title: Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis.
abstract: Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for "acute" intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral "maintenance" therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with Toxoplasma gondii, developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials.
authors.affiliation: Department of Medical Microbiology and Immunology of Infection, Institute for Infection Medicine, Campus Benjamin Franklin, Charité Medical School, Berlin, Germany.
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
authors.forename: Faris Nadiem
authors.initials: FN
authors.lastname: Bushrab
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Müller
authors.forename: Hartmut
authors.initials: H
authors.lastname: Stocker
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arasteh
authors.forename: Michael
authors.initials: M
authors.lastname: Kurowski
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fitzner
authors.forename: Klaus
authors.initials: K
authors.lastname: Borner
authors.forename: Oliver
authors.initials: O
authors.lastname: Liesenfeld
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053626:Atovaquone; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007275:Injections, Intravenous; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D013058:Mass Spectrometry; D008578:Meninges / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011739:Pyrimethamine / Q000627:therapeutic use; D013411:Sulfadiazine / Q000627:therapeutic use; D016019:Survival Analysis; D016781:Toxoplasmosis, Cerebral / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D013411:Sulfadiazine; D053626:Atovaquone; D011739:Pyrimethamine