The antifungal
drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential.
Drug testing is problematic in experimental
Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of
infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess
posaconazole efficacy against acute and chronic
Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo and ex vivo imaging, with
cyclophosphamide-induced immunosuppression used to enhance the detection of relapse.
Posaconazole was found to be significantly inferior to
benznidazole as a treatment for both acute and chronic T. cruzi
infections. Whereas 20 days treatment with
benznidazole was 100% successful in achieving sterile cure,
posaconazole failed in almost all cases. Treatment of
chronic infections with
posaconazole did however significantly reduce
infection-induced
splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with
posaconazole in the acute, but not the chronic stage of
infection. This in vivo screening model for
Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial.