The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and in experimental murine\nmodels. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental\nChagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite\nburden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic\nChagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy\nthan other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo\nand ex vivo imaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole\nwas found to be significantly inferior to benznidazole as a treatment for both acute and chronic T. cruzi infections. Whereas\n20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment\nof chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence\nof parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence\nin mice treated with posaconazole in the acute, but not the chronic stage of infection. This in vivo screening model for\nChagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that\ndrugs are not advanced prematurely into clinical trial.
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