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G&H Can you describe the historic rationale for the use of antibiotic therapies in inflammatory bowel disease?
HS Antibiotics have been used to treat inflammatory bowel disease (IBD), particularly Crohn’s disease, for a number of years. Sporadic reports appear in the literature before the 1970s but the first randomized trials were conducted in the 1970s and 1980s, primarily utilizing metronidazole. Although reported outcomes have been somewhat conflicting, there does seem to be a treatment effect, which has been variously limited in terms of both magnitude and the subpopulations of patients in whom it was observed.
G&H What is the current status of antibiotic therapy, given the contemporary emphasis on evidence-based treatment models?
HS If pure evidence-based management principles are applied to the use of antibiotics in the treatment of Crohn’s disease, one might elect to use antibiotics only in limited circumstances. With respect to ulcerative colitis, there is no evidence base to support the use of antibiotics beyond several scattered small studies, primarily of nonabsorbable oral antibiotics as possible adjuvant therapy.
Despite all of the above, many clinicians still use and accept antibiotics for patients with Crohn’s disease, particularly when certain—primarily septic—complications arise. These include perianal abscesses or fistulas, as well as intra-abdominal abscesses or collections.
In these cases, antibiotics may help reduce local sepsis and facilitate drainage. Bacterial overgrowth is another well-recognized indication for antibiotic use, irrespective of the underlying disease. Bacterial overgrowth might be considered a complication of Crohn’s disease with stenosis and intestinal stasis or partial obstruction. Antibiotics constitute a well-accepted treatment modality in these instances. Another area where the evidence base for antibiotics may be somewhat more compelling, and which certainly constitutes an accepted use, is in the treatment of pouchitis in patients who have undergone colectomy for ulcerative colitis.
Although the totality of evidence from randomized controlled trials would suggest that there is little or no effect from antibiotics in the treatment of active Crohn’s disease, in the individual studies there is a consistent signal indicating that antibiotics are effective in patients who have colonic involvement.
G&H Do antibiotics have a larger role in prevention of IBD recurrence as opposed to treatment of active disease?
HS In terms of prophylactic therapy after surgery, there have been several fairly well done, reasonably sized studies from Belgium that have shown that the imidazole antibiotics, metronidazole and ornidazole, each reduce the severity of endoscopic recurrence of Crohn’s disease after ileal resection, and also may reduce the risk of clinical recurrence after surgery. At this time, this indication could be considered a valid evidence-based use.
G&H Do clinicians need to monitor patients on antibiotic therapy for any drug-related complications?
HS In both long and short courses of therapy with metronidazole, there are some potential side effects that are cause for concern. The most worrisome is the potential for peripheral neuropathy. Although there is no way of monitoring or anticipating the development of neuropathy, what clinicians should do is warn patients about the potential for this side effect when starting treatment and advise them of the symptoms to watch for. If patients experience any of the early symptoms of numbness or tingling in the hands or feet, they should immediately alert their physician.
Rare reports of tendonitis and even Achilles tendon rupture have been noted with the administration of ciprofloxacin. Again, patients should be warned to watch for any signs of tendon pain or tenderness, particularly in the Achilles tendon.
Another side effect of metronidazole, though not well documented, is its interaction with alcohol. Patients who drink while on medication can experience rapid declines in blood pressure and flushing although this is rarely seen in clinical practice.
G&H Are there special considerations in administering these antibiotics in pregnant or breastfeeding patients?
HS None of the antibiotics commonly used in treating IBD has been approved for long-term use in pregnancy. Metronidazole has been shown to be safe in short courses in pregnancy. For other antibiotics there are little or no data, and they are generally not known with certainty to be safe. Ciprofloxacin, which is commonly used in Crohn’s disease, may impair fetal cartilage development and is definitely contraindicated in pregnancy.
With regard to breastfeeding, clarithromycin is considered safe. Breastfeeding should be temporarily interrupted when administering short courses of metronidazole. Ciprofloxacin has been shown to cause problems in the joints of juvenile animals exposed to it. Although the relevance to breastfeeding is unknown, and short maternal courses are unlikely to pose problems, it should be avoided.
G&H Are there specific combinations of anti-inflammatory/immunosuppressive agents and antibiotics that provide greater efficacy?
HS Combination therapy is used in the treatment of Crohn’s disease in particular. There are not an abundance of controlled trial data comparing different drug combinations. Our group studied the topically active, anti-inflammatory steroid budesonide alone and in combination with ciprofloxacin and metronidazole for the treatment of Crohn’s disease. We found that the addition of antibiotics to budesonide therapy did not improve the clinical outcome of patients with active Crohn’s disease, with the exception of those with large intestinal involvement.
G&H What additional research is required regarding the use of antibiotics in IBD?
HS Based on research in animal models, we know that bacteria are necessary for the development of IBD, particularly Crohn’s disease. This indicates that antibiotic use is potentially therapeutic if the bacterial flora can be modified appropriately. Research is needed to determine how the bacterial flora need to be modified in order to achieve beneficial mucosal inflammatory effect and, ultimately, clinical effect. The broad-spectrum antibiotics that have been used thus far are crude tools. Research is needed to examine how to modify the bacterial flora with more precision.
G&H What about research into the link between Crohn’s disease and Mycobacterium paratuberculosis?
HS This relationship has been under investigation for some time. So far, no consistent link has been made between atypical mycobacteria and causation of Crohn’s disease. In fact, the clinical trials that have used anti-mycobacterial therapies—usually a combination of several antibiotics given together—have generally not shown specific benefit of treatment. There have been some isolated instances of positive benefit reported but on the whole the evidence does not support the idea of mycobacteria playing a critical role. Further, when mycobacteria have been looked for in the tissue of the bowel or intestine of patients with Crohn’s disease, they generally have not been found.