The Role of Antibiotics in the Management of Crohnʼs Disease

Crohn's disease (CD; OMIM 266600) is a chronic heterogeneous inflammatory disease of the gastrointestinal tract in which a complex set of gene-environment interactions underlies the development and the evolution of the transmural inflammatory response. 1 The current paradigm of the pathogenesis of Crohn's disease is focused on the genetically determined and exaggerated mucosal immune response to normal constituents of the mucosal microflora. This model is supported by data from experimental models of inflammation of the intestine as well as from patients with inflammatory bowel disease (IBD). 1,–3 Activation of the innate immune response to commensal bacteria and their products is mediated through families of pattern-recognition receptors (PRRs) that include an array of membrane, cytosolic, and soluble receptors that recognize pathogen-associated molecular patterns of microorganisms through leucine-rich repeats (LRRs)-containing domains. 4 The NOD family of proteins are cytosolic PRRs involved in the intracellular recognition of bacterial products such as lipo-polysaccharide (LPS) and peptidoglycan (PGN) derived from gram-negative and -positive bacteria, respectively. 5 The cellular signaling events elicited by these bacterial products are mediated through the cell surface toll-like receptors (TLRs) and lead to the activation of the pivotal transcription factor, NFκB. 6 Importantly, NOD2 (CARD15) genetic variants are found in significant numbers of patients with Crohn's disease and are associated with defective LPS/PGN signaling and impaired mucosal immune responses. 7 The experimental evidence derived from research focused on defining a role of pathogenic or commensal bacteria in the pathogenesis of IBD has fueled a diverse array of clinical trials using a variety of antimicrobial agents. However, the majority of these studies were uncontrolled, and only a few trials have fulfilled the stringent criteria of evidence-based medicine. Metronidazole and ciprofloxacin are the antibiotics most often used to treat mild-to-moderate luminal or fistulizing CD. This review examines the evidence arising from clinical trials attempting to define the efficacy of these antibiotics in the management of luminal Crohn's disease. Metronidazole exhibits an antimicrobial spectrum of activity against anaerobes In addition to targeting specific intestinal protozoa. 8 The bactericidal properties of metronidazole are likely explained by the reduction of the 5-nitro group to a hydroxylamine group, which binds to DNA and inhibits cell division. As well, metronidazole exhibits immunomodulatory properties. Though some clinical benefit of metronidazole has been demonstrated in randomized controlled trials (RCTs), the evidence is weak, as no study has clearly shown superiority over placebo. In an early placebo-controlled, double-blind, crossover study, Blichfeldt and co-workers 9 examined the efficacy of a 16-week regimen of metronidazole 1 g daily as adjunctive therapy. All patients were receiving sulfasalazine or prednisone. No overall benefit with metronidazole was observed in this study. However, significant improvement of symptoms and laboratory parameters was seen in 6 of the 22 patients with isolated Crohn's colitis. In two other smaller placebo-controlled studies, metronidazole failed to show any treatment benefit over placebo. 10,11 The efficacy of metronidazole 800 mg with sulfasalazine was evaluated in a subsequent Swedish cooperative randomized, double-blind, crossover study of 78 patients with active Crohn's disease. 12,13 Patients were investigated for two 4-month periods, and the outcome measures included the CDAI and plasma levels of orosomucoid. During the first 4 months, no difference in CDAI was observed between the treatment groups. However, the plasma orosomucoid level was significantly decreased in the metronidazole-treated patients. In the patients with active disease symptoms throughout the first study interval period, a significant decrease in CDAI score was seen in those patients subsequently switched to metronidazole during the latter study interval, but not for those who crossed over to sulfasalazine. Those patients who responded already during the first period remained stable during the second phase regardless of the treatment they received. However, plasma orosomucoid levels increased significantly in the sulfasalazine-treated but not in those patients who received metronidazole. Though these data suggest that the antimicrobial capabilities of metronidazole are slightly more effective than sulfasalazine in the treatment of Crohn's disease, this study underscores the limitations of crossover studies for assessment of chronic diseases, 14 and the results should be interpreted with caution. Sutherland and co-workers 15 included 105 patients with Crohn's disease in a randomized, double-blind, placebo-controlled study investigating the efficacy of two doses of metronidazole (20 and 10 mg/kg) during a 14-week period. No difference in achieving remission was observed (27% for both metronidazole doses vs 25% for the placebo). However, a significant reduction in CDAI scores, C-reactive protein levels, and serum orosomucoid concentrations in both metronidazole-treated groups was seen compared with placebo. Patients receiving metronidazole 20 mg · kg−1 · day−1 had a greater improvement in disease activity than those receiving 10 mg · kg−1 · day−1. However, this was not significant; probably reflective of the small sample size. It was noteworthy that 17 patients were withdrawn due to adverse events, but there was no difference between the groups. Subgroup analysis disclosed a beneficial effect of metronidazole in patients with ileocolonic disease or colonic disease. No effect was observed in patients with disease confined to the ileum. Side effects of short-term metronidazole therapy are common and include nausea, a metallic taste, and disulfuram-like reaction. 16 Most symptoms were mild and transient and related to daily doses greater than 20 mg · kg−1 · day−1. Resolution of symptoms usually occurs with dose reduction or cessation of therapy. However, significant sensory peripheral neuropathy is also a common side-effect of metronidazole therapy, and in some instances the neuropathy persists despite cessation of therapy. 17 No symptoms have been reported in the use of a cumulative dose of less than 30 g. Pregnant women with short-term exposure to metronidazole have no increase in the incidence of birth defects. The long-term tolerability or safety of this agent in pregnancy is not known. 18 Ciprofloxacin is a quinolone that is clinically effective against enteric pathogens and the majority of gram-negative enterobacteriaceae species. Quinolones also appear to have immunomodulatory properties. 19 Two small, nonblinded comparison trials failed to show any significant benefit of ciprofloxacin versus its competitors in the treatment of active Crohn's disease. 20,21 The group of Colombel et al 20 conducted a 6-week study of 40 patients in which they compared the efficacy of ciprofloxacin 1 g/day to mesalazine 4 g/day and observed no difference between treatment groups (56% remission with ciprofloxacin vs 55% remission with mesalazine). Prantera and co-workers 21 investigated the safety and efficacy of the combination of metronidazole and ciprofloxacin compared with methylprednisolone in 41 patients with active Crohn's disease in a partially blinded study. Consecutive patients were randomized to receive either ciprofloxacin 500 mg twice daily plus metronidazole 250 mg four times daily for 12 weeks or methylprednisolone 0.7–1 mg · kg−1 · day−1, with variable tapering to 4 mg daily. At the end of the study period, 45.5% of patients in the antibiotic group and 63% of steroid-treated patients were in clinical remission. The difference did not reach statistical significance, probably due to the small sample size. Five patients in both groups were considered treatment failures. Adverse events were seen in 27.3% of antibiotic-treated patients and in 10.6% of patients receiving steroids. More recently, the same group retrospectively evaluated the efficacy of metronidazole and/or ciprofloxacin in the treatment of acute Crohn's disease. 22 The clinical records of 233 inpatients treated for active Crohn's disease with metronidazole and/or ciprofloxacin (1 g/day each) during the period 1984–1996 were reviewed: 70.6% of the patients treated with the antibiotic combination achieved clinical remission, 72.8% with metronidazole, and 69.0% with ciprofloxacin. Remission lasted about 1 year in each group. Side effects, requiring discontinuation of therapy, were observed in 20% of patients. The efficacy of the combination of ciprofloxacin and metronidazole in active Crohn's disease was further studied in a open trial by Greenbloom and associates. 23 At the end of the 10-week treatment period, 49/72 patients reached clinical remission (68%), and 55/72 patients showed a clinical response (76%). The effect was even greater in patients with colonic disease with or without ileal involvement (84%) in comparison to patients with ileal disease alone (64%) and in patients without resection (86%) compared with those with previous resection (61%). More recently, Arnold and co-workers 24 recruited 47 adults with moderately active, therapy resistant, Crohn's disease who were randomly assigned treatment with ciprofloxacin 500 mg twice daily or placebo twice daily for 6 months. They observed a modest clinical benefit in the patients receiving ciprofloxacin. In contrast, in a larger placebo-controlled trial reported by Steinhart et al, 25 the addition of both ciprofloxacin and metronidazole to budesonide did not result in any therapeutic gain compared with budesonide monotherapy in mild to moderate Crohn's disease. Ciprofloxacin seems to be well tolerated at the therapeutic dosages. There is a deleterious effect on skeletal development seen in animals, and cases of tendon rupture associated with ciprofloxacin have been reported in humans. 26 Taken together, these data suggest that neither metronidazole nor ciprofloxacin alone are consistently effective in the management of luminal Crohn's disease. Though the combination of metronidazole and ciprofloxacin may have some beneficial effect, the antimicrobial effect is not broad and strong enough to reduce the bacterial load to the degree needed to inhibit reliably the inflammatory process. No studies of metronidazole or ciprofloxacin for maintenance of medically induced remission in patients with Crohn's disease have been conducted. Antibiotic therapy continues to be used in the management of patients with symptoms of active luminal Crohn's disease despite the absolute paucity of level one evidence in favor of these therapeutic agents. Future studies using DNA microarray technology may provide an important opportunity to examine the profile of different strains that comprise the microflora in the setting Crohn's disease. 27 Importantly, the data derived from this approach may provide new opportunities for drug discovery based on molecular mechanisms unique to the host pathogen response that are specific to Crohn's disease.

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