Abstract
BackgroundVisceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Domestic dogs are the main peridomestic reservoir, and allopurinol is the most frequently used drug for the control of infection, alone or in combination with other drugs. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies.Methodology/Principal FindingsFollowing our observation of clinical disease relapse in dogs under allopurinol treatment, we tested susceptibility to allopurinol of L. infantum isolated from groups of dogs pre-treatment, treated in remission, and with disease relapse during treatment. Promastigote isolates obtained from four treated relapsed dogs (TR group) showed an average half maximal inhibitory concentration (IC50) of 996 μg/mL. A significantly lower IC50 (P = 0.01) was found for isolates from ten dogs before treatment (NT group, 200 μg/mL), as well as for five isolates obtained from treated dogs in remission (TA group, 268 μg/mL). Axenic amastigotes produced from isolates of the TR group also showed significantly higher (P = 0.002) IC50 compared to the NT group (1678 and 671 μg/mL, respectively). The lower sensitivity of intracellular amastigotes from the TR group relative to those from the NT group (P = 0.002) was confirmed using an infected macrophage model (6.3% and 20% growth inhibition, respectively at 300 μg/mL allopurinol).ConclusionsThis is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs.
Highlights
Visceral leishmaniasis caused by L. infantum is a potentially fatal disease, which is a serious public health concern in Europe, Asia, North Africa and Latin America
This is the first study to demonstrate allopurinol resistance in L. infantum and to associate it with disease relapse in the canine host. These findings are of concern as allopurinol is the main drug used for long term control of the disease in dogs, and resistant L. infantum strains may enhance uncontrolled transmission to humans and to other dogs
We found that dogs suffer from disease relapse during treatment with allopurinol, and showed that L. infantum promastigotes isolated from treated relapsed dogs were roughly four times less susceptible to allopurinol as compared to isolates from dogs before treatment or from dogs that resolved their clinical disease during treatment
Summary
Visceral leishmaniasis caused by L. infantum is a potentially fatal disease, which is a serious public health concern in Europe, Asia, North Africa and Latin America. Among its merits are wide availability, low cost, good safety profile, lack of known resistance, and the fact that it is rarely used for the treatment of human leishmaniasis. For the latter reason, allopurinol is the only drug recommended by the World Health Organization for the treatment of CanL [1]. Since antimonials and miltefosine are not commercially available for treatment of CanL in Israel, allopurinol is currently the only drug used against this disease in dogs. Visceral leishmaniasis caused by the protozoan Leishmania infantum is a zoonotic, life threatening parasitic disease. Resistance of Leishmania strains from dogs to allopurinol has not been described before in clinical studies.
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