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Concise Reviews of Pediatric Infectious Diseases®

Nitazoxanide for Treatment of Intestinal Parasites in Children

Ochoa, Theresa J. MD*†; White, A Clinton Jr MD

Editor(s): Fisher, Margaret C. MD; Overturf, Gary D. MD

Author Information
The Pediatric Infectious Disease Journal: July 2005 - Volume 24 - Issue 7 - p 641-642
doi: 10.1097/01.inf.0000171522.79099.c5
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Studies from developing countries have highlighted the role of protozoan parasites (especially Cryptosporidium and Giardia) in persistent diarrhea. Long term consequences of diarrhea include predisposition to other enteric infections, growth and nutritional deficits and delayed cognitive development.1,2 Protozoans also are important causes of persistent diarrhea in developed countries and often are linked with water-borne (Giardia, Cryptosporidium) or food-borne (Cyclospora) outbreaks.

Fecal tests for parasites are often not obtained until children have failed symptomatic therapy.3 Most laboratories do not test stools for Cryptosporidium unless specifically requested. Studies on volunteers and children with immunodeficiencies in which polymerase chain reaction technology is used have demonstrated that many, if not most, infections are missed by standard methods.4 For example, fewer than 300 of the 403,000 estimated cases of cryptosporidiosis in the water-born outbreak in Milwaukee were confirmed by stool examination. With potentially new treatments available, it may be time to reexamine standard diagnostic and treatment approaches to diarrhea in children.

Nitazoxanide, marketed under the trade names Alinia (United States), Daxon (Mexico) and Colufase (Central America, Peru, Argentina), is a nitrothiazolylsalicylamide derivative with a broad spectrum of antiprotozoal and antihelminthic activity.5 Its mechanisms of action is believed to be inhibition of pyruvate:ferredoxin oxidoreductase enzyme-dependent electron transfer reactions, which are essential to the metabolism of anaerobic organisms.6 Nitazoxanide is well-absorbed after oral administration, with absorption improved when taken with food. The drug is rapidly converted to its active metabolite tizoxanide, which is glucuronidated and excreted in bile and urine. It was first approved in suspension form, but it is now also available as 500-mg tablets. For most indications, it is dosed every 12 hours for 3 days. The recommended dose is 100 mg (5 mL) for children 12–47 months of age, 200 mg (10 mL) for children 4–11 years of age and 500 mg for older children and adults (∼15 mg/kg/d). In general, nitazoxanide is well-tolerated, with adverse events occurring at a frequency similar to that for placebo. They included abdominal pain, diarrhea, vomiting and headache.

CLINICAL STUDIES IN CHILDREN

Cryptosporidiosis.

A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in apparently immunocompetent children and adults with persistent diarrhea in Egypt.7 By day 7, diarrhea had resolved in 39 of 49 (80%) treated with nitazoxanide compared with 20 of 49 (41%) treated with placebo. Nitazoxanide also reduced the duration of oocyst shedding. Among severely malnourished children in Zambia with chronic cryptosporidiosis, a 3-day course of therapy not only led to clinical and parasitologic improvement but also improved survival.8 Among patients not infected with human immunodeficiency virus (HIV), resolution by day 7 was noted in 14 of 25 (56%) of those treated with nitazoxanide, compared with 5 of 22 (23%) for the placebo group, and 7 of 8 of those failing treatment responded to open label nitazoxanide. Among HIV-infected patients, there was no significant response at that dose.8 Higher doses and longer duration were effective in adults with CD4 cell counts of >50.9 Studies with higher doses and longer periods are currently being conducted in children and adults with HIV.

Giardiasis.

Nitazoxanide was compared with metronidazole among children with giardiasis in Peru. By intent-to-treat analysis, 47 of 55 (85%) treated with nitazoxanide noted resolution of diarrhea, compared with 44 of 55 (80%) treated with metronidazole.10 A placebo-controlled trial demonstrated more rapid resolution in adults with giardiasis.11 Nitazoxanide is also active in vitro against metronidazole-resistant Giardia.

Other Intestinal Parasites.

Studies have suggested efficacy against other protozoan infections, such as cyclosporiasis, isosporiasis, amebiasis, microsporidiosis, Blastocystis hominis and Balantidium coli. Nitazoxanide was comparable with mebendazole in the treatment of intestinal nematodes in children,12 equivalent to albendazole in Ascaris infection and superior in trichuriasis.13 A large open label study noted eradication of infection with Ancylostoma duodenale (44 of 46 cases) and of Strongyloides (34 of 36 cases) and successful treatment of Enterobius (106 of 112 cases).14 Nitazoxanide is also effective against the tapeworms Taenia saginata and Hymenolepis nana.13,14 In a placebo-controlled trial of chronic fascioliasis in children and adults from Peru, fascioliasis was eliminated in 32 of 65 (49%) cases compared with 1 of 16 (6%) treated with placebo.15

In vitro and animal studies have demonstrated significant activity of nitazoxanide versus a number of bacteria, including Clostridium difficile and Helicobacter pylori. Studies of nitazoxanide in C. difficile colitis and as adjunctive therapy for inflammatory bowel disease are in progress.

SUMMARY

Nitazoxanide is an important new antiparasitic drug. It is effective for cryptosporidiosis in normal hosts, malnourished children and HIV patients with higher CD4 cell counts. Nitazoxanide is equivalent to metronidazole in giardiasis but may be better tolerated. It has wide spectrum activity against intestinal protozoan and helminth infections. Intestinal protozoa are important but underdiagnosed causes of persistent diarrhea in both developing and developed countries. Empiric therapy with nitazoxanide, which is effective, well-tolerated and modestly priced, may be a reasonable and more cost-effective alternative to pursuing specific diagnoses in selected populations.

NITAZOXANIDE: KEY CONCEPTS

  1. Nitazoxanide is a new antiparasitic agent with broad spectrum activity against intestinal protozoa and helminths.
  2. It has proven efficacy in cryptosporidiosis.
  3. It was initially approved for use in pediatric cryptosporidiosis and giardiasis in children 1–11 years of age.
  4. Controlled trials have demonstrated equivalent efficacy and better tolerability compared with metronidazole in giardiasis.
  5. Studies suggest efficacy against a broad range of intestinal protozoa and helminths.
  6. Nitazoxanide may prove effective in empiric therapy for persistent diarrhea.
  7. Nitazoxanide may prove to be a broad spectrum deworming agent.

REFERENCES

1. Lima AA, et al. Persistent diarrhea signals a critical period .... J Infect Dis. 2000;181:1643–1651.
2. Berkman DS, et al. Effects of stunting, diarrhoeal disease, and parasitic .... Lancet. 2002;359:564–571.
3. Guerrant RL, et al. IDSA: practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32:331–351.
4. White AC Jr. Cryptosporidiosis . . .. In: Mandell G, Bennett J, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier; 2004:3215–3228.
5. White AC Jr. Nitazoxanide: a new broad spectrum antiparasitic agent. Expert Rev Anti Infect Ther. 2004;2:43–49.
6. Rossignol J-FA. Treatment of diarrhea caused by Cryptosporidium parvum: .... J Infect Dis. 2001;184:103–106.
7. Amadi B, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children Lancet. 2002;360:1375–1380.
8. Rossignol JF, et al. A double-blind placebo-controlled study of nitazoxanide . . .. Trans R Soc Trop Med Hyg. 1998;92:663–666.
9. Ortiz JJ, et al. Randomized clinical study of nitazoxanide compared to metronidazole. Aliment Pharmacol Ther. 2001;15:1409–1415.
10. Rossignol JF, et al. Treatment of diarrhea caused by Giardia .... J Infect Dis. 2001;184:381–384.
11. Davila-Gutierrez CE, et al. Nitazoxanide compared with quinfamide and mebendazole .... Am J Trop Med Hyg. 2002;66:251–254.
12. Ortiz JJ, et al. Comparative clinical studies of nitazoxanide, albendazole and praziquantel .... Trans R Soc Trop Med Hyg. 2002;96:193–196.
13. Abaza H, et al. Nitazoxanide in the treatment of patients with intestinal protozoan and helminth infections .... Curr Ther Res. 1998;58:116–121.
14. Favennec L, et al. Double-blind, randomized, placebo-controlled study of nitazoxanide in the treatment of fascioliasis .... Aliment Pharmacol Ther. 2003;17:265–270.
Keywords:

nitazoxanide; parasites; diarrhea

© 2005 Lippincott Williams & Wilkins, Inc.