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Rifaximin versus Other Antibiotics in the Primary Treatmentand Retreatment of Bacterial Overgrowth in IBS Janet Yang Æ Hyo-Rang Lee Æ Kimberly Low ÆSoumya Chatterjee Æ Mark Pimentel Received: 13 November 2006 / Accepted: 5 April 2007 / Published online: 23 May 2007Ó Springer Science+Business Media, LLC 2007 Previous studies demonstrate improvement in antibiotics in the treatment and retreatment of IBS.
IBS after antibiotic therapy, with the greatest efficacy seenwith the antibiotic, rifaximin. The purpose of this study was to compare the efficacy of rifaximin in both the Small intestinal bacterial overgrowth Á Lactulose breath test treatment and retreatment of IBS.
Methods A retrospective chart review was conducted on Rome I-positive IBS patients. Charts were reviewed to evaluate all antibiotic treatments (rifaximin, neomycin,doxycycline, amoxicillin/clavulanate, and ciprofloxacin), Irritable bowel syndrome (IBS) is a common disorder even those predating 1 July 2004. Data collection included associated with bloating, altered bowel habits, and symptoms, breath test results (pre- and post-treatment), abdominal pain []. Although it has been reported to affect antibiotics used, and clinical response to individual anti- 15–20% of the general population [], its etiology biotic treatments before and after rifaximin availability in remains unknown. There have been several hypotheses characterizing IBS, including altered gut motility Out of 98 eligible charts, 84 patients received one peripheral and central [] sensory dysfunction, and an course of rifaximin. Fifty of these (60%) had a follow-up abnormal response to stress []. However, there has been breath test. Among these, 31 (62%) were clinical no single diagnostic test associated with IBS. Conse- responders and 19 (38%) were nonresponders. Of 31 quently, clinical criteria, such as the Rome criteria, have responders, 25 (81%) had a normal follow-up breath test been developed to aid in diagnosing and categorizing this compared with only 3 of the 19 nonresponders (16%) (P < 0.001). Of participants given rifaximin, 69% (58 out It has been noted that the symptoms of IBS are similar to of 84) had a clinical response compared with only 38% (9 those of small intestinal bacterial overgrowth (SIBO) [ out of 24) with neomycin (P < 0.01) and 44% (27 out of a condition caused by colonization of the small bowel with bacteria that normally reside in the colon. Accordingly, we Rifaximin was used as retreatment on 16 occasions, and all have demonstrated in two recent studies that abnormal lactulose breath tests (LBTs) are more prevalent in IBSsufferers compared with controls [We have alsoshown that antibiotic treatment in IBS sufferers leads tosymptomatic improvement []. Moreover, normali- J. Yang Á H.-R. Lee Á K. Low Á S. Chatterjee ÁM. Pimentel (&) zation of the LBT after antibiotic treatment correlates with GI Motility Program, GI Motility Laboratory, Cedars-Sinai the degree of clinical improvement [suggesting that Burns and Allen Research Institute, Cedars-Sinai Medical the LBT is useful in evaluating SIBO after treatment. More Center, 8730 Alden Drive, Suite 225E, Los Angeles, CA 90048, recent literature using glucose breath testing [] and small bowel culture ] confirm the concept that the small bowel of IBS patients contains more bacteria. All of these period of FDA approval of rifaximin for traveler’s diarrhea.
studies support the association between SIBO and IBS.
Only patients with a positive LBT in addition to at least The current standard of treatment for SIBO is empiric one follow-up visit were included. An abnormal breath test therapy with broad spectrum antibiotics , Tetracy- was one in which the hydrogen or methane values rose to clines are commonly used, though there have been few more than 20 ppm at or before 90 min of ingestion of 10 g controlled studies describing the most appropriate choice of lactulose. Furthermore, patients were included if they or duration of antibiotic therapy ]. Moreover, conven- had at least one treatment for their IBS based on breath test tional antibiotics often suffer from poor efficacy, with only and at least one follow-up documenting the outcome of that 30–40% of SIBO eradication reported with the use of treatment. In general, our approach for all patients was to norfloxacin and amoxicillin/clavulanic acid ]. High treat the IBS patient and positive breath test with antibiotic rates of SIBO recurrence are another problem. For exam- followed by nightly tegaserod to prevent recurrence.
ple, while Attar et al. was able to show in a clinical trial Patients with inflammatory bowel disease or other GI that both amoxicillin/clavulanic acid and norfloxacin were effective in treating SIBO, it was also noted that diarrheaquickly recurred after withdrawal of the antibiotic Data such as these have led to the use of rotating courses ofantibiotics. Multiple antibiotic retreatment courses are During data extractions, note was made of any previous concerning because they increase the likelihood of bacte- gastrointestinal surgery or any known GI disorder besides rial resistance and future treatment failure.
IBS. The number of visits to the center for follow-up was Rifaximin has recently become an antibiotic of interest also documented. Patient charts were reviewed to evaluate in the treatment of IBS and SIBO since it has a broad all prior antibiotic treatments, even those predating 1 July spectrum of coverage without the associated bacterial 2004. The breath test hydrogen and methane levels during resistance of other antibiotics [As a synthetic, the 180 min of conventional recording were documented.
nonabsorbable derivative of rifamycin, it has virtually no The overall clinical response in bowel function to each systemic absorption, minimizing adverse side effects while antibiotic was noted if available in review. Specifically, the maintaining good luminal antibacterial activity [In a review determined to find out if the patient was satisfied double-blind, randomized, controlled trial comparing the with their improvement. In most cases, the motility pro- effects of a 7-day course of rifaximin (1,200 mg/day) and gram recorded a percent overall improvement in symptoms chlortetracycline (1 g/day), Di Stefano et al. demonstrated in follow-up and, if documented, this too was recorded. In eradication of SIBO in 70% of patients treated with rif- aximin compared with 27% of patients treated with chlortetracycline, based on normalization of a glucosebreath test [Furthermore, two recent controlled trials have now demonstrated that rifaximin is superior to pla-cebo in IBS global improvement as well , Although The percent improvement in IBS overall was noted for rifaximin appears effective, studies on retreatment are 10 days of rifaximin 400 mg tid. This was compared with other previously used antibiotics. The number of partici- The objective of this study was to determine the efficacy pants with improvement of greater than 50% was used, as of rifaximin both in eradicating SIBO in IBS sufferers and well as the categorical notation of improvement or no in improving symptoms. We also aimed to compare the improvement. If data were available, the response to a efficacy of rifaximin to other antibiotics in initial and specific symptom was noted. These included bloating, diarrhea, constipation, and abdominal pain. The clinicalresponse to rifaximin was then compared between subjectswith and without normalization of their respective abnor- mality on LBT after antibiotic treatment. This included asubanalysis to evaluate the success of rifaximin in treating breath tests in which methane gas was present.
The clinical response to rifaximin was further compared A retrospective chart review was conducted on consecutive with responses of the same participant to prior antibiotic Rome I-positive IBS patients seen at the GI Motility Pro- use. Among participants in whom a single antibiotic had gram (Cedars-Sinai Medical Center) between 1 July 2004, been used on more than one occasion, the ability of the and 31 October 2005. This interval was chosen as the time subsequent use to improve symptoms or normalize the breath test was compared between rifaximin and other antibiotics. This was to evaluate antibiotic resistance andsuccess of retreatment.
In contrast to the 69% clinical response seen with rifaximintreatment, a response was seen in only 27 of the 61 patients (44%) who in the past had received any antibiotic besidesrifaximin (P < 0.01 when compared with rifaximin; When comparing the proportion of clinical responders Table Since neomycin has been studied in IBS ], we among rifaximin-treated IBS patients with those who had specifically looked at the effect of neomycin on clinical received other antibiotics, a Fisher’s exact test was used.
response. Prior to rifaximin, 24 participants had received Significance was set at P < 0.05.
neomycin, with only 9 (38%) realizing a clinicalimprovement. This was significantly lower than that seenwith rifaximin (P < 0.01). Of the 20 patients who did not respond to one or more previous trials of pre-rifaximinantibiotics, 75% (15 out of 20) still had clinical improve- After inclusion and exclusion criteria were applied, 98 Treatment of symptom recurrence with antibiotics participant charts were eligible and summarized. Of these,84 patients received at least one course of rifaximin. The For cases of recurrence, 24 participants received retreat- median duration of patient time in clinical treatment was ment with an antibiotic. Rifaximin was used as retreatment on 16 occasions, and all 16 had clinical improvement.
Rifaximin was used a third time in 4 cases, and again, all patients responded. In contrast, retreatment was only 25%effective (2 out of 8) when retreating with doxycycline, Of the 84 participants who received rifaximin, 1,200 mg augmentin, and neomycin (P < 0.0001 when compared per day, 58 (69%) had a clinical response to therapy. Of these 84 patients, 50 had a follow-up LBT. Among these,31 (62%) were clinical responders to rifaximin and 19(38%) were nonresponders (Table Normalization of theLBT was predictive of clinical response, since 25 of the 31 clinical responders to rifaximin (81%) normalized theirbreath test after treatment. This is in contrast to LBT In this retrospective chart review, we found that rifaximin normalization occurring in only 3 of the 19 participants was superior to conventional antibiotics in producing a (16%) who did not have a clinical response to rifaximin clinical response among IBS patients with an abnormal LBT. More importantly, IBS sufferers who responded to Among the 84 participants who received rifaximin, 7 antibiotic therapy and later had a relapse of symptoms had an abnormal breath test with methane production as requiring retreatment universally responded to rifaximin on well as a follow-up breath test. In these 7 methane pro- subsequent occasions. This was not the case for other ducers, 4 (57%) were clinical responders, and 3 of these 4 antibiotics as they were rarely successful in achieving methane-positive responders had a normal follow-up breath another clinical response, suggesting bacterial resistance test. None of the three treatment failures normalized their developed after a single course of a non-rifaximin antibi- breath tests (P = 0.11). In cases in which a follow-up otic. This is the first study to demonstrate the success of a breath test was not conducted in this study, 68% had a single agent in the treatment and retreatment of IBS symptoms in the context of an abnormal breath test.
The link between SIBO and IBS is supported by their similar clinical presentations. Bloating, for example, is an Table 1 Relationship between clinical response to rifaximin andfollow-up breath tests established feature of bacterial overgrowth, caused by thefermentation of nutrients by small bowel bacteria. IBS sufferers also experience bloating, with studies demon-strating excessive hydrogen and methane gas production in these individuals [Bacterial overgrowth may be the underlying etiology of this excessive gas. The LBT has been used to determine the presence of bacterial over- Table 2 Comparison of rifaximin and other antibiotics in IBS symptom response rates Initial treatment with other nonrifaximin antibiotics (61) growth, and we recently reported in two studies that Rifaximin is a nonabsorbed (<0.4% systemic absorp- abnormal LBTs are more prevalent in IBS sufferers [ tion) oral antibiotic. As a rifamycin derivative, it has compared with 20% in controls. We also showed that antibacterial activity through the inhibition of bacterial antibiotic treatment leads to symptomatic improvement in RNA synthesis [and is active against Gram-positive IBS sufferers, with an accordant normalization of the post- and Gram-negative bacteria, including both aerobes and treatment LBT. This suggests that the LBT can be used as anaerobes [In particular, it is effective against anaer- an indicator of bacterial overgrowth eradication in IBS obes such as bacteroides, lactobacilli, and clostridia, the sufferers [There are now a number of LBT studies bacteria frequently responsible for gut alterations in SIBO demonstrating an association between breath test findings patients []. As it is poorly water-soluble and mini- mally absorbed, it is also associated with less systemic More specific tests for bacterial overgrowth now cor- toxicity. Although currently approved for clinical use in the roborate the suggestion that a subset of IBS patients may treatment of traveler’s diarrhea due to E. coli ], it is have bacterial overgrowth. Glucose breath testing is be- already demonstrating utility in multiple intestinal, bacte- lieved to be a more specific tool in identifying bacterial rially-related disorders such as hepatic encephalopathy overgrowth. In two studies, glucose breath testing was ]. Importantly, rifaximin does not appear to lead to noted to be abnormal in almost 40% of IBS sufferers bacterial resistance and has a low incidence of side effects compared with only 5% of healthy individuals [ ]. The restricted use of nonabsorbed oral antibiotics More specifically, culture studies of the most proximal only for enteric infections should also reduce the devel- small bowel demonstrated >106 coliforms in aspirates of IBS sufferers 12% of the time , ]. Even more recently, A 1,200-mg daily dose of rifaximin for at least 10 days mean coliform counts were found to be elevated in IBS has been shown to be more clinically effective in the short- term treatment of SIBO compared with the more traditional Despite these data, the most important factor curtailing tetracycline antibiotics. Di Stefano et al. reported normal- the application of antibiotic therapy in IBS is the lack of ization of the glucose breath test in 70% of participants efficacy of conventional antibiotics. Since bacterial over- treated with rifaximin as opposed to only 27% treated with growth may occur from a wide range of aerobic and chlortetracycline ]. No side effects were seen, support- anaerobic flora, the most effective treatment includes drugs ing rifaximin as a safe antibiotic for bacterial overgrowth with broad spectrum antibacterial activity [However, treatment [Lauritano et al. subsequently studied dif- few controlled studies have evaluated the choice and ferent dosages of rifaximin and concluded that a 7-day duration of therapy in bacterial overgrowth. Antibiotics course of 1,200 mg/day was a good regimen to treat SIBO such as tetracyclines and fluoroquinolones have been both in terms of efficacy and tolerability [In a double shown to improve symptoms, but their widespread use has blind study by Sharara et al., rifaximin improved clinical been controversial because of high recurrence rates after symptoms in patients with functional bloating and in the antibiotic withdrawal ] as well as the increased risk of subset with IBS ]. In this study, breath test normaliza- bacterial resistance [We showed in a recent study that tion was not as apparent although clinical improvement neomycin was more effective than placebo in producing a was seen to correlate with an improvement in breath test clinical response ]. Among the participants treated with measurements. In a follow-up to this, a double blind trial of neomycin, LBT normalization correlated with a greater rifaximin in IBS has produced lasting clinical improvement clinical response; however, normalization was seen in only for 10 weeks beyond the initial 10 days of therapy [ 20% of the cases [These studies suggest that the cur- The current study substantiates the results of these ear- rent, conventional antibiotics are not adequate in eradi- lier studies by Di Stefano et al. [and Lauritano et al.
cating bacterial overgrowth. This, with the additional ], showing that rifaximin has superior efficacy in concern regarding systemic toxicity of traditional therapy, treating SIBO in IBS patients compared with other anti- has prompted the search for other antibiotics that specifi- biotics. The majority of IBS patients treated with rifaximin for the first time experienced greater clinical improvement (69%) than those treated with neomycin (38%) or other 3. Thompson WG, Heaton KW (1980) Functional bowel disorders in apparently healthy people. Gastroenterology 79:283–288 4. Kumar D, Wingate DL (1985) The irritable bowel syndrome: a responded to rifaximin, 81% had a normal follow-up LBT.
paroxysmal motor disorder. Lancet 2:973–977 In contrast, only 16% of the rifaximin nonresponders 5. Grundy D (2000) Mechanisms for the symptoms of irritable normalized their breath tests. The high rate of breath test bowel disease—possible role of vagal afferents. In: Krammer normalization in clinical responders was not seen in our H-J, Singer MV (eds) Neurogastroenterology from the basics tothe clinics. Kluwer, Boston, pp 659–663 previous study with neomycin ], suggesting that 6. Silverman DHS, Munakata JA, Ennes H et al (1997) Regional rifaximin is more effective in SIBO eradication. It also cerebral activity in normal and pathological perception of visceral confirmed that breath test normalization was predictive of 7. Whitehead WE, Crowell MD, Robinson JC et al (1992) Effects of stressful life events on bowel symptoms: subjects with irritable Although the above description of the current study bowel syndrome compared with subjects without bowel dys- supports previous data, the study goes further to suggest that rifaximin works better than other antibiotics at 8. Thompson WG, Longstreth GF, Drossman DA et al (1999) retreating cases of recurrence. Not only did patients treated Functional bowel disorders and functional abdominal pain. RomeII: a multinational consensus document on functional gastroin- with rifaximin for the first time respond, but 75% of those who became refractory to previous antibiotics improved on 9. Longstreth G, Thompson G, Chey W et al (2006) Functional a trial of rifaximin. Moreover, retreatment with rifaximin bowel disorders. Gastroenterology 130:1480–1491 for recurrence of symptoms after initial success with 10. Holt PR (1990) Diarrhea and malabsorption in the elderly.
rifaximin was almost universally successful as well. In 11. Pimentel M, Chow EJ, Lin HC (2000) Eradication of small contrast, retreatment was only 25% successful with intestinal bacterial overgrowth reduces symptoms of irritable neomycin, augmentin, or doxycycline. The reason for this bowel syndrome. Am J Gastroenterol 95:3503–3506 may be that rifaximin does not develop the bacterial 12. Pimentel M, Chow EJ, Lin HC (2003) Normalization of lactulose breath testing correlates with symptom improvement in irritable resistance typical of other antibiotics.
bowel syndrome: a double-blind, randomized, placebo-controlled One limitation of this study is that it was not a pro- spective study. Another potential criticism involves the 13. Lupascu A, Gabrielli M, Lauritano EC et al (2005) Hydrogen small percentage of patients returning for follow-up LBTs.
glucose breath test to detect bacterial overgrowth: a prevalencecase–control study in irritable bowel syndrome. Aliment Phar- This can be refuted by the fact that the majority of these patients did experience symptomatic improvement.
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This substantiates the results of our previous study suggesting again that the LBT can be used to assess 17. Soudah HC, Hasier WL, Owyang C (1991) Effect of octreotide treatment outcomes in IBS patients with SIBO. The on intestinal motility and bacterial overgrowth in scleroderma. N majority of patients who fail to respond to other antibiotics 18. Di Stefano M, Malservisi S, Veneto G et al (2000) Rifaximin versus still respond to rifaximin, both in initial and retreatment chlortetracycline in the short-term treatment of small intestinal regimens. Unlike conventional antibiotics, retreatment with bacterial overgrowth. Aliment Pharmacol Ther 14:551–556 rifaximin is universally efficacious, suggesting a lack of 19. Attar A, Flourie B, Rambaud JC et al (1999) Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea:a crossover, randomized trial. Gastroenterology 117:794–797 20. Scarpignato C, Pelosini I (2005) Rifaximin, a poorly absorbed This study was funded through an unrestricted antibiotic: pharmacology and clinical potential. Chemotherapy investigator grant with Salix Pharmaceuticals.
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