed in this paper.