Benznidazole and posaconazole in experimental Chagas disease: positive interaction in concomitant and sequential treatments

Abstract

Background: Current chemotherapy for Chagas disease is unsatisfactory due to its limited efficacy, particularly in the chronic phase, with frequent side effects that can lead to treatment discontinuation. Combined therapy is envisioned as an ideal approach since it may improve treatment efficacy whilst decreasing toxicity and the likelihood of resistance development. We evaluated the efficacy of posaconazole in combination with benznidazole on Trypanosoma cruzi infection in vivo.

Methods and findings: Benznidazole and posaconazole were administered individually or in combination in an experimental acute murine infection model. Using a rapid treatment protocol for 7 days, the combined treatments were more efficacious in reducing parasitemia levels than the drugs given alone, with the effects most evident in combinations of sub-optimal doses of the drugs. Subsequently, the curative action of these drug combinations was investigated, using the same infection model and 25, 50, 75 or 100 mg/kg/day (mpk) of benznidazole in combination with 5, 10 or 20 mpk of posaconazole, given alone or concomitantly for 20 days. The effects of the combination treatments on parasitological cures were higher than the sum of such effects when the drugs were administered separately at the same doses, indicating synergistic activity. Finally, sequential therapy experiments were carried out with benznidazole or posaconazole over a short interval (10 days), followed by the second drug administered for the same period of time. It was found that the sequence of benznidazole (100 mpk) followed by posaconazole (20 mpk) provided cure rates comparable to those obtained with the full (20 days) treatments with either drug alone, and no cure was observed for the short treatments with drugs given alone.

Conclusions: Our data demonstrate the importance of investigating the potential beneficial effects of combination treatments with marketed compounds, and showed that combinations of benznidazole with posaconazole have a positive interaction in murine models of Chagas disease.

Figure 1. Anti-Trypanosoma cruzi activity of benznidazole plus posaconazole combination therapy.

Percentage of positive results of fresh blood examination (before and after cyclophosphamide immunosuppression) and PCR assay (performed at 1^st and 6^nd month post-treatment) from mice infected with Trypanosoma cruzi Y strain. Animals were treated with daily doses 25, 50, 75 or 100 mg/kg of bodyweight (mpk) of benznidazole (Bz) and 5, 10 or 20 mpk of posaconazole (Ps) alone or combination for 20 consecutive days. &: all mice had positive results.

Figure 2. Benznidazole plus posaconazole therapy against VL-10 benznidazole resistant Trypanosoma cruzi stock.

Maximum number of trypomastigote forms detected in the peripheral blood of mice infected with Trypanosoma cruzi VL-10 strain and treated with 100 mg/kg of bodyweight (mpk) of benznidazole (Bz) or 40 mpk of posaconazole (Ps) and with Bz plus Ps combination at the following dosages: 50 or 100 mpk of Bz in combination with 10 or 20 mpk of Ps for 20 consecutive days. Benznidazole was given daily and posaconazole twice a day (b.i.d.). IC – infected and untreated animals. a, b, c - different letters indicate significant differences, and the same letters indicates similar values among parasitemia levels.