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A Randomized, Double-Blind, Placebo-Controlled Trial of Rifaximin To Prevent Travelers’ Diarrhea

Background: More than 50 million people travel annually from industrialized nations to warm climates where travelers’ diarrhea causes a substantial amount of morbidity and post-infectious irritable bowel syndrome.

Objective: The purpose of this study was to evaluate the effectiveness of rifaximin, a nonabsorbable antibiotic, for the prevention of travelers’ diarrhea.

Methods: This was a randomized, double-blind, placebo-controlled trial, which took place in Guadalajara, Mexico during July and August of 2003. Students from the U.S., attending classes in Guadalajuara were eligible for participation if they were at least 18 years of age and were enrolled within 72 hours of arrival in Mexico. Participants that presented to the clinic with diarrhea were randomized to 1 of 4 groups: rifaximin 200mg once daily, rifaximin 200mg twice daily, rifaximin 200mg three times daily, or placebo three times daily for a total of 2 weeks. There were 50, 52, 54, and 54 participants in each group respectively. All participants kept a daily log for three weeks which included symptoms and signs (rated as mild, moderate, or severe), the form and timing of all stools passed, and the timing of medication taken. The participants were monitored for enteric disease and symptoms for 3 weeks, and side effects were monitored for 5 weeks. Investigators also studied the changes in intestinal coliform flora. Participants presenting to the clinic with active diarrhea were given levofloxacin or azithromycin and were withdrawn from the efficacy portion of the study. The primary end point was occurrence of diarrhea, defined as passage of at least 3 unformed stools within a 24-hour period plus 1 or more of the following signs and symptoms of enteric infection: abdominal pain or cramps, nausea, vomiting, fever (temperature ≥ 37.8oC), fecal urgency, passage of gross blood or mucus in stool, tenesmus, or moderate to severe increase in intestinal gas. Secondary end points included comparison of the study groups for occurrence of mild diarrhea (defined as passage of 1 to 2 unformed stools plus a symptom) and number of days of occurrences of moderate to severe enteric symptoms per 100 person-days of observation. An intention to treat protocol was used in this study. The power of the study was 93% and the tests used in the statistical analyses included the Kruskal-Wallis, chi-square, and Fisher exact tests.

Results: 14.74% of participants taking rifaximin developed travelers’ diarrhea compared to 53.70% of patients in the placebo group (rate ratio, 0.27 [95% CI, 0.17 to 0.43]). There was a 72% and 77% protection rate against travelers’ diarrhea and antibiotic-treated travelers’ diarrhea respectively (P<0.001 for each). Rifaximin reduced the amount of mild diarrhea in the groups that did not report travelers’ diarrhea (P=0.02), and also reduced moderate and severe intestinal problems (P=0.009 for pain and cramps; P=0.02 for excessive gas). There was no significant difference in the adverse events between the rifaximin and placebo groups. Enterotoxigenic Eschericia coli was the major cause of diarrhea and mild diarrhea during the 2 weeks of drug administration. Although resistance did not develop to rifaximin, there were significant increases in the amount of coliform flora in the rifaximin treated groups.

Strengths: The authors made clear what the limitations were and explainined what was planned in the future to address the limitations. The authors appropriately did not extrapolate the study results to people traveling to areas where travelers’ diarrhea is mainly caused by organisms other than E.coli. Finally, the investigators enrolled excess participants in the study to maintain a high power should there be any dropouts.

Weaknesses: The inclusion criteria and methods were not always explained clearly. For example, the study stated that eligible participants who presented to the clinic with diarrhea were randomly assigned to the study. This is contradictory to the objective which states that rifaximin is being studied to “prevent” travelers’ diarrhea, as well as the primary outcome of occurrence of diarrhea. Also, the results showed no significant difference between the three rifaximin treatment groups, yet the authors arbitrarily recommended a twice daily dosing regimen when the once daily regimen was effective and would be easier and less costly for the patients to take.

Conclusion: Rifaximin was found to be significantly effective against treating travelers’ diarrhea. Whether or not it is effective against preventing travelers’ diarrhea is still in question due to the fact that according to the study protocol, all participants were randomly assigned to the trial after already developing diarrhea. The rifaximin 200mg once daily dose was just as effective as the twice or three times daily dose over placebo and would be the most logical and cost-effective treatment option. Treatments of travelers’ diarrhea caused by organisms other than E.coli in different geographical areas are still being studied.

DuPont HL, Jiang ZD, Okhuysen P, Ericsson CD, de la Cabada J, Ke S, et al. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 2005;142:805-812.

Monica Pathak, PharmD Candidate