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Review
. 2006 Jan;19(1):111-26.
doi: 10.1128/CMR.19.1.111-126.2006.

Drug resistance in leishmaniasis

Simon L Croft  1 , Shyam Sundar, Alan H Fairlamb
Affiliations
Review

Drug resistance in leishmaniasis

Simon L Croft et al. Clin Microbiol Rev. 2006 Jan.

Abstract

Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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Figures

FIG. 1.
FIG. 1.
Drugs currently used in the treatment of leishmaniasis.
FIG. 2.
FIG. 2.
Map of Bihar State, India, showing distribution of resistance to pentavalent antimonials in kala-azar-endemic areas.
FIG. 3.
FIG. 3.
Proposed mechanisms of antimony action and resistance in Leishmania spp. Levels of ornithine decarboxylase (ODC), γ-glutamylcysteine synthetase (GCS), and an intracellular P-glycoprotein (PgpA) are elevated in some laboratory-derived resistant lines (thick lines), whereas decreased Sb reductase is observed in others. Dotted lines indicate nonenzymatic steps implicated in resistance. The red arrow indicates inhibition of trypanothione reductase and other targets. Uptake of Sb(III) is mediated via an aquaglycoporin (AQP1).
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