In general, antibiotics have played a role in treating wound infections or abscesses involved in the septic complications of Crohn’s and the inflammatory bowel diseases but not so much in the primary disease processes of Crohn’s disease, UC, or pouchitis. The main rationale for using antibiotics in IBD, however, is to either decrease or alter the concentration of the bacteria or fungi or viruses that are involved in the pathogenesis of IBD. It is found that by using antibiotics, one can change the composition of the intestinal microbiota to favor the beneficial bacteria (such as Lactobacillus and Bfidobacterium that are often reduced in patients with IBD), decrease the bacterial tissue invasion and treat microabscesses or secretory products (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2660793/). Most studies involving antibiotic use in Crohn’s have shown benefit over placebo in reducing Crohn’s disease remission as shown in the table below. However, antibiotics can only alter gastrointestinal flora for a time before the bacteria return and may even promote resistance to these antibiotics by decreasing protective bacteria, especially in cases of C. Dificile in Crohn’s. Based on the possible benefit of the role of antibiotics in Crohn’s disease, there have been many studies using metronidazole, ciprofloxacin, as well as a combination of metronidazole and ciprofloxacin, rifaximin, and clarithromycin. Based on a systematic review combining 16 trials, they found that 3 trials using nitroimidazoles (active against anaerobes and of which group metronidazole is a part of), there was a combined odds ratio of 3.5 with a confidence interval of 1.94 to 6.47, showing positive benefit in long term treatment in Crohn’s. (http://cid.oxfordjournals.org/content/50/4/473.full). Ciprofloxacin (active against E. Coli) was also found to be effective in reducing Crohn disease activity scores, showing effectiveness in a controlled trial that included 47 patients who had moderately active, resistant disease on either ciprofloxacin 500mg BID or monotherapy for six months. The mean CDAI score was decreased in the ciprofloxacin group from 187 to 112 and in the placebo group from 230 to 205. Another drug possibly found useful for Crohn’s disease is rifaximin, which works by binding to the beta-subunit of the bacterial DNA-dependent RNA polymerase, which blocks the synthesis of bacterial RNA. It has activity in both gram positive and negative bacteria as well as in aerobes and anaerobes. As shown from the TARGET1 (623 patients) and TARGET2 (637 patients) trials (http://www.nejm.org/doi/full/10.1056/NEJMoa1004409), which took two identical double blind phase 3 RCTs, patients were randomly assigned to either rifaximin 550mg or placebo three times daily for 2 weeks and followed for an additional 10 weeks. The primary endpoint was the proportion of patients who had adequate relief of global IBS symptoms and the secondary endpoint was the proportion of patients who had an adequate response to treatment. From these trials, it was found that more patients in the rifaximin group (40.8% vs. 31.2%) had adequate relief of global IBS symptoms in the first 4 weeks after treatment. Patients in the rifaximin group also had better relief of bloating (39.5% vs. 28.7%). Another possible drug would be clarithromycin, a macrolide antibiotic that binds to the 50S subunit in bacterial DNA, which would eradicate some of the organisms possibly causing the granulomatous reaction in Crohn’s. An open label trial (http://www.uptodate.com/contents/antibiotics-for-treatment-of-inflammatory-bowel-diseases/abstract/16?utdPopup=true) following 25 patients with Crohn’s disease were treated with clarithromycin 250mg twice daily for four weeks with continued treatment up to 12 weeks. From this trial, around 48% achieved clinical remission whereas 64% did have an overall response. A later trial with 14 Japanese patients using clarithromycin 200mg twice daily for 4 weeks also showed a response in 57% and a remission rate of 36%. Below in the link attached is a table taken from the Can J. Gastroenterology showing the different antibiotic trials in luminal Crohn’s disease with a summary of the more recent and relevant trials using a combination of metronidazole and ciprofloxacin below: From my search, there were three main randomized control trials involving the use of metronidazole and ciprofloxacin. Two of the three trials showed that ciprofloxacin and metronidazole combination was possibly beneficial in patients with active Crohn's disease of the ileum when there is involvement of the colon. In the 2002 article by Steinhart et al., they showed combination of ciprofloxacin and metronidazole at 500mg daily each around 9 of the 17 patients with colon involvement achieved remission compared with 4 of the 16 patients on placebo (53% vs. 25%). However, if one looked at all patients, only 21 of the 64 patients who received antibiotics (33%) achieved remission compared to 25 of the 66 patients on placebo (38%). So, it would really only be beneficial in patients with colon involvement. (http://www.pulsus.com/journals/pdf_frameset.jsp?jnlKy=2&atlKy=1600&isArt=t&jnlAdvert=Gastro&adverifHCTp=&sTitle=Combination%20ciprofloxacin%20and%20metronidazole%20for%20active%20Crohn%27s%20disease%2C%20Pulsus%20Group%20Inc&VisitorType=&pdfType=fulltextpdf) and (http://www.pulsus.com/journals/abstract.jsp?sCurrPg=journal&jnlKy=2&atlKy=1600&isuKy=175&isArt=t) In the trial in 1996 per Prantera C., (http://www.ncbi.nlm.nih.gov/pubmed?term=8607501) there were 41 patients with Crohn's disease randomized to 12 weeks of ciprofloxacin 500mg BID with metronidazole 250mg four times daily of methylprednisolone 0.7-1mg/kg/day. The results showed that 10 of the 22 patients on the antibiotics (45.5%) vs 19 of the patients on steroids (63%) achieved clinical remission. The author's concluded that the combination could also be an alternative to steroids for treatment of Crohn's. In fistulizing disease, there have been remission rates as high as 50% in those using metronidazole at a high dose of 20mg/kg/day. However, nearly half of the patients taking metronidazole for an average of months had developed neurological side effects (http://www.uptodate.com/contents/antibiotics-for-treatment-of-inflammatory-bowel-diseases/abstract/36?utdPopup=true). Another trial using ciprofloxacin also showed improvement with closure of 50% of the fistulae in 40% of those using ciprofloxacin compared to 14% of those using metronidazole (http://www.uptodate.com/contents/antibiotics-for-treatment-of-inflammatory-bowel-diseases/abstract/13?utdPopup=true). Lower antibiotic doses in this case would be more effective in decreasing side effects while serving as adjuncts to immunosuppressive therapy (http://www.uptodate.com/contents/antibiotics-for-treatment-of-inflammatory-bowel-diseases/abstract/39?utdPopup=true) in a trial which showed that 73% of the (8 of 11) in the ciprofloxacin group responded better in the combination than in using infliximab alone. Thus, antibiotics using either a combination of metronidazole or ciprofloxacin or these agents alone ae used as fist-line treatments for uncomplicated perianal fistula after drainage of abscesses. These antibiotics may be continued for up to 3 months with monitoring and oftentimes in combination with other immunosuppressive agents such as azathioprine, 6-MP, or anti-TNF. The best combination therapy for treatment of Crohn’s disease or Crohn’s flares is yet to be determined, although from the studies above, it seems that combination therapies of antibiotics or antibiotics with immunosuppressants were more effective in helping patients achieve remission of their disease state. In terms of fluoroquinolone resistance, there were two studies that I found in my search regarding fluoroquinolone resistance in patients with Crohn’s Disease affected with C. Dificile. In a study by Park et al in 2014 (http://www.ncbi.nlm.nih.gov/pubmed/24296421), microorganisms as well as their resistance to ciprofloxacin were analyzed in 78 CD patients who had percutaneous drainage of their intra-abdominal abscess. The study was from March 1991 to November 2011. From their results, they found that more than 2/3 of the gram negative aerobes taken from the abscesses in CD patients were resistant to ciprofloxacin. This was a significant result in showing the high rate of resistance to a quinolone that is possibly used at a very high rate in treating abscesses and the need to consider other antibiotic treatment. In another systematic review of C. Diff infection and inflammatory disease by Udayakumar et al. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957597/), it was found that the resistance of C. Diff to antibiotics such as fluoroquinolones has been somewhat controversial. The use of fluoroquinolones per the paper seemed to be associated with an increase in a hyper-virulent strain of C. diff, BI/NAP1/027 that is associated with higher mortality and complicated disease course. The course of development of C. diff in IBD has been controversial and variable, however. One study showed that only 40% of the IBD patients (http://www.ncbi.nlm.nih.gov/pubmed/21172241) on fluoroquinolones developed C. diff in comparison to 69% of those who were non-IBD patients. However, in a study examining IBD patients, 61% of those patients developed (total 2,547 in 2004 and 2,349 in 2005) C. Dificile. Thus, there is increasing resistance to fluoroquinolones to the less hyper-virulent strain of C. Diff and it plays a role in the development of increased C. diff cases.
discoholicmusic
s-u-f-j-a-n-s-t-e-v-e-n-s
andulkaphoto