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There is a strong association between serum antibody responses to toxin A and protection against Clostridium difficile diarrhea. A parenteral C. difficile toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G (IgG) in the sera of healthy volunteers. After vaccination, the concentrations of anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations that were associated with protection in previous clinical studies. Furthermore, the median concentration of serum anti-toxin A IgG in the test group was 50-fold higher than the previous threshold. These findings support the feasibility of using a vaccine to protect high-risk individuals against C. difficile-associated diarrhea and colitis.Clostridium difficile is the most commonly known cause of nosocomial infectious diarrhea in industrialized countries (2, 9). Rates of C. difficile infection in high-risk hospital patients receiving antibiotics are as high as 31% (11,15,19). The clinical presentation of C. difficile colitis ranges from mild diarrhea to fulminant pseudomembranous colitis (2, 9). However, approximately half of the patients who are colonized by toxin-producing strains of C. difficile are asymptomatic carriers (11,15).Two recent clinical studies demonstrated that high concentrations of anti-toxin A immunoglobulin G (IgG) antibody in serum were associated with protection against C. difficile-associated diarrhea and colitis (11,12). In the first study, infected patients with serum anti-toxin A IgG concentrations of greater than 3 enzyme-linked immunosorbent assay (ELISA) units (EU) were 48-fold more likely to become asymptomatic carriers than patients with lower concentrations of anti-toxin A antibody (11). In the second study, patients who developed high concentrations of serum anti-toxin A IgG during initial episodes of C. difficile-associated diarrhea were 48-fold less likely to suffer a recurrence than those who did not show an anti-toxin A antibody response (12). These findings provide further evidence that active or passive immunization against C. difficile toxins may be effective in preventing C. difficile-associated diarrhea and colitis (1,3,5,10,13,17,20).Kotloff et al. reported recently their experience using a parenteral C. difficile vaccine containing toxoids A and B administered to healthy adult volunteers (7). To our knowledge, this is the only candidate C. difficile vaccine that has been tested in human studies. The vaccine was produced from a culture filtrate of C. difficile strain ATCC 43255 as previously described (7). Briefly, toxins A and B were partially purified by ammonium sulfate precipitation and application to an S300 Sephacryl size exclusion column, followed by inactivation with formaldehyde. The total protein concentration of the vaccine was 0.52 mg per ml, of which toxins A and B comprised about 44% at a 1.5:1 toxin A-to-toxin B ratio. Both toxoid A and toxoid B were included in the C. difficile vaccine based on preclinical observations which indicated that both toxin A and toxin B m...

Clostridium difficile is a major cause of infectious diarrhoea in hospitalised patients. Surface layer proteins (SLPs) are the most abundant surface localised proteins expressed by C. difficile. The aim of this study was to examine the humoral immune response to C. difficile SLPs and its potential role in protection from C. difficile associated diarrhoea (CDAD). Serum antibodies to SLPs from C. difficile were measured by ELISA in a cohort of 146 patients (55 patients with CDAD, 34 asymptomatic carriers, and 57 controls). No significant difference was detected in serum IgM, IgA or IgG antibody levels between cases, carriers or control groups at any of the time points tested. However, patients with recurrent episodes of C. difficile diarrhoea had significantly lower IgM-anti-SLP levels than patients with a single episode on days 1, 3, 6 and 9 (p = 0.05, p = 0.009, p = 0.02, p = 0.049). The adjusted odds ratio for recurrent diarrhoea associated with a low day 3 serum IgM anti-SLP antibody level was 24.5 (95% confidence interval; 1.6-376.3). Further studies which examine the specific anti-SLP antibody responses to the colonising strain are warranted to determine if immune responses to C. difficile SLPs play a role in protection from CDAD.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that can present with a wide array of symptoms that make treatment difficult. Current therapies are directed at relieving symptoms of abdominal pain or discomfort, bloating, constipation, and diarrhea. Pharmacologic agents used to treat IBS-associated pain include myorelaxants, peppermint oil, and peripherally acting opiates. Dicyclomine and hyoscyamine, the two myorelaxants available in the United States, have not been proven effective in reducing abdominal pain in patients with IBS. The efficacy of peppermint oil is debated, but methodological problems with existing studies preclude definitive judgment. Loperamide is ineffective for relief of abdominal pain. For IBS patients with excessive abdominal bloating, a small number of studies suggest that bacterial eradication with gut-directed antibiotics and bacterial reconstitution with nonpathogenic probiotics may reduce flatulence. For constipation-predominant (C-IBS) symptoms, current treatment options include fiber supplementation, polyethylene glycol, and tegaserod. Soluble fibers (ispaghula, calcium polycarbophil, psyllium) are more effective than insoluble fibers (wheat bran, corn fiber) in alleviating global symptoms and relieving constipation, although fiber in general has marginal benefit in treatment of overall IBS symptoms. Polyethylene glycol increases bowel frequency in chronic constipation, but its overall efficacy against IBS is unclear. Tegaserod, a 5-HT(4) agonist, demonstrates superiority over placebo in improving bowel frequency and stool consistency and alleviating abdominal pain and bloating in women with C-IBS. Overall global symptoms are modestly improved with tegaserod when compared with placebo. Additional agents under investigation for C-IBS include the ClC(2) chloride channel opener lubiprostone, mu-opioid receptor antagonist alvimopan, and 5-HT(4) agonist renzapride. For diarrhea-predominant (D-IBS) symptoms, available therapies include loperamide, alosetron, and clonidine. Alosetron, a 5-HT(3) antagonist, is superior to placebo for reducing bowel frequency, improving stool consistency, and relieving abdominal pain in women with D-IBS. However, alosetron is available under a restricted license because of concerns for ischemic colitis and severe constipation necessitating colectomy. Clonidine may be helpful in alleviating global symptoms for D-IBS patients.

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