Antibiotics & Crohn's


Although controversial, the use of properly chosen antibiotics in Crohn's disease appears beneficial. Evidence supporting the use of targeted antibiotic therapy comes in two forms: statistical evidence derived from meta-analyses of multiple formal studies and the documented clinical and endoscopic responses in patients treated with antibiotic combinations outside of formal clinical studies. This article reviews evidence from both categories that support the use of properly chosen antibiotic regimens in treating Crohn's disease, comments on the advantages and disadvantages of antibiotic therapy, and attempts to present a unifying hypothesis related to the role of enteric bacteria, mucosal immunity and antibiotic therapy. Relevant studies identified through a Medline search from 1976 to 2011 were assessed for inclusion by two independent observers who resolved any disagreements by consensus. References from all identified articles and recent review articles were cross-checked to ensure a thorough search. Papers were selected based on scientific merit as to which presented original contributions to the results.

Antibiotics in Crohn's Disease

The rationale for using antibiotics as primary treatment of Crohn's disease (CD) is based on increasing evidence implicating gut bacteria in the pathogenesis of the disease.[1] Two hypotheses involving the role of bacteria in the etiology and pathogenesis of CD have been proposed. Both hypotheses support a role for antibiotic therapy to correct the disease process and shift the involved networks toward a healthier dynamic.

One hypothesis proposes that genetically determined defects of innate immunity reacting to nonspecific antigens from commensal gut bacteria result in the dysregulated inflammatory disease phenotype.[2] In this scenario antibiotics may affect the microbial ecosystem of the gut and influence the continual cross-talk between the microbiota and the mucosal immune system in such a way that a beneficial response is obtained. This hypothesis does not explain why patients develop the disease later in life and it does not readily explain Crohn's lesions found in the esophagus,[3] duodenum,[4] liver[5] and other organs.[6]

Another hypothesis proposes that specific bacterial species infect dendritic cells and macrophages in genetically predisposed individuals.[7] Defects in the recognition and response to specific bacteria result in chronic intracellular infection of dendritic cells and macrophages. As with the first hypothesis, disturbances in autophagy, antigen presentation and downstream immune signaling are compromised. Defects of innate immune signaling result from persistent macrophage bacterial infection that occurs due to genetic defects.

As a result of these hypotheses, numerous antibiotic regimens have been employed as primary therapy to attempt to modify the gut microflora milieu and minimize colonization and invasion of harmful bacteria in CD.

Early studies (1978–1991) comparing metronidazole, a nitroimidazole with a broad-spectrum of anaerobic activity, with placebo or conventional treatment were the first to suggest a beneficial effect of antibiotics in CD. Blichfeldt et al. comparing metronidazole (1 g/day or placebo) with salazosulfapyridin versus prednisone in 22 CD patients in a double-blind crossover study found no significant clinical benefit, although six patients with colonic involvement showed improvement in symptoms and biochemical indices.[8] The Swedish Cooperative Crohn's Disease Study (1982) compared metronidazole (800 mg/day) alone versus sulfasalazine in 78 CD patients in a crossover design (1.5 g/day) for 2-month periods.[9] Reductions in Crohn's Disease Activity Index (CDAI) scores were similar for both groups at 4 months. Both metronidazole and sulfasalazine were equally effective in patients with colitis or ileocolitis but were not effective in ileitis. Patients who switched from sulfasalazine to metronidazole showed significant reductions in CDAI. This was not seen in patients who switched from metronidazole to sulfasalazine. The investigators deemed metronidazole slightly more effective than sulfasalazine in CD. Ambrose et al. compared metronidazole and cotrimoxazole in combination or alone, against placebo in 72 CD patients and found no benefit in any of the drug combinations after 1 month of treatment.[10] In 1991, Sutherland et al. trialed two metronidazole regimens – 10 and 20 mg/kg/day – versus placebo in 105 CD patients.[11] A greater proportion of patients receiving metronidazole had improved CDAI scores compared with placebo. No significant difference was observed between the 10 and 20 mg/kg/day groups. Metronidazole therapy was more effective in patients with colitis or ileocolitis versus ileitis alone, suggesting that gut flora differences between the ileum and colon may help explain the differing metronidazole effectiveness. De'Haens et al. compared metronidazole with azathioprine versus metronidazole alone to reduce recurrence of postoperative CD in high-risk patients.[12] In total, 81 patients were randomized and 19 patients discontinued the study early. Significant endoscopic recurrence was observed in 43.7% in the metronidazole/azathioprine group versus 69% of the placebo group. The authors concluded that despite the enhanced risk of recurrence, the overall incidence was rather low and probably attributable to the metronidazole treatment that all patients received. More recently, Feller and colleagues from the University of Bern, Switzerland, pooled data from 16 randomized, placebo-controlled trials involving a total of 865 patients in order to assess the effectiveness of long-term antibiotic treatment for CD.[13] The outcomes were remission in patients with active disease, or relapse in patients with inactive disease. Three trials of nitroimidazoles (206 patients) showed a significant benefit (odds ratio [OR]: 3.54). The number of patients needed to treat with nitroimidazoles to keep one additional patient in remission was 3.4 for patients with active disease and 6.1 for inactive disease.

Ciprofloxacin has also been used, in combination with metronidazole and as a monotherapy in CD, with good results ().[14–20] A meta-analysis of three trials evaluating either ciprofloxacin or metronidazole in 123 patients with perianal CD fistula, reported a statistically significant effect in reducing fistula drainage (relative risk [RR]: 0.8; 95% CI: 0.66–0.98) with no heterogeneity (I2 = 0%) and a number needed to treat of five (95% CI: 3–20).[21] Despite current European Crohn's and Colitis Organisation guidelines stating that "at present antibiotics are only considered appropriate for septic complications, symptoms attributable to bacterial overgrowth, or perineal disease"[22] additional studies in CD patients without perianal disease have also shown positive results. Peppercorn et al., treating four patients with Crohn's ileitis using ciprofloxacin for 6 weeks, reported a dramatic improvement in all patients with complete resolution of symptoms after 1 week of treatment; however, a control group was not used.[14] Three patients remained asymptomatic 3 and 6 months after treatment. One patient suffered a recurrence after 6 months and again responded to ciprofloxacin. Arnold et al. also reported benefit, treating 47 patients with moderately active, refractory CD for 6 months with ciprofloxacin.[15] Mean CDAI scores at the completion of study were 112 for the ciprofloxacin group (n = 25) and 205 for the placebo group (n = 12; p < 0.001) with an OR of 11.3, but wide confidence intervals (95% CI: 2.60–48.8). Prantera et al. comparing ciprofloxacin alone versus metronidazole alone versus ciprofloxacin and metronidazole in combination in 41 patients with active CD reported similar remission rates between the three groups (69, 73 and 71%, respectively).[16] Colombel et al. demonstrated that ciprofloxacin was as effective as mesalazine for inducing remission, reporting remission rates of 56 and 55%, respectively.[17] However, Steinhart et al. reported no significant improvement in clinical remission using budesonide, metronidazole and ciprofloxacin versus budesonide alone in 130 patients with active CD of the ileum, right colon, or both.[18] Despite the lack of improvement, a greater proportion of patients with colonic disease achieved remission in the antibiotic group (53%) versus placebo (25%).

Table 1.  Summary of ciprofloxacin studies in Crohn's disease.

Author (Year) Design Treatment groups Patients (n) Results Ref
Peppercorn (1993) Small, uncontrolled study Ciprofloxacin 4 Dramatic improvement in clinical response [14]
Colombel et al. (1999) Randomized, controlled trial Ciprofloxacin (500 mg/b.i.d.) vs mesalazine (4 g/day) 40 Remission achieved in 10 patients (56%) treated with ciprofloxacin vs 12 patients (55%) in the mesalazine group [17]
Arnold et al. (2002) Randomized, placebo-controlled trial Ciprofloxacin (500 mg/b.i.d.) vs placebo (conventional therapy maintained) 47 Both groups showed a significant decrease in mean CDAI scores at 3 months

At study conclusion, the mean CDAI score in the placebo group increased to 205, resulting in a statistically significant difference between the groups
Prantera et al. (1996) Randomized, controlled trial Combination ciprofloxacin (500 mg/b.i.d.) and metronidazole (250 mg/q.i.d.) vs methylprednisone (0.7–1 mg/kg/day) 22 Remission achieved in 10 out of 22 (46%) patients in the ciprofloxacin/metronidazole group and 12 out of 19 (63%) patients in the methylprednisone group

The difference was not significant
Prantera et al. (1998) Retrospective study Combination ciprofloxacin (1 g/day) and metronidazole (1 g/day) vs ciprofloxacin (1 g/day) alone vs metronidazole (1 g/day) alone 233 Remission achieved in 71 % in the combination group, 73% treated with metronidazole alone, 69% treated with ciprofloxacin alone [19]
Greenbloom et al. (1998) Uncontrolled study Combination ciprofloxacin (500 mg/b.i.d.) and metronidazole (250 mg/t.i.d.) vs combination ciprofloxacin (500 mg/b.i.d.), metronidazole (250 mg/t.i.d.) and prednisone (mean dose 15 mg/day) 72 Remission achieved in:

68% in the ciprofloxacin/metronidazole group

A clinical response occurred in a greater proportion of patients with colonic disease (84%) vs ileal disease (64%) [20]
Steinhart et al. (2002) Prospective, multicenter, double-blind, randomized, controlled trial Budesonide (9 mg/day), metronidazole (1 g/day) and ciprofloxacin (1 g/day) vs budesonide (9 mg/day) plus placebo 134 No significant improvement in clinical remission in the antibiotic group

By disease site, a greater proportion of patients with colonic disease achieved a higher remission rate (53%) in the antibiotic group than placebo (25%) [18]
bid.: Twice a day; CDAI: Crohn's Disease Activity Index; q.i.d.: Four times a day; t.i.d.: Three times a day.

Several recent studies have also reported on the therapeutic benefit of rifaximin, the nonabsorbed broad-spectrum antibacterial antibiotic with an excellent safety profile, in mild to moderate CD. Shafran et al. reported endoscopic and clinical improvements in treatment-naive CD patients who received rifaximin (800 mg/day) as first-line therapy for 12 weeks.[23] The same investigators found in an open trial that 43% of 29 patients with active CD achieved clinical remission with rifaximin (600 mg/day). By the end of the trial, 60% of patients were in remission.[24] Shafran et al. retrospectively reported on 68 patients with CD treated with rifaximin over a 4-year (mean: 16.6 weeks) period.[25] Most patients (94%) received rifaximin 600 mg/day; 18 patients received rifaximin monotherapy; and 31 received rifaximin with concomitant steroids. Overall, 65% achieved remission. The remission rate was greater – 70% – in patients not receiving steroids versus 58% of those who received steroids. Of note is the remission rate of 67% achieved in patients on rifaximin monotherapy, suggesting that rifaximin alone is effective in maintaining remission. Remission rates were 65% for the small intestine, 66% for multiple locations and 55% for the large intestine. A meta-analysis by Khan et al., reporting on two clinical trials involving 485 patients treated with rifaximin in CD, found rifaximin to be effective at inducing remission (RR: 0.81; 95% CI: 0.68–0.97) with no statistically significant heterogeneity between the two trials (x = 0%; Cochran Q = 0.17; df = 1; p = 0.68).[21]

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