Citation: Hotez PJ (2014) Could Nitazoxanide Be Added to Other Essential Medicines for Integrated Neglected Tropical Disease Control and Elimination? PLoS Negl Trop Dis 8(3): e2758. doi:10.1371/journal.pntd.0002758
Published: March 27, 2014
Copyright: © 2014 Peter J. Hotez. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The author has indicated that no funding was received for this work.
Competing interests: The author has declared that no competing interests exist.
New findings from two Gates Foundation–supported studies—the Global Enteric Multicenter Study and the Global Burden of Disease Study 2010—suggest the possible importance of adding coverage for intestinal protozoan infections as part of World Health Organization preventive chemotherapy initiatives.
In 2011, the World Health Organization (WHO) determined that more than 700 million people were treated with at least one essential medicine for neglected tropical diseases (NTDs) under the auspices of a global preventive chemotherapy initiative , . However, a total of at least 1.9 billion people require annual preventive chemotherapy , , so these efforts will need to be greatly expanded in order to meet NTD control and elimination targets as outlined in the 2012 London Declaration and the 2013 World Health Assembly resolution for these diseases .
The original “rapid-impact” package of NTD interventions targeted up to seven NTDs highly endemic to sub-Saharan Africa, including the three soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma, and was comprised of up to four essential NTD medicines that could include a benzimidazole anthelminthic drug (i.e., mebendazole or albendazole), ivermectin, praziquantel, and/or azithromycin , . However, it was quickly noted that either the entire rapid-impact package or some component thereof had applicability outside of Africa (with modifications depending on the specific NTDs being targeted) . By controlling or eliminating the seven major NTDs, this approach could potentially effect a global disease burden reduction almost as important as HIV/AIDS, tuberculosis, or malaria control , .
As global preventive chemotherapy efforts expanded, it also became apparent that they could produce important collateral public health benefits that were not originally anticipated, including overall reductions in child mortality from the azithromycin component  and coverage for additional NTDs such as food-borne trematodiases, scabies, and yaws , , . There are equally important efforts underway to broaden the interventions to include water, sanitation, and hygiene (WASH) initiatives . Thus, in the decade since rapid impact was originally proposed, there are new uses and approaches for preventive chemotherapy.
In the last year, two important studies were published that could alter how we think about current preventive chemotherapy approaches. The first, known as the Global Enteric Multicenter Study (GEMS) for diarrheal diseases, made the surprising finding that cryptosporidiosis is one of the most important causes of infectious diarrhea in children in developing countries . The second is the Global Burden of Disease Study 2010 (GBD 2010), which found that, together, cryptosporidiosis and amoebiasis exceed the disease burden–as measured in disability-adjusted life years (DALYs) or in deaths—of any helminth infection now currently being targeted for preventive chemotherapy (Table 1) , . Although there are important disagreements in the NTD community about whether the DALYs for helminth infections (and other NTDs) were underestimated , both GEMS and GBD 2010 provide important information to our community that we need to consider in deciding whether it is possible to add coverage for cryptosporidiosis and amoebiasis as part of global preventive chemotherapy efforts.
A potential candidate drug for use in mass drug administration programs to target intestinal protozoa is the nitrothiazole benzamide drug, nitazoxanide (Figure 1) . The development program for nitazoxanide was led by Jean Francois Rossignol in the 1970s, initially as a veterinary anthelminthic agent, but the drug was subsequently shown to be active against intestinal protozoa and some human helminths, as well as anaerobic bacteria . It was approved in 2002 by the United States Food and Drug Administration, initially as an oral suspension for pediatric use (100 mg/5 ml) against cryptosporidiosis and giardiasis, and subsequently as 500 mg tablets for adults . According to The Medical Letter, the recommended therapeutic dosage is administered over three days .
Image source: http://commons.wikimedia.org/wiki/File:Nitazoxanide.svg, accessed December 26, 2013.
Although the initial indication for nitazoxanide was for cryptosporidiosis and giardiasis, subsequent investigative research has revealed that the drug is effective for amoebiasis caused by Entamoeba histolytica and could be used to treat both invasive intestinal amoebiasis and colonization with E. histolytica . Moreover, nitazoxanide is active against a number of nonprotozoan parasites, including the intestinal tapeworm Hymenolepis nana , with variable efficacy against the soil-transmitted nematodes –. It was recently shown to be an ineffective drug for the treatment of human trichuriasis . Nitazoxanide has also shown promise for the treatment of diarrhea caused by the bacterium Clostridium dificile ,  and for viral gastroenteritis caused by rotavirus, norovirus, and possibly other enteric viruses –. The drug or its derivatives has shown further promise as an innovative treatment for hepatitis C infection .
Because of its broad-spectrum activity against a variety of intestinal pathogens, there has been interest in evaluating nitazoxanide as a potential agent for public health control. Among Mexican children, the drug showed promise for reducing the burden of a variety of intestinal parasites , while Rossignol et al. have proposed nitazoxanide for the empiric treatment of pediatric diarrhea . To date, the medicine has an excellent overall safety spectrum, with occasional gastrointestinal disturbances and headache, and rarely (according to The Medical Letter), allergies, yellow discoloration of the sclera, and other rare side effects .
The possibility of adding nitazoxanide to current regimens used for WHO preventive chemotherapy initiatives as a means to broaden coverage against intestinal protozoa and possibly other pathogens has the potential of significantly increasing preventive chemotherapy's impact on reducing global disease burdens of parasitic infections and NTDs. However, to even consider adding nitazoxanide, there are quite a few operational research questions that would need to be addressed. Among them is that most likely nitazoxanide would need to be administered alongside other NTD drugs in the rapid-impact package as an annual single dose. It is unclear whether a single dose of 500 mg of the drug, or even a 1 g dose as used in a trichuriasis field study in Pemba, Tanzania , would have a significant impact in terms of reducing intestinal parasitism associated with Cryptosporidium partum or E. histolytica, especially in field conditions in a highly disease-endemic country of Africa or Asia.
Another important issue is selecting the optimal targeted age group. According to the GEMS study, cryptosporidiosis has its most important impact on preschool children, especially children under the age of two . Today, a significant percentage of deworming (i.e., mass drug administration of a benzimidazole anthelminthic agent for soil-transmitted helminth infections) is conducted on preschool-aged children—more than 250 million preschool children were treated in 2011 , and there is a rationale for extending schistosomiasis coverage with praziquantel for preschool-aged children . Is there an opportunity to simultaneously administer nitazoxanide with these anthelminthics? An alternative possibility is the co-administration of nitazoxanide with intermittent preventive treatment of malaria in infants (IPTi) or children (IPTc) .
Added concerns are the drug compatibilities and, of course, the safety and efficacy of co-administering NTD medicines with nitazoxanide. There is also the issue of cost—could nitazoxanide join other essential NTD medicines as a donated drug? Certainly the impact of providing nitazoxanide in programs of mass drug administration must also be further evaluated for the potential to promote drug resistance.
Such aspects would have to be carefully addressed in well-conducted and supervised programs of operational research in appropriately resource-poor settings. However, the potential benefits of adding cryptosporidiosis and amoebiasis targets to current preventive chemotherapy regimens may be sufficiently important to warrant next steps in evaluating nitazoxanide in this context.
- 1. World Health Organization (2013) Monitoring and evaluation of preventive chemotherapy. Wkly Epidemiol Rec 88: 17–24.
- 2. World Health Organization (2013) Rolling out and scaling up integrated preventive chemotherapy for selected neglected tropical diseases. Wkly Epidemiol Rec 88: 161–172.
- 3. Hotez PJ (2013) NTDs V.2.0: “Blue marble health” – neglected tropical disease control and elimination in a shifting health policy landscape. PLOS Negl Trop Dis 7: e2570.
- 4. Fenwick A, Molyneux D, Nantulya V (2005) Achieving the Millennium Development Goals. Lancet 365: 1029–1030.
- 5. Molyneux DH, Hotez PJ, Fenwick A (2005) “Rapid-impact interventions”: how a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLOS Med 2: e336.
- 6. World Health Organization (2006) Preventive Chemotherapy in Human Helminthiases. Coordinated use of anthelminthic drugs in control interventions: a manual for health professionals and programme managers. Available: http://whqlibdoc.who.int/publications/2006/9241547103_eng.pdf. Accessed 26 December 2013.
- 7. Hotez PJ, Molyneux DH, Fenwick A, Ottesen E, Ehrlich Sachs S, et al. (2006) Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLOS Med 3: e102.
- 8. Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, et al. (2007) Control of neglected tropical diseases. N Engl J Med 357: 1018–1027.
- 9. Porco TC, Gebre T, Ayele B, House J, Keenan J, et al. (2009) Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial. JAMA 302: 962–968.
- 10. Keiser J, Duthaler U, Utzinger J (2010) Update on the diagnosis and treatment of food-borne trematode infections. Curr Opin Infect Dis 23: 513–520.
- 11. Hotez PJ, Velasquez RM, Wolf JE (2014) Neglected Tropical Skin Diseases: Their Global Elimination through Integrated Mass Drug Administration? JAMA Dermatology. In press.
- 12. Freeman MC, Ogden S, Jacobson J, Abbott D, Addiss DG, et al. (2013) Integration of water, sanitation, and hygiene for the prevention and control of neglected tropical diseases: a rationale for inter-sectoral collaboration. PLOS Negl Trop Dis 7: e2439.
- 13. Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, et al. (2013) Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet 382: 209–222.
- 14. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, et al. (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095–2128.
- 15. Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, et al. (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2197–2223.
- 16. Hotez PJ, Alvarado M, Basanez MG, Bolliger I, Rupert Bourne, et al.. (2014) The global burden of disease study 2010: interpretation and implications for the neglected tropical diseases. PLOS Negl Trop Dis In press.
- 17. Aslam S, Musher DM (2007) Nitazoxanide: clinical studies of a broad-spectrum anti-infective agent. Future Microbiol 2: 583–590.
- 18. The Medical Letter (2010) Drugs for Parasitic Infections. Treat Guidel Med Lett 8 ((Suppl)) e1–20 Available: http://gorgas.dom.uab.edu/syllabus/2013/03_Parasites/RxParasitesMedicalLetter.pdf. Accessed 27 February 2014.
- 19. Rossignol JF, Kabil SM, El-Gohary Y, Younis AM (2007) Nitazoxanide in the treatment of amoebiasis. Trans R Soc Trop Med Hyg 101: 1025–1031.
- 20. Chero JC, Saito M, Bustos JA, Blanco EM, Gonzalvez G, et al. (2007) Hymenolepis nana infection: symptoms and response to nitazoxanide in field conditions. Trans R Soc Trop Med Hyg 101: 203–205.
- 21. Diaz E, Mondragon J, Ramirez E, Bernal R (2003) Epidemiology and control of intestinal parasites with nitazoxanide in children in Mexico. Am J Trop Med Hyg 68: 384–385.
- 22. Delgado OM, Fernandez G, Silva S, Ramirez O, Romero J, et al. (2008) Preliminary evidence of nitazoxanide activity on Toxocara canis in a mouse model. Int J Antimicrobial Agents 31: 175–187.
- 23. Hu Y, Ellis BL, Yiu YY, Miller MM, Urban JF, et al. (2013) An extensive comparison of the effect of the anthelminthic classes on diverse nematodes. PLOS One 8: e70702.
- 24. Speich B, Ame SM, Ali SM, Alles R, et al. (2012) Efficacy and safety of nitazoxanide, albendazole, and nitazoxanide-albendazole against Trichuris trichiura infection: a randomized controlled trial. PLOS Negl Trop Dis 6: e1685.
- 25. Musher DM, Logan N, Bressler AM, Johnson DP, Rossignol JF (2009) Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis 48: e41–6.
- 26. Venugopal AA, Johnson S (2012) Current state of Clostridium difficile treatment options. Clin Infect Dis 55 ((Suppl 2)) S71–76.
- 27. Rossignol JF, El-Gohary M (2006) Nitazoxanide in the treatment of viral gastroenteritis: a randomized double-blind placebo-controlled clinical trial. Aliment Pharmacol Ther 24: 1423–1430.
- 28. Rossignol JF, Abou Zekry M, Hussein A, Santoro MG (2006) Effect of nitazoxanide in treating rotavirus diarrhea: a randomized, double-blind, placebo-controlled trial. Lancet 368: 124–129.
- 29. Rossignol JF, El-Gohary , Yehia M (2006) Nitazoxanide in treatment of viral gastroenteris: a randomized, double-blind, placebo-controlled clinical trial. Alimentary Pharmacology & Therapeutics 24: 1423–1430.
- 30. Siddiq DM, Koo HL, Adachi JA, Viola GM (2011) Norovirus gastroenteritis successfully treated with nitazoxanide. J Infection 63: 394–397.
- 31. Rossignol JF, Elfert A, Keeffe EB (2010) Treatment of chronic hepatitis C using a 4-week lead-in with nitazoxanide before peginterferon plus nitazoxanide. J Clin Gastroenterol 44: 504–509.
- 32. Rossignol JF, Lopez-Chegne N, Julcamoro LM, Carrion ME, Bardin MC (2012) Nitazoxanide for the empiric treatment of pediatric infectious diarrhea. Trans R Soc Trop Med Hyg 106: 167–173.
- 33. World Health Organization (2013) Soil-transmitted helminthiases: number of children treated in 2011. Weekly Epidemiol Rec 88: 145–152.
- 34. Coulibaly JT, N'gbesso YK, Knopp S, Keiser J, N'Goran EK, et al. (2012) Efficacy and safety of praziquantel in preschool-aged children in an area co-endemic for Schistosoma mansoni and S. haematobium. PLOS Negl Trop Dis 6: e1917.
- 35. Sicuri E, Biao P, Hutton G, Tediosi F, Menendez C, et al. (2011) Cost-effectiveness of intermittent preventive treatment of malaria in infants (IPTi) for averting anaemia in Gabon: a comparison between intention to treat and according to protocol analyses. Malar J 10: 305.