Differential Susceptibility to Antimony in Strains and Clinical Isolates of Leishmania amazonensis from Brazil: In Vitro and In Vivo Studies and Implications for Drug Response and Treatment Failure

In Brazil, cutaneous leishmaniasis is endemic and may be caused by Leishmania amazonensis. This species is the second most prevalent species in that country, and it is responsible for localized cutaneous and diffuse cutaneous leishmaniasis. Pentavalent antimony is still the first-line drug for cutaneous leishmaniasis treatment in Brazil. In this study, we investigated the in vitro susceptibility to antimony of a panel of L. amazonensis strains and clinical isolates responsible for cutaneous and diffuse cutaneous leishmaniasis. There was a significant variation in susceptibility to antimony not only within these strains and isolates evaluated at either promastigote or intracellular amastigote stages, but also between the two parasite stages for some of these strains and isolates. Additionally, we investigated whether this in vitro susceptibility variation to antimony would affect the in vivo response to treatment, using an experimental BALB/c mouse model of cutaneous leishmaniasis infected with three strains differing in susceptibility. Despite antimony could mildly reduce the lesion size in mice infected with one of these strains, no significant reduction in the parasite burden was found in treated animals, and they were completely refractory to drug treatment. These findings indicate that antimony treatment, even at high dosages via the intraperitoneal route, was not effective against L. amazonensis infection in this animal model. Finally, this study provides a preclinical dataset of the activity of antimony against a panel of strains and isolates of a species responsible for localized cutaneous and diffuse cutaneous leishmaniasis in Brazil.