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Background: Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D).Aim: To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility.Methods: Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods.Results: Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 µg/mL] and rifampin (MIC range 0.004-0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC50 range ≤0.06-32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested.Conclusions: In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS.Gov Identifier: NCT01543178. [ABSTRACT FROM AUTHOR]

Background The efficacy of rifaximin, a nonsystemic, gut-targeted antibiotic for reducing non-constipation-predominant irritable bowel syndrome (non-C IBS) symptoms, has been demonstrated in one phase 2b and two phase 3 randomised, double-blind, placebo-controlled trials, but detailed data about rifaximin safety and tolerability during treatment and subsequent follow-up periods are lacking. Aim To assess and determine the frequency of rifaximin and placebo adverse events ( AEs) in phase 2b and phase 3 non -C IBS trials. Methods A post hoc pooled safety analysis of the phase 2b (rifaximin 275, 550, and 1100 mg twice daily for 2 weeks; 550 mg twice daily for 4 weeks) and phase 3 (rifaximin 550 mg three times daily for 2 weeks) studies was performed. Data on treatment and post-treatment AEs were collected. Patients were followed up for 12 weeks and 10 weeks post-treatment in the phase 2b and phase 3 trials, respectively. Results Patients receiving rifaximin ( n = 1103) and placebo ( n = 829) had a similar incidence of drug-related AEs (12.1% vs. 10.7%), serious AEs (1.5% vs. 2.2%), drug-related AEs resulting in study discontinuation (0.8% vs. 0.8%), gastrointestinal-associated AEs (12.2% vs. 12.2%) and infection-associated AEs (8.5% vs. 9.5%). There were no cases of Clostridium difficile colitis or deaths. Conclusions The safety and tolerability profile of rifaximin during treatment and post-treatment was comparable to placebo. Future research should define the safety and tolerability profile, including risk of C. difficile colitis and microbial antibiotic resistance, with repeated courses of rifaximin in patients with non-constipation-predominant irritable bowel syndrome (ClinicalTrials.gov: NCT00269412, NCT00731679, and NCT00724126). [ABSTRACT FROM AUTHOR]

Background Clinical trial design is challenging in irritable bowel syndrome ( IBS) due in part to a high placebo effect. We postulated that the mere presence of an adverse event ( AE) may unmask patients in clinical trials who are assigned to the active agent, and this may lead to higher reported efficacy. Methods We evaluated therapies receiving at least a Grade 1B from the American College of Gastroenterology Task Force for IBS or which passed recent phase III clinical trials. Therapies with AE data derived from less than 50 patients in each study arm were excluded. Statistically significant excess AE were identified, risk difference was calculated for each AE, and incidence of AE in the treatment arm was reported. We examined the relationship of attributable drug benefit, defined as the reciprocal of number-needed-to-treat found in literature, with various measures of AE incidence. Key Results Attributable drug benefit correlated significantly with average AE risk difference, calculated as treatment arm AE incidence minus placebo arm AE incidence (R2 = 0.70, p = 0.039), and also with highest treatment arm AE incidence (R2 = 0.70, p = 0.038) for each therapy. There were also trends toward correlation with average treatment arm AE incidence (R2 = 0.54, p = 0.096) and highest AE risk difference (R2 = 0.63, p = 0.059) for each therapy. Conclusions & Inferences Our study suggests that higher AE incidence on active therapy is associated with more beneficial patient-reported outcomes in IBS clinical trials. This raises the issue of spontaneous unblinding. [ABSTRACT FROM AUTHOR]

Background Campylobacter jejuni infection is a leading cause of gastroenteritis and post infectious irritable bowel syndrome ( PI- IBS). Unanswered questions include the role of cytokines, effects on gut flora, and why IBS is not more prevalent in countries with higher gastroenteritis rates. Therefore, we determined the effects of early and repeat C. jejuni infections on post infectious phenotypes, gut flora, and cytokine levels in a rat model of functional bowel and microbial changes. Methods Sprague-Dawley rats were gavaged with 108 cfu C. jejuni as juveniles and again as adults (J+/A+), as adults only (J-/A+), or vehicle (controls). Stool consistency during acute colonization, post infectious stool wet weight, total bacteria and Methanobrevibacter smithii levels in bowel segments, and ileal cytokines were evaluated. Key Results C. jejuni colonization was longer for first exposures as juveniles (43.4 ± 1.7 days) vs. adults (30.4 ± 3.5 days) (P < 0.01) and shortest for second exposures (10.5 ± 1.7 days, P < 0.05). Small intestinal bacterial overgrowth ( SIBO) was more prevalent in J+/A+ (47%) than J-/A+ rats (26%) (P = 0.019), but J-/A+ rats had greater stool consistency alterations (P < 0.01). Ileal β-defensin 2, TLR-4, IL-8, and β-defensin 6 levels were increased in J-/A+ rats and further increased in J+/A+ rats; TNF-α was highest and IL6 lowest in J-/A+ rats. Total bacteria increased, and M. smithii decreased, with successive infections. Conclusions & Inferences We conclude that C. jejuni infection results in long-term alterations in small bowel flora, including methanogens. Mucosal defense mediators appear related to the number of infections, but not to SIBO development or the development of functional bowel phenotypes. [ABSTRACT FROM AUTHOR]

DIARRHEAL COMPONENT (IBS-D/M) A novel second-generation blood test quantifies anti-vinculin and anti-CdtB biomarkers to rule-in a diagnosis of IBS-D/M. This study seeks to estimate the economic impact associated with the second-generation blood test compared to the standard exclusionary approach for diagnosing IBS-D/M. Methods A cost-minimization decision tree was constructed in TreeAge Pro 2019. The budget impact model determined savings of $0.52 per-member-per-month when 50% of patients with possible IBS-D/M take the second-generation blood test. Conclusions This model demonstrates potential savings of $253 - $1446 per patient for the second-generation blood test compared to exclusionary diagnosis of IBS-D/M by reducing the need for expensive diagnostic procedures, with annual aggregate plan savings of $6.2M possible when 50% of potential IBS-D/M patients utilize the second-generation blood test. [Extracted from the article]

A letter to the editor is presented in response to an article about the potential role of small intestinal bacterial overgrowth in irritable bowel syndrome in the 2008 issue.