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Antimicrobial Agents and Chemotherapy, December 2004, p. 4848-4854, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4848-4854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Atovaquone Maintenance Therapy Prevents Reactivation of Toxoplasmic Encephalitis in a Murine Model of Reactivated Toxoplasmosis

Ildiko R. Dunay,1,2 Markus M. Heimesaat,1 Faris Nadiem Bushrab,3 Rainer H. Müller,3 Hartmut Stocker,4 Keikawus Arasteh,4 Michael Kurowski,5 Rudolf Fitzner,6 Klaus Borner,6 and Oliver Liesenfeld1*

Department of Medical Microbiology and Immunology of Infection, Institute for Infection Medicine,1 Institute of Clinical Chemistry and Pathobiochemistry, Campus Benjamin Franklin, Charité Medical School,6 Department of Pharmaceutics, Biotechnology and Quality Management, Free University of Berlin,3 Vivantes Auguste-Viktoria Klinikum,4 HIV-Lab, c/o Vivantes Auguste-Viktoria Klinikum, Berlin, Germany,5 Department of Medical Microbiology, Semmelweis University Budapest, Budapest, Hungary2

Received 4 June 2004/ Returned for modification 6 July 2004/ Accepted 26 August 2004

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.

* Corresponding author. Mailing address: Institute for Infection Medicine, Department of Medical Microbiology and Immunology of Infection, Charité Campus Benjamin Franklin, Hindenburgdamm 27, D-12203 Berlin, Germany. Phone: (49) 30-8445-3630. Fax: (49) 30-8445-3830. E-mail: Oliver.Liesenfeld{at}charite.de.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4848-4854, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4848-4854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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