Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts

We have studied the in vivo activity of the new experimental triazole deriv ative SCH 56592 (posaconazole) against a variety of strains of the protozoa n parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chaga s' disease, in both immunocompetent and immunosuppressed murine hosts. The T. cruzi strains used in the study were previously characterized as suscept ible (CL), partially resistant (Y), or highly resistant (Colombiana, SC-28, and VL-10) to the drugs currently in clinical use, nifurtimox and benznida zole. Furthermore, all strains are completely resistant to conventional ant ifungal azoles, such as ketoconazole. In the first study, acute infections with the CL,Y,and Colombiana strains in both normal and cyclophosphamide-im munosuppressed mice were treated orally, starting 4 days postinfection (p.i .), for 20 consecutive daily doses. The results indicated that in immunocom petent animals SCH 56592 at 20 mg/kg of body weight/day provided protection (80 to 90%) against death caused by all strains, a level comparable or sup erior to that provided by the optimal dose of benznidazole (100 mg/kg/day). Evaluation of parasitological cure revealed that SCH 56592 was able to cur e 90 to 100% of the surviving animals infected with the CL and Y strains an d 50% of those which received the benznidazole- and nifurtimox-resistant Co lombiana strain. Immunosuppression markedly reduced the mean survival time of untreated mice infected with any of the strains, but this was not observ ed for the groups which received SCH 56592 at 20 mg/kg/day or benznidazole at 100 mg/kg/day. However, the overall cure rates were higher for animals t reated with SCH 56592 than among those treated with benznidazole, The resul ts were confirmed in a second study, using the same model but a longer (43- dose) treatment period. Finally, a model for the chronic disease in which o ral treatment was started 120 days p.i. and consisted of 20 daily consecuti ve doses was investigated. The results showed that SCH 56592 at 20 mg/kg/da y was able to induce a statistically significant increase in survival of an imals infected with all strains, while benznidazole at 100 mg/kg/day was ab le to increase survival only in animals infected with the Colombiana strain . Moreover, the triazole was able to induce parasitological cures in 50 to 60% of surviving animals, irrespective of the infecting strain, while no cu res were obtained with benznidazole. Taken together, the results demonstrat e that SCH 56592 has in vivo trypanocidal activity, even against T. cruzi s trains naturally resistant to nitrofurans, nitroimidazoles, and conventiona l antifungal azoles, and that this activity is retained to a large extent i n immunosuppressed hosts.