In vivo susceptibility to benznidazole of Trypanosoma cruzi strains from the western Brazilian Amazon

Abstract

Abstractobjective To assess the susceptibility of Trypanosoma cruzi strains from Amazon to benznidazole. methods We studied 23 strains of T. cruzi obtained from humans in the acute phase of Chagas disease, triatomines and marsupials in the state of Amazonas and from chronic patients and triatomines in the state of Paraná , Brazil. The strains were classified as TcI (6), TcII (4) and TcIV (13). For each strain, 20 Swiss mice were inoculated: 10 were treated orally with benznidazole 100 mg/kg/day (TBZ group) for 20 consecutive days and 10 comprised the untreated control group (NT). Fresh blood examination, haemoculture (HC), PCR, and ELISA were used to monitor the cure.results The overall cure rate was 60.5% (109/180 mice) and varied widely among strains. The strains were classified as resistant, partially resistant or susceptible to benznidazole, irrespective of discrete typing units (DTUs), geographical origin or host. However, the TcI strains from Amazonas were significantly (P = 0.028) more sensitive to benznidazole than the TcI strains from Paraná . The number of parasitological, molecular and serological parameters that were significantly reduced by benznidazole treatment also varied among the DTUs; the TBZ group of mice inoculated with TcIV strains showed more reductions (8/9) than those with TcI and TcII strains.conclusions Benznidazole resistance was observed among natural populations of the parasite in the Amazon, even in those never exposed to the drug.

Impact of Benznidazole on Infection Course in Mice Experimentally Infected with Trypanosoma cruzi I, II, and IV

“…The overall parasitemia clearance rate of 53.6% obtained in this study with FBE, HC, and cPCR on blood was not very different from the cure rates obtained in a previous study (60.5%) 17 that used these same techniques, classically used in cure control of CD in the past, in addition to the enzyme-linked immunosorbent assay (ELISA) test to evaluate most of these strains and suggested that a considerable proportion of animals are not parasitologically cured. Negative blood test results only indicate that the parasitemia levels were below the limit of detection of the methods used and provide no information on the parasite burden in the extravascular organs.…”

“…16 The susceptibilities of these strains to BZ varied from 0% to 100%, and there was no correlation between this parameter and the DTU strain classifications, as reported previously. 17 However, TcII showed a higher proportion of BZ-sensitive strains, i.e., whose inoculated animals exhibited a sustained parasitemia clearance after treatment with BZ and TcIV resistant ones. Small differences between parasitemia clearance rates of each strain or DTU of the current study and the cure rates obtained in the previous study 17 might be caused by the developmental stages used for inoculation and the techniques used to monitor cure, and the selection (as a result of laboratory manipulation) of different genotypes that might be present within the same strain.…”

“…17 However, TcII showed a higher proportion of BZ-sensitive strains, i.e., whose inoculated animals exhibited a sustained parasitemia clearance after treatment with BZ and TcIV resistant ones. Small differences between parasitemia clearance rates of each strain or DTU of the current study and the cure rates obtained in the previous study 17 might be caused by the developmental stages used for inoculation and the techniques used to monitor cure, and the selection (as a result of laboratory manipulation) of different genotypes that might be present within the same strain. 31 The beneficial effect of BZ treatment was shown when the parasitological, molecular, and histopathological parameters were assessed.…”

“…To date, knowledge about these T. cruzi DTUs in the Amazon region is scarce, and pioneer studies from our group present a detailed understanding of the genetic, biological, and histopathological characteristics of parasites belonging to TcI and IV DTUs. [13][14][15][16][17] The goal of etiologic treatment of CD is the parasite elimination from the infected individual, thereby inhibiting clinical evolution and breaking the disease transmission chain. 18 Histologically, the acute phase of trypanosomiasis is a systemic infection, and intracellular forms of the parasite can be found in all organs.…”

Trypanosoma cruzi I genotype among isolates from patients with chronic Chagas disease followed at the Evandro Chagas National Institute of Infectious Diseases (FIOCRUZ, Brazil)

“…Together, these reports evidenced that the TcI strains were usually the most resistant to trypanocidal treatment, TcII stocks presented greatly variable responses, and TcVI isolates were the most susceptible. However, these associations have not been fully confirmed by other authors [69][70][71] . Accordingly, further long-term studies are necessary to investigate this issue, especially those monitoring the treatment responses of patients with Chagas disease whose parasite DTU has been identified.…”