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

Abstract

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 .

Aspartic peptidase of Phialophora verrucosa as target of HIV peptidase inhibitors: blockage of its enzymatic activity and interference with fungal growth and macrophage interaction

“…In clinical practice, for instance, HIV-PIs are administered in combination with antiretroviral regimens for acquired immunodeficiency syndrome therapy 53 . Drugs toxicity in the CBM treatment and the increase of resistant strains have driven studies on a combined therapy 54,55 . The benefits of this therapy are well-known and include a broad spectrum efficacy, greater potency than monotherapy, reduction emergence of resistance as well as improvements in both safety and tolerability [56][57][58] .…”

Descrição Da Farmacoterapia Da Cromoblastomicose: Revisão Da Literatura

“…Cladophialophora carrionii é o patógeno predominante em regiões secas e semidesérticas da Austrália, África do Sul, Venezuela e Cuba, enquanto Fonsecaea pedrosoi é o agente mais comum encontrado em zonas tropicais úmidas, como Amazônia e regiões temperadas da América Latina (13) . Outros fungos dematiáceos têm sido associados com menor frequência a CBM, entre eles temos: Phialophora verrucosa, Rhinocladiella aquaspersa, Exophiala dermatitidis, Exophiala jeanselmei e Exophiala spinifera (14,15) . De acordo com processo fisiopatológico da CBM, a infecção ocorre após traumatismo da pele e inoculação traumática de fungos dematiáceos (16) .…”

Treatment of chromoblastomycosis with a combination of debulking surgery, intralesional amphotericin B, and oral terbinafine

“…Amphotericin B via intravenous route had been tried successfully in a few case reports but is not used in routine practice due to systemic side effects. A combination of intralesional AMB and oral terbinafine 500 mg daily have proven curative against melanized fungi in vitro and in vivo , 6,7 showing shorter duration of therapy without side effects. In these studies, intralesional AMB solution was used at a dose of 0.25–0.5 mg per square centimeter, and this was repeated three times weekly or once every 2 weeks 7,8 .…”

“…A combination of intralesional AMB and oral terbinafine 500 mg daily have proven curative against melanized fungi in vitro and in vivo , 6,7 showing shorter duration of therapy without side effects. In these studies, intralesional AMB solution was used at a dose of 0.25–0.5 mg per square centimeter, and this was repeated three times weekly or once every 2 weeks 7,8 . In our patient, the same dose of AMB was used once weekly to reduce the anticipated side effects such as local necrosis.…”