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Background  Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated  in vitro  and  in vivo  MIL exposure.    Methods  Syngeneic  Leishmania donovani  lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector,  Lutzomyia longipalpis .    Results  Promastigotes of both  in vitro  and  in vivo  MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the  miltefosine transporter  ( LdMT ) gene.  In vitro  selected promastigotes showed a lower rate of metacyclogenesis whereas the  in vivo  derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector.    Conclusions  Recurrent  in vitro  and  in vivo  MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector.

Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection