Synergistic effect of terbinafine and amphotericin B in killing Fonsecaea nubica in vitro and in vivo

Chromoblastomycosis is a chronic fungal infection. Itraconazole and terbinafine are the most recommended antifungal drugs for chromoblastomycosis, while amphotericin B is not usually recommended. A patient with chromoblastomycosis in our hospital showed poor clinical responses to itraconazole and terbinafine. The fungus isolated from the lesions of this patient was identified as Fonsecaea nubica and numbered zssy0803. In vitro antifungal susceptibilities of F. nubica zssy0803 to terbinafine, amphotericin B, itraconazole, voriconazole and caspofungin were evaluated, as well as the combinations of terbinafine with the other four antifungals. The combined effect of terbinafine and amphotericin B on other 20 clinical F. nubica strains was also evaluated. The minimal inhibitory concentrations of terbinafine, amphotericin B, itraconazole, voriconazole and caspofungin on F. nubica zssy0803 were 0.25 μg/mL, 2 μg/mL, 1 μg/mL, 4 μg/mL and 8 μg/mL, respectively. The combination of terbinafine and amphotericin B showed the lowest fractional inhibitory concentration index of 0.28 to F. nubica zssy0803 in comparison with combinations of terbinafine and the other four antifungal drugs. The combination of terbinafine and amphotericin B was also synergistic for all the other 20 F. nubica strains. Then, the combination of oral terbinafine (500 mg/day) and intralesional injections of amphotericin B (1 mg/mL) was used to treat this patient. After this combined therapy for 25 weeks and terbinafine monotherapy for additional 12 weeks, the patient was cured. These findings indicate for the first time that terbinafine and amphotericin B are synergistic in killing F. nubica both in vitro and in vivo.