Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis

Abstract

Over 1 billion people globally are estimated to be infected with Toxoplasma gondii with severe or unknown consequences and no safe and effective therapies are available against congenital or persistent chronic infection. We propose that atovaquone and diclazuril synergistically protect against fetal-maternal toxoplasmosis. Methods: Programmed pregnant mice were treated with atovaquone and diclazuril monotherapy, or combined (atovaquone + diclazuril) therapy and infected with tachyzoites (0, 300, 600) and the course of infection was studied. Results: Infected dams with low dose (300) developed moderate toxoplasmosis complications and treatments were similarly effective with minor differences between monotherapies. In contrast, major differences were observed amongst varied treatments during high-dose (600) infection and severe related-toxoplasmosis complications as follows. Dams developed hydrothorax, ascities and excess weight gain. Combined therapy (<i> &#80</i> < 0.01) and to a lesser extent diclazuril monotherapy ( <i> &#80</i> < 0.05) protected dams from excess weight, hydrothorax, and ascities. Infected dams exhibited splenomegaly, hepatomegaly and severe hepatitis. Combined therapy synergistically normalized pathology ( <i> &#80</i> < 0.001) and to a lesser degree monotherapy (diclazuril <i> &#80</i> < 0.01, and atovaquone <i> &#80</i> < 0.05) protected dams from hepatitis and splemomegaly. Additionally, behavioral response to pain stimuli and fetal weight and fetal numbers were significantly preserved in treated dams. Conclusions: This is the first report describing combined atovaquone and diclazuril therapy a) to be safe in pregnancy, b) to exert novel synergistic effects, and c) to protect dams and their nested fetuses against adverse effects of severe toxoplasmosis.