1. Introduction

2. Overview of the market

3. Pharmacology

4. Pharmacodynamics in IBS

5. Proof-of-concept,

dose-finding studies

6. Phase II studies in IBS

7. Phase III studies in IBS

8. Results of retreatment studies

9. Safety data

10. Regulatory affairs

11. Conclusions

12. Expert opinion

Drug Evaluation

Rifaximin for the treatment ofirritable bowel syndromeFilippo Cremonini† & Anthony Lembo†Harvard Medical School, Center for Clinical and Translational research in Gastrointestinal

Motility, Beth Israel Deaconess Medical Center, Division of Gastroenterology, Boston, MA, USA

Introduction: Few therapeutic options are available for irritable bowel syn-

drome (IBS). Lubiprostone is approved by the FDA for IBS with constipation,

and alosetron in IBS with diarrhea (IBS-D). It has been proposed that altera-

tions in the bowel microflora may play a role in the pathophysiology of IBS,

and that modulation of the microflora holds therapeutic potential. Rifaximin

is a nonsystemic antibiotic that has shown efficacy in IBS.

Areas covered: This narrative review covers the treatment options available

for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical

pharmacology and results of clinical studies from proof of concept to the lat-

est Phase III and retreatment studies in IBS are summarized. Challenges to

rifaximin use, safety issues and regulatory data are also discussed.

Expert opinion: The evidence supports rifaximin as an emerging treatment for

IBS. Strategies for appropriate patient selection need to be further developed,

and continued efficacy of rifaximin over repeated treatment courses needs to

be better characterized.

Keywords: diarrhea, irritable bowel, nonabsorbable antibiotic, rifaximin

Expert Opin. Pharmacother. (2012) 13(3):433-440

1. Introduction

The irritable bowel syndrome (IBS) is defined as the presence of recurrent abdom-inal pain in association with altered bowel habit in the absence of an organic cause(Table 1) [1]. Although IBS is a common disorder that is associated with significantnegative impact on health-related quality of life (HRQOL), therapeutic optionsremain limited, particularly in patients with IBS and diarrhea (IBS-D). Laboratorystudies suggest different composition of the microbiome between patients with IBSand asymptomatic controls [2,3]. The prevalence of small intestinal bacterial over-growth (SIBO) in IBS and control has been investigated in several studies using lac-tulose hydrogen breath testing. While early case-control studies suggested anassociation between SIBO and IBS [4], more recent data pointed to a weaker associ-ation [5] and to the inadequacy of lactulose hydrogen breath testing to support adiagnosis of SIBO in IBS [6]. Currently, the role of microbiota in the generationof symptoms in IBS is far from being clarified.

Despite the unclear pathogenic role of gut bacterial composition, several clinicaltrials of antibiotics aimed at altering gut microbiota to improve IBS symptoms havebeen performed.

Rifaximin is a nonsystemic antibiotic [7], which has shown efficacy in non-constipated IBS (Box 1).

The aim of the present review is to critically review the rationale, efficacy andsafety of rifaximin in IBS and to discuss challenges and implications of its use inthis patient population.

10.1517/14656566.2012.651458 © 2012 Informa UK, Ltd. ISSN 1465-6566 433All rights reserved: reproduction in whole or in part not permitted

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2. Overview of the market

At present, there are few safe and effective treatment optionsfor patients with IBS-D. Targets of therapy have includedrestoring normal gut motility and secretion, and modulatingvisceral pain [8]. Loperamide has been shown to decrease intes-tinal transit, thereby improving stool frequency, consistencyand urgency, but with little effect on abdominal pain or dis-comfort [9]. The 5-HT3 receptor antagonist alosetron is theonly medication currently approved by the FDA for patientswith IBS-D. Unfortunately, alosetron is associated with sig-nificant constipation and ischemic colitis, and is currentlyavailable through the prescribing program [10]. Other 5-HT3

antagonists are under development [11]. Probiotics, such asBifidobacteria and Lactobacilli, have been purported to havesome efficacy in IBS-D, as well as antidepressants such as ami-triptyline; however, for both of these therapeutic modalities,there are a few studies available; their results are heteroge-neous and, in some instances, the study quality appearslow [12,13]. Sequestration of bile acids, with agents such as cho-lestyramine and colesevelam, has also been proposed as apotential treatment [14]. Thus far, one small proof-of-conceptstudy of colesevelam in IBS-D has shown effect on transit andstool consistency [15].The lack of well-established patient reported outcome

instruments [16] has led to the FDA to recommend InterimEndpoints for IBS treatment trials, which are equally centeredon both improvement in bowel habits and pain based onsymptoms that are both important and bothersome to

patients. For IBS with diarrhea (IBS-D), the FDA recom-mended Interim Endpoint require patients to report a weeklyaverage reduction of ‡ 30% in their worse daily abdominalpain score, compared with baseline and a weekly average stoolconsistency score £ 5 on the Bristol stool scale form(Table 2) [17].

3. Pharmacology

Rifaximin is a derivative of rifamycin and is comparable withrifampicin for its antibacterial activity. Unlike rifampin, rifax-imin possesses a pyridoimidazole ring, which largely preventsits intestinal absorption [18].

The antibacterial effects of rifaximin are delivered by bindingthe beta-subunit of the bacterial DNA-dependent RNA poly-merase, resulting in the inhibition of bacterial RNA synthesis.Rifaximin does not bind to RNApolymerase in eukaryotic cells,thus does not affect human cell production [19].

3.1 Antibacterial activityThe spectrum of rifaximin activity is broad and includesGram-positive and Gram-negative aerobic and anaerobic bac-teria [18]. In vitro, activity against most enteric pathogens hasbeen demonstrated, confirmed by ex vivo studies with284 pathogens from patients with travelers’ diarrhea devel-oped in Caribbean and African countries [20]. When com-pared with other antibiotics, rifaximin has a lower rate offecal nonpathogenic eradication, resulting in reduceddepletion of normal gastrointestinal flora [18].

Box 1. Drug summary.

Drug name RifaximinPhase PreregistrationIndication Irritable bowel syndromePharmacology description Protein 50S ribosomal subunit inhibitor, DNA-directed

RNA polymerase inhibitor, RNA synthesis inhibitorRoute of administration OralChemical structure

O

N

O

N

N O

O

O

O

O

O

OO

O

Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and

Citeline (http://informa.citeline.com).

Rifaximin

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3.2 PharmacokineticsIrrespective of the integrity of intestinal mucosa, an oral doseof rifaximin results in less of 1% of the drug dose detectable inblood, urine or bile, and more than 96% of the oral dose isexcreted in the stools. 25-Desacetylrifaximin is the onlyknown metabolite of rifaximin and is found in minimalamounts (< 0.01% of the oral rifaximin dose) in the urine [18].The plasma protein binding of rifaximin is moderate, being68% in health [18].

While plasma minimal inhibitory concentrations are usedto determine susceptibility of bacterial species to a definiteantibiotic, this has limited application to rifaximin, which isminimally absorbed following a nonlinear pharmacokinet-ics [18], and the goal of oral administration is achieving highrifaximin concentration in the target district (i.e., the gut).The average rifaximin fecal concentrations of 8000 mcg/g inthe stools are reported after 3 days of treatment at 400 mgtwice daily dose [21].

4. Pharmacodynamics in IBS

4.1 Altering the microbiomeThe term ‘microbiome’ refers to the complex ecosystem thatencompasses the gastrointestinal flora, which involves approx-imately 100 trillion bacteria and 300 -- 500 bacterialspecies [22].

Evidence supporting a role for alterations in the gut micro-biome in the pathogenesis of IBS is still largely circumstantialand can be summarized in the following findings: i) the fre-quent development of IBS following an episode of acute gas-troenteritis [23], ii) the demonstration of differences betweenIBS patients and control subjects in their qualitative andquantitative composition of the gut microflora [3], which isstill subject of further investigation, and iii) the reports ofimprovement of IBS symptoms after treatment with

antibiotics, probiotics and prebiotics, agents that can alterthe gut microbiome [12]. It must be highlighted that evidenceis in most cases still limited and that these points, even whentaken together, still do not definitely imply a pathogenic link.

4.2 Experience with systemically absorbable

antibiotics and with neomycinSystemic antibiotics have been used, with variable results, inIBS and SIBO. Tetracyclines have shown a generally lowSIBO eradication rate (about 30%) and have no direct activityagainst anaerobes and only low activity against Bacteroides [24].

Metronidazole 400 mg t.i.d. reduced hydrogen and meth-ane gas excretion in a study of 13 patients with IBS [25]. In acomparative trial of amoxicillin--clavulanic acid, norfloxacinand of the prebiotic Saccharomyces boulardii for the treatmentof diarrhea with SIBO, a greater number of subjects reportedimprovement in bowel movement frequency with norfloxacin(90%) and amoxicillin--clavulanic acid (60%) than withS. boulardii [26].

Systemically absorbed antibiotics, however, all have signifi-cant potential for mild and even severe side effects and allergicreactions, and for inducing antibiotic resistance.

Neomycin is an aminoglycoside antibiotic, only 3% ofwhich is absorbed after oral administration from the gastroin-testinal tract [27]. In a study of 111 IBS patients, patientsreceiving 10 days of neomycin (500 mg twice daily) had a35% improvement in an IBS composite score comparedwith only 11% of patients who received placebo [28]. Impor-tantly, the best outcome was observed in the small numberof patients who had normalization of their lactulose breathtest (75% improvement) [29]. The potential of significantside effects, including oto- and nephrotoxicity, and bacterialresistance has limited its use in clinical practice.

5. Proof-of-concept, dose-finding studies

5.1 Studies enrolling patients with functional

bloatingA double-blind, randomized controlled study comparingrifaximin with activated charcoal for 7 days included34 patients with functional bloating (defined as excessive pas-sage of flatus, bloating, abdominal discomfort or pain withoutstructural or biological abnormalities) and 21 healthy con-trols [30]. Rifaximin 400 mg twice daily for 7 days was associ-ated with significant improvement in overall severity ofsymptoms with a trend, although not statistically significant,to improve bloating and abdominal pain, compared withcharcoal. Rifaximin also resulted in significant reduction inH2 production among functional bloating patients, but notin healthy controls. The lack of effect of rifaximin on abdom-inal pain and bloating could be attributed to the limited studypower, with only 18 patients receiving rifaximin.

Sharara and colleagues (Sharara) evaluated 124 patientswith bloating and flatulence (58% also met the criteria for

Table 1. Rome III criteria for the diagnosis of irritable

bowel syndrome.

Irritable bowel syndrome

Diagnostic criterion*Recurrent abdominal pain or discomfortz at least 3 days/monthin the last3 months associated with two or more of the following:

Improvement with defecationOnset associated with a change in the frequency of stoolOnset associated with a change in the form (appearance)of stool

Source: Rome Foundation website (http://www.romecriteria.org/), accessed

July 31, 2011.

In pathophysiology research and clinical trials, a pain/discomfort frequency of

at least 2 days a week during screening evaluation is recommended for

subject eligibility.

*Criterion fulfilled for the last 3 months with symptom onset at least

3 months prior to diagnosis.z‘Discomfort’ means an uncomfortable sensation not described as pain.

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Expert Opin. Pharmacother. (2012) 13(3) 435

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IBS) who were randomized to rifaximin 400 mg b.i.d. or pla-cebo for 10 days [31]. Overall, 41.3% of subjects on rifaximinversus 22.9% of those on placebo had global symptomimprovement. This improvement was still evident 10 daysafter treatment. Sub-analysis of only IBS patients showedglobal symptom improvement with rifaximin in 40.5% com-pared with only 18.2% with placebo. Hydrogen breath excre-tion decreased significantly with rifaximin responders andcorrelated with improvement in symptoms particularly bloat-ing; however, it is important to note that none of the patientshad an abnormal lactulose breath test at baseline. While thisstudy would suggest clear benefit in IBS relief with relativelysmall doses of rifaximin, this study had a somewhat lowerobserved placebo response than that observed in other studiesof IBS [32].

5.2 Studies enrolling patients with SIBO not using

symptoms as inclusion criteriaThe effects two doses of rifaximin, 800 and 1200 mg/day eachfor 7 days, on changes in intestinal H2 production wereassessed in 90 consecutive patients with SIBO based on a pos-itive H2 glucose breath test, a diagnostic tool less sensitive butmore specific as it is less prone than the H2 lactulose breathtest to yield false positives [33]. This study found 60% ofpatients receiving 1200 mg of rifaximin were normalized theirH2 production compared with 27% of patients who receivedrifaximin 800 mg and only 17% of those who received pla-cebo. Unfortunately, the prevalence of symptoms was notreported in this study; however, one could only argue that asbacterial overgrowth is prevalent in IBS and this populationwas recruited in a gastroenterology tertiary referral setting, aproportion of the study participants would meet criteria forIBS diagnosis.A subsequent study from the same group focused on the

1600- and 1200-mg rifaximin dose each for 7 days, with thesame study design and again on 80 consecutive patients withSIBO defined by a positive H2 glucose test [34]. Normalization

rates of H2 production improved further with 1600 mg ofrifaximin reaching 80% compared with 58% in patientsreceiving 1200 mg of rifaximin. In this study 63 of the80 patients fulfilled the Rome II Criteria for IBS. Nearly50% of the IBS patients had IBS-predominant diarrhea.

6. Phase II studies in IBS

A US predominantly single-center study explored the efficacyof the 400 mg t.i.d. dose in placebo-controlled trial of87 IBS patients. The trial enrolled IBS patients meetingRome I criteria, irrespective of their predominant bowelhabit. In this trial, global symptom improvement and bloat-ing were significantly better for rifaximin compared with pla-cebo after a 10-day course, and this improvement wassustained at 10-week follow-up [35]. The mean improvementin overall IBS symptoms after 10 weeks was 36.4%for patients receiving rifaximin and 22.1% for patientsreceiving placebo. Rifaximin did not significantly improveabdominal pain, constipation or diarrhea. Additional analy-ses suggested that rifaximin effect was greater in IBS patientswithout constipation.

The next Phase II study explored the effect of several differ-ent doses of rifaximin for duration up to 1 month. The studywas powered only for the 1100-mg dose (550 mg twice daily)for 14 days compared with placebo. In total, 388 patientswith IBS-D were randomized to either 550 mg b.i.d. of rifax-imin or placebo for 14 days. After 2 weeks of rifaximin or pla-cebo, all subjects received 2 additional weeks of placebo, andtheir symptoms response was followed for 12 weeks. Rifaxi-min was superior to placebo in adequate relief of IBS symp-toms during the first 4 weeks (52 vs 44%, respectively), atweek 4 and during all 4 weeks of treatment. At 12 weeks offollow-up, 62% of patients who received rifaximin versus49% of those who received placebo reported adequate relief.These differences were mirrored by similar significantdifferences in the relief of bloating [36].

Table 2. Combined endpoints for pain intensity and consistency in irritable bowel syndrome with diarrhea (IBS-D),

entry criteria and definition of responder suggested as adequate by the FDA in its draft guidance for clinical trials

in IBS.

Co-primary endpoints Entry criteria Definition of responder

Pain intensity Pain intensity Pain intensityAND Weekly average of worst abdominal

pain in past 24 h score of > 3.0in a 0 -- 10 point scale

Decrease in weekly average ofworst abdominal pain in past 24 hscore of > 30% compared with baseline

Stool consistencyAND ANDStool consistency Stool consistencyWeekly average > Type 6 BSS Weekly average of < Type 5 BSS (< Type 2

BSS can be considered an adverse event)

Adapted from the FDA draft guidance document, published online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/

UCM205269.pdf; accessed July 31, 2011.

BSS: Bristol stool scale.

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7. Phase III studies in IBS

Following the results of the Phase II studies, two identicallarge Phase III randomized placebo controlled trials (TAR-GET 1 and TARGET 2) were performed in the US andCanada [37]. Together these studies randomized 1260 non-constipated Rome II IBS patients with mild-to-moderateIBS symptoms to rifaximin (550 mg three times daily for2 weeks) or placebo and were followed for an additional10 weeks. More than 70% of patients were female and thevast majority of patients were having IBS with diarrhea. Theprimary endpoint, the proportion of patients who had ade-quate relief of global IBS symptoms for at least 2 of the4 weeks beginning after completion of 14 days of treatment(i.e., weeks 3 through 6), was met by 41% of patients receiv-ing rifaximin versus 31.7% of those receiving placebo. Thekey secondary endpoint, the proportion of patients who hadadequate relief of IBS-related bloating for at least 2 of the4 weeks after completion of treatment (i.e., weeks 3 through6), was met in 40.2% of patients receiving rifaximincompared with 30.3% of patients receiving placebo.

Other secondary endpoints included the proportion ofpatients reporting relief on the daily assessments of IBS symp-toms, bloating and abdominal pain and discomfort, stool con-sistency and the composite endpoint of abdominal pain andstool consistency, an endpoint specifically requested bythe FDA.

All these secondary endpoints were significantly better inthe rifaximin groups compared with placebo, in the analysesfrom the individual studies and in the pooled results.

Improvement in IBS symptoms with rifaximin persistedthroughout the 12-week study (i.e., during the 10 weeks aftercompletion of rifaximin treatment). The odds ratio of main-taining adequate symptom relief on rifaximin versus placebothroughout the entire duration of the study was 1.4 (95%CI 1.17 -- 1.77) and for maintaining adequate relief of bloat-ing was 1.4 (1.15 -- 1.75). The relative proportion of patientsreporting adequate relief from IBS symptoms remained con-sistent throughout the 12 weeks of the study, with a therapeu-tic gain of approximately 10%, although its effect appeared tobe declining in magnitude. Of note, in the individual TAR-GET 1 study, there were no significant differences betweenrifaximin and placebo observed in weekly adequate relief ofbloating during the third month of follow-up.

Using daily responses for the analysis of durability ofresponse of all the secondary symptom endpoints, includingweekly and daily bloating, abdominal pain, stool consistencyand the composite endpoint of abdominal pain and stool con-sistency, the patients who received rifaximin had significantodds ratios for response on all endpoints throughout theentire study duration, compared with those receiving placebo.Ancillary analyses of mean improvements from baseline indaily symptom scores also showed superiority of rifaximin toplacebo. Lactulose breath test was not performed in thisclinical study.

8. Results of retreatment studies

There is uncertainty about the need for and frequency andefficacy of retreatment with rifaximin. As the proposed mech-anism of action of rifaximin in IBS is based on underlyingSIBO or on imbalances in normal gut flora, there is the pos-sibility that at some point after antibiotic treatment, such con-dition may relapse, leading to recurrent symptoms. Ifunderlying motility disturbance is present and is linked togut flora imbalance, antibiotic treatment may only temporar-ily correct such imbalances. A small exploratory study showedno evidence of clinical resistance to rifaximin in a smallstudy [38] while a more recent retrospective chart review foundno evidence for a decrease in efficacy. In this study,522 patients treated with rifaximin at a tertiary referral centerover 4 years were identified of which 71 patients with non-constipated IBS underwent retreatment with rifaximin, someof whom had up to five treatments with the antibiotic [39].The response to each repeat rifaximin cycle remained high(approximately 75%). The median duration of benefit fromtreatment was 4 months.

While this study suggests that repeat rifaximin treatmentwould retain efficacy in non-constipated IBS, caution shouldbe applied given the retrospective nature of the report, thelack of a control group and of standardized measures to assessclinical response.

A separate retrospective chart review from the same group,retrieving data of IBS patients treated for SIBO, shows thatafter antibiotic treatment with rifaximin or other agents, twoprokinetics, erythromycin or tegaserod, were administeredwith a bedtime dose to prevent or delay symptom recurrencein patients with disturbed fasting motility, extending symp-tom durability from and average of 41 -- 195 days [40]. Thisapproach might not be applicable to patients with non-constipated IBS and in those with normal motility, and wouldnot be feasible after the withdrawal of tegaserod from the mar-ket. Others have also suggested that probiotics could be usedfor the purpose of prolonging symptom benefit fromrifaximin [41].

9. Safety data

No significant adverse events have been reported during theclinical trials of rifaximin performed to date in IBS. Even inmore vulnerable patient populations, such as in patientswith chronic liver disease treated with rifaximin at the550-mg b.i.d. dose, a comparable incidence of minor adverseevents was noted between rifaximin and placebo.

There remains concern that, at least theoretically, treatmentwith rifaximin would lead to the incidence of resistant entericmicroorganisms. Isolated reports have described the emer-gence of resistant staphylococcal species [42] in the skin ofhealthy volunteers associated with rifaximin administration,and the existence of resistant Clostridium difficile strainsin vitro [43].

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Expert Opin. Pharmacother. (2012) 13(3) 437

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10. Regulatory affairs

In 2009, rifaximin has been granted priority-review classifica-tion status by the FDA in IBS. Priority-review classification isattributed to drugs that have potential for major advances intreatment or that can offer treatment in areas where no ade-quate therapy is available. Following review of the pivotalPhase III trial data in February 2011, FDA requested furtherevidence on retreatment with rifaximin for recurrent IBSsymptoms in the anticipation of a complete response letter.A retreatment study with two up to 4-week, randomized con-trolled periods of repeat rifaximin treatment, after an initial4-week treatment phase, has subsequently been proposed bythe drug manufacturer at a November 2001 FDA advisorycommittee meeting.While retrospective data have been published on retreat-

ment since the FDA response, at the time of writing thisreview, it is still uncertain whether additional retreatmenttrials will be needed and planned.

11. Conclusions

Rifaximin is currently approved for the treatment of travelers’diarrhea and for the treatment of hepatic encephalopathy.Evidence suggests that rifaximin could be considered as

potential treatment for non-constipated IBS. The epidemio-logical relevance of IBS, the lack of treatments available fornon-constipated IBS and the potential for IBS symptomremission with a short-term treatment course could makerifaximin an attractive option in this condition despite thelimited therapeutic benefit.The results across Phase II and Phase III studies are consis-

tent for global and adequate relief of IBS symptoms. Themore recent Phase III studies suggest significant improvementof adequate relief of global IBS symptoms and on a range ofsecondary endpoints.There are multiple remaining issues. First, the 10 -- 15%

therapeutic gain of rifaximin over placebo seen in Phase IIIstudies is modest. One might argue that the therapeutic gainwould be greater if there were reliable diagnostic tools to char-acterize patients with IBS with significant microbiome alter-ation. No evidence points, so far, to specific microbialchanges that are successfully reversed by rifaximin, leadingto IBS symptom improvement. Thus, a better patient charac-terization using the microbiome as a biomarker for the pur-pose of antibiotic treatment remains hypothetical, and onecannot assume that patients with non-constipated IBS willrespond to rifaximin indiscriminately. As breath tests for

SIBO are unreliable, and as there is no clear evidence thatSIBO is involved in IBS pathogenesis, optimal strategies forpatients selection to optimize therapeutic gain are unclear.

Second, the theoretical possibility of induction of resis-tant microorganisms remains despite the poor systemicabsorption of rifaximin. In addition, the administration ofan antibiotic to a population as large as the IBS patientpopulation could potentially lead to unfavorable disruptionsof the gut and environmental microecology. Until dataon larger number of patients treated on with rifaximinare available, this question on potential safety issuesremains unanswered.

Third, there is lack of understanding if the drug maintainsits efficacy over repeated treatment courses. Available evidenceon retreatment is only retrospective, and only a prospective,randomized, controlled trial conducted on subjects with priortreatment failure will appropriately address this issue.

12. Expert opinion

If approved, rifaximin will be a novel treatment option fornon-constipated IBS. The novelty of this treatment modalityis the short duration of the treatment regimen, accompaniedby the sustained benefit that extends well beyond thetreatment length.

The lack of reported and expected systemic side effects withrifaximin is another major advantage of the drug.

These elements potentially would make rifaximin a ‘must-try’ strategy for most patients with non-constipated IBS,regardless of other concomitant treatments.

Physicians could favor such an approach regardless of thepresence of documented small intestinal bacterial overgrowth,as data suggest that testing for overgrowth is neither accuratenor significantly predictive of positive treatment outcome.

Further prospective data need to confirm clinically relevantefficacy of retreatment of retreatment with rifaximin inpatients with initial nonresponse and in those with IBS symp-toms recurrence. This is necessary for the drug to be approvedby the FDA for the indication of non-constipated IBS.

If the approval occurs, it is likely that rifaximin wouldposition itself among the first-step options for IBS treatment.

Declaration of interest

A Lembo is a consultant for Salix Pharmaceuticals.F Cremonini declares no conflict of interest and has receivedno payment in preparation of this manuscript.

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AffiliationFilippo Cremonini† MD MSc PhD &

Anthony Lembo MD†Author for correspondence

Harvard Medical School,

Center for Clinical and Translational research in

Gastrointestinal Motility,

Beth Israel Deaconess Medical Center,

Division of Gastroenterology,

330 Brookline Avenue, Boston, MA 02215,

USA

E-mail: fcremoni@bidmc.harvard.edu

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