Compassionate Use of Nitazoxanide for the Treatment of Clostridium Difficile Infection

Clostridium difficile is the leading cause of nosocomial diarrheal disease associated with
antibiotic therapy. This is a debilitating condition with substantial morbidity and a
mortality that may be around 2-3%. There has been an enormous increase in this disease at the
VA Medical Center during the past two years, just as has occurred at other hospitals
throughout the United States.

Currently recommended therapy for this condition is metronidazole, given orally. About 15-20%
of patients fail to respond to initial therapy with metronidazole, and another 20% relapse
after treatment. Relapses may be treated with another course of metronidazole; about one-half
will respond to this therapy. The failures are treated with oral vancomycin, but this drug
also has a failure rate of 10-20%. There is, at present, no other accepted therapy (although
some articles in the literature favor vancomycin with ingested bacteria from benign species).
Furthermore, there is a strong risk to the emergence of resistant bacteria when hospitalized
patients are treated with oral vancomycin.

Nitazoxanide is an FDA approved drug that is marketed in the U.S. and has been widely used
throughout the world to treat parasitic diseases of the gastrointestinal tract; several
million children have been treated with this drug during the past decade. Nitazoxanide has
been approved as an antiprotozoal agent for oral administration in pediatric patients, ages 1
through 11, with diarrhea. The drug acts by interfering with anaerobic metabolic pathways,
and it has been shown to have excellent in vitro activity against C. difficile. We
hypothesized that this drug was both safe and effective as an alternative in patients who
have diarrheal disease caused by C. difficile. The IRB approved a double-blind protocol to
compare metronidazole with nitazoxanide, and we have treated a total of 16 patients so far
under this protocol.

In our IRB-approved double blind study (by design, two thirds of the subjects have been
randomized to the nitazoxanide), our patients have appeared to have a good response rate --
so good, in fact, that we think that nitazoxanide may be a better drug to treat this
infection than either metronidazole or vancomycin.

Inclusion Criteria:

- Patient must be > 18 years of age

- Clinical diagnosis of C. difficile associated disease, based on the new onset of
diarrhea, abdominal discomfort, or otherwise unexplained fever or leukocytosis

- Diagnosis of C. difficile colitis proven by positive assay for C. difficile toxin in
feces

- Disease has been treated, and the symptoms failed to respond to treatment with
metronidazole or vancomycin, or symptoms promptly relapsed after completing a course
of therapy with either of these drugs

- Able to take oral medication

Exclusion Criteria:

- Patients with other recognized causes of diarrhea or colitis

- Women of child bearing age who are pregnant, breast feeding, or not using birth
control

- Patients taking coumadin, phenytoin, celecoxib, or losartan

- Patients with renal insufficiency (BUN or creatinine >2 times baseline)

- Serious systemic disorder incompatible with the study