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Antimicrobial Agents and Chemotherapy, February 2003, p. 467-474, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.467-474.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro Parasiticidal Effect of Nitazoxanide against Echinococcus multilocularis Metacestodes

Marianne Stettler,1 Renate Fink,1 Mirjam Walker,1 Bruno Gottstein,1 Timothy G. Geary,2 Jean François Rossignol,3 and Andrew Hemphill1*

Institute of Parasitology, Faculties of Veterinary Medicine and Medicine, University of Berne, CH-3012 Berne, Switzerland,1 Pharmacia Animal Health, Kalamazoo, Michigan 49001-0199,2 The Romark Institute for Medical Research, Tampa, Florida 336073

Received 5 July 2002/ Returned for modification 1 October 2002/ Accepted 28 October 2002

When humans serve as inadvertent intermediate hosts for Echinococcus multilocularis, disease (alveolar echinococcosis [AE]) may result from the expanding parasite metacestode in visceral organs, mostly in the liver. Benzimidazole carbamate derivatives such as mebendazole and albendazole are used for chemotherapeutic treatment of AE. However, these treatments are, in most cases, parasitistatic rather than parasiticidal. As treatment is discontinued, a recurrence of parasite growth has been observed in many AE patients with nonradical resections. The only curative treatment for AE is radical surgical resection of the parasite tissue and support by chemotherapy. As there is a need for new treatment options for AE, the in vitro efficacy of nitazoxanide (NTZ), a broad-spectrum drug used against intestinal parasites and bacteria, was investigated. We showed that in vitro treatment of E. multilocularis metacestodes with NTZ induced high levels of alkaline phosphatase activity in the medium. Concurrently, distinct morphological and ultrastructural alterations were detected. Most significantly, two distinct types of alterations were observed as soon as after 3 h of NTZ treatment. At first, the drug induced a peripheral output of membranous vesicles from the tegumental membrane into the laminated layer. Simultaneously, germinal layer-associated undifferentiated cells produced large vacuoles filled with lipid-like and often electron-dense membranous segments. Other alterations were observed at later time points, including vacuolization of the germinal layer, accumulation of lipid droplets, and lastly, loss of microtriches and separation of the laminated and germinal layers. The pattern of damage induced by NTZ was different from the alterations earlier observed in albendazole sulfoxide-treated vesicles. The nonviability of NTZ-treated metacestodes was confirmed through bioassay, i.e., inoculation of treated and untreated parasites into mice. These experiments demonstrate the in vitro parasiticidal effect of NTZ on E. multilocularis metacestodes.

* Corresponding author. Mailing address: Institute of Parasitology, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland. Phone: 41 31 6312384. Fax: 41 31 6312477. E-mail: hemphill{at}ipa.unibe.ch.

Antimicrobial Agents and Chemotherapy, February 2003, p. 467-474, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.467-474.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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