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Antimicrobial Agents and Chemotherapy, September 2008, p. 3106-3112, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00207-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Efficacy of Pyrvinium Pamoate against Cryptosporidium parvum Infection In Vitro and in a Neonatal Mouse Model{triangledown}

Autumn S. Downey,1 Curtis R. Chong,2 Thaddeus K. Graczyk,1,3,4 and David J. Sullivan1*

Department of Molecular Microbiology and Immunology,1 Department of Environmental Health Sciences, Division of Environmental Health Engineering,3 Johns Hopkins Center for Water and Health, Johns Hopkins Bloomberg School of Public Health,4 Department of Pharmacology and Molecular Sciences, Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 212052

Received 13 February 2008/ Returned for modification 21 May 2008/ Accepted 18 June 2008

No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 µM paromomycin or 27 µM chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a >90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205. Phone: (410) 502-2522. Fax: (410) 955-0105. E-mail: dsulliva{at}jhsph.edu

{triangledown} Published ahead of print on 30 June 2008.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3106-3112, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00207-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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