Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice

Author:

Diniz Lívia de Figueiredo12,Mazzeti Ana Lia1,Caldas Ivo Santana12,Ribeiro Isabela3,Bahia Maria Terezinha1

Affiliation:

1. Laboratório de Doenças Parasitárias, Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, Minas Gerais, Brazil

2. Laboratório de Parasitologia Básica, Instituto de Ciências Biomédicas, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil

3. Drugs for Neglected Disease initiative (DNDi), Geneva, Switzerland

Abstract

ABSTRACT Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. The first set of experiments assessed the range of E1224 doses required to induce parasitological cure using Trypanosoma cruzi strains with different susceptibilities to benznidazole (Y and Colombian). All E1224 doses were effective in suppressing the parasitemia and preventing death; however, parasitological cure was observed only in mice infected with Y strain. Considering these results, we evaluated the effect of combined treatment against Colombian, a multidrug-resistant T. cruzi strain. After exclusion of antagonistic effects using in vitro assays, infected mice were treated with E1224 and benznidazole in monotherapy or in combination at day 4 or 10 postinoculation. All treatments were well tolerated and effective in suppressing parasitemia; however, parasitological and PCR assays indicated no cure among mice treated with monotherapies. Intriguingly, the outcome of combination therapy was dependent on treatment onset. Early treatment using optimal doses of E1224-benznidazole induced a 100% cure rate, but this association could not eliminate a well-established infection. The beneficial effect of combination therapy was evidenced by further reductions of the patent parasitemia period in the group receiving combined therapy compared with monotherapies. Our results demonstrated a positive interaction between E1224 and benznidazole against murine T. cruzi infection using a multidrug-resistant strain and highlighted the importance of a stringent experimental model in the evaluation of new therapies.

Funder

Drugs for Neglected Tropical Diseases Initiative

Federal University of Ouro Preto

Fundação de Amparo à Pesquisa do Estado de Minas Gerais

MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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