Nancy A. Melville

June 07, 2011

June 7, 2011 (Milan, Italy) — A rifaximin "chaser" appears to be effective in decreasing recurrent diarrhea among patients who have already been through conventional therapy for Clostridium difficile, according to research presented here at the 21st European Congress of Clinical Microbiology and Infectious Diseases.

Previous uncontrolled case studies have shown that rifaximin (Xifaxan, Salix), a nonabsorbable rifamycin antibiotic approved in the United States for the treatment of traveler's diarrhea, decreases diarrhea in patients with irritable bowel syndrome. Researchers consider the therapy helpful in decreasing recurrent diarrhea in patients with C difficile when given after a 10- to 14-day course of conventional antibiotic therapy.

In this double-blind placebo-controlled pilot study, researchers randomized 68 patients with C difficile to 1 of 2 groups: rifaximin 400 mg 3 times daily, given immediately after finishing conventional antibiotic therapy with oral vancomycin or metronidazole for 20 days (n = 33); or placebo (n = 35) for 20 days.

Of the 68 patients, 24 (35%) had recurrent diarrhea, either due to recurrent C difficile (23.5%) or self-reported diarrhea (11.5%).

The patients were followed for 3 months and assessed for diarrhea recurrence, C difficile recurrence, and self-reported diarrhea not related to C difficile after a period of wellness.

The results indicated that 7 of 33 (21%) patients in the rifaximin group had recurrent diarrhea, compared with 17 of 35 (49%) in the placebo group (P = .010).

Five of 33 (15%) patients in the rifaximin group had a recurrence of C difficile, compared with 11 of 35 (31%) patients in the placebo group (P = .087). Self-reported diarrhea occurred in 2 of 33 (6%) patients in the rifaximin group and in 6 of 35 (17%) patients in the placebo group (P = .17).

The mechanism by which rifaximin targets C difficile makes it a potentially useful drug to switch to after conventional antibiotics fail to resolve recurrent diarrhea related to the infection, said the study's lead author, Kevin W. Garey, PharmD, MS, associate professor and chair of the Department of Clinical Sciences and Administration at University of Houston College of Pharmacy in Texas.

"The other antibiotics (oral vancomycin or metronidazole) kill C difficile but they also kill enteric flora. Rifaximin has in vitro susceptibility to C difficile but does not kill other enteric flora," he said. "It is therefore quite selective for C difficile and allows enteric flora to regrow and potentially decrease recurrence rates."

The study might have had stronger results if it had extended beyond 3 months and included more patients, said Dale N. Gerding, MD, assistant chief of staff for research at Hines VA Hospital in Illinois.

"It appears the study was terminated too early and did not reach statistical significance for reduction of CDI [C difficile infection] recurrence, which is the major target for the rifaximin chaser approach," he said. "Had they studied more patients, it is likely that it would have shown statistical significance for reducing CDI recurrence."

He noted that the thrice-daily dose used in the study might not be necessary. "It is also not clear why it had to be given 3 times a day for 20 days, which is likely to be very expensive," Dr. Gerding said. "A 2-week course twice a day might have worked just as well. It would be of interest to know if the patients who failed the rifaximin chaser developed resistant organisms."

Rifaximin can offer a chance for patients to switch from the prolonged use of other antibiotics, Dr. Gerding said.

"Multiple or prolonged courses of metronidazole are to be avoided" because of the possibility that they might induce a neuropathy — which can be a very troublesome side effect — that may not go away."

"In addition, after a patient has had more than 1 recurrence, it is generally recommended by guidelines that a vancomycin regimen using a tapering dose and then pulse dosing be used. If this fails, a rifaximin chaser can be tried; if that fails, some patients are treated with a stool transplant (to restore the normal protective bowel flora)," he said.

Stuart Johnson, PhD, who has published research on rifaximin for recurrent C difficile diarrhea, said he also does not feel that the higher-dose regimen is necessary.

"Dr. Garey and colleagues are to be commended for studying a variation of this approach in a randomized placebo-controlled fashion. Although their starting population was different than our patients, the principle is the same," said Dr. Johnson, who is from the Loyola University Stritch School of Medicine in Chicago, Illinois.

"Like [Dr. Gerding], I am not convinced that the longer treatment (3 weeks) and higher dose/regimen (400 mg 3 times daily) was necessary, but it appeared to work for decreasing recurrent diarrhea. It would have been helpful to have a larger study to see if they could have found a statistically significant difference for recurrent CDI."

Further treatment studies are planned to investigate rifaximin as an initial treatment for C difficile–related diarrhea.

"I do think the most promise that this drug has demonstrated to date is its use as add-on therapy, so our study only looked at recurrent diarrhea," Dr. Garey said.

The study received support from Salix. Dr. Gerding reports holding patents for the treatment and prevention of CDI licensed to ViroPharma; being a consultant for Merck, ViroPharma, Optimer, Cubist, TheraDoc, Medicines Co, Pfizer, Astellas, and Actelion; and receiving research grants from Merck, Eurofins Medinet, GOJO, Optimer, Sanofi-Pasteur, and ViroPharma. Dr. Johnson reports serving as consultant for Optimer, ViroPharma, Astellas, Pfizer, Cubist, and Bio-K+.

21st European Congress of Clinical Microbiology and Infectious Diseases (ECCMID): Poster 1544. Presented May 9, 2011.