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Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation
Mark Pimentel, M.D., Anthony Lembo, M.D., William D. Chey, M.D., Salam Zakko, M.D., Yehuda Ringel, M.D., Jing Yu, Ph.D., Shadreck M. Mareya, Ph.D., Audrey L. Shaw, Ph.D., Enoch Bortey, Ph.D., and William P. Forbes, Pharm.D. for the TARGET Study Group
N Engl J Med 2011; 364:22-32January 6, 2011
Comments open until January 12, 2011
Abstract
Article
References
Citing Articles (1)
Comments
Background
Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS.
Full Text of Background...
Methods
In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study.
Full Text of Methods...
Results
Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups.
Full Text of Results...
Conclusions
Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.)
Full Text of Discussion...
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Source Information
From Cedars–Sinai Medical Center, Los Angeles (M.P.); Beth Israel Deaconess Medical Center and Harvard Medical School — both in Boston (A.L.); University of Michigan Health System, Ann Arbor (W.D.C.); Connecticut Gastroenterology Institute at Bristol Hospital, Bristol (S.Z.); University of North Carolina at Chapel Hill, Chapel Hill (Y.R.); and Salix Pharmaceuticals, Morrisville, NC (J.Y., S.M.M., A.L.S., E.B., W.P.F.).
Address reprint requests to Dr. Forbes at 1700 Perimeter Park Dr., Morrisville, NC 27560.
Members of the TARGET Study Group are listed in the Supplementary Appendix, available at NEJM.org.
Media in This Article
Figure 1Study Design.
Figure 2Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies.
Article Activity
1 article has cited this article
The irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurring symptoms of abdominal pain, bloating, and altered bowel function in the absence of structural, inflammatory, or biochemical abnormalities.1 IBS often does not respond to current treatment options, including dietary and lifestyle modifications, fiber supplementation, psychological therapy, and pharmacotherapy.2,3 Because no reliable biologic or structural markers have been identified, the effects of pharmacotherapy are typically assessed by asking patients to report whether they had adequate relief of IBS symptoms (with a binary response of yes or no).4 Given the limitations of available therapies, there is an unmet medical need for novel therapeutic approaches.
Patients with IBS may have alterations in the intestinal microbiota,5-7 thus leading investigators to consider targeting the intestinal microbiota for the treatment of this condition. Although some patients have had improvement with neomycin therapy, clinical trials have shown that it has marginal efficacy, and side effects limit the use of the drug.8 The use of systemic antibiotics has been reported with mixed results.9
Rifaximin (Xifaxan, Salix Pharmaceuticals) is an oral, nonsystemic, broad-spectrum antibiotic that targets the gut and is associated with a low risk of bacterial resistance.10-12– It has shown efficacy in small-scale studies of IBS. 13,14 We present the results of two large-scale, identically designed, multicenter trials — TARGET 1 and TARGET 2 — of 3 months' duration that examined the relief of IBS symptoms after a 2-week course of rifaximin.
Methods
Study Patients
Eligible patients were at least 18 years of age; had undergone a colonoscopic examination within the previous 2 years; had received a diagnosis of and had current symptoms of IBS (as assessed according to the Rome II diagnostic criteria for IBS15), in particular, symptoms of abdominal pain and discomfort; and did not have adequate relief of global IBS symptoms and of IBS-related bloating at both the time of screening and the time of randomization. Eligible patients rated the average daily amount of abdominal pain and of bloating as a score of 2 to 4.5 on a 7-point Likert scoring system (with 0 indicating not at all; 1, hardly; 2, somewhat; 3, moderately; 4, a good deal; 5, a great deal; and 6, a very great deal) and rated the average daily consistency of their stools as 3.5 or more on a 5-point scale for stool consistency (with 1 indicating very hard; 2, hard; 3, formed; 4, loose; and 5, watery) over the course of at least 7 days.
Exclusion criteria were constipation-predominant IBS (according to the definition in the Rome II criteria15), a history of inflammatory bowel disease, diabetes, unstable thyroid disease, previous abdominal surgery (other than cholecystectomy or appendectomy), human immunodeficiency virus infection, and renal or hepatic disease. Patients were excluded if they were currently taking alosetron, tegaserod, lubiprostone, warfarin, or antipsychotic, antispasmodic, antidiarrheal, probiotic, or narcotic drugs or if they had taken antibiotics within the previous 14 days or rifaximin within 60 days before signing the informed-consent form for the study. Patients were allowed to take antidepressant agents of the selective serotonin-reuptake inhibitor and tricyclic antidepressant classes, provided that they had been taking a stable dose for at least 6 weeks. All patients provided written informed consent before study-related procedures were initiated.
Study Design and Procedures
The protocols were approved by the institutional review board or independent ethics committee at each center, and the studies were conducted in accordance with applicable laws and regulations (see the Supplementary Appendix, available with the full text of this article at NEJM.org). After a screening phase of 7 to 13 days, eligible patients were randomly assigned with the use of an interactive voice-response system to either rifaximin or placebo, in a 1:1 ratio. The randomization code was computer-generated, and randomization was performed in blocks of four, stratified according to center. After completing the 14-day study-treatment period, patients were evaluated for 10 additional weeks. Study visits were conducted on days 1, 7, 14, 28, and 84, and patients were monitored by means of telephone calls on days 42, 56, and 70. Efficacy assessments were obtained daily by means of an interactive voice-response system over the course of the entire study (Figure 1Figure 1Study Design.).
The protocol was designed by Salix Pharmaceuticals in collaboration with the academic authors. Data were collected by investigators at each center (see the Supplementary Appendix) and were monitored by Quintiles (a contract research organization) under the supervision of Salix Pharmaceuticals. The data were analyzed by personnel at Salix Pharmaceuticals, in collaboration with the academic authors. All the authors participated in the interpretation of the data and in the writing of the manuscript. The first two authors wrote the first draft of the manuscript, and all the authors, in addition to an employee of Salix, assisted in the revision of subsequent drafts. All the authors made the decision to submit the manuscript for publication. The trial protocol, including the statistical analysis plan, is available at NEJM.org. All the authors vouch for the completeness and veracity of the data and analyses, as well as the fidelity of this report to the trial protocol.
Efficacy and Safety End Points
The primary end point was the proportion of patients who had adequate relief of global IBS symptoms for at least 2 of the 4 weeks during the primary evaluation period (weeks 3 through 6). This end point was determined from the response (yes or no) to the following question, which was asked weekly: "In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?" The threshold for clinical relevance — adequate relief during at least 2 weeks per month — was defined prospectively. In addition, the proportion of patients who reported that they had adequate relief during at least 2 weeks per month ("monthly response") during months 1, 2, and 3 was assessed to identify the onset and duration of the therapeutic effect. Patients who started to take antibiotics (other than the study medication) or who took more than two doses of a medication that was prohibited per the study protocol were considered not to have had a response to treatment starting from the time the medication was initiated, regardless of their response data.
The key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating during the primary evaluation period, was determined from the response (yes or no) to the weekly question, "In regard to your symptoms of bloating, as compared with the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating?" The onset and duration of relief of bloating were also assessed in an analysis of monthly response, as described above for the primary end point.
For other secondary end points, the proportion of patients who had relief was determined from the patients' daily assessments of IBS symptoms, bloating, and abdominal pain and discomfort (as rated on a 7-point scale); relief was defined as a score of either 0 (not at all) or 1 (hardly) for at least 50% of the days in a given week or a score of 0 (not at all), 1 (hardly), or 2 (somewhat) for 100% of the days in a given week for at least 2 of the 4 weeks during a given month.
An exploratory end point, which was included at the request of the Food and Drug Administration (FDA), was the proportion of patients who had relief of the composite of abdominal pain and discomfort and loose or watery stools (as measured by improvement in stool consistency), on the basis of daily assessments. Relief was defined as a decrease of at least 30% from baseline in weekly mean ratings of IBS-related abdominal pain or discomfort and a weekly mean stool-consistency score of less than 4 (with 4 indicating loose stools and lower scores indicating more formed stools) for at least 2 of the 4 weeks during a given month. This exploratory end point is consistent with the recommended composite end point for IBS with diarrhea in a recently released draft of FDA guidelines.16 Safety assessments included the monitoring of adverse events, results of clinical laboratory testing, findings from physical examinations, and vital signs.
Statistical Analysis
We estimated the sample size for each study assuming that 40% of the patients in the placebo group and 55% in the rifaximin group would meet the criteria for the primary end point (i.e., would have adequate relief of global IBS symptoms, as assessed weekly) for at least 2 of the first 4 weeks after treatment. With these assumptions, a sample of 300 patients would be needed in each group for the studies to have 95% power to show the 15-percentage-point difference between the groups, at a significance level of 0.05.
All efficacy and safety analyses were performed on a modified intention-to-treat population, which included all patients who received at least one dose of the study drug. Missing data were imputed with the use of the last-observation-carried-forward method, whereby missing values were replaced with the last nonmissing value; baseline values were not carried forward. Two sensitivity analyses were conducted, one in which missing data were regarded as indicating that the patients who terminated the study prematurely had had no relief of symptoms, and the other in which missing data were imputed with the use of the multiple-imputation method.
Binary data (i.e., data on the proportion of patients who had or did not have adequate relief of symptoms) were analyzed with the use of logistic regression; fixed-effect terms included the study group and the analysis center. There were five analysis centers, which we formed prospectively by grouping the study centers according to geographic region in order to assess the effects of geographic location on the end points. For the analysis of ordinal data (i.e., data on the number of months in which patients had relief for at least 2 weeks per month), we used the proportional-odds model for the ordinal outcome. The number of consecutive months with relief during the first 3 months after treatment was summed for each patient, so that each patient received a score of 0, 1, 2, or 3.
We analyzed the changes from baseline in continuous outcomes (i.e., symptom scores) by fitting fixed-effects linear models to the data. An initial model with terms for treatment, analysis center, baseline ratings of the response variable, and interaction of baseline ratings with treatment was fitted. The interaction term was tested at the 0.05 level. A nonsignificant interaction was dropped from the model in subsequent analyses.
Spearman correlation analyses were applied to the mean change from baseline in daily assessments of adequate relief of IBS symptoms (yes or no) to determine whether the weekly assessments of adequate relief paralleled the pattern seen with the daily assessments. Safety data were summarized with the use of descriptive statistics.
Results
Study Patients
A total of 1260 patients who had IBS without constipation were enrolled in the studies (623 patients in TARGET 1 and 637 in TARGET 2) and underwent randomization at one of 179 investigative sites in the United States (1217 patients) and Canada (43 patients) (Figure 2Figure 2Enrollment, Randomization, and Follow-up in the TARGET 1 and TARGET 2 Studies.). The studies were conducted in parallel from June 2008 through August 2009. In TARGET 1, all the patients who underwent randomization took at least one dose of the study drug. In TARGET 2, two patients (one in each group) underwent randomization but did not receive a study drug. Thus, 1258 patients received at least one dose of the study drug and were included in the modified intention-to-treat population. More than 90% of the patients completed the entire 12-week study. The baseline characteristics of the patients were similar in the two studies and across treatment groups (Table 1Table 1Demographic and Baseline Characteristics of the Modified Intention-to-Treat Population in the Two Studies.). The rate of adherence to the study drug, defined as the use of at least 70% of the dispensed tablets, was at least 97% in both study groups in both studies.
Efficacy during the Primary Evaluation Period (Weeks 3 through 6)
Adequate Relief of Global IBS Symptoms
Significantly more patients in the rifaximin group than in the placebo group met the criteria for the primary end point of adequate relief of global IBS symptoms for at least 2 of the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined) (Figure 3AFigure 3Analyses of Primary, Key Secondary, and Other Secondary End Points.). The last-observation-carried-forward method was applied in the case of 5.8% of the patients in the rifaximin group and 5.7% of the patients in the placebo group in TARGET 1 and in the case of 5.4% in the rifaximin group and 8.4% in the placebo group in TARGET 2. Overall, sensitivity analyses that were performed to address the effect of missing values yielded results that were consistent with those of the primary efficacy analysis (see the Supplementary Appendix). On the basis of daily assessments of IBS symptoms, the proportion of patients with a response to treatment, as rated on a 7-point scale during the primary evaluation period, was significantly greater in the rifaximin group than in the placebo group (42.7% vs. 30.6%, P<0.001, in TARGET 1; 37.8% vs. 28.4%, P=0.007, in TARGET 2; 40.2% vs. 29.5%, P<0.001, in the two studies combined) (Figure 3A).
Adequate Relief of IBS-Related Bloating
Significantly more patients in the rifaximin group than in the placebo group met the criteria for the key secondary end point, adequate relief of IBS-related bloating for at least 2 of the first 4 weeks after treatment (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined) (Figure 3A). Sensitivity analyses that were performed to assess the effect of missing values yielded similar results (see the Supplementary Appendix). On the basis of daily assessments of IBS-related bloating as rated on a 7-point scale during the same primary evaluation period, a significantly greater proportion of patients in the rifaximin group than in the placebo group had relief (39.2% vs. 32.5%, P=0.05, in TARGET 1; 43.5% vs. 30.9%, P<0.001, in TARGET 2; 41.3% vs. 31.7%, P<0.001, in the two studies combined) (Figure 3A).
Relief of IBS-Related Abdominal Pain and Loose or Watery Stools
A significantly greater proportion of patients in the rifaximin group than in the placebo group had relief of IBS-related abdominal pain and discomfort during the primary evaluation period (44.3% vs. 36.3%, P=0.03, in TARGET 1; 42.9% vs. 34.4%, P=0.02, in TARGET 2) (Figure 3A). In an assessment of the composite end point of abdominal pain or discomfort and loose or watery stools, significantly more patients in the rifaximin group than in the placebo group had relief during the primary evaluation period (46.6% vs. 38.5%, P=0.04, in TARGET 1; 46.7% vs. 36.3%, P=0.008, in TARGET 2), and a significantly greater proportion of patients in the rifaximin group had relief with respect to the individual components of this end point (Figure 3A).
Efficacy during the Entire Study Period (Months 1 through 3)
Durability of Response on the Basis of Weekly Assessment
In analyses of the monthly response evaluated on the basis of weekly assessments, more patients in the rifaximin group than in the placebo group in both studies had adequate relief of global IBS symptoms within the first month, with continued relief during the first 2 months and during all 3 months in both studies (P=0.05 in TARGET 1, P=0.005 in TARGET 2, and P<0.001 in the two studies combined, for relief during all 3 months) (Figure 3B). With respect to IBS-related bloating, in TARGET 1, significantly more patients in the rifaximin group than in the placebo group had adequate relief in the first month, with continued relief during the first 2 months, but there were no significant between-group differences with respect to relief during all 3 months; in TARGET 2, significant benefits of rifaximin were seen with respect to IBS-related bloating for all 3 months (P=0.10 in TARGET 1, P=0.003 in TARGET 2, and P=0.001 in the two studies combined, for relief during all 3 months) (Figure 3B). The percentages of patients in each group with adequate relief of global IBS symptoms in TARGET 1 and TARGET 2 are provided in Figure 4Figure 4Percentage of Patients with Adequate Relief of Global IBS Symptoms in the TARGET 1 and TARGET 2 Studies Combined., and in Figure 1A and 1B in the Supplementary Appendix.
Durability of Response on the Basis of Daily Assessment
The analyses of monthly response evaluated on the basis of daily assessments also support a durable response to rifaximin in patients with IBS over the course of 3 months. Patients treated with rifaximin, as compared with patients who received placebo, had adequate relief of global IBS symptoms during the entire 3 months of the study (P=0.003 in TARGET 1, P=0.01 in TARGET 2, and P<0.001 in the two studies combined) and of IBS-related bloating (P=0.01 in TARGET 1, P<0.001 in TARGET 2, and P<0.001 in the two studies combined) (Figure 3B).
An analysis of the monthly response evaluated on the basis of daily assessments of IBS-related abdominal pain and discomfort showed that significantly more patients in the rifaximin group than in the placebo group had relief for the entire 3 months (P=0.05 in TARGET 1, P=0.04 in TARGET 2, and P=0.01 in the two studies combined) (Figure 3B). An analysis of the monthly response evaluated on the basis of the assessment of the composite end point of abdominal pain and stool consistency also showed a significant benefit with rifaximin as compared with placebo (P=0.04 in TARGET 1, P=0.01 in TARGET 2, and P=0.001 in the two studies combined) (Figure 3B).
The mean improvement from baseline in daily symptom scores (global IBS symptoms, IBS-related bloating, IBS-related abdominal pain or discomfort, stool consistency, and the percentage of days with stool urgency) was greater for the patients who received rifaximin than for the patients who received placebo (Figure 2 through 6 in the Supplementary Appendix).
Responsiveness and Construct Validity of Patient-Reported Outcomes
The response of patients with respect to adequate relief of global IBS symptoms and of IBS-related bloating was consistent with the response with respect to other IBS-related assessments. In addition, patients who had adequate relief of global IBS symptoms and of IBS-related bloating had greater improvements in daily symptom-severity scores than did patients who did not have adequate relief, regardless of study group, during each week in each study (P<0.001).
We tested the validity of using assessments of global IBS symptoms to measure changes in IBS symptoms by examining the correlation between these measures and changes in daily severity scores and bowel function; the results support the validity and usefulness of the primary end point of global IBS symptoms. Evidence for convergent validity (Spearman's correlation of 0.40 or higher) was observed between weekly adequate relief of global IBS symptoms and measures of daily symptom severity and bowel function.
Safety
The safety profile of rifaximin was similar to that of placebo (Table 2Table 2Adverse Events during the 12-Week Study.). Serious adverse events were recorded in 10 patients in the rifaximin group (1.6%) and 15 patients in the placebo group (2.4%). There were no cases of Clostridium difficile–associated diarrhea or ischemic colitis. No deaths were reported.
Discussion
Treating IBS is important because the symptoms cause substantial impairment in health-related quality of life, leading to increased use of health resources and reduced work productivity.17-20 These two phase 3 studies showed that a short course of rifaximin leads to sustained amelioration of the symptoms of IBS without constipation in a subgroup of affected patients.
The antibiotic effect of rifaximin is the presumed mechanism for its sustained beneficial effects in patients with IBS. A response to antibiotic therapy in patients with IBS has been shown to correlate with normalization of the results of lactulose hydrogen breath tests.8,13 However, there is debate about which antibiotic-related effect is most important. On the basis of existing data, there are three reasonable explanations: rifaximin affects gut bacteria and reduces bacterial products that negatively affect the host, the effect on gut flora reduces local mucosal engagement of bacteria such as the immune responses of the host, or the antibiotic alters both the bacteria and the host response. Whatever the final pathway, the durable effects suggest that rifaximin is affecting an underlying cause of IBS that is linked to an alteration in the intestinal microbiota.6,7,21,22 Some patients in both of our studies did not have a response to treatment, a finding that is consistent with the results of other placebo-controlled clinical trials involving patients with IBS23-25 and that may reflect differences in the underlying cause of the symptoms.
Similar percentages of patients in the rifaximin group and in the placebo group had adverse events. In this short-term study, the incidence of infections was similar in the two groups, and there were no cases of C. difficile–associated diarrhea or ischemic colitis.
In summary, the results of these two phase 3 studies showed that treatment with rifaximin at a dose of 550 mg three times daily for 14 days provides better relief of symptoms of IBS than does placebo for up to 10 weeks after completion of therapy.
Supported by Salix Pharmaceuticals.
Dr. Pimentel reports receiving grant support (to his institution) and consulting fees and honoraria from Salix Pharmaceuticals and reports that Cedars–Sinai Medical Center holds patents licensed by Salix Pharmaceuticals; Dr. Lembo reports receiving consulting fees from Salix Pharmaceuticals, Ironwood Pharmaceuticals, Prometheus, Ardelyx, Theravance, GlaxoSmithKline, and AstraZeneca, receiving payment for participation in several advisory-board meetings relating to the development of rifaximin for the treatment of IBS, and receiving payment as a member of the speakers' bureau of Salix Pharmaceuticals; Dr. Chey reports receiving consulting fees and honoraria from Procter & Gamble, Ortho-McNeil, Prometheus, and Salix Pharmaceuticals, payment for the development of educational presentations, and payment or reimbursement for travel and accommodations from Procter & Gamble, Prometheus, and Salix Pharmaceuticals; Dr. Zakko reports receiving grant support (to his institution), consulting fees, payment for the development of educational presentations, and payment or reimbursement for travel and accommodations from Salix Pharmaceuticals and holding stock in Salix Pharmaceuticals; Dr. Ringel reports receiving consulting fees from Salix Pharmaceuticals, Ironwood Pharmaceuticals, Procter & Gamble, Pfizer, and Danisco, participating in several advisory-board meetings related to the development of rifaximin for the treatment of IBS, receiving payment for the development of educational presentations and as a member of the speakers' bureau of Salix Pharmaceuticals, and receiving research grants from Danisco USA, General Mills, and SmartPill. Drs. Yu, Mareya, and Bortey report being employees of and holding stock in Salix Pharmaceuticals; Dr. Shaw reports being an employee of Salix Pharmaceuticals and reports that she holds stock in the company; and Dr. Forbes reports being an officer and employee of Salix Pharmaceuticals and holding stock in the company.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
Source Information
From Cedars–Sinai Medical Center, Los Angeles (M.P.); Beth Israel Deaconess Medical Center and Harvard Medical School — both in Boston (A.L.); University of Michigan Health System, Ann Arbor (W.D.C.); Connecticut Gastroenterology Institute at Bristol Hospital, Bristol (S.Z.); University of North Carolina at Chapel Hill, Chapel Hill (Y.R.); and Salix Pharmaceuticals, Morrisville, NC (J.Y., S.M.M., A.L.S., E.B., W.P.F.).
http://www.nejm.org/doi/full/10.1056/NEJMoa1004409#t=article
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Editorial
Antibiotic Therapy for the Irritable Bowel Syndrome
Jan Tack, M.D., Ph.D.
N Engl J Med 2011; 364:81-82January 6, 2011
Article
References
The irritable bowel syndrome (IBS) is one of the most common conditions seen in clinical practice. The number of effective pharmacologic agents for IBS is limited, and therapeutic innovation is hampered by a lack of complete understanding of the pathophysiology of the syndrome, which is probably heterogeneous.1 Alterations in the bacterial flora are increasingly considered to be a relevant pathogenetic factor.2 Consequently, probiotics are being studied as treatment for IBS, but the magnitude of improvement in symptoms with probiotics is limited.2 Some studies have suggested that there are beneficial effects with poorly absorbed antibiotics, but the results of the studies have been questioned because of issues with patient selection, the choice of end point, and the statistical analysis, and, most of all, because lactulose breath test results were interpreted as indicative of small-intestine bacterial overgrowth.3-6
In this issue of the Journal, Pimentel et al. report the results of two identically designed, large, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) of rifaximin, a poorly absorbed antibiotic, in patients with IBS without constipation.7 A total of 1260 patients were randomly assigned to receive rifaximin, at a dose of 550 mg three times daily, or placebo for 2 weeks, followed by a 10-week posttreatment follow-up period. The primary end point was the proportion of patients who reported adequate relief of IBS symptoms, as assessed by responses (yes or no) to a question about relief of symptoms that was asked weekly during the first 4 weeks after treatment. The key secondary end point was the proportion of patients reporting adequate relief of bloating during the same period.
In both studies, patients consistently met the criteria for relief of global IBS symptoms and IBS-related bloating. In the rifaximin groups, as compared with the placebo groups, a significantly higher proportion of patients reported adequate relief of IBS symptoms (41% vs. 32% in the two trials combined, P<0.001) or bloating (40% vs. 30%, P<0.001) for at least 2 of the first 4 weeks. Similarly significant results were obtained in an analysis of relief of symptoms during the 10-week period after the end of the double-blind treatment phase.
These large, high-quality, multicenter studies confirm that, as a group, patients who have IBS without constipation have a significantly better response to rifaximin than to placebo. Rifaximin is a poorly absorbed antibiotic with broad-spectrum activity against gram-negative bacteria, gram-positive bacteria, and anaerobes, including Clostridium difficile. It has been extensively used in the treatment and prevention of travelers' diarrhea, for which it has shown a favorable side-effect and safety profile, with low risk for the development of resistance.8
The TARGET studies have some attractive findings. First, the sustained benefit over at least 10 weeks, after a short treatment course, is appealing. Second, the beneficial effects of rifaximin include its effects on bloating, which is one of the most challenging symptoms of IBS. Third, the similarity of the results in both studies confirms the reproducibility of the therapeutic effect. On the other hand, the therapeutic gain, with the rates of response to treatment (i.e., adequate relief) ranging between 9 and 12% more with rifaximin than with placebo, is in the lower spectrum of what is considered to be clinically relevant.9 Although it is clear that not all patients have a response with rifaximin, the available data suggest that a subgroup of patients may have a substantial response.5,7 It is unclear whether this group can be identified by demographic characteristics, symptoms, or results of lactulose breath testing. Most important, IBS is a chronic disorder, and although the therapeutic effect persists after the 2-week treatment period, the response over time suggests that there is some loss of efficacy, as compared with placebo, with respect to certain symptoms toward the end of the 10-week follow-up period. It is unknown whether patients would have a favorable response again with retreatment.
The mechanism underlying the beneficial effect of rifaximin with respect to symptoms of IBS is a matter of controversy. Initial studies of poorly absorbed antibiotics for the treatment of patients with IBS were based on the hypothesis that a large proportion of these patients had small-intestine bacterial overgrowth, a disorder characterized by the presence of abnormally high numbers of bacteria in the small intestine.7 Initial studies reported the presence of small-intestine bacterial overgrowth in up to 80% of patients, on the basis of a rapid rise in breath hydrogen during lactulose breath testing. However, this test is prone to false positive results, and several other investigators failed to reproduce these high incidences.10 When the standard method of jejunal aspiration and bacterial culturing was used, small-intestine bacterial overgrowth was found in only 4% of patients with IBS.10 More recently, it was suggested that the use of proton-pump inhibitors conferred a predisposition to enhanced bacterial colonization of the small intestine.10 Most studies assessing poorly absorbed antibiotics in the treatment of patients with IBS, including the present study, do not report or adjust for the concomitant use of proton-pump inhibitors, so this remains an area of controversy. The most likely mode of action of rifaximin is a reduction in overall bacterial load, especially in the large bowel.8 This may lead to decreased bacterial fermentation and less bloating, possibly in combination with decreased secretion of bacterial products or host responses to bacterial products that contribute to the generation of symptoms.
Neither rifaximin nor any other antibiotic has been approved for the treatment of IBS, and the Food and Drug Administration is currently reviewing the new-drug application for rifaximin for the treatment of patients who have IBS without constipation and IBS-related bloating. With three studies confirming the efficacy of the drug after a short-term regimen and a relatively short follow-up period,5,7 rifaximin has the potential to provide a welcome addition to the limited armamentarium of agents that are available to treat IBS. Moreover, rifaximin had a favorable safety profile in these studies, with no treatment-associated major adverse events and no cases of C. difficile colitis. At the current stage of knowledge, however, clinicians should proceed with caution. IBS is a chronic condition, and some regulatory authorities recommend that studies be conducted that will address the efficacy of rifaximin when it is used for continued or intermittent treatment of IBS (see www.tga.gov.au/docs/pdf/euguide/ewp/078597en.pdf), and this seems to be even more appropriate in the case of antibiotic therapy that may have a risk of inducing resistance over time. Furthermore, taking into account the high prevalence of IBS in the general population, the effect that larger-scale use of poorly absorbed antibiotics may have on antibiotic-resistance profiles should be taken into account.6 Studies aimed at better identifying the patients with IBS who may have a response to rifaximin and, especially, studies that will assess the longer-term effect of rifaximin treatment are eagerly awaited. Until this information becomes available, it seems prudent to restrict the use of nonabsorbable antibiotics to patients in whom small-intestine bacterial overgrowth has been confirmed, or to single-treatment cycles in patients who have IBS without constipation and who have not had a response to currently available symptom-directed therapies.1
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Source Information
From the Department of Pathophysiology, Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium.
http://www.nejm.org/doi/full/10.1056/NEJMe1011211
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Use of acid-suppressive drugs and risk of pneumonia: systematic review and meta-analysis
Chun-Sick Eom, Christie Y. Jeon, Ju-Won Lim, Eun-Geol Cho, Sang Min Park and Kang-Sook Lee
From the Department of Family Medicine (Eom, Lim, Cho, Park), Seoul National University Hospital, Seoul, Republic of Korea; the Department of Epidemiology (Jeon), Harvard School of Public Health, Boston, USA; and the Department of Preventive Medicine (Lee), College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
Dr. Sang Min Park, Department of Family Medicine, Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul, 110-744, Republic of Korea. E-mail sangmin.park.snuh@gmail.com
Dr. Kang-Sook Lee, Department of Preventive Medicine, College of Medicine, Catholic University of Korea, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea. E-mail leekangs@catholic.ac.kr
Background: Observational studies and randomized controlled trials have yielded inconsistent findings about the association between the use of acid-suppressive drugs and the risk of pneumonia. We performed a systematic review and meta-analysis to summarize this association.
Methods: We searched three electronic databases (MEDLIN E [PubMed], Embase and the Cochrane Library) from inception to Aug. 28, 2009. Two evaluators independently extracted data. Because of heterogeneity, we used randomeffects meta-analysis to obtain pooled estimates of effect.
Results: We identified 31 studies: five case–control studies, three cohort studies and 23 randomized controlled trials. A meta-analysis of the eight observational studies showed that the overall risk of pneumonia was higher among people using proton pump inhibitors (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.11–1.46, I2 90.5%) and histamine2 receptor antagonists (adjusted OR 1.22, 95% CI 1.09–1.36, I2 0.0%). In the randomized controlled trials, use of histamine2 receptor antagonists was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI 1.01–1.48, I2 30.6%).
Interpretation: Use of a proton pump inhibitor or histamine2 receptor antagonist may be associated with an increased risk of both community- and hospital-acquired pneumonia. Given these potential adverse effects, clinicians should use caution in prescribing acid-suppressive drugs for patients at risk.
http://www.cmaj.ca/cgi/content/abstract/cmaj.092129v1
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Current Opinion in Gastroenterology:
January 2010 - Volume 26 - Issue 1 - p 17-25
doi: 10.1097/MOG.0b013e328333dc8d
Gastrointestinal infections: Edited by Mitchell Cohen
Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases
Purpose of review: Rifaximin is gaining attention for its potential activity in a multitude of gastrointestinal diseases. We review the unique pharmaceutical properties of this antibiotic and the published evidence in the literature regarding the use of rifaximin for different gastrointestinal disorders.
Recent findings: Rifaximin is a gastrointestinal-selective antibiotic with a broad spectrum of antimicrobial activity, an excellent safety profile, minimal drug interactions, and negligible impact on the intestinal microbiome. Rifaximin is currently approved in the United States for the treatment of travelers' diarrhea caused by noninvasive diarrheagenic Escherichia coli and is approved in more than 30 other countries for a variety of gastrointestinal disorders. Considerable research with this medication has been conducted for the treatment and prevention of travelers' diarrhea, the treatment of portal systemic encephalopathy, Clostridium difficile infection, small bowel intestinal overgrowth, irritable bowel syndrome, inflammatory bowel disease, pouchitis, and colonic diverticular disease.
Summary: Rifaximin is effective for the treatment of travelers' diarrhea and can be considered as the treatment of choice for uncomplicated travelers' diarrhea. When invasive travelers' diarrhea pathogens are suspected, an alternative antibiotic should be administered. Rifaximin appears promising as a chemoprophylaxis for travelers' diarrhea and as a treatment of portal systemic encephalopathy. This antibiotic may be effective for other gastrointestinal diseases, but more well designed clinical studies are needed to confirm its efficacy for these off-label indications. Future studies will determine whether the development of significant bacterial resistance will limit rifaximin use.
http://journals.lww.com/co-gastroenterology/Abstract/2010/01000/Rifaximin__a_unique_gastrointestinal_selective.5.aspx
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Antibiotics that reduce gut bacteria linked to obesity
By Steve Connor, Science Editor
Tuesday, 3 May 2011
Scientists believe that the widespread use of antibiotics may be playing a significant role in exacerbating the obesity epidemic.
Growing evidence suggests that oral antibiotic medicines may be affecting the growth of beneficial bacteria in the human intestine which is influencing whether some people put on weight when they overeat or take too little exercise, they said.
The latest study, which has yet to be published in a peer-reviewed scientific journal, centres on a technique for counting the bacterial genes in the human intestine. It found that lean people are likely to have a more diverse community of gut flora compared to obese individuals.
Previous work has already established a difference in the gut bacteria of lean and overweight people, but the latest work is being seen as lending support to the controversial idea that bacteria-killing antibiotics may be playing a role in predisposing some people to being fat.
"It is a very real possibility," said Stanislav Dusko Ehrlich, a microbiologist at the French National Institute for Agricultural Research in Jouy-en-Josas, who was part of the Meta-HIT consortium of pan-European scientists who carried out the work.
"What we have found is that bacterial communities in the gut appear to be different between lean and obese people. We can't be certain whether that perturbation is the cause, contribution or consequence of being overweight. But these bacteria are candidates for being a cause and that must be investigated," he said.
Previous studies on laboratory mice and farm animals have established a link between gut flora, the use of antibiotics and an increase in body fat, but scientists have been wary of extrapolating these findings to humans.
The study investigated the bacterial genes found in the gut flora of 177 Danish people, 55 of whom were lean, with the rest either overweight or obese. Scientists in the Meta-HIT consortium found that most people in the study carried in their intestines around 600,000 distinct bacterial genes. But about a third of the obese participants had only about 360,000 bacterial genes – about 30 or 40 per cent fewer – which suggests they possessed a distinctly poorer community of gut flora, which is typically composed of about 160 different species of microbial lifeforms.
Microbes that live inside us
* The healthy human gut contains 100 trillion microbial cells, 10 times as many as the human cells that comprise the body.
* About 1,000 species of microbe can live in the human gut, but at any one time a person typically has about 160.
* Members of the same family tend to have similar communities of gut bacteria.
* The two dominant groups of gutbacteria, the Bacteroidetes and the Firmicutes, help us to break down food.
http://www.independent.co.uk/news/science/antibiotics-that-reduce-gut-bacteria-linked-to-obesity-2278042.html
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Latest FDA watch list includes GI drugs
The FDA put 16 drugs on its quarterly watch list, identified through the Adverse Event Reporting System. McNeil Consumer Healthcare's diarrhea treatment Imodium and over-the-counter proton pump inhibitors are among the products, for risks of pancreatitis and diarrhea linked to Clostridium difficile, respectively. However, a drug's presence on the list does not mean patients should stop taking the therapy. The FDA suggests that patients with questions speak with their physician.
http://www.medscape.com/viewarticle/762205
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Ironwood faces 3-month FDA delay for potential IBS drug linaclotide
Boston Business Journal by Julie M. Donnelly, Reporter
Date: Monday, April 23, 2012, 2:03pm EDT
Ironwood Pharmaceuticals and its partner Forest Laboratories Inc. have announced the U.S. Food and Drug Administration will delay its approval decision for the companies' potential drug for irritable bowel syndrome (IBS), called linaclotide.
The delay is due to the agency's request for an additional analysis of existing clinical data, the companies said. The FDA has not requested a new clinical trial.
The drug candidate was submitted to the FDA in August 2011 and a decision was expected in June. In February the company had received an encouraging sign that the approval process was on schedule, sending shares up 7 percent.
FDA action is now expected by September. Cambridge, Mass-based Ironwood and New York-based Forest continue to plan for a 2012 launch.
The efficacy and safety of linaclotide was studied in a clinical trial program of more than 2,800 patients for the treatment of irritable bowel syndrome with constipation and chronic constipation.
Ironwood and Forest plan to co-promote linaclotide in the U.S. Ironwood has out-licensed linaclotide to Almirall for European development and commercialization, and to Astellas Pharma Inc. for development and commercialization in Japan, Indonesia, Korea, the Philippines, Taiwan, and Thailand.
http://www.bizjournals.com/boston/news/2012/04/23/ironwood-faces-three-month-fda-delay.html
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FDA NEWS RELEASE
For Immediate Release: Aug. 30, 2012
FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation
The U.S. Food and Drug Administration today approved Linzess (linaclotide) to treat chronic idiopathic constipation and to treat irritable bowel syndrome with constipation (IBS-C) in adults.
According to the National Institutes of Health, an estimated 63 million people are affected by chronic constipation. Chronic idiopathic constipation is a diagnosis given to those who experience persistent constipation and do not respond to standard treatment. Additionally, an estimated 15.3 million people are affected by IBS. IBS-C is a subtype characterized mainly by abdominal pain and by hard or lumpy stools at least 25 percent of the time and loose or watery stools less than 25 percent of the time.
Linzess is a capsule taken once daily on an empty stomach, at least 30 minutes before the first meal of the day. Linzess helps relieve constipation by helping bowel movements occur more often. In IBS-C, it may also help ease abdominal pain.
"No one medication works for all patients suffering from these gastrointestinal disorders," said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "With the availability of new therapies, patients and their doctors can select the most appropriate treatment for their condition."
The safety and effectiveness of Linzess for the management of IBS-C were established in two, double-blind studies. A total of 1,604 patients were randomly assigned to take 290 micrograms of Linzess or a placebo for at least 12 weeks. Results showed Linzess was more effective in reducing the amount of abdominal pain and increasing the number of complete spontaneous bowel movements compared with placebo.
The safety and effectiveness of Linzess for the management of chronic idiopathic constipation also were established in two, double-blind studies. A total of 1,272 patients were randomly assigned to take Linzess at doses of 145 mcg or 290 mcg or a placebo for 12 weeks. Results from these studies showed patients taking Linzess experienced more complete spontaneous bowel movements than those taking the placebo. The 290 mcg dose is not approved for chronic constipation because studies indicated it was no more effective than the 145 mcg dose.
Linzess is approved with a Boxed Warning to alert patients and health care professionals that the drug should not be used in patients 17 years of age and younger. The most common side effect reported in during the clinical studies was diarrhea.
Linzess is co-marketed by Ironwood Pharmaceuticals Inc., based in Cambridge, Mass., and Forest Pharmaceuticals Inc.,
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317505.htm
Safer Alternatives to Linzess
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PPI, NSAID use linked to IBS symptoms
Keszthelyi D. BMC Gastroenterol. 2012;doi:10.1186/1471-230X-12-121.
October 9, 2012
Patients with IBS reported more use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs before onset of their symptoms than controls in a recent study.
In a retrospective, observational study, researchers evaluated 287 patients with IBS who had been taking one or more proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRI), diuretics or angiotensin-converting enzyme (ACE) inhibitors within 6 months of the onset of IBS symptoms. They were matched by age and sex with 287 controls.
Patients with IBS reported significantly more PPI and NSAID use than controls (21.2% vs. 5.2% for PPIs; 20.55% vs. 3.8% for NSAIDs), and the two medications were more frequently used in conjunction among those with IBS (7.6% of patients compared with 0%, P<.001). SSRI use was also more common among participants with IBS (10.84% vs. 2.1%). Diuretics and ACE inhibitors, included as control medications, were used similarly between groups.
Patients with IBS were significantly more likely to have comorbidities, including psychiatric comorbidities (40.4% compared with 3.5%; OR=16.6; 95% CI, 7.9-34.8) and GERD or functional dyspepsia (25.2% vs. 9.8%; OR=2.0; 95% CI, 1.1-3.5) than controls. Rheumatoid arthritis also was more common among IBS patients (6.1% vs. 0%).
After adjusting for comorbidities, investigators observed significant associations between IBS and PPI (OR=2.1, 1.1-4.1) and NSAID use (OR=5.2, 2.5-11.0), but not with SSRI (OR=0.9, 0.3-2.7). The associations with PPIs and NSAIDs remained significant after excluding patients with psychiatric comorbidities (OR=3.0, 1.3-7.0 for PPIs; OR=4.1, 1.7-9.6 for NSAIDs) and those with RA or arthritis (OR=3.1, 1.5-6.2 for PPIs; OR=5.7, 2.65-12.2 for NSAIDs) from analysis (95% CI for all).
"Prescribing PPIs for upper GI complaints or NSAIDs for pain relief may potentially trigger mechanisms resulting in symptom generation representative for IBS," the researchers wrote. "Further research should include prospective evaluation of PPI users and NSAID users monitoring the development of IBS symptoms in relation to drug exposure to ascertain whether this increased exposure to PPIs and NSAIDs should be considered as legitimate etiological factors in IBS."
http://www.healio.com/gastroenterology/irritable-bowel-syndrome/news/online/%7B48a99177-5185-4271-91f3-98429715516c%7D/ppi-nsaid-use-linked-to-ibs-symptoms
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Some Antidepressants May Raise Risk for Gastro Infection
Researchers aren't sure why these meds are linked to chances of contracting C. difficile
TUESDAY, May 7 (HealthDay News) -- People who take certain types of antidepressants may be at higher risk for potentially deadly Clostridium difficile infection, a new study suggests.
This type of infection is one of the most common caught by hospital patients and causes more than 7,000 deaths each year in the United States. Several medications are thought to increase the risk for this infection, including antidepressants.
In this study, University of Michigan researchers examined C. difficile infection in people with and without depression, and found that those with major depression had a 36 percent higher risk than those without depression. Older, widowed people were 54 percent more likely to catch C. difficile than older married people. People who lived alone had a 25 percent higher risk than those who lived with others.
The researchers then investigated if there was a link between antidepressants and C. difficile infection. They found that only two -- Remeron (mirtazapine) and Prozac (fluoxetine) -- increased the risk, and that each drug doubled the risk.
The findings, published May 6 in the journal BMC Medicine, should improve identification and early treatment of C. difficile infection in people taking these antidepressants, the researchers said.
The reason for the increased risk of infection in people taking the antidepressants is unknown, and people who have been prescribed the drugs need to keep taking them unless their doctor tells them otherwise, the researchers said. The research showed an association between antidepressant use and increased risk of contracting the infection, but it did not prove a cause-and-effect link.
"Depression is common worldwide," study leader Dr. Mary Rogers said in a university news release. "We have long known that depression is associated with changes in the gastrointestinal system."
"The interaction between the brain and the gut, called the 'brain-gut axis,' is fascinating and deserves more study," Rogers said. "Our finding of a link between depression and Clostridium difficile should help us better identify those at risk of infection and perhaps encourage exploration of the underlying brain-gut mechanisms involved."
More information
The American Academy of Family Physicians has more about C. difficile infection.
-- Robert Preidt
SOURCE: BMC Medicine, news release, May 6, 2013
Last Updated: May 07, 2013
Health News Copyright © 2013 HealthDay. All rights reserved.
http://consumer.healthday.com/Article.asp?AID=676154
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