Rifaximin For Gastrointestinal Disorders

Abstract and Commentary

By Mary-Louise Scully, MD

Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA

Dr. Scully reports no relevant financial relationship related to this field of study

Synopsis: Rifaximin, a poorly absorbed rifamycin drug, may have potential for the treatment of a variety of gastrointestinal disorders including hepatic encephalopathy, Clostridium difficile-associated diarrhea, and irritable bowel syndrome.

Source: Adachi JA, DuPont HL. Rifaximin: A Novel Nonabsorbed Rifamycin for Gastrointestinal Disorders. Clin Infect Dis. 2006;42:541-547.

Potential new uses of rifaximin are examined in a recent CID article by Adachi and DuPont. Rifaximin, a semisynthetic derivative of rifamycin, received FDA approval in May of 2004, for the treatment of traveler’s diarrhea in patients 12 years of age and older caused by non-invasive strains of E. coli. The drug was first approved in Italy in 1987, and is now approved for use in 17 other countries throughout the world. Similar to other rifamycins, rifaximin binds to the β subunit of the bacterial DNA-dependent RNA polymerase, inhibiting the initiation of chain formation in RNA synthesis.

Gastric fluids do not inactivate rifaximin, and it is poorly absorbed with a bioavailability of < 0.4% in the blood following oral administration. The approved dosage of rifaximin for treatment of traveler’s diarrhea is 200 mg 3 times a day for 3 days. Recently, in one randomized, double-blind, placebo-controlled study in Mexico, rifaximin was shown to be effective for prevention of traveler’s diarrhea as well.1 Rifaximin is not recommended for use in diarrhea accompanied by fever or blood in the stool, as efficacy has not yet been established for the treatment of diarrhea due to pathogens other than E. coli, such as Campylobacter jejuni, Shigella, and Salmonella spp. Because of negligible oral absorption, dosage adjustments in renal insufficiency and hepatic dysfunction, even patients with hepatic encephalopathy, are not necessary.

Attention is now shifting towards exploring some other potential uses of rifaximin in various gastrointestinal disorders. Several studies suggest there may be another role for rifaximin in the treatment of hepatic encephalopathy. In double-blind studies where rifaximin dosed at 400 mg 3 times a day, it was compared to lactulose. A reduction in ammonia levels and an improvement in cognitive function were also noted with rifaximin treatment. Another study showed rifaximin to be equivalent to neomycin in the treatment of hepatic encephalopathy.

Rifaximin may play a role in the treatment of C. difficile-associated diarrhea. Another possible use may include small bowel overgrowth. Rifaximin appears to be effective in reducing small bowel flora and intestinal gas production which should then improve the abdominal distention, bloating, and flatulence associated with irritable bowel syndrome. In one double-blind study, 34 patients with irritable bowel syndrome were randomized to receive rifaximin or activated charcoal. The rifaximin group did experience a reduced production of H2, decreased severity of symptoms, and reduction in abdominal girth but neither group had improvement in bloating, abdominal pain, or production of CH4.2

Lastly, the use of rifaximin is being examined for inflammatory bowel disease. In a small, randomized, double-blind, placebo-controlled study of 26 patients with ulcerative colitis refractory to steroids, the rifaximin group had a nonsignificant improvement in 64% of subjects compared to 42% of subjects in the placebo group.3 Another study looked at the use of rifaximin plus ciprofloxacin in patients with pouchitis (inflammation of the ileal reservoir after pouch surgery for ulcerative colitis). Eighty-nine percent of the 18 patients treated with rifaximin plus ciprofloxacin for 15 days demonstrated clinical improvement.4 For patients with active Crohn’s disease, one open-label study of rifaximin given for 16 weeks showed clinical remission in 62% of patients.5

Commentary

An effort to examine the use of rifaximin in other gastrointestinal diseases is welcome. As a medication for traveler’s diarrhea, the cost, frequency of dosing, and the lack of approval for use of pathogens other than E.coli have limited its usefulness. For example, a 3-day course of a generic ciprofloxacin is now about $8.00, whereas 3 days of rifaximin will likely cost a traveler about $34.00. Also, the broader spectrum of activity of the quinolones or azithromycin for the bacterial pathogens of traveler’s diarrhea other than just E. coli is an important reason why most physicians’ prescribing practices have not widely changed. Of course, in the future, as drug resistance issues continue to emerge, rifaximin may play a greater role, especially if it is found to be effective against invasive forms of traveler’s diarrhea, such as Campylobacter, Salmonella, and Shigella species. Studies are apparently being planned in Thailand to address this issue.

Three late-phase studies are now enrolling patients.6 The first study will look at the efficacy of rifaximin dosed at 550 mg twice daily in the prevention of hepatic encephalopathy. The second study will address the usefulness of rifaximin in irritable bowel syndrome. A recent double-blind, placebo-controlled trial of 124 patients with irritable bowel syndrome showed rifaximin dosed at 400 mg twice a day was safe and effective for abdominal bloating and flatulence.7 The newer study planned will examine more patients (525 patients) and higher doses of rifaximin (275 mg, 550 mg, or 1100 mg twice daily). The third study enrolling patients is to examine rifaximin use in treatment of C. difficile-associated diarrhea. It is a vancomycin comparator, 300 subject, Phase III trial of rifaximin dosed at 400 mg 3 times a day. This study is very timely amidst reports of increasing rates and severity of C. difficile-associated disease and the emergence of a strain of C. difficile capable of producing levels of toxin A and B that are 16 to 23 times higher than control strains.8

Development of resistance is an appropriate concern with any new antibacterial agent. Rifampin has a long track record of clinical use and is well known to be a stimulant of resistance, but so far this appears to occur at a lower frequency with rifaximin. Presently, there does not appear to be evidence of cross-resistance between rifampin and rifaximin but further studies on this important issue will be needed.

References

  1. DuPont HL, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Rifaximin to Prevent Travelers’ Diarrhea. Ann Intern Med. 2005;142:805-812. Erratum in: Ann Intern Med. 2005;142:I30.
  2. DiStefano M, et al. Non-Absorbable Antibiotics for Managing Intestinal Gas Production and Gas-Related Symptoms. Aliment Pharmacol Ther. 2000;14:1001-1008.
  3. Gionchetti P, et al. Rifaximin in Patients with Moderate or Severe Ulcerative Colitis Refractory to Steroid-Treatment: A Double-Blind, Placebo-Controlled Trial. Dig Dis Sci. 1999;44:1220-1221.
  4. Gionchetti P, et al. Antibiotic Combination Therapy in Patients with Chronic, Treatment-Resistant Pouchitis. Aliment Pharmacol Ther. 1999;13:713-718.
  5. Shafran I, Johnson LK. An Open-Label Evaluation of Rifaximin in the Treatment of Active Crohn’s Disease. Curr Med Res Opin. 2005;21:1165-1169.
  6. www.salix.com/newsroom/20060111.asp
  7. Sharara AI, et al. A Randomized Double-Blind Placebo-Controlled Trial of Rifaximin in Patients with Abdominal Bloating and Flatulence. Am J Gastroenterol. 2006;101:326-333.
  8. Warny M, et al. Toxin Production By An Emerging Strain of Clostridium difficile Associated with Outbreaks of Severe Disease in North America. Lancet. 2005;366:1079-1084.