Combined treatment of miltefosine and paromomycin delays the onset of experimental drug resistance in Leishmania infantum

Citation: Hendrickx S, Van den Kerkhof M, Mabille D, Cos P, Delputte P, Maes L, et al. (2017) Combined treatment of miltefosine and paromomycin delays the onset of experimental drug resistance in Leishmania infantum. PLoS Negl Trop Dis 11(5): e0005620.
Published: May 15, 2017

Background: Since miltefosine monotherapy against visceral leishmaniasis (VL) caused by Leishmania donovani has been discontinued in the Indian subcontinent due to an increase in the number of treatment failures, single dose liposomal amphotericin B is now advocated as a treatment option of choice. Paromomycin-miltefosine combination therapy can be used as substitute first-line treatment in regions without cold-chain potential. Previous laboratory studies in the closely related species Leishmania infantum have demonstrated that paromomycin monotherapy fairly rapidly selects for resistance producing a phenotype with increased fitness. Given the possible clinical implications of these findings for the current field situation, the present study aimed to identify the potential hazards of paromomycin-miltefosine combination therapy.
Principal findings: Drug interaction studies using the fixed-ratio isobologram method revealed an indifferent interaction between paromomycin and miltefosine. In hamsters infected with L. infantum, the combination resulted in cumulative efficacy in reducing parasite burdens in the liver, spleen and bone marrow. Selected resistant lines against the single drugs did not display cross-resistance. When the intracellular amastigote stage was repeatedly exposed to the paromomycin-miltefosine combination, either in vitro or in vivo, no significant susceptibility decrease towards either drug was noted.
Conclusions: These results suggest that implementation of paromomycin-miltefosine combination therapy indeed could represent a safe and affordable treatment option for L. donovani VL as miltefosine appears to overrule the anticipated rapid development of PMM resistance.

Author summary: Liposomal amphotericin B is presently being used as first-line treatment option against visceral leishmaniasis in the Indian subcontinent. However, the need for temperature-controlled transport and storage limits its widespread use in rural areas. Previous studies already suggested that paromomycin-miltefosine combination therapy could be a valuable alternative, side passing some of the disadvantages associated with monotherapy, such as development of drug resistance. As the first reports of miltefosine resistant clinical isolates have already surfaced and paromomycin resistance could be easily induced under laboratory conditions, it remains essential to assess the risk of developing resistance against both drugs upon combination therapy. This study evaluated the efficacy of combined therapy against a Leishmania species closely related to the agent found in the Indian subcontinent, using both in vitro and in vivo models with the aim to select multidrug-resistant species by simultaneous exposure to paromomycin and miltefosine. The combination of both drugs in the hamster model resulted in a cumulative efficacy but did not lead to a significant susceptibility decrease, indicating that paromomycin-miltefosine combination therapy may represent a safe and affordable treatment option for visceral leishmaniasis.


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