Treating Microbiota and/or the Barrier Dig Dis 2013;31:379–384 DOI: 10.1159/000354704
Antibiotics and Inflammatory Bowel Diseases Maria Lia Scribano Cosimo Prantera Gastroenterology Operative Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
Abstract Inflammatory bowel diseases are characterized by an altered composition of gut microbiota (dysbiosis) that may contribute to their development. Antibiotics can alter the bacterial flora, and a link between antibiotic use and onset of Crohn’s disease (CD), but not ulcerative colitis, has been reported. The hypothesis that Mycobacterium avium subspecies paratuberculosis (MAP) could be an etiologic agent of CD has not been confirmed by a large study on patients treated by an association of antibiotics active against MAP. The observations supporting a role of intestinal microbiota in CD pathogenesis provide the rationale for a therapeutic manipulation of the intestinal flora through the employment of antibiotics. However, current data do not strongly support a therapeutic benefit from antibiotics, and there is still controversy regarding their use as primary therapy for treatment of acute flares of CD, and for postoperative recurrence prevention. Nevertheless, clinical practice and some studies suggest that a subgroup of patients with colonic involvement, early disease, and abnormal laboratory test of inflammation may respond better to antibiotic treatment. Since their long-term use is frequently complicated by a high rate of side effects, the use of antibiotics that work locally appears to be promising. © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0379$38.00/0 E-Mail [email protected] www.karger.com/ddi
Antibiotics as an Eliciting Factor of Inflammatory Bowel Disease
The etiopathogenesis of inflammatory bowel disease (IBD) remains still unknown, but the emerging evidence suggests that changes in the composition of the intestinal microbiota (dysbiosis) may contribute to IBD development [1–3]. Antibiotics can alter the bacterial microflora, by interfering with resistance against opportunistic microorganisms [4]. Therefore, the use of antibiotics could be a potential risk factor for IBD. Some studies have evaluated the possible association between the assumption of antibiotics and the appearance of inflammatory lesions, reporting a link with the onset of Crohn’s disease (CD), but not ulcerative colitis [4–7]. The largest study, recently published, showed a strong association between CD and prior antibiotic use in 577,627 Danish children, thus suggesting that antibiotics can increase the risk of developing CD (fig. 1) [8]. The authors evaluated a young population because the development of the gut immune system occurs in early childhood and is influenced by the intestinal microbiota.
Antibiotics as a Treatment of Inflammatory Bowel Disease
The hypothesis that gut bacteria may play a role in the pathogenesis of CD lesions is supported by several experimental and clinical observations. Bacteria are the Maria Lia Scribano Gastroenterology Operative Unit Azienda Ospedaliera San Camillo-Forlanini Circonvallazione Gianicolense 87, IT–00152 Rome (Italy) E-Mail marialiascribano @ virgilio.it
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Key Words Antibiotics · Crohn’s disease · Inflammatory bowel disease · Gut microbiota
Table 1. Randomized, placebo-controlled trials of antimycobacterial therapy
Reference (first author)
Drug(s)
Elliot, 1982 [11] Shaffer, 1984 [12] Basilisco, 1989 [13] Afdhal, 1991 [14] Swift, 1994 [15] Prantera, 1994 [16] Selby, 2007 [17]
Patients, n
sulfadoxine + pyrimethamine ethambutol + rifampicin rifabutin clofazimine rifampicin + ethambutol + isoniazid ethambutol + clofazimine + dapsone + rifampicin rifabutin + clarithromycin + clofazimine
51 27 24 49 126 40 213
Time, months
Remission, % active
control
12 12 6 12 24 9 24
33
41.6 NS
42 48
50 25 NS
50 43
22.2 26 relapsed
7+ courses 5–6 courses 3–4 courses 1–2 courses 0 course 0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Rate ratio relative to 0 antibiotic course
Fig. 1. Antibiotic use and IBD in 577,627 Danish children.
cause of animal and human intestinal diseases similar to IBD and live predominantly in gut areas which are commonly affected by CD lesions, such as colon, terminal ileum, especially after the loss of the ileocecal valve, and upstream from strictures. The luminal content is necessary for causing intestinal lesions, and CD inflammation does not appear when it is diverted from the gut, whereas restoration of bowel continuity or infusion of fecal material into the bypassed intestine rapidly results in recurrence of the disease [9, 10]. Antibiotics against a Specific Pathogen The presence of atypical mycobacteria in CD gut tissue reported several years ago and the similarity between CD, tuberculous enteritis and Johne’s disease of ruminants, caused by Mycobacterium avium subspecies paratuberculosis (MAP), have led to test the efficacy of antimycobacterial drugs in CD patients (table 1) [11–17]. 380
Dig Dis 2013;31:379–384 DOI: 10.1159/000354704
However, clinical trials have failed to show any significant clinical benefit for antibiotics active against atypical mycobacteria. These drugs, in fact, appear to be ineffective in active CD without a course of corticosteroid therapy, as showed by a meta-analysis that evaluated eight studies, employing different combinations of antimycobacterial drugs. In 2007, Selby et al. [17] performed the largest and controversial trial of anti-MAP therapy in inducing and maintaining CD remission. A combination of clarithromycin, rifabutin and clofazimine, or placebo, was administered to 213 Australian patients for up 2 years, in addition to a 16-week course of prednisolone. The only significant efficacy was observed at 16 weeks, when antibiotics were associated to corticosteroids, confirming the data reported by the previous meta-analysis. In conclusion, this study does not support an efficacy of antimycobacterial therapy as treatment of a CD-active phase, without a period of steroids. Therefore, the trial did not confirm the role of MAP as an etiologic CD agent, but several objections to this conclusion have been raised [18–22]. The hypothesis that mycobacteria could be a causative agent for CD cannot be definitely eradicated, and the theory that an infectious agent may commence the inflammatory process continues to be plausible [23]. Antibiotics for Correcting Dysbiosis Dysbiosis observed in CD patients is considered involved in the development and maintenance of the chronic intestinal inflammation that characterizes this disease, by inducing an altered immune response in genetically susceptible hosts [24].
Scribano/Prantera
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Color version available online
NS = Not significant.
Table 2. Antibiotic trials as primary therapy in acute flares
Reference (first author)
Antibiotic (dose)
Patients, n
Time, weeks
Control
active
Ursing, 1982 [37] Sutherland, 1991 [38]
metronidazole (800 mg/day) metronidazole (10 or 20 mg/kg)
78 99
16 16
sulfasalazine placebo
Colombel, 1999 [39] Arnold, 2002 [40] Prantera, 1996 [41]
ciprofloxacin (500 mg bid) ciprofloxacin (500 mg bid) ciprofloxacin (500 mg bid) + metronidazole (500 mg bid) ciprofloxacin (500 mg bid) + metronidazole (250 mg tid) clarithromycin (1,000 mg/day)
40 47 41
6 26 12
72
10
mesalamine placebo methylprednisolone 0.7–1 mg/kg –
41
12
placebo
Greenbloom, 1998 [42] Leiper, 2008 [35]
Remission, % control
NS 27 36 56
25
68
–
26
27
55 p < 0.001 45.5 63
Gut mucosa is separated from the intestinal lumen by a mucous layer. After mucous layer removal, aerobic culture of colonic biopsies in CD patients shows a high concentration of bacteria, primarily Escherichia coli, while in healthy individuals it is sterile [25]. An increased presence of E. coli, particularly the adherent-invasive E. coli (AIEC) pathovar, has been reported by several studies in CD tissue [3, 26, 27]. Pathogenic AIEC are able to colonize the intestinal mucosa by adhering to epithelial cells, to invade these cells, and to survive and replicate within macrophages, inducing the secretion of large amounts of tumor necrosis factor-α [28]. Nowadays, AIEC are perhaps the most likely candidate organisms in promoting the CD inflammatory process. In addition, a decreased number of protective bifidobacteria, lactobacilli and the more recently studied Faecalibacterium prausnitzii, Bacteroide fragilis and Firmicutes, has been reported in CD patients [25, 29]. Genetic susceptibly in some subjects with CD is related to polymorphisms in the NOD2/CARD15 gene, suggesting that individuals with mutations in NOD2 present defective intestinal immune responses to gut microbiota. About 20% of CD patients are homozygous for NOD2 variants and they may have an increased susceptibility to CD localized at the ileum [30]. Moreover, a loss of immunologic tolerance to the commensal flora has been observed in patients with active IBD [31]. On the assumption of these and other data, antibiotics are employed as primary therapy for treatment of acute flares, and for postoperative recurrence prevention [32–34].
Antibiotics as Primary Therapy in Active Crohn’s Disease The data supporting the role of AIEC in the pathogenesis of CD provide the rationale for a therapeutic manipulation of the intestinal flora through the use of antibiotics active against these bacteria. Some antibiotics, such as clarithromycin and ciprofloxacin, are able to penetrate macrophages and may therefore be effective in eradicating the bacteria. However, a randomized, placebo-controlled trial performed with clarithromycin, at a dose of 1 g for 3 months, in 41 patients with active CD, was stopped because no difference in the remission or response rate between the antibiotic and placebo was observed [35]. Metronidazole and ciprofloxacin are the most frequent studied and employed antibiotics, even though their role as primary therapy in active CD remains controversial. Metronidazole, active against some parasites and most anaerobic bacteria, including Bacteroides and Clostridium species, was first reported to be effective in CD in an open study in 1975 [36]. Ciprofloxacin is a quinolone derivative with a selective suppressive effect on the intestinal microflora. Not only E. coli, but also other Enterobacteriaceae are especially sensitive to this antibiotic, which, on the contrary, does not particularly affect anaerobic bacteria. Several randomized clinical trials have evaluated the efficacy of these antibiotics, used alone or in combination, at inducing remission in CD (table 2) [35, 37–42]. The results of these studies have shown that patients with colonic localization get more benefit from antibiotics, probably because of the higher bacterial concentration in the colon than in the small bowel. In addition, the asso-
Antibiotics and Inflammatory Bowel Diseases
Dig Dis 2013;31:379–384 DOI: 10.1159/000354704
381
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NS = Not significant.
382
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twice daily in patients with moderate CD was performed. At the end of the 12-week treatment period, significantly more patients treated with the dose of 800 mg twice a day were in remission, compared to patients on placebo (62 vs. 43%) [48]. Remission rates in patients who received 400 and 800 mg twice daily were higher than in patients treated with placebo, but without reaching the statistical significance. The lack of a dose-response relationship was probably caused by the higher number of subjects who discontinued the therapy because of AEs in the 1,200 mg twice-daily group. The post hoc exploratory subgroup analysis showed that early-stage disease (defined as first diagnosis ≤3 years before enrolment in the study) and colonic involvement appeared to be associated with a higher response to the antibiotic therapy. In addition, patients with CRP level >5 mg/l were significantly more likely to achieve remission. Overall, the safety profile of rifaximinEIR was good, as the incidence of AEs was similar between patients on active drug and placebo, indicating that rifaximin could be used for a long period of time. However, a case of C. difficile infection was reported in a patient on rifaximin 800 mg twice daily, 20 days after the end of the treatment period. Although rifaximin has been successfully employed in the treatment of C. difficile infection in metronidazole-unresponsive patients, it is probable that rare clones of rifaximin-resistant C. difficile can arise [49]. Antibiotics for Prevention of Postoperative Recurrence Postoperative management after intestinal resection represents one of the major aims in CD treatment. It has been observed that the gut microbiota plays an important role in determining the recurrence of lesions, and antibiotics have been evaluated for prevention of recurrence after surgery in three randomized placebo-controlled trials [50–52]. In the first study, patients treated with metronidazole, at a dose of 20 mg/kg/day for 3 months, had a significantly reduced incidence of severe endoscopic recurrence and a delay of symptomatic recurrence at 1 year [50]. However, a higher percentage of side effects was experienced by the patients on active drug compared to the placebo group. Ornidazole, another nitroimidazole antibiotic, which has the same bacterial activity with a better safety profile, was later evaluated by the same authors [51]. After 1 year of treatment, at a dose of 1 g/day, clinical recurrence rate was significantly reduced, but more than 30% of patients discontinued the antibiotic because of side effects. In another, more recent study, metronidazole (250 mg 3 times daily) given for 3 months was associated to azathioprine or placebo, given for 12 months, in 81 CD patients at high risk of postoperative recurrence Scribano/Prantera
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ciation of ciprofloxacin and metronidazole to budesonide for treatment of active CD may improve the outcome when the colon is involved [43]. However, the small number of patients enrolled in the trials, the uncertain results and the appearance of adverse events (AEs) have limited antibiotics use in clinical practice as an alternative to steroids for treatment of active CD. The beneficial action of antibiotic therapy seems to be related to a long-term treatment that is frequently complicated by an elevated number of side effects. The incidence of side effects reported with metronidazole varies between 10 and 20%, according to the dose and the length of therapy. The most frequent are gastrointestinal intolerance, neurotoxicity and metallic taste. Resolution of symptoms usually occurs with dosage reduction or therapy discontinuation. However, peripheral neuropathy, that is an AE of long-term use, sometimes persists despite cessation of treatment. The percentage of side effects reported in the studies on ciprofloxacin is variable, but often the patients also received other concomitant medications. Gastrointestinal intolerance, skin reactions, increase in transaminase level have been described, and, in particular, there is concern about the possible infection by Clostridium difficile. This infection, in fact, is a growing problem in the general population and, especially, in IBD patients, because it can induce IBD relapse. Two retrospective studies, assessing the connection between IBD and C. difficile-associated disease (CDAD), reported a higher incidence of CDAD in IBD than non-IBD patients and a later American evaluation showed that in patients with IBD the mortality related to CDAD was four times greater than in patients without IBD [44–46]. Therefore, the increasing rate of C. difficile infection has alerted the clinicians in charge of CD patients and limited the use of ciprofloxacin. Nonabsorbed antibiotic therapy, unlike systemic antibiotics, is characterized by a very low risk of systemic toxicity or AEs. Rifaximin is a minimally absorbed antibiotic with a broad spectrum of antibacterial activity, covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. An exploratory study showed that a gastroresistant formulation of rifaximin (extended intestinal release (EIR)) (rifaximin-EIR) at a dose of 800 mg twice a day for 12 weeks was significantly superior to placebo, in a subgroup of patients with mild to moderately active CD and an elevated level of C-reactive protein (CRP) [47]. Subsequently, a larger, placebo-controlled trial on the use of rifaximin-EIR at a dose of 400, 800 and 1,200 mg
[52]. Overall rate of significant endoscopic recurrence at 3 and 12 months after surgery was rather low, probably ascribable to the antibiotic treatment that all patients initially received. The study treatment was well tolerated and only 3 patients discontinued the therapy in the first 3 months because of side effects, probably related to metronidazole. As recurrence prevention requires a prolonged therapy, that is complicated by an elevated rate of side effects, rifaximin, characterized by a high tolerability, should be used in this setting.
otics may be effective in CD patients [53–55], but European Crohn’s and Colitis Organisation (ECCO) consensus statements consider these drugs appropriate only in the treatment of septic complications of CD, symptoms attributable to bacterial overgrowth, or perianal disease [56]. Nevertheless, clinical practice and some studies suggest that antibiotics can be useful in a subgroup of patients with colonic location, early disease, and positive laboratory tests of inflammation. Since their use is frequently burdened by an elevated number of AEs, the employment of antibiotics which work locally, such as rifaximin, is promising, but further studies are needed.
Conclusion
Current data do not strongly support a therapeutic benefit from antibiotics and there is still controversy regarding their use. Some meta-analyses show that antibi-
Disclosure Statement The authors have no conflicts of interest to disclose.
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48 Prantera C, Lochs H, Grimaldi M, Danese S, Scribano ML, 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. Gastroenterology 2012;142:473–481. 49 Patrick Basu P, Dinani A, Rayapudi K, Pacana T, Shah NJ, Hampole H, Krishnaswamy NV, Mohan V: Rifaximin therapy for metronidazole-unresponsive Clostridium difficile infection: a prospective pilot trial. Ther Adv Gastroenterol 2010;3:221–225. 50 Rutgeerts P, Hiele M, Geboes K, Peeters M, Penninckx F, Aerts R, Kerremans R: Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995;108:1617–1621. 51 Rutgeerts P, Van Assche G, Vermeire S, D’Haens G, Baert F, Noman M, Aerden I, De Hertogh G, Geboes K, Hiele M, D’Hoore A, Penninckx F: Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2005;128:856–861. 52 D’Haens G, Vermeire S, Van Assche G, Noman M, Aerden I, Van Olmen G, Rutgeerts P: Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn’s disease: a controlled randomized trial. Gastroenterology 2008;135:1123–1129. 53 Rahimi R, Nikfar S, Rezaie A, Abdollahi M: A meta-analysis of broad spectrum antibiotic therapy in patients with active Crohn’s disease. Clin Ther 2006;28:1983–1988. 54 Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M: Long-term antibiotic treatment for Crohn’s disease: systematic review and meta-analysis of placebo-controlled trials. Clin Infect Dis 2010;50:473–480. 55 Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Marshall JK, Talley NJ, Moayyedi P: Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011;106:661–673. 56 Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D’Hoore A, Gassull M, Gomollón F, Hommes DW, Michetti P, O’Morain C, Oresland T, Windsor A, Stange EF, Travis SP; European Crohn’s and Colitis Organisation (ECCO): The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010;4:28–62.
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Antibiotics and Inflammatory Bowel Diseases Maria Lia Scribano Cosimo Prantera Gastroenterology Operative Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
Abstract Inflammatory bowel diseases are characterized by an altered composition of gut microbiota (dysbiosis) that may contribute to their development. Antibiotics can alter the bacterial flora, and a link between antibiotic use and onset of Crohn’s disease (CD), but not ulcerative colitis, has been reported. The hypothesis that Mycobacterium avium subspecies paratuberculosis (MAP) could be an etiologic agent of CD has not been confirmed by a large study on patients treated by an association of antibiotics active against MAP. The observations supporting a role of intestinal microbiota in CD pathogenesis provide the rationale for a therapeutic manipulation of the intestinal flora through the employment of antibiotics. However, current data do not strongly support a therapeutic benefit from antibiotics, and there is still controversy regarding their use as primary therapy for treatment of acute flares of CD, and for postoperative recurrence prevention. Nevertheless, clinical practice and some studies suggest that a subgroup of patients with colonic involvement, early disease, and abnormal laboratory test of inflammation may respond better to antibiotic treatment. Since their long-term use is frequently complicated by a high rate of side effects, the use of antibiotics that work locally appears to be promising. © 2013 S. Karger AG, Basel
© 2013 S. Karger AG, Basel 0257–2753/13/0314–0379$38.00/0 E-Mail [email protected] www.karger.com/ddi
Antibiotics as an Eliciting Factor of Inflammatory Bowel Disease
The etiopathogenesis of inflammatory bowel disease (IBD) remains still unknown, but the emerging evidence suggests that changes in the composition of the intestinal microbiota (dysbiosis) may contribute to IBD development [1–3]. Antibiotics can alter the bacterial microflora, by interfering with resistance against opportunistic microorganisms [4]. Therefore, the use of antibiotics could be a potential risk factor for IBD. Some studies have evaluated the possible association between the assumption of antibiotics and the appearance of inflammatory lesions, reporting a link with the onset of Crohn’s disease (CD), but not ulcerative colitis [4–7]. The largest study, recently published, showed a strong association between CD and prior antibiotic use in 577,627 Danish children, thus suggesting that antibiotics can increase the risk of developing CD (fig. 1) [8]. The authors evaluated a young population because the development of the gut immune system occurs in early childhood and is influenced by the intestinal microbiota.
Antibiotics as a Treatment of Inflammatory Bowel Disease
The hypothesis that gut bacteria may play a role in the pathogenesis of CD lesions is supported by several experimental and clinical observations. Bacteria are the Maria Lia Scribano Gastroenterology Operative Unit Azienda Ospedaliera San Camillo-Forlanini Circonvallazione Gianicolense 87, IT–00152 Rome (Italy) E-Mail marialiascribano @ virgilio.it
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Key Words Antibiotics · Crohn’s disease · Inflammatory bowel disease · Gut microbiota
Table 1. Randomized, placebo-controlled trials of antimycobacterial therapy
Reference (first author)
Drug(s)
Elliot, 1982 [11] Shaffer, 1984 [12] Basilisco, 1989 [13] Afdhal, 1991 [14] Swift, 1994 [15] Prantera, 1994 [16] Selby, 2007 [17]
Patients, n
sulfadoxine + pyrimethamine ethambutol + rifampicin rifabutin clofazimine rifampicin + ethambutol + isoniazid ethambutol + clofazimine + dapsone + rifampicin rifabutin + clarithromycin + clofazimine
51 27 24 49 126 40 213
Time, months
Remission, % active
control
12 12 6 12 24 9 24
33
41.6 NS
42 48
50 25 NS
50 43
22.2 26 relapsed
7+ courses 5–6 courses 3–4 courses 1–2 courses 0 course 0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Rate ratio relative to 0 antibiotic course
Fig. 1. Antibiotic use and IBD in 577,627 Danish children.
cause of animal and human intestinal diseases similar to IBD and live predominantly in gut areas which are commonly affected by CD lesions, such as colon, terminal ileum, especially after the loss of the ileocecal valve, and upstream from strictures. The luminal content is necessary for causing intestinal lesions, and CD inflammation does not appear when it is diverted from the gut, whereas restoration of bowel continuity or infusion of fecal material into the bypassed intestine rapidly results in recurrence of the disease [9, 10]. Antibiotics against a Specific Pathogen The presence of atypical mycobacteria in CD gut tissue reported several years ago and the similarity between CD, tuberculous enteritis and Johne’s disease of ruminants, caused by Mycobacterium avium subspecies paratuberculosis (MAP), have led to test the efficacy of antimycobacterial drugs in CD patients (table 1) [11–17]. 380
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However, clinical trials have failed to show any significant clinical benefit for antibiotics active against atypical mycobacteria. These drugs, in fact, appear to be ineffective in active CD without a course of corticosteroid therapy, as showed by a meta-analysis that evaluated eight studies, employing different combinations of antimycobacterial drugs. In 2007, Selby et al. [17] performed the largest and controversial trial of anti-MAP therapy in inducing and maintaining CD remission. A combination of clarithromycin, rifabutin and clofazimine, or placebo, was administered to 213 Australian patients for up 2 years, in addition to a 16-week course of prednisolone. The only significant efficacy was observed at 16 weeks, when antibiotics were associated to corticosteroids, confirming the data reported by the previous meta-analysis. In conclusion, this study does not support an efficacy of antimycobacterial therapy as treatment of a CD-active phase, without a period of steroids. Therefore, the trial did not confirm the role of MAP as an etiologic CD agent, but several objections to this conclusion have been raised [18–22]. The hypothesis that mycobacteria could be a causative agent for CD cannot be definitely eradicated, and the theory that an infectious agent may commence the inflammatory process continues to be plausible [23]. Antibiotics for Correcting Dysbiosis Dysbiosis observed in CD patients is considered involved in the development and maintenance of the chronic intestinal inflammation that characterizes this disease, by inducing an altered immune response in genetically susceptible hosts [24].
Scribano/Prantera
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Color version available online
NS = Not significant.
Table 2. Antibiotic trials as primary therapy in acute flares
Reference (first author)
Antibiotic (dose)
Patients, n
Time, weeks
Control
active
Ursing, 1982 [37] Sutherland, 1991 [38]
metronidazole (800 mg/day) metronidazole (10 or 20 mg/kg)
78 99
16 16
sulfasalazine placebo
Colombel, 1999 [39] Arnold, 2002 [40] Prantera, 1996 [41]
ciprofloxacin (500 mg bid) ciprofloxacin (500 mg bid) ciprofloxacin (500 mg bid) + metronidazole (500 mg bid) ciprofloxacin (500 mg bid) + metronidazole (250 mg tid) clarithromycin (1,000 mg/day)
40 47 41
6 26 12
72
10
mesalamine placebo methylprednisolone 0.7–1 mg/kg –
41
12
placebo
Greenbloom, 1998 [42] Leiper, 2008 [35]
Remission, % control
NS 27 36 56
25
68
–
26
27
55 p < 0.001 45.5 63
Gut mucosa is separated from the intestinal lumen by a mucous layer. After mucous layer removal, aerobic culture of colonic biopsies in CD patients shows a high concentration of bacteria, primarily Escherichia coli, while in healthy individuals it is sterile [25]. An increased presence of E. coli, particularly the adherent-invasive E. coli (AIEC) pathovar, has been reported by several studies in CD tissue [3, 26, 27]. Pathogenic AIEC are able to colonize the intestinal mucosa by adhering to epithelial cells, to invade these cells, and to survive and replicate within macrophages, inducing the secretion of large amounts of tumor necrosis factor-α [28]. Nowadays, AIEC are perhaps the most likely candidate organisms in promoting the CD inflammatory process. In addition, a decreased number of protective bifidobacteria, lactobacilli and the more recently studied Faecalibacterium prausnitzii, Bacteroide fragilis and Firmicutes, has been reported in CD patients [25, 29]. Genetic susceptibly in some subjects with CD is related to polymorphisms in the NOD2/CARD15 gene, suggesting that individuals with mutations in NOD2 present defective intestinal immune responses to gut microbiota. About 20% of CD patients are homozygous for NOD2 variants and they may have an increased susceptibility to CD localized at the ileum [30]. Moreover, a loss of immunologic tolerance to the commensal flora has been observed in patients with active IBD [31]. On the assumption of these and other data, antibiotics are employed as primary therapy for treatment of acute flares, and for postoperative recurrence prevention [32–34].
Antibiotics as Primary Therapy in Active Crohn’s Disease The data supporting the role of AIEC in the pathogenesis of CD provide the rationale for a therapeutic manipulation of the intestinal flora through the use of antibiotics active against these bacteria. Some antibiotics, such as clarithromycin and ciprofloxacin, are able to penetrate macrophages and may therefore be effective in eradicating the bacteria. However, a randomized, placebo-controlled trial performed with clarithromycin, at a dose of 1 g for 3 months, in 41 patients with active CD, was stopped because no difference in the remission or response rate between the antibiotic and placebo was observed [35]. Metronidazole and ciprofloxacin are the most frequent studied and employed antibiotics, even though their role as primary therapy in active CD remains controversial. Metronidazole, active against some parasites and most anaerobic bacteria, including Bacteroides and Clostridium species, was first reported to be effective in CD in an open study in 1975 [36]. Ciprofloxacin is a quinolone derivative with a selective suppressive effect on the intestinal microflora. Not only E. coli, but also other Enterobacteriaceae are especially sensitive to this antibiotic, which, on the contrary, does not particularly affect anaerobic bacteria. Several randomized clinical trials have evaluated the efficacy of these antibiotics, used alone or in combination, at inducing remission in CD (table 2) [35, 37–42]. The results of these studies have shown that patients with colonic localization get more benefit from antibiotics, probably because of the higher bacterial concentration in the colon than in the small bowel. In addition, the asso-
Antibiotics and Inflammatory Bowel Diseases
Dig Dis 2013;31:379–384 DOI: 10.1159/000354704
381
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NS = Not significant.
382
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twice daily in patients with moderate CD was performed. At the end of the 12-week treatment period, significantly more patients treated with the dose of 800 mg twice a day were in remission, compared to patients on placebo (62 vs. 43%) [48]. Remission rates in patients who received 400 and 800 mg twice daily were higher than in patients treated with placebo, but without reaching the statistical significance. The lack of a dose-response relationship was probably caused by the higher number of subjects who discontinued the therapy because of AEs in the 1,200 mg twice-daily group. The post hoc exploratory subgroup analysis showed that early-stage disease (defined as first diagnosis ≤3 years before enrolment in the study) and colonic involvement appeared to be associated with a higher response to the antibiotic therapy. In addition, patients with CRP level >5 mg/l were significantly more likely to achieve remission. Overall, the safety profile of rifaximinEIR was good, as the incidence of AEs was similar between patients on active drug and placebo, indicating that rifaximin could be used for a long period of time. However, a case of C. difficile infection was reported in a patient on rifaximin 800 mg twice daily, 20 days after the end of the treatment period. Although rifaximin has been successfully employed in the treatment of C. difficile infection in metronidazole-unresponsive patients, it is probable that rare clones of rifaximin-resistant C. difficile can arise [49]. Antibiotics for Prevention of Postoperative Recurrence Postoperative management after intestinal resection represents one of the major aims in CD treatment. It has been observed that the gut microbiota plays an important role in determining the recurrence of lesions, and antibiotics have been evaluated for prevention of recurrence after surgery in three randomized placebo-controlled trials [50–52]. In the first study, patients treated with metronidazole, at a dose of 20 mg/kg/day for 3 months, had a significantly reduced incidence of severe endoscopic recurrence and a delay of symptomatic recurrence at 1 year [50]. However, a higher percentage of side effects was experienced by the patients on active drug compared to the placebo group. Ornidazole, another nitroimidazole antibiotic, which has the same bacterial activity with a better safety profile, was later evaluated by the same authors [51]. After 1 year of treatment, at a dose of 1 g/day, clinical recurrence rate was significantly reduced, but more than 30% of patients discontinued the antibiotic because of side effects. In another, more recent study, metronidazole (250 mg 3 times daily) given for 3 months was associated to azathioprine or placebo, given for 12 months, in 81 CD patients at high risk of postoperative recurrence Scribano/Prantera
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ciation of ciprofloxacin and metronidazole to budesonide for treatment of active CD may improve the outcome when the colon is involved [43]. However, the small number of patients enrolled in the trials, the uncertain results and the appearance of adverse events (AEs) have limited antibiotics use in clinical practice as an alternative to steroids for treatment of active CD. The beneficial action of antibiotic therapy seems to be related to a long-term treatment that is frequently complicated by an elevated number of side effects. The incidence of side effects reported with metronidazole varies between 10 and 20%, according to the dose and the length of therapy. The most frequent are gastrointestinal intolerance, neurotoxicity and metallic taste. Resolution of symptoms usually occurs with dosage reduction or therapy discontinuation. However, peripheral neuropathy, that is an AE of long-term use, sometimes persists despite cessation of treatment. The percentage of side effects reported in the studies on ciprofloxacin is variable, but often the patients also received other concomitant medications. Gastrointestinal intolerance, skin reactions, increase in transaminase level have been described, and, in particular, there is concern about the possible infection by Clostridium difficile. This infection, in fact, is a growing problem in the general population and, especially, in IBD patients, because it can induce IBD relapse. Two retrospective studies, assessing the connection between IBD and C. difficile-associated disease (CDAD), reported a higher incidence of CDAD in IBD than non-IBD patients and a later American evaluation showed that in patients with IBD the mortality related to CDAD was four times greater than in patients without IBD [44–46]. Therefore, the increasing rate of C. difficile infection has alerted the clinicians in charge of CD patients and limited the use of ciprofloxacin. Nonabsorbed antibiotic therapy, unlike systemic antibiotics, is characterized by a very low risk of systemic toxicity or AEs. Rifaximin is a minimally absorbed antibiotic with a broad spectrum of antibacterial activity, covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. An exploratory study showed that a gastroresistant formulation of rifaximin (extended intestinal release (EIR)) (rifaximin-EIR) at a dose of 800 mg twice a day for 12 weeks was significantly superior to placebo, in a subgroup of patients with mild to moderately active CD and an elevated level of C-reactive protein (CRP) [47]. Subsequently, a larger, placebo-controlled trial on the use of rifaximin-EIR at a dose of 400, 800 and 1,200 mg
[52]. Overall rate of significant endoscopic recurrence at 3 and 12 months after surgery was rather low, probably ascribable to the antibiotic treatment that all patients initially received. The study treatment was well tolerated and only 3 patients discontinued the therapy in the first 3 months because of side effects, probably related to metronidazole. As recurrence prevention requires a prolonged therapy, that is complicated by an elevated rate of side effects, rifaximin, characterized by a high tolerability, should be used in this setting.
otics may be effective in CD patients [53–55], but European Crohn’s and Colitis Organisation (ECCO) consensus statements consider these drugs appropriate only in the treatment of septic complications of CD, symptoms attributable to bacterial overgrowth, or perianal disease [56]. Nevertheless, clinical practice and some studies suggest that antibiotics can be useful in a subgroup of patients with colonic location, early disease, and positive laboratory tests of inflammation. Since their use is frequently burdened by an elevated number of AEs, the employment of antibiotics which work locally, such as rifaximin, is promising, but further studies are needed.
Conclusion
Current data do not strongly support a therapeutic benefit from antibiotics and there is still controversy regarding their use. Some meta-analyses show that antibi-
Disclosure Statement The authors have no conflicts of interest to disclose.
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