Combinations of antimicrobial agents were tested against 35 strains of zygomycetes. The interaction between amphotericin B and rifampin was synergistic or additive. Flucytosine alone was inactive and, upon combination with amphotericin B, synergy was not achieved. The combination of amphotericin B with terbinafine was synergistic for 20% of strains, and the interaction between terbinafine and voriconazole was synergistic for 44% of strains. Antagonism was not observed.Zygomycosis is an aggressive infection occurring mostly in patients with diabetic ketoacidosis or neutropenia or in patients receiving corticosteroids (35). Despite antifungal therapy, mortality remains very high, particularly in the pulmonary and disseminated forms of the disease (21,26,42). Amphotericin B is the drug of choice for treatment, but its use is limited by its narrow therapeutic index (14). Few studies have been carried out to test antifungal combinations against zygomycetes in vitro (5, 41) or in animal models of zygomycosis (40). Combination of amphotericin B with rifampin has proven to be synergistic in vitro against yeasts (4,8,13,27), dimorphic fungi (25, 36), Aspergillus (19, 24), and Rhizopus (5). Nevertheless, in animal models of fungal infections, results for this combination have been conflicting (10,16). Interaction between amphotericin B and flucytosine has been shown to be additive or synergistic against yeasts in vitro and in vivo in animal models as well as in patients (34). With Aspergillus, indifferent-to-synergistic and in some instances antagonistic interactions have been reported for this combination (7,19). Terbinafine is a sterol biosynthesis inhibitor that is primarily used for superficial mycoses, but its current applications are extending (33). Although the potential of this antifungal for zygomycosis is unknown, terbinafine exhibits low MICs against some zygomycete isolates (22). Combination of amphotericin B with terbinafine displayed synergistic interaction in Candida albicans (2) and in Aspergillus spp. (38), and this combination has been used successfully in patients for the treatment of aspergillosis (39) and zygomycosis (12,31). Synergy between terbinafine and azoles has also been demonstrated in yeasts (2, 3, 15) and in filamentous fungi (28,38,43). The combination of terbinafine with voriconazole has rarely been investigated (38,43).The aim of this study was to investigate the in vitro interactions of amphotericin B with rifampin, flucytosine, and terbinafine as well as the interaction of terbinafine with voriconazole against zygomycetes.A total of 35 isolates were tested. These comprised 15 Rhizopus spp. (8 R. oryzae and 7 R. microsporus) isolates, 10 Absidia corymbifera isolates, 6 Mucor spp. (3 M. hiemalis, 1 M. circinelloides, 1 M. racemosus, and 1 M. rouxii) isolates, 3 Rhizomucor spp. (2 R. pusillus and 1 R. miehei) isolates, and 1 Cunninghamella bertholletiae isolate. Candida krusei ATCC 6258 and Candida parapsilosis ATCC 22019 were included to ensure quality control. The drugs that were tested ...