The Effect of a Nonabsorbed Oral Antibiotic (Rifaximin) on the Symptoms of the Irritable Bowel Syndrome

Context Few trials have evaluated the effects of antibiotics on symptoms of the irritable bowel syndrome (IBS). Contribution In this double-blind trial, 87 patients with IBS were randomly assigned to either rifaximin (400 mg 3 times daily) or placebo for 10 days. Over a 10-week follow-up period, the rifaximin recipients reported global improvements in overall symptoms and less bloating more frequently than the placebo recipients. No major differences in abdominal pain, diarrhea, or constipation were observed between the groups. Cautions The duration of therapy and follow-up was short. Implications Rifaximin may improve some symptoms in some patients with IBS. The Editors The irritable bowel syndrome (IBS) is one of the most common chronic medical conditions (16), yet its cause is unknown. Among other contributors, alterations in gut flora have been identified as potentially important. Results of recent studies indicate that up to 84% of patients with IBS have an abnormal lactulose breath test result, suggesting small-intestinal bacterial overgrowth (7, 8). On the basis of this concept, the antibiotic neomycin can statistically significantly improve the symptoms of IBS (7, 8). In addition, the effect of neomycin correlates with the elimination of bacterial overgrowth, as indicated by the normalization of the lactulose breath test result (7, 8). Although neomycin seems to improve symptoms, it effectively eliminates bacterial overgrowth in only about 25% of patients with IBS (8). Furthermore, side effects limit the use of neomycin. Low efficacy also applies to other antibiotics (for example, doxycycline and amoxicillinclavulanate) that have been previously investigated for treating bacterial overgrowth (9). An ideal antibiotic for IBS is, arguably, one with negligible systemic absorption, minimal side effects, and high efficacy for bacterial overgrowth. Rifaximin is a gut-selective antibiotic with negligible systemic absorption (0.4%) and broad-spectrum activity in vitro against gram-positive and gram-negative aerobes and anaerobes (10). On the basis of this broad spectrum, eradication rates with rifaximin in bacterial overgrowth are as high as 70% (11). Furthermore, rifaximin has a similar tolerability profile to that of placebo and has known activity against Clostridium difficile (12). These properties make it a good candidate for treating a condition that is as common as IBS. Our study aimed to determine whether the nonabsorbed antibiotic rifaximin is more effective than placebo in reducing symptoms in adults with IBS. Methods Setting and Participants Our study was conducted at the Cedars-Sinai Medical Center, Los Angeles, California, and the University of Chicago, Chicago, Illinois. We recruited patients with IBS through advertising in local media (radio and news publications). We did not recruit patients from the IBS clinics of the Cedars-Sinai Gastrointestinal Motility Program to avoid enrollment of tertiary care patients. The institutional review board of both centers approved the study, and all patients provided written informed consent. Patients between 18 and 65 years of age who met Rome I criteria (13) were eligible. Exclusion criteria were the presence of underlying conditions that are known to predispose to bacterial overgrowth, including diabetes; narcotic use; previous bowel resection; inflammatory bowel disease; cirrhosis; known bowel adhesions; or any known chronic gastroenterological disease, such as celiac disease. We excluded patients who were taking tegaserod and antidepressants unless these treatments were discontinued before study entry. We also excluded participants who reported taking an oral antibiotic within the previous 3 months. After participant inclusion and exclusion, we recruited 84 participants from the Cedars-Sinai Medical Center and 3 participants from the University of Chicago. We followed participants in special research clinics at both centers. Randomization and Interventions Eligible patients completed a 7-day stool diary that was based on the Bristol stool form scale (14). Patients returned to the clinic after a 12-hour fast and completed a symptom questionnaire about the preceding 7 days of symptoms. We then randomly assigned patients to double-blind treatment with 400 mg of rifaximin 3 times daily for 10 days or a matching placebo. We chose this dosage on the basis of a previous study that demonstrated the efficacy of rifaximin in bacterial overgrowth (11). The randomization of rifaximin versus placebo was conducted outside of Cedars-Sinai Medical Center in a 1:1 ratio into blocks of 4 patients. The allocation sequence was determined and coded at Salix Pharmaceuticals, Morrisville, North Carolina. Since this was an investigator-initiated study, the rifaximin and placebo were distributed to the Cedars-Sinai Medical Center, and nonstratified medicine and placebo were sent to the University of Chicago in groups of 4 as enrollment progressed. The medicine and placebo were prepackaged to conceal content at all times. Research personnel who were involved in product distribution were also blinded to package content. Assessments and Follow-up After completing the 10-day course of study medication, patients immediately began another stool diary for 7 days then returned to complete a follow-up questionnaire and to return their pill container for a pill count to determine adherence. Patients then entered the follow-up phase, during which they completed a weekly self-administered symptom questionnaire at home that documented their symptoms for an additional 9 weeks (for a total of 10 weeks of post-treatment follow-up). During this time, we asked participants to fax their responses to the research office. When a fax was not received on the appropriate day, research assistants called patients to ensure adherence. During this phase of study, no physician interaction occurred. During the last week of follow-up, patients completed a daily stool diary. At the end of the follow-up period, patients returned to the clinic for a final visit, which included another symptom questionnaire. For the initial symptom questionnaire, patients were asked to indicate the severity of each of 9 symptoms (abdominal pain, diarrhea, constipation, bloating, urgency, incomplete evacuation, mucus, sense of incomplete evacuation, and gas) on a visual analogue scale (VAS) ranging from 0 mm to 100 mm, with 100 mm being extreme. We used all 9 symptoms to verify IBS criteria in patients, but we assigned only diarrhea, constipation, abdominal pain, and bloating a priori as treatment end points. We asked patients to rate the severity of their symptoms on the VAS again 7 days after the completion of rifaximin treatment or placebo. Furthermore, we asked patients to provide a percentage of global improvement in their overall IBS symptoms from 0% to 100%. We chose global improvement since the Rome Consensus Group considers it to be the preferred end point measure in IBS treatment studies (15). Patients then rated the severity of their symptoms on the VAS and rated global improvement again each week for 8 weeks of follow-up and at the final visit to provide a total of 10 weeks of follow-up data. Table 1 depicts the number of patients with outcomes at various time points during the study. Table 1. Study Recruitment and Enrollment Summary At the first follow-up visit, physicians evaluated adverse events by asking patients, in an open-ended manner, whether they had experienced adverse events while receiving therapy and to elaborate on any that occurred. Although breath testing and breath methane level determinations were performed, we do not report them in our paper. Statistical Analysis We determined the number of patients for the study on the basis of the neomycin effect in a recent double-blind study for IBS on global improvement (8). To detect a difference of 35% (SD, 50%) with a power of 90%, we needed to assign 44 participants per group. Assuming a dropout rate of 10%, we calculated that approximately 96 patients would need to be recruited. The primary end point was global improvement in IBS symptoms during follow-up. As seen in Figure 1 , data were not available for all 10 weeks of follow-up. Figure 1. Study flow chart. We assessed the primary end point (percentage of global improvement) across the 10 weeks of follow-up by using an approach analogous to a repeated measures analysis of variance. Specifically, we used a mixed model with visit week (at 10 levels), treatment group (rifaximin or placebo), and group-by-week interaction as the fixed factors and patient as the random factor. The interaction and group factors were the main factors of interest in the analyses. We estimated mixed models by using the restricted maximum likelihood method. Because the global improvement percentage varied widely across week for most individuals, we considered week to be a categorical variable in the mixed model. Within-patient correlation across time was addressed by an autoregressive (first-order) model for the covariance structure. Missing data were mostly intermittent, and we assumed them to be missing at random. The normality assumption was rarely satisfied in either group at any week. However, at least 34 observations were recorded per group per week and the sample sizes were well-balanced, so we used the mixed-model analysis. We analyzed models with a single covariate (baseline diarrhea, constipation, abdominal pain, or bloating severity score). The covariate models did not improve the fit nor did they change the substantive results. Hence, we presented the simpler (no covariate) model results. We used a similar mixed-model approach to assess the secondary end points of abdominal pain, bloating, diarrhea, and constipation. Within-patient correlation was modeled by an autoregressive covariance structure. The normality assumption was rarely satisfied for the diarrhea outcome, with a similar floor effect for the primary outcome.