Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

Expert Opinion on Drug Safety

Volumn 15, Issue 7, 2016, Pages 983-991

  Ponziani, Francesca Romana ^a   Pecere, Silvia ^a   Lopetuso, Loris ^a   Scaldaferri, Franco ^a   Cammarota, Giovanni ^a   Gasbarrini, Antonio ^a  

^a FONDAZIONE POLICLINICO UNIVERSITARIO A GEMELLI IRCCS   (Italy)

Author keywords

gut barrier; gut microbiota; IBS; rifaximin; safety

Indexed keywords

RIFAXIMIN; ANTIINFECTIVE AGENT; GASTROINTESTINAL AGENT; RIFAMYCIN;

ABDOMINAL DISCOMFORT; ABDOMINAL DISTENSION; ANTIBIOTIC RESISTANCE; ARTICLE; ASCITES; CELLULITIS; CONSTIPATION; DIARRHEA; DIZZINESS; DRUG METABOLISM; DRUG PENETRATION; DRUG SAFETY; DYSPEPSIA; FEVER; FLATULENCE; HEADACHE; HUMAN; INTESTINE FLORA; IRRITABLE COLON; KIDNEY INFECTION; NAUSEA; PERITONITIS; PNEUMONIA; RETREATMENT; RHINOPHARYNGITIS; SEPSIS; SEPTIC SHOCK; SINUSITIS; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; IRRITABLE BOWEL SYNDROME; MICROBIOLOGY; PATHOLOGY; TREATMENT OUTCOME;

ANTI-INFECTIVE AGENTS; DRUG RESISTANCE, MICROBIAL; GASTROINTESTINAL AGENTS; GASTROINTESTINAL MICROBIOME; HUMANS; IRRITABLE BOWEL SYNDROME; RIFAMYCINS; TREATMENT OUTCOME;

EID: 84969895321     PISSN: 14740338     EISSN: 1744764X     Source Type: Journal    
DOI: 10.1080/14740338.2016.1186639     Document Type: Article

References (83)

1. G.F.Longstreth, W.G.Thompson, W.D.Chey, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491.
2. A.C.Ford, P.Moayyedi, B.E.Lacy, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109:S2–S26.
3. H.L.Dupont Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Ther. 2014;39:1033–1042.
4. F.Sommer, F.Bäckhed. The gut microbiota–masters of host development and physiology. Nat Rev Microbiol. 2013;11:227–238.
5. M.Pimentel. Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther. 2016;43:37–49.
6. M.Pimentel, E.J.Chow, H.C.Lin. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503–3506.•• This interesting review highlights the potential mechanisms of action of rifaximin in the management of irritable bowel syndrome, suggesting that rifaximin may lead to a decrease in bacterial fermentation and to a reduction in clinical symptoms through its direct and indirect bactericidal effects.
7. M.Majewski, R.W.McCallum. Results of small intestinal bacterial overgrowth testing in irritable bowel syndrome patients: clinical profiles and effects of antibiotic trial. Adv Med Sci. 2007;52:139–142.
8. E.Pyleris, E.J.Giamarellos-Bourboulis, A.Pistiki, et al. Intestinal overgrowth in irritable bowel syndrome. Presented at: United European Gastroenterology Week; 2012 Oct 20–24; Amsterdam, the Netherlands.
9. M.Pimentel, E.J.Chow, H.C.Lin. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412–419.
10. M.Pimentel, V.Funari, E.J.Giamarellos-Bourboulis, et al. The first large scale deep sequencing of the duodenal microbiome in irritable bowel syndrome reveals striking differences compared to healthy controls. Gastroenterology. 2013;144:S–59.
11. J.-M.Si, Y.-C.Yu, Y.J.Fan, et al. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol. 2004;10:1802–1805.
12. J.Mättö, L.Maunuksela, K.Kajander, et al. Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome-a longitudinal study in IBS and control subjects. FEMS Immunol Med Microbiol. 2005;43:213–222.
13. H.K.Bradley, G.M.Wyatt, C.E.Bayliss, et al. Instability in the faecal flora of a patient suffering from food-related irritable bowel syndrome. J Med Microbiol. 1987;23:29–32.
14. E.Malinen, T.Rinttilä, K.Kajander, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005;100:373–382.
15. J.Maukonen, J.Mättö, R.Satokari, et al. PCR DGGE and RT-PCR DGGE show diversity and short-term temporal stability in the Clostridium coccoides-Eubacterium rectale group in the human intestinal microbiota. FEMS Microbiol Ecol. 2006;58:517–528.
16. A.Swidsinski, J.Weber, V.Loening-Baucke, et al. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol. 2005;43:3380–3389.
17. A.Kassinen, L.Krogius-Kurikka, H.Mäkivuokko, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133:24–33.
18. E.Pyleris, E.J.Giamarellos-Bourboulis, D.Tzivras, et al. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci. 2012;57:1321–1329.
19. E.J.Giamarellos-Bourboulis, J.Tang, E.Pyleris, et al. Molecular assessment of differences in the duodenal microbiome in subjects with irritable bowel syndrome. Scand J Gastroenterol. 2015;50:1076–1087.
20. H.A.Halvorson, C.D.Schlett, M.S.Riddle. Postinfectious irritable bowel syndrome–a meta-analysis. Am J Gastroenterol. 2006;101:1894–1899.
21. M.Thabane, D.T.Kottachchi, J.K.Marshall. Systematic review and meta-analysis: the incidence and prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:535–544.
22. J.Jalanka, A.Salonen, S.Fuentes, et al. Microbial signatures in post-infectious irritable bowel syndrome toward patient stratification for improved diagnostics and treatment. Gut Microbes. 2015;6:364–369.
23. A.P.Kerckhoffs, M.Samsom, M.E.van der Rest, et al. Lower Bifidobacteria counts in both duodenal mucosa- associated and fecal microbiota in irritable bowel syndrome patients. World J Gastroenterol. 2009;15:2887–2892.
24. Z.-D.Jiang, S.Ke, H.L.Dupont. Rifaximin-induced alteration of virulence of diarrhoea-producing Escherichia coli and Shigella sonnei. Int J Antimicrob Agents. 2010;35:278–281.
25. E.L.Brown, Q.Xue, Z.-D.Jiang, et al. Pretreatment of epithelial cells with rifaximin alters bacterial attachment and internalization profiles. Antimicrob Agents Chemother. 2010;54:388–396.
26. S.A.Hirota. Understanding the molecular mechanisms of rifaximin in the treatment of gastrointestinal disorders - a focus on the modulation of host tissue function. Mini Rev Med Chem. 2015;16:206–217.
27. J.Cheng, Y.M.Shah, X.Ma, et al. Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of human pregnane X receptor activation. J Pharmacol Exp Ther. 2010;335:32–41.
28. S.Fiorucci, E.Distrutti, A.Mencarelli, et al. Inhibition of intestinal bacterial translocation with rifaximin modulates lamina propria monocytic cells reactivityand protects against inflammation in a rodent model of colitis. Digestion. 2002;66:246–256.
29. P.Brigidi, E.Swennen, F.Rizzello, et al. Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis. J Chemother. 2002;14:290–295.
30. S.Maccaferri, B.Vitali, A.Klinder, et al. Rifaximin modulates the colonic microbiota of patients with Crohn’s disease: an in vitro approach using a continuous culture colonic model system. J Antimicrob Chemother. 2010;65:2556–2565.
31. R.N.Fedorak. Understanding why probiotic therapies can be effective in treating IBD. J Clin Gastroenterol. 2008;42:S111–S115.
32. M.Ventura, S.O’Flaherty, M.J.Claesson, et al. Genome-scale analyses of health-promoting bacteria: probiogenomics. Nat Rev Microbiol. 2009;7:61–71.
33. H.Sokol, B.Pigneur, L.Watterlot, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105:16731–16736.
34. D.Xu, J.Gao, M.Gillilland3rd, et al. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology. 2014;146:484–496.
35. M.Zareie, K.Johnson-Henry, J.Jury, et al. Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut. 2006;55:1553–1560.
36. N.Borruel, M.Carol, F.Casellas, et al. Increased mucosal tumour necrosis factor alpha production in Crohn’s disease can be downregulated ex vivo by probiotic bacteria. Gut. 2002;51:659–664.
37. M.Llopis, M.Antolin, M.Carol, et al. Lactobacillus casei downregulates commensals’ inflammatory signals in Crohn’s disease mucosa. Inflamm Bowel Dis. 2009;15:275–283.
38. C.M.Thomas, T.Hong, J.P.van Pijkeren, et al. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 2012;7:e31951.
39. A.Ait-Belgnaoui, W.Han, F.Lamine, et al. Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction. Gut. 2006;55:1090–1094.
40. S.Soldi, S.Vasileiadis, F.Uggeri, et al. Modulation of the gut microbiota composition by rifaximin in non-constipated irritable bowel syndrome patients: a molecular approach. Clin Exp Gastroenterol. 2015;8:309–325.
41. F.R.Ponziani, F.Scaldaferri, V.Petito, et al. The role of antibiotics in gut microbiota modulation: the eubiotic effects of rifaximin. Dig Dis. 2016;34:269–278.
42. M.Pimentel, S.Park, J.Mirocha, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557–563.•• In this important double-blind, randomized, placebo-controlled study, participants were randomly assigned to receive 400 mg of rifaximin three times daily for 10 days or placebo. The trial demonstrated that rifaximin was associated with a statistically superior improvement in IBS symptoms than placebo, and that this was maintained through 10 weeks of follow-up.
43. A.I.Sharara, E.Aoun, H.Abdul-Baki, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol. 2006;101:326–333.
44. L.Cuoco, M.Salvagnini. Small intestine bacterial overgrowth in irritable bowel syndrome: a retrospective study with rifaximin. Minerva Gastroenterol Dietol. 2006;52:89–95.
45. E.Scarpellini, M.Gabrielli, C.E.Lauritano, et al. High dosage rifaximin for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2007;25:781–786.
46. J.Yang, H.-R.Lee, K.Low, et al. Rifaximin versus other antibiotics in the primary treatment and retreatment of bacterial overgrowth in IBS. Dig Dis Sci. 2008;53:169–174.
47. A.Lembo, S.F.Zakko, N.L.Ferreira, et al. Rifaximin for the treatment of diarrhea associated irritable bowel syndrome: short term treatment leading to long term sustained response. Gastroenterology. 2008;134:A–545.
48. S.Peralta, C.Cottone, T.Doveri, et al. Small intestine bacterial overgrowth and irritable bowel syndrome-related symptoms: experience with rifaximin. World J Gastroenterol. 2009;15:2628–2631.
49. M.Pimentel, A.Lembo, W.D.Chey, et al.; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22–32.•• This important paper is the backbone of the current knowledge on the clinical effects of rifaximin in IBS without constipation, showing that 2-week rifaximin treatment provides significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools.
50. M.Di Stefano, P.Tana, C.Mengoli, et al. Colonic hypersensitivity is a major determinant of the efficacy of bloating treatment in constipation-predominant irritable bowel syndrome. Intern Emerg Med. 2011;6:403–411.
51. P.Meyrat, E.Safroneeva, A.M.Schoepfer. Rifaximin treatment for the irritable bowel syndrome with a positive lactulose hydrogen breath test improves symptoms for at least 3 months. Aliment Pharmacol Ther. 2012;36:1084–1093.
52. M.Pimentel, C.Chang, K.S.Chua, et al. Antibiotic treatment of constipation-predominant irritable bowel syndrome. Dig Dis Sci. 2014;59:1278–1285.
53. S.B.Menees, M.Maneerattannaporn, H.M.Kim, et al. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012;107:28–35.•• In this systematic review and meta-analysis, the effect of rifaximin on global symptoms relief in IBS patients is confirmed, and it also highlights a similar incidence of adverse events between patients receiving rifaximin or placebo across all studies. Furthermore, serious AEs in rifaximin group were rare (<1%) and similar to placebo group.
54. M.-S.Kim, W.Morales, A.A.Hani, et al. The effect of rifaximin on gut flora and Staphylococcus resistance. Dig Dis Sci. 2013;58:1676–1682.
55. A.Pistiki, I.Galani, E.Pyleris, et al. In vitro activity of rifaximin against isolates from patients with small intestinal bacterial overgrowth. Int J Antimicrob Agents. 2014;43:236–241.
56. C.Darkoh, L.M.Lichtenberger, N.Ajami, et al. Bile acids improve the antimicrobial effect of rifaximin. Antimicrob Agents Chemother. 2010;54:3618–3624.
57. I.Posserud, P.-O.Stotzer, E.S.Björnsson, et al. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007;56:802–808.• This study included 62 patients with IBS who underwent small-bowel manometry and culture of jejunal aspirate, demonstrating that a mild increase in small-bowel bacteria counts was more common in IBS patients, representing the basis for following investigations.
58. F.C.Lessa, C.V.Gould, L.C.McDonald. Current status of Clostridium difficile infection epidemiology. Clin Infect Dis. 2012;55:S65–S70.
59. J.S.Bajaj, A.C.Barrett, E.Bortey, et al. Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis. Aliment Pharmacol Ther. 2015;41:39–45.
60. N.Kimer, A.Krag, L.L.Gluud. Safety, efficacy, and patient acceptability of rifaximin for hepatic encephalopathy. Patient Prefer Adherence. 2014 18;8:331–338.
61. K.D.Clin Mullen, A.J.Sanyal, N.M.Bass, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Gastroenterol Hepatol. 2014;12:1390–1397.
62. J.H.Tabibian, A.Gossard, M.El-Youssef, et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am J Ther. 2014 Jun 9. doi:10.1097/MJT.0000000000000102.
63. C.Prantera, H.Lochs, M.Grimaldi, et al.; Retic Study Group (Rifaximin-Eir Treatment in Crohn’s Disease). Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012;142:473–481.
64. J.Flores, H.L.Dupont, Z.-D.Jiang, et al. A randomized, double-blind, pilot study of rifaximin 550 mg versus placebo in the prevention of travelers’ diarrhea in Mexico during the dry season. J Travel Med. 2011;18:333–336.
65. A.M.K.Sanyal, N.M.Bass, T.Frederick, et al. Rates of commonly occurring infections in cirrhosis patients remain stable during long-term rifaximin treatment. J Hepatol. 2012;56:S255–S256.
66. J.G.O’Leary, K.R.Reddy, F.Wong, et al. Long-term antibiotic and proton-pump inhibitor use are strong predictors of recurrent infections in cirrhosis: a prospective multi-center study from NACSELD. J Hepatol. 2013;58:S97.
67. P.Tandon, A.Delisle, J.E.Topal, et al. High prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a US liver center. Clin Gastroenterol Hepatol. 2012;10:1291–1298.
68. N.M.Bass, K.D.Mullen, A.Sanyal, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–1081.
69. E.Mattila, P.Arkkila, P.S.Mattila, et al. Rifaximin in the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2013;37:122–128.
70. Irritable Bowel Syndrome With Diarrhea (IBS-D) Rifaximin Re-Treatment Study (TARGET3). Available from: https://clinicaltrials.gov/ct2/show/results/NCT01543178?sect=X4370156#othr
71. P.Schoenfeld, M.Pimentel, L.Chang, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39:1161–1168.
72. Z.D.Jiang, S.Ke, E.Palazzini, et al. In vitro activity and fecal con-centration of rifaximin after oral administration. Antimicrob Agents Chemother. 2000;44:2205–2206.
73. C.Scarpignato, I.Pelosini. Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy. 2005;51:36–66.
74. C.De Leo, C.Eftimiadi, G.C.Schito. Rapid disappearance from the intestinal tract of bacteria resistant to rifaximin. Drugs Exp Clin Res. 1986;12:979–981.
75. H.L.DuPont, Z.-D.Jiang. Influence of rifaximin treatment on the susceptibility of intestinal Gram-negative flora and enterococci. Clin Microbiol Infect. 2004;10:1009–1011.
76. V.Kothary, E.J.Scherl, B.Bosworth, et al. Rifaximin resistance in Escherichia coli associated with inflammatory bowel disease correlates with prior rifaximin use, mutations in rpoB, and activity of Phe-Arg-β-naphthylamide-inhibitable efflux pumps. Antimicrob Agents Chemother. 2013;57:811–817.
77. T.Valentin, E.Leitner, A.Rohn, et al. Rifaximin intake leads to emergence of rifampin-resistant staphylococci. J Infect. 2011;62:34–38.
78. J.Jolley. High-dose rifaximin treatment alleviates global symptoms of irritable bowel syndrome. Clin Exp Gastroenterol. 2011;4:43–48.
79. S.M.Finegold, D.Molitoris, M.-L.Vaisanen. Study of the in vitro activities of rifaximin and comparator agents against 536 anaerobic intestinal bacteria from the perspective of potential utility in pathology involving bowel flora. Antimicrob Agents Chemother. 2009;53:281–286.
80. C.B.Trapnell, M.Connolly, H.Pentikis, et al. Absence of effect of oral rifaximin on the pharmacokinetics of ethinyl estradiol/norgestimate in healthy females. Ann Pharmacother. 2007;41:222–228.
81. H.S.Pentikis, M.Connolly, C.B.Trapnell, et al. The effect of multiple-dose, oral rifaximin on the pharmacokinetics of intravenous and oral midazolam in healthy volunteers. Pharmacotherapy. 2007;27:1361–1369.
82. E.Scarpellini, V.Giorgio, M.Gabrielli, et al. Rifaximin treatment for small intestinal bacterial overgrowth in children with irritable bowel syndrome. Eur Rev Med Pharmacol Sci. 2013;17:1314–1320.
83. C.Blandizzi, G.C.Viscomi, A.Marzo, et al. Is generic rifaximin still a poorly absorbed antibiotic? A comparison of branded and generic formulations in healthy volunteers. Pharmacol Res. 2014;85:39–44.