Rifaximin in the treatment of inflammatory bowel disease

The gut microbiota plays a role in promoting and maintaining inflammation in inflammatory bowel diseases (IBD),hence the rationale for the use of antibiotics in the treatment of those disorders.Antibiotics,however, may induce untoward effects,especially during long- term therapy.Rifaximin polymer is an antibacterial agent that is virtually unabsorbed after oral adminis- tration and is devoid of systemic side effects.Rifaximin has provided promising results in inducing remission of Crohn's disease(up to 69%i...     

Role of antibiotics in the management of inflammatory bowel disease: a review

The current model of pathogenesis for inflammatory bowel disease (IBD) is a dysregulated immune system that is triggered by an environmental factor in a genetically susceptible individual. Although much about this model remains unproven, it is believed that bacteria are often the environmental factor driving the inflammatory response. This is supported by indirect evidence that antibiotics are of benefit in the treatment of Crohn's disease (CD) and pouchitis, and observations that enteric infections may result in activation of ulcerative colitis disease activity. In CD, limited studies have demonstrated that metronidazole, ciprofloxacin, and rifaximin improve clinical disease activity, and this is more pronounced in the treatment of colonic disease and for perianal fistulas (with metronidazole and ciprofloxacin). In addition, limited evidence supports the use of metronidazole in the prevention of recurrence after resection in CD. Antibiotics have not shown substantial benefit in the treatment of ulcerative colitis, but a variety of antimicrobial agents have a definite role in the treatment of acute and recurrent or chronic pouchitis. The absence of specifically identified organisms that are primarily responsible for the observed clinical picture remains the challenge to confirming the relationship between bacteria and IBD. A proposal for future therapies is provided that might include a combination therapy aimed at both a reduction in pathogenetic bacteria and immune modulation to achieve the most durable remission of disease.     

Antibiotics for inflammatory bowel disease: do they work?

A growing amount of evidence indicates that the intestinal flora plays a pathogenic role in inflammatory bowel disease (IBD): hence, the use of anti-bacterial agents as ancillary treatment in patients with ulcerative colitis, or Crohn's disease. While the results with anti-tubercular agents remain inconclusive, antibiotic treatment in IBD is usually carried out with either metronidazole or ciprofloxacin, or both. Controlled trials are scarce and, although both antibiotics appear to provide clinical benefit, definitive conclusions cannot be drawn and precise therapeutic guidelines cannot be suggested. The best results are achieved in the long-term treatment of Crohn's disease and in the management of pouchitis, or of perianal Crohn's disease. Long-term tolerability of antibiotic treatment may be poor due to the appearance of systemic side-effects. The use of non-absorbable anti-bacterial agents such as rifaximin deserves further investigation.     

Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn’s disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn’s disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.     

The role of antibiotics in inflammatory bowel disease

Opinion statement Broad-spectrum antibiotics are the mainstay of therapy for patients with Crohn’s disease (CD) who present with localized peritonitis due to a microperforation bacterial overgrowth secondary to chronic strictures. They are essential adjuncts to drainage therapy for CD-associated abscesses and for complicated perineal disease. The lack of well-designed, placebo-controlled trials has led to much skepticism about the efficacy of antibiotics as primary therapy for CD. However, a careful review of the experience with antibiotics, including clinical observations and controlled trials, leads to the conclusion that antibiotics have a role as primary therapy in active uncomplicated CD. The efficacy of their response must be considered in well-defined subsets of patients. Ciprofloxacin and metronidazole, the two most widely studied antibiotics, are effective therapy for patients with active ileocolonic and colonic disease and have been shown to reduce recurrence rates after ileocolonic resection. The benefits of these drugs are less clear for patients with uncomplicated ileal disease. Additionally, ciprofloxacin and metronidazole may also serve as an adjunct to immunomodulator therapy. The role of antimycobacterial therapy in treatment of CD is an attractive alternative, and hopefully this therapy will be further clarified when results of ongoing trials become available. In toxic patients with fulminant ulcerative colitis (UC), with or without megacolon, broad-spectrum antibiotics should be a part of the treatment program. In less severely ill patients requiring hospitalization, antibiotics may be given to cover for the potential of a superimposed infection until the workup for infection, including Clostridium difficile is completed. There may be a subset of patients with severe nontoxic colitis with persistent fever and bandemia after steroid therapy who respond to antibiotics, but to date controlled trials have not shown efficacy in this group. Antibiotics should not be routinely used for mild to moderately ill patients with UC, although a trial of ciprofloxacin is not unreasonable prior to colectomy for otherwise refractory patients. The use of rifaximin in UC requires further evaluation in larger studies.     

Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis

The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn's disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73-0.99, P=0.03). There was moderate heterogeneity between results (I(2)=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66-0.98) with no heterogeneity (I(2)=0%) and an number needed to treat 5 (95% CI=3-20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46-0.84), with no heterogeneity (I(2)=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43-0.96). There was moderate heterogeneity (I(2)=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.     

Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Antibiotics are usually prescribed to cure infections but they also have significant modulatory effects on the gut microbiota. Several alterations of the intestinal bacterial community have been reported during antibiotic treatment, including the reduction of beneficial bacteria as well as of microbial alpha-diversity. Although after the discontinuation of antibiotic therapies it has been observed a trend towards the restoration of the original condition, the new steady state is different from the previous one, as if antibiotics induced some kind of irreversible perturbation of the gut microbial community. The poorly absorbed antibiotic rifaximin seem to be different from the other antibiotics, because it exerts non-traditional effects additional to the bactericidal/bacteriostatic activity on the gut microbiota. Rifaximin is able to reduce bacterial virulence and translocation, has anti-inflammatory properties and has been demonstrated to positively modulate the gut microbial composition. Animal models, culture studies and metagenomic analyses have demonstrated an increase in Bifidobacterium, Faecalibacterium prausnitzii and Lactobacillus abundance after rifaximin treatment, probably consequent to the induction of bacterial resistance, with no major change in the overall gut microbiota composition. Antibiotics are therefore modulators of the symbiotic relationship between the host and the gut microbiota. Specific antibiotics, such as rifaximin, can also induce eubiotic changes in the intestinal ecosystem; this additional property may represent a therapeutic advantage in specific clinical settings.     

Antibiotics and probiotics in treatment of inflammatory bowel disease

Many experimental and clinical observations suggest that intestinal microflora plays a potential role in the pathogenesis of inflammatory bowel disease (IBD). Manipulation of the luminal content using antibiotics or probiotics represents a potentially effective therapeutic option. The available studies do not support the use of antibiotics in ulcerative colitis (UC). Antibiotics are effective in treating septic complications of Crohn's disease (CD) but their use as a primary therapy is more controversial, although this approach is frequently and successfully adopted in clinical practice. There is evidence that probiotic therapy may be effective in the prevention and treatment of mild to moderate UC. In contrast, a lack of successful study data at present precludes the widespread use of probiotics in the treatment of CD. Both antibiotics and probiotics appear to play a beneficial role in the treatment and prevention of pouchitis and further trials are warranted to fully quantify their clinical efficacy.     

Gut microbiota and inflammatory bowel disease

Bacteria play an important role in the pathogenesis of inflammatory bowel disease (IBD), its complications and its symptoms. Antibiotics can decrease tissue invasion and eliminate aggressive bacterial species. They are used in IBD to treat infective complications and for altering bacterial flora, which may result in specific anti-inflammatory effects. In addition, suppression of bacterial metabolic activities or direct effects of antibiotics on intestinal structures and functions may result in symptoms which cannot be differentiated from symptoms caused by inflammation. Although current clinical trials do not fulfill criteria of evidence-based treatment, a few placebo- or standard treatment-controlled studies suggest that metronidazole and ciprofloxacin are effective in Crohn's colitis and ileocolitis, perianal fistulae and pouchitis. Administration of probiotics, prebiotics and synbiotics can restore a predominance of beneficial species. However, beneficial effects of probiotics in IBD are modest, strain-specific and limited to certain manifestations of disease and duration of use of the probiotic. For probiotics there is reasonable evidence of efficacy in relapse prevention in chronic pouchitis and ulcerative colitis, and suggestive evidence for postoperative prevention in pouchitis. Therapeutic manipulation of the intestinal flora offers considerable promise for treating IBD, but must be supported by large controlled therapeutic trials before widespread clinical acceptance. These agents may become a component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents. Probiotic strategies, based on metagenomic or metabonomic analyses, and new classes of probiotics might play an important role in the future management of IBD.     

Treatment of inflammatory bowel disease with antibiotics

Although antibiotics are clearly recognized as having a role in treating the infectious complications of inflammatory bowel diseases (IBD), their impact in the primary treatment of IBD has long been an area of speculation. Over the past decade there is increasing evidence that luminal gut bacteria play a role in the pathogenesis of IBD, particularly Crohn's disease. Compelling evidence that normal commensal bacteria induce chronic intestinal inflammation in susceptible rodents provides an excellent rationale for treatment of human IBD with antibiotics. This article summarizes published studies of antibiotics in IBD patients and reviews available data for the use of antibiotic therapy in Crohn's disease and ulcerative colitis.     

The therapeutic potential of antibiotics and probiotics in the treatment of pouchitis

Pouchitis is the most frequent long-term complication of pouch surgery for ulcerative colitis. There is consistent evidence on the implication of bacterial flora in the pathogenesis of pouchitis, and there is evidence for a therapeutic role of antibiotics and probiotics in therapy of this disease. Antibiotics, particularly ciprofloxacin and metronidazole, are the mainstay of treatment for acute pouchitis. In chronic refractory pouchitis, after having excluded other diagnoses (infections, Crohn’s disease of the pouch, ischemia and irritable pouch), antibiotic combination therapy is the treatment of choice. The highly concentrated probiotic mixture VSL#3 has been shown to be effective in prevention of pouchitis onset and in maintaining antibiotic-induced remission.     

Restoring the gut microbiome for the treatment of inflammatory bowel diseases

Fecal microbiota transplantation(FMT)is considered to be a highly successful therapy for recurrent and refractory Clostridium difficile infection(CDI)based on recent clinical trials.The pathogenesis of inflammatory bowel diseases(IBD)is thought to be due in part to perturbations in the gut microflora that disrupt homeostasis.FMT restores essential components of the microflora which could reverse the inflammatory processes observed in IBD.Case reports and series for the treatment of IBD by FMT have shown promise with regards to treatment success and safety despite the limitations of the reporting.Future studies will determine the optimal delivery and preparation of stool as well as the conditions under which the recipient will derive maximal benefit.The long term consequences of FMT with regards to infection,cancer,auto-immune,and metabolic diseases are not known and will require continued regulation and study.Despite these limitations,FMT may be beneficial for the treatment of ulcerative colitis and Crohn’s disease,particularly those with concurrent CDI or with pouchitis.     

Inflammatory bowel disease in the Hubei Province of China

AIM: To analyze clinical features and response to treatment in inflammatory bowel disease (IBD) patients from the Hubei Province of China.METHODS: Clinical data was collected retrospectively from 74 patients with IBD [66 with ulcerative colitis (UC) and 8 with Crohn’s disease (CD)] admitted to The Second Hospital, Hubei Medical University from 1986 to 1995.RESULTS: The most common symptoms in IBD patients were abdominal pain, diarrhea, blood and mucus in stool, and constipation. Extraintestinal manifestations of IBD were not common. In these patients, inflammation was predominantly located in the sigmoid and left colon in UC cases, and in the ileum and colon in CD cases. Treatment with sulphasalazine and corticosteroids was effective in 95% of UC cases; However, about 42% of UC patients showed disease recurrence during the follow-up period of 1.11 years. Five out of eight CD patients had part of their intestine removed, whereas three were treated with anti-tuberculosis drugs or the antibiotic metronidazole. Out of four patients we followed up for 1-8 years, one died of severe complications after surgery, two experienced recurrence while in treatment with drugs, and one remained in remission under sulphasalazine treatment after surgery.CONCLUSION: Five percent of the patients reported a family history of IBD. About 34% of the patients were smokers and 32% of the patients were alcoholic. Epidemiological studies are urgently needed in the Hubei Province of China to assess the role that genetics and environmental factors play in the pathogenesis of inflammatory bowel diseases.     

The role of antimicrobials in Crohn’s disease

This review summarizes literature regarding the role of antimicrobials for induction and maintenance of Crohn’s disease (CD) remission. PubMed was searched (1966 to October 2012) for controlled trials involving adults and written in English. Five of the 13 identified studies showed benefit with the use of ciprofloxacin, metronidazole and rifaximin for induction of remission. Eight studies showed no benefit using ciprofloxacin, metronidazole, combination of metronidazole and ciprofloxacin or clarithromycin and rifaximin. Four of the five studies showed benefit based on colonic location. Perianal CD with draining fistulas responded in one of two studies. Two studies in postileocolonic resection demonstrated benefit of metronidazole or ornidazole in reducing CD recurrence. Antimicrobials, especially metronidazole, are promising for inducing remission in patients with colonic CD and preventing recurrence in postileocolonic resection.     

Proteomic insights on the metabolism in inflammatory bowel disease

Inflammatory bowel diseases(IBD)are chronic and relapsing inflammatory conditions of the gut that include Crohn's disease and ulcerative colitis.The pathogenesis of IBD is not completely unraveled,IBD are multi-factorial diseases with reported alterations in the gut microbiota,activation of different immune cell types,changes in the vascular endothelium,and alterations in the tight junctions’structure of the colonic epithelial cells.Proteomics represents a useful tool to enhance our biological understanding and to discover biomarkers in blood and intestinal specimens.It is expected to provide reproducible and quantitative data that can support clinical assessments and help clinicians in the diagnosis and treatment of IBD.Sometimes a differential diagnosis of Crohn's disease and ulcerative colitis and the prediction of treatment response can be deducted by finding meaningful biomarkers.Although some non-invasive biomarkers have been described,none can be considered as the“gold standard”for IBD diagnosis,disease activity and therapy outcome.For these reason new studies have proposed an“IBD signature”,which consists in a panel of biomarkers used to assess IBD.The above described approach characterizes“omics”and in this review we will focus on proteomics.     

Expert opinion:Experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn’s disease as well. Not much was ever made of the role of sulfasalazine for Crohn’ s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn’s colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn’s disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn’s disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960’s and 1970’s and its trial for Crohn’s disease published in the New England Journal of Medicine in 1980?     

Antibiotics for the treatment of hepatic encephalopathy

The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.     

Management of inflammatory bowel disease in adults

Optimal care of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, requires a broad understanding of disease pathophysiology and therapeutic alternatives. The goals of therapy are accurate diagnosis and timely treatment to both induce and maintain a clinical remission and improve patient quality of life. Most patients can be adequately treated using a combination or aminosalicylates, antibiotics, and corticosteroids, though many patients with Crohn's disease will require immunomodulators, such as azathioprine or 6-mercaptopurine. The development of novel biologic therapies, particularly infliximab, have dramatically improved our ability to medically manage more severe Crohn's disease and ulcerative colitis patients. This review will focus on the medical management of inflammatory bowel disease in adults.     

Can control of gut microbiota be a future therapeutic option for inflammatory bowel disease?

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities, Crohn’s disease and ulcerative colitis. Accumulated evidence indicates that an aberrant immune activation caused by the interplay of genetic susceptibility and environmental impact on the gut microbiota may be involved in the pathogenesis of IBD. Rapid advances in next-generation sequencing technology have enabled a number of studies to identify the alteration of the gut microbiota, termed dysbiosis, in IBD. Moreover, the alteration in the metabolites derived from the gut microbiota in IBD has also been described in many studies. Therefore, microbiota-based interventions such as fecal microbiota transplantation (FMT) have attracted attention as a novel therapeutic option in IBD. However, in clinical trials, the efficacy of FMT for IBD remains controversial. Additional basic and clinical studies are required to validate whether FMT can assume a complementary role in the treatment of IBD. The present review provides a synopsis on dysbiosis in IBD and on the association between the gut microbiota and the pathogenesis of IBD. In addition, we summarize the use of probiotics in IBD and the results of current clinical trials of FMT for IBD.     

Therapeutic modulation of gut microbiota in inflammatory bowel disease: More questions to be answered

Patients with inflammatory bowel disease (IBD) exhibit impaired control of the microbiome in the gut, and ‘dysbiosis’ is commonly observed. Western diet is a risk factor for the development of IBD, but it may have different effects on gut microbiota between IBD and non‐IBD individuals. Exclusive enteral nutrition (EEN) can induce remission in pediatric Crohn's disease with a decrease in gut microbial diversity. Although there are some theoretical benefits, actual treatment effects of prebiotics and probiotics in IBD vary. High‐quality studies have shown that VSL#3 (a high‐potency probiotic medical food containing eight different strains) exhibits benefits in treating ulcerative colitis, and gut microbial diversity is reduced after treated with VSL#3 in animal models. The effect of fecal microbiome transplantation on IBD is controversial. Increasing microbial diversity compared with impaired handling of bacteria presents a dilemma. Antibiotics are the strongest factors in the reduction of microbiome ecological diversity. Some antibiotics may help to induce remission of the disease. Microbiome alteration has been suggested to be an intrinsic property of IBD and a potential predictor in diagnosis and prognosis. However, the effects of therapeutic modulations are variable; thus, more questions remain to be answered.