Evaluation of susceptibility in vitro of clinical and dog isolates of Leishmania spp. to alternative drugs

Abstract

Leishmaniasis is a parasitic disease caused by protozoa of the genus Leishmania. In Brazil, cutaneous leishmaniasis is caused mainly by Leishmania (Viannia) braziliensis and L. (Leishmania) amazonensis, the former being the most prevalent species. Visceral leishmaniasis is caused by L. (L.) infantum. In recent years, leishmaniasis has presented an increasing number of cases in Brazil, mainly in urban areas. The treatment of leishmaniasis in Brazil basically consists of the use of pentavalent antimonials, amphotericin B and pentamidine, these drugs have a highly variable clinical response, are expensive and parenterally administrated and have several side effects. Due to these problems reported in leishmaniasis chemotherapy in Brazil, it is necessary to evaluate alternative drugs with better effectiveness for the treatment of leishmaniasis. Amphotericin B has been used in Brazil in cases of non-response to treatment with antimonials and in cases of HIV co-infection. The liposomal form of amphotericin B, administered in a single dose, has been considered the recommended drug along with miltefosine for the chemotherapy of visceral leishmaniasis in India, both with very satisfactory results. This oral drug has been shown to be highly effective, with cure rates greater than 90% in the treatment of visceral leishmaniasis in Southeast Asia caused by L. (L.) donovani. In Brazil, only two clinical studies using miltefosine have been conducted. These studies have shown an efficacy of about 70% for infections caused by L. (V.) braziliensis and L. (V.) guyanensis in patients with cutaneous leishmaniasis, both with superior efficacy when compared to treatment using pentavalent antimonial. Paromomycin is a broad-spectrum aminoglycoside antibiotic that has been shown to be an effective oral agent for a large number of infectious agents, from bacteria to intestinal protozoa. Recent clinical studies have demonstrated paromomycin highly effective in the treatment of visceral leishmaniasis, with cure rates higher than 90% when administered intramuscularly in patients with the disease in Southeast Asia. In this project, we propose to investigate the activity of miltefosine and amphotericin B in vitro in species responsible for cutaneous leishmaniasis, as well as in clinical isolates from patients with cutaneous leishmaniasis. In total, 17 clinical isolates previously available in the laboratory will be evaluated. The paromomycin susceptibility in isolates of dogs from the municipality of Embu-Guaçu (intracellular amastigote form) will also be evaluated. These results will provide data on the limitations of the use of amphotericin B in the clinic and the potential of miltefosine and paromomycin as a therapeutic alternative for the treatment of leishmaniasis in Brazil. (AU)