Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease.
Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC₅₀ to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC₅₀ of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brasil.
Margoth
M
Moreno
Daniella A
DA
D'ávila
Marcelo N
MN
Silva
Lúcia Mc
LM
Galvão
Andrea M
AM
Macedo
Egler
E
Chiari
Eliane D
ED
Gontijo
Bianca
B
Zingales
D000328:Adult; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009593:Nitroimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D021261:Parasitic Sensitivity Tests; D016896:Treatment Outcome; D014344:Trypanocidal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics
D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C009999:benzonidazole