Antibiotics have a role in treating infectious complications of Crohn’s disease, including perianal and intra-abdominal abscesses, and in the longer term management of perianal fistulizing disease, and prevention of recurrence after ileocecal resection. Antibiotics may also play a role to a lesser extent in reducing mucosal inflammation in luminal Crohn’s disease. It is hypothesized that the effect of antibiotics on intestinal inflammation may be mediated through alterations of the intestinal microbiota, resulting in a decreased antigenic stimulus in patients with a genetic predisposition to immune dysregulation.

Antibiotics that have historically been used for Crohn’s disease include metronidazole and ciprofioxacin, although more recent studies have evaluated a potential role for rifaximin. Studies of metronidazole in active Crohn’s disease have not consistently signaled a clear benefit over placebo,  although there has been a suggestion of symptom reduction in patients with colonic disease. A small randomized controlled trial of combination ciprofioxacin and metronidazole versus methylprednisolone in active Crohn’s disease showed similar rates of clinical remission at 12 weeks. Unfortunately, long-term use of metronidazole is associated with many side effects, including peripheral neuropathy, dysgeusia, and nausea, causing a significant percentage of patients to discontinue the therapy.

In the treatment of perianal fistulizing disease,  an open-label study of metronidazole showed complete or advanced healing in 15 of 18 patients treated with metronidazole .

However, only 28 % of patients were able to stop the medication without fistula recurrence.  In patients with recurrent fistulizing disease after cessation of metronidazole,  healing was again observed when metronidazole was re-introduced.  A small pilot study of ciprofioxacin for perianal disease showed a numerical improvement in patients with complete fistula closure (40 % versus 12.5 %), but this was not statistically significant given the small sample size.

Two other studies have shown that antibiotics can enhance the effect of TNF inhibitors for healing of perianal fistulas.  A recent study of adalimumab in combination with ciprofioxacin showed that patients treated with the antibiotic and anti-TNF agent together had a significantly greater rate of clinical response (defined as 50 % closure of fistulas)  and remission (defined as complete closure of fistulas) at week 12, compared with those patients treated with adalimumab alone .  However,  this effect was not sustained at week 24 after the antibiotic was stopped.  In a similar study of infiiximab plus ciprofioxacin, there was a trend toward improved efficacy using the combination of medications compared with infiiximab monotherapy (73 % versus 39 %), but this was not statistically significant given the small sample size.

Rifaximin is a non-absorbable antibiotic with a broad-spectrum of activity against intestinal microbes. The lack of absorption results in fewer systemic side effects and improved long-term tolerability,  making rifaximin an appealing candidate for treatment of Crohn’s disease.  Several studies have demonstrated a modest clinical benefit for rifaximin in maintaining steroid-induced remission,  and inducing response or remission in active luminal disease.

In a meta-analysis of antimicrobial therapy for Crohn’s disease, antibiotics as a general category were superior to placebo for induction of remission (RR 0.85 for lack of remission), and rifamycin derivatives including rifaximin appeared to be most effective for this purpose.  Antibiotics also reduced fistula drainage (RR 0.8) and relapse of quiescent disease (RR 0.62). Overall, antibiotics may be more effective for colonic disease, due to the higher burden of bacteria in this area, and they have a particular role as adjunctive therapy for healing of perianal fistulas. However, traditional antibiotics including metronidazole and ciprofioxacin require continued therapy to maintain effectiveness and have frequent side effects, thus limiting their use.  Studies of rifaximin suggest a benefit for treating mucosal inflammation without major identified side effects, although the benefits appear to be relatively small at this point. 

### R. A. Fausel , MD
T. L. Zisman , MD, MPH
Division of Gastroenterology, University of Washington Medical Center , 1959 NE Pacific Street, Box 356424 , Seattle , WA 98195 , USA

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