Abstract
BackgroundBecause topical therapy is easy and usually painless, it is an attractive first-line option for the treatment of localized cutaneous leishmaniasis (LCL). Promising ointments are in the final stages of development. One main objective was to help optimize the treatment modalities of human LCL with WR279396, a topical formulation of aminoglycosides that was recently proven to be efficient and safe for use in humans.Methodology/Principal FindingsC57BL/6 mice were inoculated in the ear with luciferase transgenic L. major and then treated with WR279396. The treatment period spanned lesion onset, and the evolution of clinical signs and bioluminescent parasite loads could be followed for several months without killing the mice. As judged by clinical healing and a 1.5-3 log parasite load decrease in less than 2 weeks, the 94% efficacy of 10 daily applications of WR279396 in mice was very similar to what had been previously observed in clinical trials. When WR279396 was applied with an occlusive dressing, parasitological and clinical efficacy was significantly increased and no rebound of parasite load was observed. In addition, 5 applications under occlusion were more efficient when done every other day for 10 days than daily for 5 days, showing that length of therapy is a more important determinant of treatment efficacy than the total dose topically applied.Conclusions/SignificanceOcclusion has a significant adjuvant effect on aminoglycoside ointment therapy of experimental cutaneaous leishmaniasis (CL), a concept that might apply to other antileishmanial or antimicrobial ointments. Generated in a laboratory mouse-based model that closely mimics the course of LCL in humans, our results support a schedule based on discontinuous applications for a few weeks rather than several daily applications for a few days.
Highlights
Of the 350 million people exposed to the risk of Leishmania parasite inoculation and further development, 2 million each year experience the discomfort and potential complications of cutaneous leishmaniasis (CL)
WR279396, a thirdgeneration aminoglycoside ointment that contains 15% paromomycin formulated in a hydrophilic vehicle as well as a second aminoglycoside, 0.5% gentamicin, was designed to be effective but non-irritative
When initiating the cutaneous disease named cutaneous leishmaniasis (CL), Leishmania parasites develop within the parasitophorous vacuoles of phagocytes residing in and/or recruited to the dermis, a process leading to more or less chronic dermis and epidermis-damaging inflammatory processes
Summary
Of the 350 million people exposed to the risk of Leishmania parasite inoculation and further development, 2 million each year experience the discomfort and potential complications of cutaneous leishmaniasis (CL). WR279396, a thirdgeneration aminoglycoside ointment that contains 15% paromomycin formulated in a hydrophilic vehicle as well as a second aminoglycoside, 0.5% gentamicin, was designed to be effective but non-irritative. This new formulation was recently shown to be efficient and safe for the treatment of L. major localized cutaneous leishmaniasis (LCL) (Ben Salah, Buffet et al.,submitted and [14]). Very encouraging, this result is only one step toward a simple and applicable therapy for this neglected disease. One main objective was to help optimize the treatment modalities of human LCL with WR279396, a topical formulation of aminoglycosides that was recently proven to be efficient and safe for use in humans
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