Combination of Clofazimine and Atovaquone as a Potent Therapeutic Regimen for the Radical Cure of Babesia microti Infection in Immunocompromised Hosts

Abstract

Human babesiosis caused by Babesia microti can be fatal in immunocompromised patients, and the currently used drugs are often ineffective. A recent study found that clofazimine clears B. microti Munich strain in immunocompromised mice. In the present study, we investigated the efficacies of clofazimine and 2-drug combinations involving clofazimine, atovaquone, and azithromycin against B. microti Peabody mjr strain in immunocompromised mice. Treatment with clofazimine alone, clofazimine plus azithromycin, and atovaquone plus azithromycin was ineffective and failed to eliminate the parasites completely, while a 44-day treatment with clofazimine plus atovaquone was highly effective and resulted in a radical cure.

Efficacy of clofazimine and nitazoxanide combination in treating intestinal cryptosporidiosis and enhancing intestinal cellular regeneration in immunocompromised mice

“…In this study, we used a combination of half the dose of CFZ with half the dose of NTZ. This was based on observations from previous studies of Tuvshintulga et al (2021) who reported excellent efficacy and complete clearance of Babesia microtti infection after 44-days of treatment with a combination of half dose of CFZ and atovaquone in immunocompromised mice. Furthermore, Ammerman et al (2018) used a half dose of CFZ to add potent bactericidal and treatment-shortening activity to the first-line regimen in M. tuberculosis -infected BALB/c mice.…”

Phosphatidylinositol 4-kinase is a viable target for the radical cure of Babesia microti infection in immunocompromised hosts

“…Hence, the radical cure of babesiosis remains challenging in severely immunocompromised patients. In the recent past, a few compounds have been reported as promising drugs against human babesiosis, namely endochin-like quinolones (ELQs) ( Lawres et al., 2016 ; Chiu et al., 2021 ), tafenoquine ( Mordue and Wormser, 2019 ; Liu et al., 2021 ), and clofazimine ( Tuvshintulga et al., 2022 ). ELQs showed inhibitory effects against apicomplexan parasites by targeting Cytb ( Doggett et al., 2012 ; Stickles et al., 2015 ).…”

“…Clofazimine combined with ATO was also evaluated as a candidate for human babesiosis. Uninterrupted treatment of clofazimine with ATO resulted in the radical cure of B. microti -infected SCID mice in 44 days ( Tuvshintulga et al., 2022 ). Phosphatidylinositol kinases (PIKs) are essential in the regulation of cell proliferation, survival, and membrane trafficking ( Hassett and Roepe, 2018 ).…”

“…This timeline was followed since early clinical manifestations are observed when parasitemia exceeds 1% in babesiosis patients ( Akel and Mobarakai, 2017 ). Daily treatment with 20 mg/kg MMV390048, 20 mg/kg ATO plus 20 mg/kg AZI, and 0.2 ml vehicle (sesame oil) was given orally to each group, respectively ( Batiha et al., 2020 ; Tuvshintulga et al., 2022 ). These treatments were discontinued when mice tested negative by PCR detection of B. microti 18S ribosomal RNA (18S-rRNA) gene.…”

“…Gene amplification was performed following a previously described protocol ( Persing et al., 1992 ). The Cytb and rpl4 mutations were determined by Sanger sequencing ( Tuvshintulga et al., 2022 ). The obtained sequence was aligned with the wild type sequence.…”