title: Allopurinol Resistance in Leishmania infantum from Dogs with Disease Relapse.
abstract: BACKGROUND
  Visceral 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.
  
  
  RESULTS
  Following 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Koret School of Veterinary Medicine, The Hebrew University, Rehovot, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yasur-Landau
authors.affiliation: Department of Microbiology and Molecular Genetics, IMRIC, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Jaffe
authors.affiliation: Department of Animal Sciences, The Hebrew University, Rehovot, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: David
authors.affiliation: Koret School of Veterinary Medicine, The Hebrew University, Rehovot, Israel.
authors.forename: Gad
authors.initials: G
authors.lastname: Baneth
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use; D004283:Dog Diseases / Q000188:drug therapy / Q000469:parasitology*; D004285:Dogs; D004351:Drug Resistance; D018314:Leishmania infantum / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology / Q000662:veterinary*
chemical_list: D000963:Antimetabolites; D000981:Antiprotozoal Agents; D000493:Allopurinol