Ravuconazole is an experimental
triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in humans. In this work, we investigated the in vitro and in vivo activities of this compound against Trypanosoma cruzi.
Ravuconazole showed very potent in vitro
anti-T. cruzi activity with minimal inhibitory concentrations (MIC) of 300 and 1 nM against the extracellular epimastigote and intracellular amastigote forms, respectively. As with other
azole derivatives,
ravuconazole at the MIC led to an essentially complete depletion of the epimastigotes' endogenous C4,14-desmethyl
sterols and their replacement by di- and tri-methylated
sterols. In murine acute models of acute
Chagas disease, it was found that
ravuconazole treatment led to high levels of parasitological cures, but only when given twice a day (b.i.d.), consistent with its short terminal half-life in mice (4 h). Furthermore, it was found that this curative activity was restricted towards nitrofuran/
nitroimidazole-susceptible (CL) and partially
drug-resistant (Y) strains of T. cruzi, with no curative activity in animals infected with the fully
drug-resistant Colombiana strain. No curative activity occurred in a chronic model of the disease. No toxic side effects were observed resulting from treatment with the
triazole.
Ravuconazole is a very potent and specific
anti-T. cruzi agent in vitro but its in vivo activity in mice is limited, probably due to its unfavourable pharmacokinetic properties in this animal model. However, these results do not necessarily rule out the potential utility of
ravuconazole in the treatment of human T. cruzi
infections.