A 32-year-old female presents to the GI clinic complaining of ongoing symptoms of irritable bowel syndrome (IBS). Her primary complaints are bloating, gas, abdominal pain/discomfort, frequent loose stools, and bowel urgency. The diagnosis of diarrhea-predominant IBS was made 2 years ago and based on Rome II criteria. Physical examination, history, stool cultures, and colonoscopy yielded no significant findings. She has tried diet modification, stress reduction, antispasmodics, antidepressants, antidiarrheals,and probiotics. Except for some resolution of stool consistency with the antidiarrheal agents, her symptoms have been unrelieved.
CLINICAL QUESTION
In a 32-year-old female with diarrhea-predominant IBS, would rifaximin (Xifaxan) provide adequate global relief of symptoms?
BACKGROUND
IBS is a functional GI disorder characterized by abdominal pain and discomfort associated with constipation, diarrhea, or both, as well as abdominal bloating and gas. The exact etiology is unknown, but it is thought to be multifactorial. There may be some linkage to small-intestinal bacterial overgrowth (SIBO). Based on lactulose breath tests, the estimated prevalence of SIBO in those with IBS has varied from 10% to 84%.1 Bacterial overgrowth may contribute to symptoms in a subset of IBS patients, possibly those with postinfectious IBS. Current treatment for IBS is focused on lifestyle changes and various pharmacotherapy individualized to the patient's most bothersome symptoms. Various treatments are available, although most are not uniformly effective.2
Rifaximin is a minimally absorbed, broad-spectrum antibiotic that has good safety and side effect profiles and has been associated with a low risk for bacterial resistance. It is currently approved by the FDA for use in traveler's diarrhea and hepatic encephalopathy.
SEARCH CRITERIA AND
RESULTS
A search of the PubMed and Cochrane databases using the keywords rifaximin AND irritable bowel syndrome, with limits of humans, English language, and studies within the past 10 years, retrieved 38 articles. A majority of the articles addressed SIBO and traveler's diarrhea. No meta-analyses on rifaximin's use in IBS were found. There were reviews regarding the medication and traveler's diarrhea or SIBO but no systematic reviews about IBS and rifaximin. A follow-up, focused PubMed search of rifaximin AND IBS treatment with clinical trial limit and no language limits retrieved a total of eight articles. Another search, using the Clinical Queries tool of PubMed in the therapy domain with both narrow and broad scopes, did not identify additional articles. After reviewing the handful of articles that were applicable to the clinical question, two studies were selected. The first study, a recent, large, multicenter, randomized controlled trial (RCT), had a higher level of evidence and more direct focus on the clinical question. It investigated the effects of rifaximin on global IBS symptoms and on abdominal bloating3 and was an elaboration of a smaller RCT by the same group.4 The second study, which had a lower level of evidence, was a recently published retrospective cohort study that examined retreatment with rifaximin and subsequent duration of symptom relief.5 Notably, all three studies had the same lead author.
EVALUATING THE EVIDENCE
In the first study identified, Pimentel and colleagues conducted parallel, phase 3, double-blind RCTs (TARGET1 and TARGET2) within two separate multicenter groups (N = 1,260).3 Subjects were older than 18 years (average age, 46 years), mostly female (75%), and mostly white (90%). All patients had IBS based on Rome II criteria and had undergone a colonoscopic examination in the 2 years prior to enrollment. The patients were randomly assigned to receive either rifaximin 550 mg or placebo three times daily for 2 weeks, after which they were followed for an additional 10 weeks. At the conclusion of the 14-day treatment period, patients were assessed in the clinic and through telephone interviews. The patients evaluated their average daily amount of abdominal pain/discomfort/bloating versus stool consistency on separate Likert scales and responded to a general question about overall relief of symptoms since starting the study. Relief of symptoms was defined as a decrease of at least 30% from baseline in weekly mean ratings of IBS-related abdominal pain and discomfort and a weekly mean stool consistency score of less than 4 for at least 2 of the 4 weeks during a given month. Results were analyzed in a modified intention-to-treat fashion. All patients who took at least one dose of the drug or placebo were included in their respective categories, with only two (of 1,260) patients not included in the analysis after refusing any dose.
During weeks 3 to 6, 254 (41%) of 624 patients on rifaximin improved globally, whereas of 634 on placebo, 201 (32%) showed improvement. This absolute rate difference of 9% allows calculation of the number needed to treat (NNT), which was equal to 12, with a 95% confidence interval (CI) of 7-27.6 The odds ratio for the relief of global IBS symptoms on rifaximin versus placebo during the entire 3-month study was 1.44 (95% CI, 1.17-1.77; P <.001). No differences in side effect rates were reported between the treatment and placebo groups.
A higher-than-usual placebo response rate is often seen in controlled trials of pharmacologic treatment for IBS.1 A systematic review conducted to examine the placebo response rate seen in 45 placebo-controlled RCTs for IBS treatments highlighted that the average placebo response rate was 40.2% (95% CI, 35.9%-44.4%), with a range of 16% to 71%.7 In this context, the studies by Pimentel and colleagues had relatively low and acceptable placebo rates.
A second concern was possible development of antibiotic resistance, either as a side effect or as a loss of efficacy. Rifaximin is structurally similar to rifampin, which is occasionally used to treat staphylococcal foreign body infections.8 When concerns of resistance and cross-resistance were raised in response to the publication of their study, the researchers pointed out that gut flora resistance was not seen in their study population or in others treated with rifaximin.
Also worth noting is that the 2011 RCT study by Pimentel and colleagues was funded by a grant from Salix Pharmaceuticals, which manufactures rifaximin. The authors noted that the data collection and interpretation were done independently.