Combination treatment of topical nystatin and systemic meglumine antimoniate in the BALB/c - Leishmania(Leishmania) amazonensis model.

Treating leishmaniasis remains challenging. This study provides evidence of the beneficial effect of combining two clinically approved drugs, topical nystatin and systemic meglumine antimoniate, in an experimental model of cutaneous leishmaniasis. BALB/c mice infected with Leishmania (L.) amazonensis were treated with monotherapy or in three different combination regimens, using meglumine antimoniate at low (5 mg Sb5+/kg/day), medium (10 mg Sb5+/kg/day), or high doses (20 mg Sb5+/kg/day) in association with topical nystatin cream (125 IU/animal). Polawax cream was used as the placebo control group. By the second treatment week, all combination regimens reduced paw lesion size, and by the fourth week, a further decrease in parasite burden was observed in the footpad and draining lymph nodes. Toxicity analyses indicated that low- and medium-dose meglumine antimoniate, whether used alone or in combination, caused less hepatic and muscle damage compared to the high-dose regimen. Based on the favorable efficacy and safety profile, the medium-dose combination was prioritized for further analyses. This regimen modulated the local immune response, with reduced IFN-γ and increased IL-6 levels in footpad tissue, along with lower IFN-γ levels in draining lymph nodes. Animals treated with the medium-dose combination exhibited visibly improved paw appearance. Ultrastructural evaluation confirmed the presence of intracellular parasites with marked structural damage. Taken together, these findings suggest that the combined use of topical nystatin and meglumine antimoniate may represent a promising therapeutic strategy for cutaneous leishmaniasis, requiring further mechanistic investigations and translational studies before any clinical application.