Clinical Trial: Therapeutic Induction of Endogenous Antibiotics

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Therapeutic Induction of Endogenous Antibiotics for Improved Recovery in Shigellosis

Brief Summary: 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.

Detailed Summary:

Study design: A double blind randomized clinical trial with subsequent follow-up.

Study Subjects: Adult male and female patients attending the Clinical Research and Service Center (CRSC) of ICDDR,B and Matlab Hospital will be screened for participation in the study.

Randomization:

According to a computer-generated randomization list, patients full filling the entry criteria will be randomized to either intervention group (Pivmecellinam plus butyrate enema) or control group (Pivmecellinam plus normal saline enema). Butyrate enema will contain 80 mmol/L of butyrate in normal saline (pH 7.2). Placebo enema will contain normal saline(pH 7.2)

Case management:

After enrollment, the patients will be admitted in the study ward of ICDDRB Dhaka and Matlab hospital. A standard clinical history and clinical examination will be performed by one of the investigators or study physician. All patients will receive Pivmecillinam, 400 mg, 8 hourly for 5 days. The intervention group will receive butyrate enema 80 ml of 80 mM sodium butyrate, 12 hourly for 72 hours while the placebo group will get 80 ml of normal saline 12 hourly for 72 hours. All patients will receive the usual hospital food three times a day (breakfast, lunch and supper). The patients will remain in the study ward for 5 days to enable identification of any relapse cases.

Procedure for butyrate enema:

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 plasti
Sponsor: International Centre for Diarrhoeal Disease Research, Bangladesh

Current Primary Outcome: 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 ]

Original Primary Outcome: Same as current

Current Secondary Outcome: 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 ]

Original Secondary Outcome: Same as current

Information By: International Centre for Diarrhoeal Disease Research, Bangladesh

Dates:
Date Received: December 2, 2008
Date Started: January 2005
Date Completion:
Last Updated: December 6, 2011
Last Verified: December 2008