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Antimicrobial Agents and Chemotherapy, August 1998, p. 1959-1965, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Efficacy of Nitazoxanide against Cryptosporidium parvum in Cell Culture and in Animal Models

Cynthia M. Theodos,1 Jeffrey K. Griffiths,1,2 Jennifer D'Onfro,1 Alexandra Fairfield,3 and Saul Tzipori1,*

Division of Infectious Diseases, Tufts University School of Veterinary Medicine, North Grafton,1 and Department of Family Medicine and Community Health and Department of Medicine, Tufts University School of Medicine, Boston,2 Massachusetts, and Opportunistic Infections Research Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland3

Received 19 November 1997/Returned for modification 9 February 1998/Accepted 11 May 1998

Nitazoxanide (NTZ), a drug currently being tested in human clinical trials for efficacy against chronic cryptosporidiosis, was assessed in cell culture and in two animal models. The inhibitory activity of NTZ was compared with that of paromomycin (PRM), a drug that is partially effective against Cryptosporidium parvum. A concentration of 10 µg of NTZ/ml (32 µM) consistently reduced parasite growth in cell culture by more than 90% with little evidence of drug-associated cytotoxicity, in contrast to an 80% reduction produced by PRM at 2,000 µg/ml (3.2 mM). In contrast to its efficacy in vitro, NTZ at either 100 or 200 mg/kg of body weight/day for 10 days was ineffective at reducing the parasite burden in C. parvum-infected, anti-gamma-interferon-conditioned SCID mice. Combined treatment with NTZ and PRM was no more effective than treatment with PRM alone. Finally, NTZ was partially effective at reducing the parasite burden in a gnotobiotic piglet diarrhea model when given orally for 11 days at 250 mg/kg/day but not at 125 mg/kg/day. However, the higher dose of NTZ induced a drug-related diarrhea in piglets that might have influenced its therapeutic efficacy. As we have previously reported, PRM was effective at markedly reducing the parasite burden in piglets at a dosage of 500 mg/kg/day. Our results indicate that of all of the models tested, the piglet diarrhea model most closely mimics the partial response to NTZ treatment reported to occur in patients with chronic cryptosporidiosis.

* Corresponding author. Mailing address: Division of Infectious Diseases, Tufts University School of Veterinary Medicine, 200 Westboro Rd., Building 20, North Grafton, MA 01536. Phone: (508) 839-7955. Fax: (508) 839-7977. E-mail: stzipori{at}infonet.tufts.edu.

Antimicrobial Agents and Chemotherapy, August 1998, p. 1959-1965, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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