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Therapeutic Effects and Mechanisms of Action of Rifaximin in Gastrointestinal Diseases

  • Herbert L. DuPont
    Correspondence
    Correspondence: Address to Herbert L. DuPont, MD, MACP, The University of Texas School of Public Health, 1200 Herman Pressler, Suite 733, Houston, TX 77030.
    Affiliations
    Center for Infectious Diseases, The University of Texas School of Public Health, Baylor College of Medicine, Baylor St. Luke’s Medical Center, Kelsey Research Foundation, Houston, TX
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      Abstract

      Emerging preclinical and clinic evidence described herein suggests that the mechanism of action of rifaximin is not restricted to direct antibacterial effects within the gastrointestinal tract. Data from this study were derived from general and clinical trial–specific PubMed searches of English-language articles on rifaximin available through December 3, 2014. Search terms included rifaximin alone and in combination (using the Boolean operation “AND”) with travelers' diarrhea, hepatic encephalopathy, liver cirrhosis, irritable bowel syndrome, inflammatory bowel disease, and Crohn's disease. Rifaximin appears to reduce bacterial virulence and pathogenicity by inhibiting bacterial translocation across the gastrointestinal epithelial lining. Rifaximin was shown to decrease bacterial adherence to epithelial cells and subsequent internalization in a bacteria- and cell type–specific manner, without an alteration in bacterial counts, but with a down-regulation in epithelial proinflammatory cytokine expression. Rifaximin also appears to modulate gut-immune signaling. In animal models of inflammatory bowel disease, rifaximin produced therapeutic effects by activating the pregnane X receptor and thereby reducing levels of the proinflammatory transcription factor nuclear factor κB. Therefore, for a given disease state, rifaximin may act through several mechanisms of action to exert its therapeutic effects. Clinically, rifaximin 600 mg/d significantly reduced symptoms of travelers’ diarrhea (eg, time to last unformed stool vs placebo [32.0 hours vs 65.5 hours, respectively; P=.001]). For the prevention of hepatic encephalopathy recurrence, data indicate that treating 4 patients with rifaximin 1100 mg/d for 6 months would prevent 1 episode of hepatic encephalopathy. For diarrhea-predominant irritable bowel syndrome, a significantly greater percentage (40.7%) of patients treated with rifaximin 1650 mg/d for 2 weeks experienced adequate global irritable bowel syndrome symptom relief vs placebo (31.7%; P<.001). Rifaximin may be best described as a gut microenvironment modulator with cytoprotection properties, and further studies are needed to determine whether these putative mechanisms of action play a direct role in clinical outcomes.

      Abbreviations and Acronyms:

      AE (adverse event), CDAI (Crohn’s Disease Activity Index), EIR (extended intestinal release), IBS (irritable bowel syndrome), IBS-D (diarrhea-predominant irritable bowel syndrome)
      Article Highlights
      • Rifaximin is an oral, nonsystemic agent that exerts bactericidal and bacteriostatic effects by binding to the β subunit of bacterial DNA–dependent RNA polymerase and inhibiting bacterial RNA synthesis.
      • Rifaximin has been investigated for various gastrointestinal diseases, including travelers’ diarrhea, hepatic encephalopathy and other cirrhosis-related complications, diarrhea-predominant irritable bowel syndrome, and Crohn disease.
      • Emerging evidence suggests that the mechanism of action of rifaximin is not restricted to direct antibacterial effects in the gastrointestinal tract.
      • The author proposes that rifaximin has a multifaceted mechanism of action that includes direct antimicrobial effects, inhibition of bacterial translocation across the gut mucosal epithelium and subsequent alteration in the release and/or absorption of endotoxin and bacterial metabolites, and modulation of gut-immune signaling.
      • The complex mechanism of action suggests that rifaximin is best classified as a gut microenvironment modulator, with cytoprotection and bacterial colonization resistance properties.
      Rifaximin has been available for nearly 30 years and is currently approved in at least 41 countries around the world. Rifaximin (C43H51N3O11) is a nonsystemic structural analogue of rifampin that inhibits the synthesis of bacterial RNA by binding to the β subunit of bacterial DNA–dependent RNA polymerase (Figure 1).

      Xifaxan (rifaximin) tablets [package insert]. Raleigh, NC: Salix Pharmaceuticals; 2014.

      • DuPont H.L.
      Biologic properties and clinical uses of rifaximin.
      • Descombe J.J.
      • Dubourg D.
      • Picard M.
      • Palazzini E.
      Pharmacokinetic study of rifaximin after oral administration in healthy volunteers.
      Thus, it has been traditionally identified as an antibiotic, with support coming from its apparent modulation of the gut microbiota. Rifaximin is indicated for the treatment of travelers’ diarrhea caused by noninvasive Escherichia coli strains and also for reducing the risk of recurrence of overt hepatic encephalopathy.
      • DuPont H.L.
      Biologic properties and clinical uses of rifaximin.
      This review provides a brief narrative overview of the disease states for which rifaximin is indicated or has potential therapeutic efficacy, followed by a discussion of the putative mechanisms of action of rifaximin.
      Figure thumbnail gr1
      Figure 1Chemical structure of rifaximin (C43H51N3O11).
      Reprinted from Xifaxan (rifaximin) tablets [package insert],

      Xifaxan (rifaximin) tablets [package insert]. Raleigh, NC: Salix Pharmaceuticals; 2014.

      with permission from Salix Pharmaceuticals, Ltd.

      Data Sources and Searches

      A PubMed search was conducted for English-language articles on rifaximin available through December 3, 2014. The search terms included rifaximin alone and in combination (using the Boolean operator “AND”) with each of the following terms: travelers’ diarrhea, hepatic encephalopathy, liver cirrhosis, irritable bowel syndrome, inflammatory bowel disease, and Crohn’s disease. A general search was conducted, followed by a search of clinical trials only. Articles were selected with 2 aims: (1) to identify articles that provided epidemiological data and/or a comprehensive overview of travelers’ diarrhea, hepatic encephalopathy and other complications of liver cirrhosis, irritable bowel syndrome (IBS), and Crohn disease; and (2) to identify articles that reported clinical trial results or any other relevant clinical findings. An additional search included the terms rifaximin AND mechanism of action, rifaximin AND pharmacodynamics, rifaximin AND pharmacokinetics, rifaximin AND (immune system OR immune function OR immune signaling), rifaximin AND bacteria, rifaximin AND (antibiotic OR antimicrobial), and rifaximin AND (gut microbiota OR gut mucosa). Articles were selected from this search with the aim of identifying those reporting data related to the mechanism of action of rifaximin.

      Travelers’ Diarrhea

      Travelers’ diarrhea is common among international travelers, affecting up to 50% of all travelers.

      Travelers’ diarrhea. Centers for Disease Control and Prevention website. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. Published November 21, 2006. Accessed October 29, 2014.

      • Steffen R.
      • van der Linde F.
      • Gyr K.
      • Schär M.
      Epidemiology of diarrhea in travelers.
      • Shah N.
      • DuPont H.L.
      • Ramsey D.J.
      Global etiology of travelers’ diarrhea: systematic review from 1973 to the present.
      Symptoms of travelers’ diarrhea typically occur suddenly and include diarrhea, abdominal cramping, nausea, vomiting, and general malaise.

      Travelers’ diarrhea. Centers for Disease Control and Prevention website. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. Published November 21, 2006. Accessed October 29, 2014.

      • DuPont H.L.
      Systematic review: the epidemiology and clinical features of travellers’ diarrhoea.
      Travelers’ diarrhea is caused primarily by exposure to a bacterial enteric pathogen; enterotoxigenic E coli and enteroaggregative E coli are the most common causative pathogens.

      Travelers’ diarrhea. Centers for Disease Control and Prevention website. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. Published November 21, 2006. Accessed October 29, 2014.

      • Shah N.
      • DuPont H.L.
      • Ramsey D.J.
      Global etiology of travelers’ diarrhea: systematic review from 1973 to the present.
      • DuPont H.L.
      Systematic review: the epidemiology and clinical features of travellers’ diarrhoea.
      Most cases of travelers’ diarrhea are mild in intensity, and symptoms are generally self-limited; about 90% of cases resolve within 1 week, and 98% resolve within 1 month of symptom onset.

      Travelers’ diarrhea. Centers for Disease Control and Prevention website. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. Published November 21, 2006. Accessed October 29, 2014.

      • DuPont H.L.
      Systematic review: the epidemiology and clinical features of travellers’ diarrhoea.
      Antibiotics are typically prescribed for moderate to severe cases of travelers’ diarrhea.

      Travelers’ diarrhea. Centers for Disease Control and Prevention website. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. Published November 21, 2006. Accessed October 29, 2014.

      • DuPont H.L.
      Systematic review: the epidemiology and clinical features of travellers’ diarrhoea.
      Although considered an acute illness, evidence suggests that travelers’ diarrhea can lead to chronic disease, including reactive arthritis and postinfectious IBS.
      • Connor B.A.
      • Riddle M.S.
      Post-infectious sequelae of travelers' diarrhea.
      Data from randomized clinical trials support the efficacy and tolerability of rifaximin in the treatment of travelers’ diarrhea.
      • DuPont H.L.
      • Ericsson C.D.
      • Mathewson J.J.
      • et al.
      Rifaximin: a nonabsorbed antimicrobial in the therapy of travelers’ diarrhea.
      • DuPont H.L.
      • Jiang Z.D.
      • Ericsson C.D.
      • et al.
      Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial.
      • Taylor D.N.
      • Bourgeois A.L.
      • Ericsson C.D.
      • et al.
      A randomized, double-blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers’ diarrhea.
      In a randomized double-blind study, adults who visited a travel health clinic in Mexico, Guatemala, India, or Peru were treated for acute diarrhea with rifaximin 200 mg thrice daily (n=197), placebo thrice daily (n=101), or standard of care (ciprofloxacin 500 mg twice daily plus placebo once daily [n=101]).
      • Taylor D.N.
      • Bourgeois A.L.
      • Ericsson C.D.
      • et al.
      A randomized, double-blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers’ diarrhea.
      The primary end point was time to last unformed stool; secondary end points were clinical wellness (lack of watery stools and ≤2 soft stools in 24 hours, with no clinical symptoms besides mild gas or flatulence, or no unformed stools in 48 hours in the absence of fever, with or without clinical symptoms) and treatment failure (defined as clinical deterioration or symptom worsening despite treatment lasting at least 24 hours or continuation of symptoms after treatment with the study drug for at least 5 days [120 hours] or at least 24 hours of therapy).
      Rifaximin significantly reduced the time to last unformed stool than did placebo (32.0 hours vs 65.5 hours, respectively; P=.001).
      • Taylor D.N.
      • Bourgeois A.L.
      • Ericsson C.D.
      • et al.
      A randomized, double-blind, multicenter study of rifaximin compared with placebo and with ciprofloxacin in the treatment of travelers’ diarrhea.
      Rifaximin was as efficacious as ciprofloxacin in reducing the time to last unformed stool (32.0 hours vs 28.8 hours, respectively; P=.35). The percentage of patients who reported improvement in clinical wellness was significantly greater with rifaximin (76.6%) than with placebo (61.4%) (P=.004) and similar to that with ciprofloxacin (78.2%; P=.74). The percentage of patients who experienced treatment failure was lower with rifaximin than with placebo (14.7% vs 26.7%, respectively; P=.01). However, the rate of treatment failure was lower with ciprofloxacin than with rifaximin (6.9% vs 14.7%, respectively; P=.05). The incidence of adverse events (AEs) was similar in treatment groups, and the most common AEs with rifaximin were headache (8.0% vs 9.0% with placebo) and constipation (4.0% vs 5.0% with placebo).
      Rifaximin may also have utility as travelers’ diarrhea prophylaxis for travelers to high-risk regions,
      • DuPont H.L.
      • Jiang Z.D.
      • Okhuysen P.C.
      • et al.
      A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea.
      • Martinez-Sandoval F.
      • Ericsson C.D.
      • Jiang Z.D.
      • et al.
      Prevention of travelers’ diarrhea with rifaximin in US travelers to Mexico.
      although it is not clear which patient groups should be encouraged to use chemoprophylaxis. Travelers’ diarrhea prophylaxis could have important clinical implications, such as preventing associated long-term complications of travelers’ diarrhea (eg, postinfectious IBS).
      • Connor B.A.
      • Riddle M.S.
      Post-infectious sequelae of travelers' diarrhea.

      Complications of Liver Cirrhosis

      Hepatic encephalopathy, a potentially reversible complication of cirrhosis, is associated with neuromuscular dysfunction and various neuropsychiatric symptoms.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.
      Hepatic encephalopathy is classified into several grades, from minimal (covert) to overt, according to symptom severity.
      • Vilstrup H.
      • Amodio P.
      • Bajaj J.
      • et al.
      Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.
      Patients with minimal hepatic encephalopathy show mild cognitive impairment that is often clinically undetectable, except through specific psychometric testing. Patients with overt hepatic encephalopathy exhibit clinical symptoms, with pronounced and various degrees of alteration or impairment in cognition, behavior, personality, mood, psychomotor function, sleep patterns, and consciousness.
      The pathophysiology of hepatic encephalopathy is uncertain but is believed to be multifactorial. Combined action of the accumulation of gut-derived microbial toxins, inflammation, and oxidative stress is hypothesized to cause brain alterations such as cerebral edema, which underlie the pathogenesis of hepatic encephalopathy.
      • Riordan S.M.
      • Williams R.
      Gut flora and hepatic encephalopathy in patients with cirrhosis.
      • Sturgeon J.P.
      • Shawcross D.L.
      Recent insights into the pathogenesis of hepatic encephalopathy and treatments.
      • Garcovich M.
      • Zocco M.A.
      • Roccarina D.
      • Ponziani F.R.
      • Gasbarrini A.
      Prevention and treatment of hepatic encephalopathy: focusing on gut microbiota.
      As liver disease progresses, portosystemic shunting occurs, and the liver becomes less capable of removing neurotoxins from the bloodstream, resulting in increased levels of systemic gut-derived neurotoxins, particularly ammonia.
      • Riordan S.M.
      • Williams R.
      Gut flora and hepatic encephalopathy in patients with cirrhosis.
      • Sturgeon J.P.
      • Shawcross D.L.
      Recent insights into the pathogenesis of hepatic encephalopathy and treatments.
      • Garcovich M.
      • Zocco M.A.
      • Roccarina D.
      • Ponziani F.R.
      • Gasbarrini A.
      Prevention and treatment of hepatic encephalopathy: focusing on gut microbiota.
      Treatment of hepatic encephalopathy typically involves medical stabilization of the patient and possible hospitalization in the intensive care unit, elimination of potential precipitating factors (eg, dehydration and hypokalemia), correction of glucose and electrolyte levels, and reduction in systemic levels of gut-derived neurotoxins.
      • Prakash R.
      • Mullen K.D.
      Mechanisms, diagnosis and management of hepatic encephalopathy.
      • Romero-Gómez M.
      • Montagnese S.
      • Jalan R.
      Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.
      Multiple randomized clinical trials have evaluated rifaximin for the management or prevention of hepatic encephalopathy.
      • Kimer N.
      • Krag A.
      • Møller S.
      • Bendtsen F.
      • Gluud L.L.
      Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy.
      In a randomized, double-blind, placebo-controlled clinical trial of rifaximin, Bass et al
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      studied adults with cirrhosis and a history of 2 or more episodes of hepatic encephalopathy in the previous 6 months who were in remission at the time of enrollment (Conn score, 0 or 1). Patients were randomized to receive rifaximin 550 mg (n=140) or placebo (n=159) twice daily for 6 months.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      The primary end point was time to the first breakthrough episode of hepatic encephalopathy (defined as an increase in Conn score to ≥2 or, if the baseline Conn score was 0, a Conn score of 1 plus a 1-unit increase in asterixis grade).
      Rifaximin 1100 mg/d significantly reduced the risk of recurrence of hepatic encephalopathy, with 31 patients (22.1%) in the rifaximin group and 73 patients (45.9%) in the placebo group experiencing a breakthrough episode of hepatic encephalopathy during the 6-month trial (hazard ratio, 0.42; 95% CI, 0.28-0.64; P<.001).
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      Treating 4 patients with rifaximin for 6 months would prevent 1 episode of hepatic encephalopathy (ie, number needed to treat, 4). Rifaximin also decreased the risk of hepatic encephalopathy–related hospitalization than did with placebo, achieving a 50% relative risk reduction (P=.01); treating 9 patients with rifaximin for 6 months would prevent 1 hepatic encephalopathy–related hospitalization (ie, number needed to treat, 9). Rates of AEs were similar between the rifaximin and placebo groups; the most common AEs reported during rifaximin treatment were peripheral edema, nausea, dizziness, and fatigue. The long-term safety of rifaximin 1100 mg/d has been supported by a 24-month open-label maintenance of hepatic encephalopathy remission study, in which AE rates did not increase in comparison with rates reported during the 6-month randomized trial.
      • Mullen K.D.
      • Sanyal A.J.
      • Bass N.M.
      • et al.
      Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy.
      Rifaximin may also influence the long-term prognosis of patients with cirrhosis. In a small European case-control study, rifaximin 1200 mg/d significantly increased overall survival and the 5-year cumulative probability of remaining free of hepatic encephalopathy in patients with alcohol-related decompensated cirrhosis and ascites.
      • Vlachogiannakos J.
      • Viazis N.
      • Vasianopoulou P.
      • Vafiadis I.
      • Karamanolis D.G.
      • Ladas S.D.
      Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis.

      Diarrhea-Predominant IBS

      Approximately 30 to 45 million adults (∼10%-15%) in North America have IBS.
      • Saito Y.A.
      • Schoenfeld P.
      • Locke III, G.R.
      The epidemiology of irritable bowel syndrome in North America: a systematic review.
      • Lovell R.M.
      • Ford A.C.
      Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis.
      Although IBS may occur at any age, most adults with IBS (67.3%) are 25 to 54 years of age.
      • Hungin A.P.S.
      • Chang L.
      • Locke G.R.
      • Dennis E.H.
      • Barghout V.
      Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact.
      Irritable bowel syndrome is commonly associated with abdominal pain or discomfort (eg, bloating) and altered bowel function, and symptoms may be either chronic or episodic.
      • Longstreth G.F.
      • Thompson W.G.
      • Chey W.D.
      • Houghton L.A.
      • Mearin F.
      • Spiller R.C.
      Functional bowel disorders.
      • Brandt L.J.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • et al.
      American College of Gastroenterology Task Force on Irritable Bowel Syndrome
      An evidence-based position statement on the management of irritable bowel syndrome.
      Altered bowel function in IBS is typically categorized as diarrhea predominant (IBS-D), constipation predominant, or mixed.
      • Longstreth G.F.
      • Thompson W.G.
      • Chey W.D.
      • Houghton L.A.
      • Mearin F.
      • Spiller R.C.
      Functional bowel disorders.
      • Brandt L.J.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • et al.
      American College of Gastroenterology Task Force on Irritable Bowel Syndrome
      An evidence-based position statement on the management of irritable bowel syndrome.
      The etiology of IBS is multifactorial and likely involves genetic factors and alterations in immune, motor, and sensory responses to various stimuli.
      • Connor B.A.
      • Riddle M.S.
      Post-infectious sequelae of travelers' diarrhea.
      • Camilleri M.
      Peripheral mechanisms in irritable bowel syndrome.
      Therapies for the treatment of IBS-D have historically been limited, and patients may use multiple avenues of treatment including dietary modification, psychological interventions (eg, behavior modification), over-the-counter medications, and prescription therapies.

      Moleski SM. Irritable bowel syndrome (IBS) (spastic colon). Merck website. http://www.merckmanuals.com/home/digestive_disorders/irritable_bowel_syndrome_ibs/irritable_bowel_syndrome_ibs.html?qt=irritable%20bowel%20syndrome&alt=sh. Updated August 2013. Accessed January 22, 2015.

      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      In May 2015, rifaximin was approved for the treatment of IBS-D in adults, and several studies support the effiacy and safety of rifaximin in the treatment of IBS-D.
      • Pimentel M.
      • Park S.
      • Mirocha J.
      • Kane S.V.
      • Kong Y.
      The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial.
      • Sharara A.I.
      • Aoun E.
      • Abdul-Baki H.
      • Mounzer R.
      • Sidani S.
      • Elhajj I.
      A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence.
      • Jolley J.
      High-dose rifaximin treatment alleviates global symptoms of irritable bowel syndrome.
      • Pimentel M.
      • Lembo A.
      • Chey W.D.
      • et al.
      TARGET Study Group
      Rifaximin therapy for patients with irritable bowel syndrome without constipation.
      • Pimentel M.
      • Morales W.
      • Chua K.
      • et al.
      Effects of rifaximin treatment and retreatment in nonconstipated IBS subjects.
      • Weinstock L.B.
      Long-term outcome of rifaximin therapy in non-constipation irritable bowel syndrome.
      In 2 identically designed, randomized, double-blind, placebo-controlled clinical trials (TARGET 1 and 2; N=1260), adults with a diagnosis and current symptoms of IBS without constipation were randomized to receive either rifaximin 550 mg thrice daily or placebo for 14 days.
      • Pimentel M.
      • Lembo A.
      • Chey W.D.
      • et al.
      TARGET Study Group
      Rifaximin therapy for patients with irritable bowel syndrome without constipation.
      The primary end point was adequate relief from global IBS symptoms (based on yes/no response to question for the previous 7-day period) during 2 weeks or more of the first 4 weeks posttreatment; the key secondary end point was adequate relief from IBS-related bloating (based on yes/no response to question for the previous 7-day period) during 2 weeks or more of the first 4 weeks posttreatment.
      A significantly greater percentage of patients receiving rifaximin reported that their global IBS symptoms (40.7% vs 31.7% for placebo; P<.001) and IBS-associated bloating (40.2% vs 30.3% for placebo; P<.001) had been adequately relieved during the first 4 weeks posttreatment in the pooled TARGET 1 and 2 studies.
      • Pimentel M.
      • Lembo A.
      • Chey W.D.
      • et al.
      TARGET Study Group
      Rifaximin therapy for patients with irritable bowel syndrome without constipation.
      In terms of durability of response, a significantly greater percentage of patients in the rifaximin group vs the placebo group reported adequate relief from global IBS symptoms over a 12-week period (2 weeks of treatment plus 10 weeks of posttreatment follow-up; P<.001, pooled studies). During this 12-week period, a greater percentage of patients receiving rifaximin than those receiving placebo reported adequate relief from IBS-related bloating, although the difference was significant only in the TARGET 2 study (P=.003). The incidence of AEs was similar in the 2 treatment groups, with headache, upper respiratory tract infection, and abdominal pain being the most common AEs in the rifaximin group.

      Crohn Disease

      Crohn disease is a lifelong relapsing-remitting condition that is associated with chronic inflammation of 1 or more regions of the intestinal tract.
      • Hovde Ø.
      • Moum B.A.
      Epidemiology and clinical course of Crohn’s disease: results from observational studies.

      Walfish AE, Sachar DB. Crohn disease. Merck website. http://www.merckmanuals.com/home/digestive_disorders/inflammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn&alt=sh. Updated April 2013. Accessed January 22, 2015.

      • D’Incà R.
      • Caccaro R.
      Measuring disease activity in Crohn’s disease: what is currently available to the clinician.
      Crohn disease is typically diagnosed before the age of 30 years, and symptoms include chronic diarrhea, abdominal cramping and pain, loss of appetite, weight loss, and fever.
      • Hovde Ø.
      • Moum B.A.
      Epidemiology and clinical course of Crohn’s disease: results from observational studies.

      Walfish AE, Sachar DB. Crohn disease. Merck website. http://www.merckmanuals.com/home/digestive_disorders/inflammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn&alt=sh. Updated April 2013. Accessed January 22, 2015.

      The incidence and prevalence of Crohn disease have increased during the past several decades,
      • Hovde Ø.
      • Moum B.A.
      Epidemiology and clinical course of Crohn’s disease: results from observational studies.

      Walfish AE, Sachar DB. Crohn disease. Merck website. http://www.merckmanuals.com/home/digestive_disorders/inflammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn&alt=sh. Updated April 2013. Accessed January 22, 2015.

      and the condition can lead to serious complications, including intestinal blockage, abdominal abscesses, fistulas, and anal fissures.
      • Hovde Ø.
      • Moum B.A.
      Epidemiology and clinical course of Crohn’s disease: results from observational studies.

      Walfish AE, Sachar DB. Crohn disease. Merck website. http://www.merckmanuals.com/home/digestive_disorders/inflammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn&alt=sh. Updated April 2013. Accessed January 22, 2015.

      • D’Incà R.
      • Caccaro R.
      Measuring disease activity in Crohn’s disease: what is currently available to the clinician.
      Various pharmacologic therapies are included in the management algorithm for Crohn disease, such as anti-inflammatory, immunomodulatory, and antidiarrheal agents, as well as antibiotics.

      Walfish AE, Sachar DB. Crohn disease. Merck website. http://www.merckmanuals.com/home/digestive_disorders/inflammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn&alt=sh. Updated April 2013. Accessed January 22, 2015.

      Surgery is commonly required in patients who develop complications.

      Walfish AE, Sachar DB. Crohn disease. Merck website. http://www.merckmanuals.com/home/digestive_disorders/inflammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn&alt=sh. Updated April 2013. Accessed January 22, 2015.

      Although rifaximin is not approved for the treatment of Crohn disease, emerging evidence suggests that rifaximin
      • Shafran I.
      • Johnson L.K.
      An open-label evaluation of rifaximin in the treatment of active Crohn’s disease.
      • Prantera C.
      • Lochs H.
      • Campieri M.
      • et al.
      Antibiotic treatment of Crohn’s disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin.
      or the investigational formulation of rifaximin-extended intestinal release (EIR) may be efficacious in the treatment of Crohn disease.
      • Prantera C.
      • Lochs H.
      • Grimaldi M.
      • Danese S.
      • Scribano M.L.
      • Gionchetti P.
      Retic Study Group (Rifaximin-Eir Treatment in Crohn’s Disease)
      Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease.
      A randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy and tolerability of rifaximin-EIR 400 mg (n=104), 800 mg (n=98), or 1200 mg (n=99) twice daily vs placebo (n=101) for 12 weeks in adults with active Crohn disease.
      • Prantera C.
      • Lochs H.
      • Grimaldi M.
      • Danese S.
      • Scribano M.L.
      • Gionchetti P.
      Retic Study Group (Rifaximin-Eir Treatment in Crohn’s Disease)
      Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease.
      The primary end point was disease remission (Crohn’s Disease Activity Index [CDAI] score of <150 points at week 12); the secondary end points were clinical response (maintenance of clinical remission at weeks 14 and 24) and treatment failure (failure to reduce the CDAI score by ≥70 points from baseline after treatment for 1 month or an increase of >100 points in the CDAI score from baseline at any time).
      Twelve weeks after treatment initiation, patients treated with rifaximin-EIR 800 mg twice daily were significantly more likely to achieve clinical remission of Crohn disease than patients receiving placebo (62.2% vs 42.6%; P=.005).
      • Prantera C.
      • Lochs H.
      • Grimaldi M.
      • Danese S.
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      • Gionchetti P.
      Retic Study Group (Rifaximin-Eir Treatment in Crohn’s Disease)
      Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease.
      Patients treated with rifaximin-EIR 400 or 1200 mg twice daily also reported higher rates of remission than did those treated with placebo, although the differences were not statistically significant. Patients treated with rifaximin-EIR 800 mg twice daily also reported a higher clinical response rate than did those treated with placebo (72.0% vs 56.0%; P=.02) and a lower treatment failure rate (25.5% vs 44.6%; P=.005) at the 12-week follow-up visit. Although not statistically significant compared with placebo, higher clinical response rates were also noted with rifaximin-EIR 400 and 1200 mg twice daily. Adverse events occurred at a similar rate in treatment groups, with the most common drug-related AEs being headache, symptoms of Crohn disease, and nausea.

      One Drug, Multiple Therapeutic Domains—Rifaximin as a Gut Microenvironment Modulator

      Given the multiple established and potential therapeutic indications for rifaximin, it is relevant to question the possible mechanism(s) of action by which it exerts these diverse therapeutic effects. It is well established that rifaximin acts within the gastrointestinal tract, given its nonsystemic absorption.

      Xifaxan (rifaximin) tablets [package insert]. Raleigh, NC: Salix Pharmaceuticals; 2014.

      • DuPont H.L.
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      • Descombe J.J.
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      • Picard M.
      • Palazzini E.
      Pharmacokinetic study of rifaximin after oral administration in healthy volunteers.
      Rifaximin is also known to exert direct bactericidal and bacteriostatic effects through the inhibition of bacterial RNA synthesis.

      Xifaxan (rifaximin) tablets [package insert]. Raleigh, NC: Salix Pharmaceuticals; 2014.

      • DuPont H.L.
      Biologic properties and clinical uses of rifaximin.
      • Brown E.L.
      • Xue Q.
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      • Xu Y.
      • DuPont H.L.
      Pretreatment of epithelial cells with rifaximin alters bacterial attachment and internalization profiles.
      In a randomized, double-blind clinical trial of rifaximin vs ciprofloxacin for the treatment of travelers’ diarrhea, stool samples were collected for an in vitro assessment of the antimicrobial activity of rifaximin against bacterial enteropathogenic isolates (Table).
      • DuPont H.L.
      • Jiang Z.D.
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      • et al.
      Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial.
      Forty-four bacterial isolates were obtained from the rifaximin group, representing 3 pathogens (enterotoxigenic E coli, Salmonella, and Shigella). All 3 pathogens were susceptible to rifaximin in vitro, with minimum inhibitory concentrations of 256 μg/mL or less and an overall minimal inhibitory concentration required to inhibit growth of 90% of organisms ranging from 0.25 to 32 μg/mL, which is substantially lower than fecal concentrations reported with rifaximin (4000-8000 μg/g).
      • DuPont H.L.
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      • et al.
      Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial.
      TableMICs of Rifaximin Against Bacterial Isolates From Patients With Travelers’ Diarrhea
      ETEC = enterotoxigenic Escherichia coli; MIC = minimal inhibitory concentration; MIC50 = minimal inhibitory concentration required to inhibit growth of 50% of organisms; MIC90 = minimal inhibitory concentration required to inhibit growth of 90% of organisms.
      From Clin Infect Dis,
      • DuPont H.L.
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      • et al.
      Rifaximin versus ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind clinical trial.
      with permission.
      OrganismNo. of isolatesMIC50 (μg/mL)MIC90 (μg/mL)MIC range (μg/mL)
      ETEC3616320.5-128
      Shigella5646416-256
      Salmonella3161616
      a ETEC = enterotoxigenic Escherichia coli; MIC = minimal inhibitory concentration; MIC50 = minimal inhibitory concentration required to inhibit growth of 50% of organisms; MIC90 = minimal inhibitory concentration required to inhibit growth of 90% of organisms.
      The direct antimicrobial activities of rifaximin appear to be centered on certain regions within the gastrointestinal tract. For example, in an animal model, rifaximin exposure resulted in a sustained reduction in duodenal bacterial levels but had no effect on colonic bacterial levels (Figure 2).
      • Kim M.S.
      • Morales W.
      • Hani A.A.
      • et al.
      The effect of rifaximin on gut flora and Staphylococcus resistance.
      In vitro studies suggest that the relative lack of drug effect in the colon may be related to the lower solubility of rifaximin in aqueous environments, such as that found in the colon as compared with the higher solubility of rifaximin in the presence of physiological concentrations of bile acids, such as those found in the small intestine.
      • Darkoh C.
      • Lichtenberger L.M.
      • Ajami N.
      • Dial E.J.
      • Jiang Z.D.
      • DuPont H.L.
      Bile acids improve the antimicrobial effect of rifaximin.
      Figure thumbnail gr2
      Figure 2In an animal model, treatment with rifaximin for 10 days and subsequent assessment 30 days posttreatment indicated a decrease in bacterial counts as measured by qPCR, but a long-term effect was restricted to the duodenum. qPCR = quantitative polymerase chain reaction. ∗P=.08.
      From Dig Dis Sci,
      • Kim M.S.
      • Morales W.
      • Hani A.A.
      • et al.
      The effect of rifaximin on gut flora and Staphylococcus resistance.
      with permission.
      Patients with cirrhosis have a relatively low concentration of bile acids within the small intestine; this is believed to contribute to gastrointestinal dysbiosis and chronic inflammation due to an overgrowth of pathogenic bacteria, increased endotoxin levels, and secondary stimulation of a potent inflammatory response.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      • Ridlon J.M.
      • Alves J.M.
      • Hylemon P.B.
      • Bajaj J.S.
      Cirrhosis, bile acids, and gut microbiota: unraveling a complex relationship.
      The low concentration of bile acids within the small intestine of patients with cirrhosis theoretically would reduce the solubility of rifaximin and thus reduce its direct antimicrobial effects in the small intestine. The results of several studies, however, suggest additional mechanisms of action of rifaximin that may not depend on bile acids in the small intestine. In a 2013 study of 20 patients with cirrhosis and minimal hepatic encephalopathy, open-label administration of rifaximin 550 mg twice daily for 8 weeks produced an improvement in cognitive function that was associated with a reduction in endotoxemia and a substantial increase in the relative serum levels of carbohydrate metabolites and long-chain fatty acids (which promote brain function), without any major alterations in the microbial composition of the stool.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      This effect may be related to a shift toward carbohydrate-using Lactobacilli in the small intestine; a recent study found that the ability of rifaximin to prevent the development of stress-induced mucosal inflammation in an animal model was associated with a relative increase in Lactobacilli in the small intestine.
      • Xu D.
      • Gao J.
      • Gillilland III, M.
      • et al.
      Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats.
      In an animal model of colitis, the therapeutic effect of rifaximin was associated with the inhibition of bacterial translocation across the mucosal epithelia,
      • Fiorucci S.
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      • Morelli A.
      Inhibition of intestinal bacterial translocation with rifaximin modulateslamina propria monocytic cells reactivity and protects against inflammation in a rodent model of colitis.
      and this effect theoretically would inhibit the translocation of urease-producing bacteria and reduce systemic neurotoxic levels of ammonia.
      • Riordan S.M.
      • Williams R.
      Gut flora and hepatic encephalopathy in patients with cirrhosis.
      • Sturgeon J.P.
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      Recent insights into the pathogenesis of hepatic encephalopathy and treatments.
      • Garcovich M.
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      • Ponziani F.R.
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      Prevention and treatment of hepatic encephalopathy: focusing on gut microbiota.
      Collectively, these findings suggest that the clinical effects of rifaximin in hepatic encephalopathy may be exerted, in part, through a mechanism that is distinct from the direct antibacterial effects in the small intestine and might involve alterations in bacterial translocation and the release and/or absorption of endotoxin, ammonia, carbohydrate intermediates, and long-chain fatty acids.
      Patients with IBS may have localized gastrointestinal factors that play a role in clinical symptoms, such as gut microbiota dysbiosis, comorbid small intestinal bacterial overgrowth, increased intestinal permeability, and/or chronic mucosal inflammation.
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      In an animal model of inflammatory bowel disease, rifaximin produced therapeutic effects by activating the pregnane X receptor and thereby reducing levels of the proinflammatory transcription factor nuclear factor κB.
      • Cheng J.
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      Of note, allelic variants in the pregnane X receptor gene and alterations in the expression of its target genes have been associated with inflammatory bowel disease in humans.
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      As noted above, the therapeutic effect of rifaximin in an animal model of colitis was associated with the inhibition of bacterial translocation across the mucosal epithelia.
      • Fiorucci S.
      • Distrutti E.
      • Mencarelli A.
      • Barbanti M.
      • Palazzini E.
      • Morelli A.
      Inhibition of intestinal bacterial translocation with rifaximin modulateslamina propria monocytic cells reactivity and protects against inflammation in a rodent model of colitis.
      In vitro studies suggest that the inhibition of bacterial translocation is related to a reduction in bacterial attachment and internalization in epithelial cells. Indeed, rifaximin was shown to decrease bacterial adherence to epithelial cells and subsequent internalization in a bacteria- and cell type–specific manner, without an alteration in bacterial counts, but with a down-regulation in epithelial proinflammatory cytokine expression (Figure 3).
      • Brown E.L.
      • Xue Q.
      • Jiang Z.D.
      • Xu Y.
      • DuPont H.L.
      Pretreatment of epithelial cells with rifaximin alters bacterial attachment and internalization profiles.
      Thus, rifaximin may have interrelated effects on bacterial translocation and immune function that are distinct from its direct antibacterial effects and are beneficial in the treatment of IBS.
      Figure thumbnail gr3
      Figure 3In an in vitro model, rifaximin treatment of HEp-2 (laryngeal) cells decreased EAEC bacterial adhesion (A) and rifaximin treatment of A549 (lung) cells after incubation with Bacillus anthracis decreased bacterial internalization (B). EAEC = enteroaggregative Escherichia coli. ∗P<.002.
      From Antimicrob Agents Chemother,
      • Brown E.L.
      • Xue Q.
      • Jiang Z.D.
      • Xu Y.
      • DuPont H.L.
      Pretreatment of epithelial cells with rifaximin alters bacterial attachment and internalization profiles.
      with permission.
      As in patients with cirrhosis and IBS, patients with Crohn disease present with gut microbiota dysbiosis and chronic mucosal inflammation, and they exhibit dysfunction of innate immunity, including immune-mediated bacterial killing.
      • Sartor R.B.
      Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis.
      • Scribano M.L.
      • Prantera C.
      Use of antibiotics in the treatment of Crohn’s disease.
      Allelic variants in genes for numerous inflammatory mediators and mediators of the innate immune response have been linked to Crohn disease and associated immune dysfunction.
      • Sartor R.B.
      Genetics and environmental interactions shape the intestinal microbiome to promote inflammatory bowel disease versus mucosal homeostasis.
      • Scribano M.L.
      • Prantera C.
      Use of antibiotics in the treatment of Crohn’s disease.
      A double-blind, placebo-controlled clinical trial found that among patients with Crohn disease, those who had high levels of C-reactive protein (an immune mediator produced primarily in the liver and considered a marker of inflammation) were more likely to achieve disease remission after treatment with rifaximin 1600 mg/d than with placebo over 12 weeks (odds ratio, 6.0; 95% CI, 1.2-31.2; P=.03).
      • D’Incà R.
      • Caccaro R.
      Measuring disease activity in Crohn’s disease: what is currently available to the clinician.
      • Prantera C.
      • Lochs H.
      • Campieri M.
      • et al.
      Antibiotic treatment of Crohn’s disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin.
      These findings suggest that the mechanism of action of rifaximin in the treatment of Crohn disease is not restricted to direct antimicrobial effects in the small intestine but may involve modulation of innate immunity and the inflammatory response in the gastrointestinal tract. Overall, data continue to accumulate, supporting that rifaximin has a multifaceted mechanism of action with efficacy in various gastrointestinal disorders (Figure 4).
      Figure thumbnail gr4
      Figure 4Proposed mechanisms of action of rifaximin as a gut microenvironment modulator with cytoprotection properties and effects on various gastrointestinal conditions. HE = hepatic encephalopathy; IBS-D = diarrhea-predominant irritable bowel syndrome; TD = travelers’ diarrhea.

      Conclusion

      Mechanistic data continue to emerge to help explain the efficacy of rifaximin in various gastrointestinal disorders, including travelers’ diarrhea, hepatic encephalopathy and other complications of cirrhosis, IBS-D, and Crohn disease. First, rifaximin clearly has direct antimicrobial effects that are exerted primarily within the small intestine. Second, rifaximin may reduce bacterial virulence and pathogenicity by inhibiting bacterial translocation across the gut mucosal epithelia, which may then reduce the release and/or absorption of endotoxin and bacterial metabolites, stabilize the gut mucosa, and render the mucosa resistant to bacterial inflammation. Third, rifaximin may modulate gut-immune signaling, perhaps via alterations in gene transcription that reduce or reverse levels of proinflammatory immune mediators and the chronic proinflammatory response associated with many gastrointestinal diseases. For a given disease state, rifaximin may act through 1 or more of these mechanisms of action to exert its therapeutic effects, and therefore rifaximin may be best described as a gut microenvironment modulator with cytoprotection properties. However, further research is needed to determine whether these various proposed mechanisms of action play a direct role in observed clinical outcomes.

      Acknowledgments

      Technical editorial and medical writing support was provided, under direction of the author, by Mary Beth Moncrief, PhD, and Karamarie Fecho, PhD, Synchrony Medical Communications, LLC, West Chester, PA, with support from Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA. Salix did not actively contribute to the article content or interpretation, and reviewed for scientific accuracy only, and had no role in the decision to submit the article for publication.

      Supplemental Online Material

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