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. 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. 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, duodenum, liver and other organs.
Another hypothesis proposes that specific bacterial species infect dendritic cells and macrophages in genetically predisposed individuals. 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. 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. 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. In 1991, Sutherland et al. trialed two metronidazole regimens – 10 and 20 mg/kg/day – versus placebo in 105 CD patients. 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. 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. 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). 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" 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. 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. 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). Colombel et al. demonstrated that ciprofloxacin was as effective as mesalazine for inducing remission, reporting remission rates of 56 and 55%, respectively. 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. 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|||
|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|||
|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|||
|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%)|||
|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%)|||
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. 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. Shafran et al. retrospectively reported on 68 patients with CD treated with rifaximin over a 4-year (mean: 16.6 weeks) period. 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).
Resources and References
- Perencevich M, Burakoff R. Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm. Bowel Dis. 12(7), 651–664 (2006).
- Podolsky DK. Inflammatory bowel disease. N. Engl. J. Med. 347, 417–429 (2002).
- Akbulut S, Yavuz B, Koseoglu T et al. Crohn's disease with isolated esophagus and gastric involvement. Turk. J. Gastroenterol. 15(3), 196–200 (2004).
- Malleson P. Isolated gastroduodenal Crohn's disease in a ten-year-old girl. Postgrad. Med. J. 56, 294–296 (1980).
- Kotanagi H, Sone S, Fukuoka T et al. Liver abscess as the initial manifestation of colonic Crohn's disease: report of a case. Surgery Today 21(3), 348–351 (2007).
- Ulnick KM, Perkins J. Extraintestinal Crohn's disease: case report and review of the literature. Ear Nose Throat J. 80(2), 97–100 (2001).
- Sartor BR. Pathogenesis of Crohn's disease and ulcerative colitis: specific theories. Nat. Clin. Prac. Gastroenterol. Hepatol. 3(7), 390–407 (2006).
- Blichfeldt P, Blonhoff JP, Myhre E et al. Metronidazole in Crohn's disease. A double-blind cross-over clinical trial. Scand. J. Gastroenterol. 13, 123–127 (1978).
- Ursing B, Alm T, Barany F et al. A comparative study of metronidazole and sulfasalazine for active Crohn's disease: the cooperative Crohn's disease study in Sweden. II Result. Gastroenterology 83, 550–562 (1982).
- Ambrose NS, Allan RN, Keighley MR et al. Antibiotic therapy for treatment in relapse of intestinal Crohn's disease. Dis. Colon Rectum 28, 81–85 (1985).
- Sutherland L, Singleton J, Sessions J et al. Double-blind, placebo controlled trial of metronidazole in Crohn's disease. Gut 32, 1071–1075 (1991).
- De'Haens GR, Vermeire S, Van Assche G et al. Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn's disease: a controlled randomized trial. Gastroenterology 135(4), 1123–1129 (2008).
- Feller M, Huwiler K, Schoepfer A et al. Long-term antibiotic treatment for Crohn's disease: systematic review and meta-analysis of placebo-controlled trials. Clin. Infect Dis. 50(4), 473–480 (2010). Systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effectiveness of long-term antibiotic therapy. The authors concluded that long-term treatment with nitroimidazoles or clofazimine appear to be effective in patients with Crohn's disease (CD).
- Peppercorn MA. Is there a role for antibiotics as primary therapy in Crohn's disease? J. Clin. Gatroenterol. 17, 235–237 (1993).
- Arnold GL, Beaves MR, Pyrjdun VO et al. Preliminary study of ciprofloxacin in active Crohn's disease. Inflamm. Bowel Dis. 8, 10–15 (2002).
- Prantera C, Zannoni F, Scribano ML et al. An antibiotic treatment regimen for the treatment of active Crohn's disease. A randomized controlled clinical trial of metronidazole plus ciprofloxacin. Am. J. Gastroenterol. 91, 328–332 (1996).
- Colombel JF, Lehman M, Cassagnou M et al. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETARD). Am. J. Gastroenterol. 94, 674–678 (1999).
- Steinhart AH, Feagan BG, Wong CJ et al. Combined budesonide and antibiotic therapy for active Crohn's disease. A randomized controlled trial. Gastroenterology 123, 33–40 (2002).
- Prantera C, Berto E, Scribano ML et al. Use of antibiotics in the treatment of active Crohn's disease. Experience with metronidazole and ciprofloxacin. Ital. J. Gastroenterol. Hepatol. 30, 602–606 (1998).
- Greenbloom SL, Steinhart AH, Greenberg GR. Combination ciprofloxacin and metronidazole for active Crohn's disease. Can. J. Gastroenterol. 12, 53–56 (1998).
- Khan K, Ullman T, Ford A et al. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am. J. Gastroenterol. 106(4), 661–673 (2011). Comprehensive systematic review of RCTs evaluating the use of all antibacterial therapy in inflammatory bowel disease. A diverse number of antibiotics were tested including anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles and rifaximin either alone or in combination and found that there was a statistically significant effect of antibiotics in inducing remission in active CD compared with placebo (relative risk of active CD not in remission: 0.85; 95% CI: 0.73–70.99; p = 0.03).
- Dignass A, Van Assche G, Lindsay JO et al. The second European evidence-based consensus on the diagnosis and management of Crohn's Disease: current management. J. Crohn's Colitis 4, 28–62 (2010).
- Shafran I. Burgeunder P. Rifaximin for the treatment of newly diagnosed Crohn's disease: a case series. Am. J. Gasteroenterol. 103, 2158–2160 (2008).
- Shafran I, Johnson LK. An open-label evaluation of rifaximin in the treatment of active Crohn's disease. Curr. Med. Res. Opin. 21, 1165–1169 (2005).
- Shafran I, Burgunder P. Adjunctive antibiotic therapy with rifaximin may help reduce Crohn's disease activity. Dig. Dis. Sci. 55, 1079–1084 (2010).
- Warren J, Rees H, Cox T. Remission of Crohn's disease with tuberculosis chemotherapy. N. Engl. J. Med. 314, 182 (1986).
- Schultz M, Rieder H, Hersh T et al. Remission of Crohn's disease with antibacterial chemotherapy. Lancet 330, 1391–1392 (1987).
- Ward M, McManus JP. Dapsone in Crohn's disease. Lancet 1, 1236–1237 (1975).
- Prantera C, Argentieri R, Mangiarotti R et al. Dapsone and remission of Crohn's disease. Lancet 1(8584), 536 (1988).
- Prantera C, Bothamley G, Levenstein S et al. Crohn's disease and mycobacteria: two cases of Crohn's disease with high anti-mycobacterial antibody levels cured by dapsone therapy. Biomed. Pharmacother. 43(4), 295–299 (1989).
- Shaffer JL, Hughes S, Linaker BD et al. Controlled trial of rifampicin and ethambutol in Crohn's disease. Gut 25, 203–205 (1984).
- Jarnerot G, Rolny P, Wickbom G et al. Antimycobacterial therapy ineffective in Crohn's disease after a year. Lancet 1, 164–165 (1989).
- Swift GL, Srivastava ED, Stone R et al. Controlled trial of anti-tuberculosis chemotherapy for two years in Crohn's disease. Gut. 35, 363–368 (1994).
- Rutgeerts P, Geboes K, Vantrappen G et al. Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum. J. Clin. Gastroenterol. 15, 24–28 (1992).
- Hampson S, Parker M, Saverymutter S et al. Quadruple antimycobacterial chemotherapy in Crohn's disease: results at 9 months of a pilot study in 20 patients. Aliment. Pharmacol. Ther. 3(4), 343–352 (1989).
- Prantera C, Kohn A, Mangiarotti R et al. Antimycobacterial therapy in Crohn's disease: results of a controlled double-blind trial with a multiple antibiotic regimen. Am. J. Gastroenterol. 89(4), 513–518 (1994).
- Afdhal NH, Long A, Lennon J et al. Controlled trial of antimycobacterial therapy in Crohn's disease: clofazimine versus placebo. Dig. Dis. Sci. 36, 449–453 (1991).
- Graham DY, Al-Assi MT, Robinson M. Prolonged remission in Crohn's disease following therapy for Mycobacterium paratuberculosis infection. Gastroenterology 108, A826 (1995).
- Leiper M. Open label trial of oral clarithromycin in active Crohn's disease. Aliment. Pharmacol. Ther. 14(6), 801–806 (2000).
- Inoue S, Nakase H, Matsuura M et al. Open label trial of clarithromycin therapy in Japanese patients with Crohn's disease. J. Gastro. Hepatol. 22, 984–988 (2007).
- Mitchell JD, Bishop A, Cafaro A et al. Anatomic lung resection for nontuberculous mycobacterial disease. Ann. Thorac. Surg. 85, 1887–1893 (2008).
- Gangadharam PR, Perumal, VK, Jairam, BT et al. Activity of rifabutin alone or in combination with clofazimine or ethambutol or both against acute and chronic experimental Mycobacterium intracellulare infections. Am. Rev. Respir. Dis. 136, 329–333 (1987).
- Hornick DB, Dayton CS, Bedell GN et al. Nontuberculous mycobacterial lung disease. Substantiation of a less aggressive approach. Chest 93(3), 550–555 (1988).
- Chiodini RJ. Antimicrobial activity of rifabutin in combination with two and three other antimicrobial agents against strains Mycobacterium avium paratuberculosis. J. Antimicrob. Chemother. 27, 171–176 (1991).
- Blasquez J, Oliver A, Gomez-Gomez JM. Mutation and evolution of antibiotic resistance: antibiotics as promoters of antibiotic resistance? Curr. Drug Targets 3(4), 345–349 (2002).
- Ghebremichael S, Svenson SB, Kallenius G et al. Antimycobacterial synergism of clarithromycin and rifabutin. Scan. J. Infect. Dis. 28, 387–390 (1996).
- Rastogi N, Goh KS, Labrousse V. Activity of clarithromycin compared with those of other drugs against Mycobacterium paratuberculosis and further enhancement its extracellular and intracellular activities by ethambutol. Antimicrob. Agents Chemother. 36, 2843–2846 (1992).
- Gui GPH, Thomas PRS, Tizard MLV et al. Two-year outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics. J. Antimicrob. Chemother. 39(3), 393–400 (1997).
- Douglas A, Bramble MG, Silcock JC. Antimycobacterial treatment for Crohn's disease: does it prevent surgery and how fast does it act? Gut 48, A89 (2000).
- Borody TJ, Leis S, Warren EF et al. Treatment of severe Crohn's disease using antimycobacterial triple therapy – approaching a cure? Dig. Liver Dis. 34(1), 29–38 (2002).
- Shafran I, Kugler L, El-Zaatari FA et al. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease. Dig. Liver Dis. 34(1), 22–28 (2002).
- Borody TJ, Bilkey S, Wettstein AR et al. Australian Gastroenterology Week Meeting. Brisbane, Queensland, Australia, 19–22 October 2005.
- Borody TJ, Bilkey S, Wettstein AR et al. Anti-mycobacterial therapy in Crohn's disease heals mucosa with longitudinal scars. Dig. Liver Dis. 39(5), 438–444 (2007). Report on the prolonged use of anti-Mycobacterium avium paratuberculosis therapy in CD. 22 patients (56.4%; 22 out of 39) experiencing profound healing with unusual scarring. Scars receded in two out of six patients (33.3%) who had >3 years of treatment as full healing occurred, implying a more complete healing not seen with standard anti-inflammatory and immunosuppressant drugs.
- Selby W, Pavli P, Crotty B et al. Two-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease. Gastroenterology 132(7), 2313–2319 (2007). RCT of CD patients treated with antimycobacterial therapy. A remission rate of 66% was achieved in CD patients treated with antimycobacterial therapy at 16 weeks (p = 0.02) despite suboptimal dosing of two of the three antibiotics and incomplete dissolution of clofazimine.
- Behr M, Kapur V. The evidence for Mycobacterium paratuberculosis in Crohn's disease. Curr. Opin. Gastroenterol. 24(1), 17–21 (2008).
- Biroulet LP, Neut C, Colombel JF. Antimycobacterial therapy in Crohn's disease: the end of a long controversy? Prac. Gastro. 1, 11–17 (2008).
- Yunzhao RR, Pan F, Parvez S et al. Clofazamine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS One 3(12), e4009 (2008).
- Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn's disease: the ACCENT 1 randomised trial. Lancet 359, 1541–1549 (2002).
- Keunstner J. Australian Crohn's Antibiotic Study opens new horizons. Gastroenterology 133(5), 1743–1744 (2007).
- Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 132(1), 52–65 (2007).
- Moore TJ, Cohen MR, Furberg CD et al. Serious adverse drug events reported to the Food and Drug Administration, 1998–2005. Arch. Intern. Med. 167(16), 1752–1759 (2007).
- Lees C, Ali A, Thompson AI, Ho GT et al. The safety profile of anti-TNF therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up. Aliment. Pharmacol. Ther. 29(3), 286–297 (2009).
- Chamberlin W, Ghobrial G, Chehtane M et al. Successful treatment of a Crohn's disease patient infected with bacteremic Mycobacterium paratuberculosis. Am. J. Gastroenterol. 102, 689–691 (2007). Case report of a patient with longstanding active CD who achieved total clinical remission following treatment with clarithromycin, rifabutin and levofloxacin that resulted in resolution of abdominal pain, diarrhea and fatigue; suppression of Mycobacterium avium paratuberculosis markers; and complete mucosal normalization on colonoscopy. This case report is the first of its kind to correlate CD resolution with suppression of Mycobacterium avium paratuberculosis markers.
- Rahimi R, Shekoufeh N, Rezaie A et al. A meta-analysis of broad-spectrum antibiotic therapy in patients with active Crohn's disease. Clin. Ther. 28(12), 1983–1988 (2006).
- Netea MG, Joosten LA. A NOD for autophagy. Nature Med. 16, 28–30 (2010).
- Hayee B, Rahman F, Sewell G et al. Crohn's disease as an immunodeficiency. Expert Rev. Clin. Immunol. 6(4), 585–596 (2010).
- Korzenik JR, Dieckgraefe BK, Valentine JF et al. Sargramostim for active Crohn's disease. N. Engl. J. Med. 352, 2193–2201 (2005).
- Nicoletti F, Conrad D, Wang A et al. 16α-bromoepiandrosterone (HE2000) limits non-productive inflammation and stimulates immunity in lungs. Clin. Exp. Immunol. 158(3), 308–316 (2009).
- Levin BR, Bull JJ. Population and evolutionary dynamics of phage therapy. Nat. Rev. Micro. 2, 166–173 (2004).
- Excerpted from “Primary Treatment of Crohn’s Disease,” Combined Antibiotics Taking Center Stage. William Chamberlin, Thomas J Borody, Jordana Campbell. Expert Rev Clin Immunol. 2011;7(6):751-760.