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Antibiotics for the Treatment of Ulcerative Colitis

Information source: University of Dundee
Information obtained from ClinicalTrials.gov on November 03, 2008
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Colitis, Ulcerative

Intervention: Cefuroxime (Drug); Ciprofloxacin (Drug); Clarithromycin (Drug); Cotrimoxazole (Drug); Coamoxiclav (Drug); metronidazole (Drug); neomycin (Drug); rifaximin (Drug); Vancomycin (Drug); Doxycycline (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: University of Dundee

Official(s) and/or principal investigator(s):
George T Macfarlane, BSCc, PHD, Principal Investigator, Affiliation: University of Dundee
John H Cummings, MBChB MSc MA, Principal Investigator, Affiliation: University of Dundee
Sandra Macfarlane, BSc, PhD, Principal Investigator, Affiliation: University of Dundee

Overall contact:
Helen D Steed, MBChB, MRCP, Phone: 01382 496321, Email: helensteed@doctors.org.uk

Summary

Ulcerative colitis (UC) is an acute and chronic inflammatory bowel disease, whose cause is unknown. However, it is widely accepted that bacteria living in the large bowel are essential for the development of the disease. Intuitively, therefore, a logical approach to treatment would be to use antibiotics. Howevere, antimicrobial chemotherapy has been unsuccessful in managing acute colitis, and has had only limited benefit in long-term treatment. The failure of antibiotics in UC arises from the fact that no-one has tried to identify which bacteria are involved in causing disease, and equally importantly, nobody has targeted appropriate antibiotics to knock out the specific bacteria in question, in a sysstematic way. Despite this, increasing evidence implicates bacteria living on the lining of the bowel being involved in UC. Our aim, therefore is to identify bacteria colonising the mucosal surface in the lower large intestine and to determine the antibiotic sensitivities of those we beleive to be particularly involved in the disease, such as enterococcit, peptostreptococci and enterobacteria. Because we have already studied resistance to antimicorbial in many mucosal isolate, we plan ot focus on using a combination of two antibiotics in this work. A controlled trial will test the benefit of using these antibiotics over a period of one month and then the patients will be followed up over a six month period. We will be looking for significant long-term improvements, and a reduction in drug use following antibiotic therapy.

Clinical Details

Official title: Use of Antibiotics to Eradicate Bacterial Pathogens Colonising the Colonic Mucosa in Ulcerative Colitis Patients

Study design: Treatment, Non-Randomized, Open Label, Historical Control, Single Group Assignment, Efficacy Study

Primary outcome: Sigmoidoscopy score 0,1 and 7 months

Secondary outcome:

Mucosal immune markers: human beta defensins, proinflammatory cytokines

haemtaology indices

biochemical indicies

clinical activity index

bowel habit diary

all at 0, 1 and 7 months

Detailed description: It is now widely acknowledged, as a result of experimental studies over the last 30 years, tht the mucosal flora of hte large bowel are essential to the pathogenesis of ulcerative colitis. Whilst treatment with antibiotics, therefore, might seem a logical approach, a number of clinical trials have proved disappointing. This is because the principal bacteria involved in the inflammatory process have not been identified and their sensitivities to the antibacterials determined. Moreover, we are only now beginning to understand the physiology of biofilm populations on mucosal surfaces, one property of which is antibiotic resistance. Our own studies have show a distinctive bacterial populatio nof the mucosa with UC patients with reduced numbers of protective bifidobacteria and increased enterobacteria which we have linked to disease activity. Antibiotic resistance to commonly used gut antibiotics is widespread in these bacteria.

Our study, therefore, will commence with multiple biopsies of the distal large bowel mucosa being taken in patients with active UC and detailed microbiological characterisation of the flora using viable counting, chemotaxonomy and molecular approaches. Antibiotic sensitivities of the likely pathogens will be determined and dissemination of antibiotic resistance genes in the mucosal microbiota followed using real time PCR. Markers of mucosal immune response including proinflammatory cytokines and human betea defensins will also be measured. Two weeks after initial biopsies, the patient will return to pur reserach IBD clinic where the appropriate combination of antibiotics will be prescribed and these will be taken for one month. A further assessment will occur at teh end of this period including mucosal biopsies. endpoints will include clinical activity index, bowel habit diaries, sigmoidoscopy score, mucosal immune markers and routine haematology adn biochemical indices. Because fo the long term effect of antibiotics on teh gut mucosa, which can last for many months, the study cannot be randomised and therefore, the run in period will be taken as a control period and the four weeks on the antibiotic will follow in all patients. The prime endpoint will be sigmoidoscopy score and the subjects will be followed up for a further six months after the study to look for longterm benefits.

Eligibility

Minimum age: 18 Years. Maximum age: 79 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Active ulcerative colitis, CAI greater than or equal to 4

Exclusion Criteria:

- Antibiotics in the last 3 months

- Probiotics

- Alteration to medications in last 3 months

Locations and Contacts

Helen D Steed, MBChB, MRCP, Phone: 01382 496321, Email: helensteed@doctors.org.uk

Ninewells Hospital and Medical School, Dundee, Angus DD1 9SY, United Kingdom; Recruiting
Nigel Reynolds, BA, FRCP, Sub-Investigator
Helen D Steed, MBChB, MRCP, Sub-Investigator
Additional Information

Related publications:

Montgomery SM, Morris DL, Thompson NP, Subhani J, Pounder RE, Wakefield AJ. Prevalence of inflammatory bowel disease in British 26 year olds: national longitudinal birth cohort. BMJ. 1998 Apr 4;316(7137):1058-9. No abstract available.

Mayberry JF, Ballantyne KC, Hardcastle JD, Mangham C, Pye G. Epidemiological study of asymptomatic inflammatory bowel disease: the identification of cases during a screening programme for colorectal cancer. Gut. 1989 Apr;30(4):481-3.

Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. Gut. 2000 Mar;46(3):336-43.

Cummings JH, Macfarlane GT, Macfarlane S. Intestinal bacteria and ulcerative colitis. Curr Issues Intest Microbiol. 2003 Mar;4(1):9-20. Review.

Onderdonk AB, Bartlett JG. Bacteriological studies of experimental ulcerative colitis. Am J Clin Nutr. 1979 Jan;32(1):258-65. No abstract available.

Macfarlane S, Furrie E, Cummings JH, Macfarlane GT. Chemotaxonomic analysis of bacterial populations colonizing the rectal mucosa in patients with ulcerative colitis. Clin Infect Dis. 2004 Jun 15;38(12):1690-9. Epub 2004 May 25.

Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O'neil DA, Macfarlane GT. Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut. 2005 Feb;54(2):242-9.

Starting date: July 2006
Ending date: December 2007
Last updated: October 10, 2006

Page last updated: November 03, 2008

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