Efficacy assessments of SF001, a next-generation polyene antifungal, in a neutropenic mouse model of invasive fusariosis.

Abstract

Fusariosis has high mortality rates with limited treatment options. Owing to its rarity, comparative clinical trials are hard to perform. SF001 is a novel, next-generation polyene drug, rationally designed to reduce potential for systemic toxicity, with long-acting, potent, broad-spectrum fungicidal activity. We compared the in vitro activity and in vivo efficacy of SF001 with liposomal amphotericin B (LAMB) in treating immunosuppressed mice infected with hematogenously disseminated fusariosis. The minimum inhibitory concentration (MIC) of SF001 and LAMB against Fusarium solani or Fusarium oxysporum strains (at 100% inhibition) ranged between 0.5-8 µg/mL and 1->16 µg/mL, respectively. In the hematogenously disseminated fusariosis model, treatment with SF001 or LAMB enhanced the median survival time vs placebo (7, 10, and 9 days at 3, 7.5, and 30 mg/kg of SF001, respectively, and 12.5 days for LAMB at 7.5 mg/kg vs 6.5 days for placebo, P < 0.0001). SF001 and LAMB treatment enhanced the overall survival by day 21 (40% and 25% for SF001 at 7.5 mg/kg and 30 mg/kg, respectively, 30% for LAMB at 7.5 mg/kg and 0% for placebo). The survival data were mirrored in the kidney and brain fungal burden results with ~2-3 log₁₀ reduction in conidial equivalents/gram for either treatment vs placebo. Furthermore, the reduction in tissue fungal burden was corroborated by histopathological data from target organs, showing reduced or no abscesses in SF001- or LAMB-treated mice. Our data show comparable activity of SF001 to LAMB, thereby supporting the continued development of SF001 for the treatment of invasive fusariosis.