Therapeutic Induction of Endogenous Antibiotics - Full Text View

Purpose

Shigellosis is one of the major causes of morbidity and mortality in many developing countries. The continued emergence of antibiotic resistant strains has complicated the treatment of shigellosis and has increased the cost of treatment markedly. Antimicrobial peptides are considered as endogenous antibiotic. A mixture of these antimicrobial peptides (LL-37 and beta-defensin) drenches the mucosal epithelial surfaces forming a barrier for invading microorganisms. Recently, we found that Shigella down-regulates the expression of LL-37 and beta-defensin 1 (HBD-1) in the colon of patients during acute shigellosis thereby facilitating bacterial invasion. Both LL-37 and HBD-1 could inhibit the growth of various microbes e.g. S. dysenteriae type 1, S. flexneri, and S. boydii. Our study indicated that bacterial DNA might be a potential mediator for the down- regulation in vitro. Down-regulation of LL-37 and HBD-1 was also seen in watery diarrhea caused by other pathogens. Thus, bacteria-mediated down-regulation of our front line defenses could be one strategy evolved by the pathogens to subvert this host-defense mechanism. gene encoding LL-37 in cultured epithelial cell lines were up-regulated when treated with butyrate; butyrate decreased the severity of Shigella infections in rabbit model. We could reproduce our findings from human i.e. downregulation of CAP-18 (the rabbit homologue to human LL-37) in colon epithelia after infection with Shigella flexneri. CAP-18 reappeared after treatment of the infected rabbits with sodium butyrate. Thus, the rabbit model demonstrated the proof of principal. In this study, we aim to assess the efficacy of sodium butyrate enema in reduction of clinical symptoms and / severity, reduction of inflammatory responses and induction of endogenous antibiotic activity in the rectum in adult patients with shigellosis.

Condition	Intervention	Phase
Shigellosis	Biological: Sodium Butyrate Biological: Saline	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Basic Science
Official Title:	Therapeutic Induction of Endogenous Antibiotics for Improved Recovery in Shigellosis

Resource links provided by NLM:

MedlinePlus related topics: Antibiotics Cholera Endoscopy

Drug Information available for: Sodium butyrate

U.S. FDA Resources

Further study details as provided by International Centre for Diarrhoeal Disease Research, Bangladesh:

Primary Outcome Measures:

The primary endpoints of the study is to assess the efficacy of sodium butyrate enema in adult patients with shigellosis in marked improvement in clinical, endoscopic and histological findings. [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To study the effect of sodium butyrate on the induction of endogenous antibiotic peptides in the rectum in adults with shigellosis. [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Enrollment:	80
Study Start Date:	January 2005
Study Completion Date:	January 2009
Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of butyrate solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.	Biological: Sodium Butyrate Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of butyrate solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.
Placebo Comparator: 2 Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of saline solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.	Biological: Saline Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of saline solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Arms

Assigned Interventions

Active Comparator: 1

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of butyrate solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Biological: Sodium Butyrate

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of butyrate solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Placebo Comparator: 2

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of saline solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Biological: Saline

Patients will be instructed to lie on a bed (cholera cot) in left lateral position. A soft rectal catheter will be introduced by a nurse/physician, through which 80 ml of saline solution will be instilled slowly with a 50 ml plastic syringe. Patients will be asked to retain the enema for at least ½ hour by remaining supine for 30 minutes after the administration. However, if a patient cannot retain the enema for 30 minutes, he will be given a second round of enema immediately after defecation.

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

18-55 years of age
duration of diarrhoea 0-4 days
culture-confirmed Shigella spp (all Shigella spp) in stool on enrolment

Exclusion Criteria:

who received antimicrobial treatment before attending the ICDDR,B hospital
clinical symptoms of other concomitant infections (such as chronic respiratory infections, other concomitant gastrointestinal infections)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00800930

Locations

Bangladesh
ICDDR,B
Dhaka, Bangladesh, 1212
Dhaka Hospital & Matlab Hospital
Dhaka, Bangladesh, 1212

Sponsors and Collaborators

International Centre for Diarrhoeal Disease Research, Bangladesh

Swedish International Development Cooperation Agency (SIDA)

Karolinska Institutet

Investigators

Principal Investigator:

Rubhana Raqib, Ph.D.

International Centre for Diarrhoeal Disease Research, Bangladesh

More Information

Publications:

Raqib R, Sarker P, Bergman P, Ara G, Lindh M, Sack DA, Nasirul Islam KM, Gudmundsson GH, Andersson J, Agerberth B. Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9178-83. Epub 2006 Jun 1.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Raqib R, Sarker P, Mily A, Alam NH, Arifuzzaman AS, Rekha RS, Andersson J, Gudmundsson GH, Cravioto A, Agerberth B. Efficacy of sodium butyrate adjunct therapy in shigellosis: a randomized, double-blind, placebo-controlled clinical trial. BMC Infect Dis. 2012 May 10;12:111.

Responsible Party:	International Centre for Diarrhoeal Disease Research, Bangladesh
ClinicalTrials.gov Identifier:	NCT00800930 History of Changes
Other Study ID Numbers:	2004-031
Study First Received:	December 2, 2008
Last Updated:	December 6, 2011
Health Authority:	Bangladesh: Ethical Review Committee

Keywords provided by International Centre for Diarrhoeal Disease Research, Bangladesh:

Shigellosis
sodium butyrate
antimicrobial peptides
LL-37
innate immunity

The aims are to assess efficacy of sodium butyrate enema in
marked improvement in clinical features
endoscopic findings
histological features
Induction of LL-37 in the rectum.

Additional relevant MeSH terms:

Dysentery, Bacillary
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Dysentery
Gastroenteritis
Gastrointestinal Diseases

Digestive System Diseases
Intestinal Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on June 17, 2013