Pharmacotherapy of two common gastrointestinal infections

June 2004

A new agent, nitazoxanide (Alinia, Romark Pharmaceuticals), has recently become available for the therapy of cryptosporidiosis and giardiasis in children. The role and use of nitazoxanide for the treatment of cryptosporidiosis will be presented. A brief review of another common gastrointestinal infection, Clostridium difficile-associated disease, will also be given.

Cryptosporidiosis

Cryptosporidium parvum is a protozoan that may infect humans, more so children than adults, resulting in primarily gastrointestinal symptoms. The oocyst is the infectious form; when orally ingested, it results in excystation and small bowel enterocyte penetration by sporozoites. This often results in watery, nonbloody diarrhea. Fever, vomiting, fatigue and anorexia may also occur, perhaps resulting in a misdiagnosis of viral gastroenteritis. In children with normal immune function, symptoms are usually self-limited, with a mean duration of diarrhea of 10 days. In children with abnormal immune function, disease can be considerably more significant, resulting in chronic diarrhea, malnutrition, extragastrointestinal involvement and even death. Transmission of C. parvum occurs primarily person-to-person by the fecal-oral route. More cases occur in the summer months because of the use of outdoor swimming pools. Unfortunately, oocysts are resistant to public pool chlorination. Laboratory diagnosis of C. parvum gastrointestinal infection depends upon identification of stool oocysts. Common laboratory testing of stool for ova and parasites likely will not identify the oocysts, and clinicians should specify testing of stool for C. parvum.

Treatment of Cryptosporidium infection in children with an intact immune system is largely supportive, as diarrheal illness is often self-limited. However, nitazoxanide has recently become available and is indicated to treat infection with Cryptosporidium (and Giardia lamblia) in children 1 to 11 years of age with normal immune function. No other FDA-approved medication is available for the treatment of C. parvum in children.

Nitazoxanide is effective for giardiasis. Metronidazole also is effective treatment for giardiasis. Compared with nitazoxanide, however, metronidazole requires a longer treatment duration (three days vs. five to seven days, respectively) and is not commercially available in liquid form, although a recipe for a 50 mg/mL suspension is commonly available. It is interesting that nitazoxanide is not approved for use in children older than 11 years or adults (the opposite occurs for many drugs – approved indications for adults, but not children). Nitazoxanide is available as a strawberry-flavored suspension.

Clinical studies

The granting of FDA approval to nitazoxanide for the treatment of cryptosporidiosis was based primarily upon two published studies. Rossignol evaluated nitazoxanide in a randomized, double-blind, placebo-controlled manner in 50 ambulatory Egyptian children (1 to 11 years of age) with C. parvum-induced diarrheal illness. The mean duration of diarrhea prior to treatment in these children was 12 to 13 days. The primary endpoints of therapy evaluation were clinical response at day 7 and parasitologic response (stool examination) at day 7 to 10 following treatment initiation. A three-day treatment course of nitazoxanide resulted in resolution of diarrhea in 88% of children, compared with 38% in patients receiving placebo (P <.05). Oocyst shedding resolved in 75% of active treatment children, compared with 20% of children receiving placebo (P <.05). There was no difference in adverse effects among active and placebo treatment groups.

Amadi evaluated nitazoxanide in 47 Zambian children (mean age 19 months, range 13-35 months), also in a randomized, double-blind, placebo-controlled manner. This study differed from the above trial in that the Zambian children were hospitalized for treatment and many were significantly malnourished. Forty-nine children with HIV were also evaluated. Assessment endpoints were similar to those used in the study by Rossignol. The mean duration of diarrheal illness at baseline was 24 days in children who did not have HIV receiving nitazoxanide and 15 days children who did not have HIV receiving placebo. Most children receiving nitazoxanide and placebo were assessed as moderately to severely malnourished (68% and 77%, respectively). After a three-day treatment course, 56% and 23% of children receiving nitazoxanide and placebo had resolved diarrheal illness, respectively (P <.05); oocyst eradication from stool occurred in 52% receiving nitazoxanide and 14% receiving placebo (P <.05). Other than parasitological response, another secondary endpoint was mortality at day 8 after therapy initiation. Among the children receiving placebo, 18% expired by day 8, compared with no children receiving nitazoxanide (P <.05). Among the 49 children with HIV (mean CD4 count, 619-620/µL), there were no significant differences in resolution of diarrhea, parasitological response or mortality. A second three-day course of nitazoxanide was given in an open-label manner to the children who did not have HIV who did not respond initially. Most of these children responded favorably to a second therapy course. There were no significant differences in adverse effects among the treatment and placebo groups.

Dosing and use

Dosing of nitazoxanide for cryptosporidiosis and giardiasis is 100 mg every 12 hours for ages 12 to 47 months and 200 mg every 12 hours for ages 48 months to 11 years. Nitazoxanide is hepatically metabolized to an active metabolite, which is highly protein-bound. While no significant drug-drug interactions have been identified, it would be prudent of clinicians prescribing nitazoxanide to consider the potential for interactions and to review the patient’s medication profile for other highly protein-bound drugs. The cost of nitazoxanide is approximately $60 (average wholesale price).

Based on the studies reviewed here, nitazoxanide has demonstrated effectiveness in treating cryptosporidiosis diarrheal disease in immunocompetent children. Because infection is often self-limited, use of nitazoxanide may not be necessary in many infected children. Nitazoxanide may be most useful for children with diarrhea persisting beyond 10 days or in children with significant complications resulting from diarrhea illness. The role of nitazoxanide in treating cryptosporidiosis in immunocompromised children is not clear, with conflicting published evidence of efficacy.

Clostridium difficile colitis

Infection with C. difficile may result in another relatively common gastrointestinal illness. Toxin A and B production by C. difficile may cause diarrhea (including blood or mucous), abdominal cramps and fever. Stool should be specifically requested to test for C. difficile toxins to confirm the diagnosis. This test will not be routinely done. Illness ranges from mild to severe and is usually associated with hospitalization and antimicrobial use. While use of nearly any antibiotic may result in C. difficile toxin production, ß-lactam antibiotics (eg, cephalosporins and penicillins) and clindamycin are most commonly implicated.

Treatment principles for C. difficile colitis and diarrhea include discontinuance of the offending antibiotic, if possible. Approximately 25% of patients will respond favorably to this intervention alone. Specific antimicrobial therapy directed toward C. difficile may be indicated for those with moderate to severe symptoms or with continuation of symptoms after the offending antibiotic has been discontinued. Metronidazole and vancomycin are both highly effective, with 80% to 100% efficacy rates from controlled trials. Metronidazole should be used for initial treatment. Therapy with vancomycin can be instituted if the patient fails a trial with metronidazole. Vancomycin should be reserved for second-line therapy to prevent or minimize development of vancomycin-resistant bacterial pathogens (ie, enterococcus, Staphylococcus aureus). Metronidazole may be given orally or intravenously; vancomycin should be given only orally. When vancomycin is used orally, monitoring of plasma levels is not necessary, as absorption is negligible. Relapses of infection are relatively common – relapse rates up to 33% within one to six weeks have been reported. Most relapses are reinfections, and numerous relapses may occur in a single patient. Relapses should be treated as initial therapy, with metronidazole preferred.

For more information:

• Rossignol JFA. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective, randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis. 2001;184:103-106.
• Amadi B. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomized controlled trial. Lancet. 2002;360:1375-1380.
• Bailey JM. Nitazoxanide treatment for giardiasis and cryptosporidiosis in children. Ann Pharmacother. 2004:38:634-640.
• Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Amer J Gastro. 1997;92:739.
• ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Amer J Health-System Pharmacy. 1998;55:1407-1411.