Antibiotics for the Treatment of Ulcerative Colitis

NCT ID: NCT00355602

Last Updated: 2009-02-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-07-31
• Study Completion Date: 2008-12-31

Brief 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. However, 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 systematic 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 colonizing the mucosal surface in the lower large intestine and to determine the antibiotic sensitivities of those the investigators believe to be particularly involved in the disease, such as enterococcit, peptostreptococci and enterobacteria. Because the investigators have already studied resistance to antimicrobial in many mucosal isolate, the investigators 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. The investigators will be looking for significant long-term improvements, and a reduction in drug use following antibiotic therapy.

Detailed Description

It is now widely acknowledged, as a result of experimental studies over the last 30 years, that the mucosal flora of the 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 population of 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 characterization 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 research 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 the end of this period including mucosal biopsies. endpoints will include clinical activity index, bowel habit diaries, sigmoidoscopy score, mucosal immune markers and routine haematology and biochemical indices. Because of the long term effect of antibiotics on the 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 long term benefits.

Conditions

Colitis, Ulcerative

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

Cefuroxime

Intervention Type: DRUG

Ciprofloxacin

Intervention Type: DRUG

Clarithromycin

Intervention Type: DRUG

Cotrimoxazole

Intervention Type: DRUG

Coamoxiclav

Intervention Type: DRUG

metronidazole

Intervention Type: DRUG

neomycin

Intervention Type: DRUG

rifaximin

Intervention Type: DRUG

Vancomycin

Intervention Type: DRUG

Doxycycline

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 79 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tenovus Scotland

OTHER

Sponsor Role: collaborator

University of Dundee

OTHER

Sponsor Role: lead

Principal Investigators

George T Macfarlane, BSCc, PHD

Role: PRINCIPAL_INVESTIGATOR

University of Dundee

John H Cummings, MBChB MSc MA

Role: PRINCIPAL_INVESTIGATOR

University of Dundee

Sandra Macfarlane, BSc, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Dundee

Locations

Ninewells Hospital and Medical School

Dundee, Angus, United Kingdom

Countries

United Kingdom

References

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Reference Type: BACKGROUND

PMID: 9552907 (View on PubMed)

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. doi: 10.1136/gut.30.4.481.

Reference Type: BACKGROUND

PMID: 2785474 (View on PubMed)

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. doi: 10.1136/gut.46.3.336.

Reference Type: BACKGROUND

PMID: 10673294 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 12691258 (View on PubMed)

Onderdonk AB, Bartlett JG. Bacteriological studies of experimental ulcerative colitis. Am J Clin Nutr. 1979 Jan;32(1):258-65. doi: 10.1093/ajcn/32.1.258. No abstract available.

Reference Type: BACKGROUND

PMID: 760501 (View on PubMed)

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. doi: 10.1086/420823. Epub 2004 May 25.

Reference Type: BACKGROUND

PMID: 15227614 (View on PubMed)

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. doi: 10.1136/gut.2004.044834.

Reference Type: BACKGROUND

PMID: 15647189 (View on PubMed)

Other Identifiers

Tenovus 134/03

Identifier Type: -

Identifier Source: org_study_id