In Vitro Susceptibility to Miltefosine of Leishmania infantum (syn. L. chagasi) Isolates from Different Geographical Areas in Brazil

Abstract

Treatment of visceral leishmaniasis in Brazil still relies on meglumine antimoniate, with less than ideal efficacy and safety, making new therapeutic tools an urgent need. The oral drug miltefosine was assayed in a phase II clinical trial in Brazil with cure rates lower than previously demonstrated in India. The present study investigated the susceptibility to miltefosine in 73 Brazilian strains of Leishmania infantum from different geographic regions, using intracellular amastigote and promastigote assays. The EC50 for miltefosine of 13 of these strains evaluated in intracellular amastigotes varied between 1.41 and 4.57 μM. The EC50 of the 73 strains determined in promastigotes varied between 5.89 and 23.7 μM. No correlation between in vitro miltefosine susceptibility and the presence of the miltefosine sensitive locus was detected among the tested strains. The relatively low heterogeneity in miltefosine susceptibility observed for the 73 strains tested in this study suggests the absence of decreased susceptibility to miltefosine in Brazilian L. infantum and does not exclude future clinical evaluation of miltefosine for VL treatment in Brazil.

3′Nucleotidase/nuclease is required for Leishmania infantum clinical isolate susceptibility to miltefosine

“… 32 Subsequently, it was found that deletion of the MSL (miltefosine susceptible locus) on chromosome 31 of the parasite was significantly correlated with miltefosine treatment failure. 33 Nevertheless, a recent study was unable to demonstrate a correlation between the absence of MSL, in L. infantum isolates from a collection, and the in vitro resistance phenotype, 34 identified in our Phase 2 clinical trial well characterized isolates. 32 , 33 …”

Current leishmaniasis drug discovery

“…23 Moreover, recent studies in Brazil, one of the most affected countries to leishmaniasis burden, demonstrated the absence of decreased susceptibility to miltefosine in L. infantum for the 73 strains tested. 24 Although the use of miltefosine has simplified the treatment, severe gastrointestinal side effects can be observed and, after the identification of some cases in endemic areas, 25 recently resistance to this drug was first reported in clinical studies. Some patients relapsed after 9-12 months after successful treatment with this drug and, additionally, its use limitations include teratogenicity and abortifacient nature, which prevents its use in pregnancy.…”

“…23 Moreover, recent studies in Brazil, one of the most affected countries to leishmaniasis burden, demonstrated the absence of decreased susceptibility to miltefosine in L. infantum for the 73 strains tested. 24…”

In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum

“…In further studies, it was suggested that this genomic region, named miltefosine sensitivity locus (MSL), confers natural resistance to the drug [ 26 ]. Although many Brazilian L. infantum isolates do not carry the MSL [ 27 ], its association with miltefosine resistance in vitro is not clear [ 28 ].…”