Resistance to antimony and treatment failure in human Leishmania (Viannia) infection.
BACKGROUND
Failure of antimonial therapy has been increasingly reported in anthroponotic visceral leishmaniasis and in cutaneous disease. The role of drug resistance in treatment failure has been difficult to ascertain because therapeutic response is multifactorial, and the efficacy of antimonial drugs depends on an effective immune response. In this study, we sought to determine whether standard treatment selects for resistant organisms and whether drug resistance contributes to treatment failure.


METHODS
We evaluated the susceptibility to antimony of 19 strains isolated before treatment with meglumine antimoniate and 21 strains isolated at treatment failure from 20 patients. The 50% effective dose (ED50) of antimony in the form of additive-free meglumine antimoniate was determined for intracellular amastigotes in human promonocytic U-937 cells.


RESULTS
Before treatment, 16% of strains (3/19) showed primary resistance (ED50 of >128 microg Sb/mL), whereas 84% (16/19) were susceptible (ED50 of <20 microg Sb/mL). However, 88% of susceptible strains (14/16) had ED90 values of >128 microg Sb/mL. At treatment failure, 40% of strains (8/20) were resistant. Secondary resistance was documented in 4 patients.


CONCLUSIONS
Primary and secondary resistance to antimony can contribute to treatment failure in American cutaneous leishmaniasis. Selection for resistance to antimony occurs during standard treatment with antimonial drugs, and primary resistance to antimony supports the plausibility of anthroponotic transmission.
Rojas
Ricardo
R
Centro Internacional de Entrenamiento e Investigaciones Medicas, Cali, Colombia, and Centre Hospitalier Universitaire Laval, Quebec, Canada.
Valderrama
Liliana
L
Valderrama
Mabel
M
Varona
Maria X
MX
Ouellette
Marc
M
Saravia
Nancy G
NG
D000293:Adolescent; D000328:Adult; D000818:Animals; D000965:Antimony / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008536:Meglumine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000077485:Meglumine Antimoniate; D008875:Middle Aged; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests; D017211:Treatment Failure; D020298:U937 Cells
D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony