Clostridium Difficile toxin by Ray Sahelian, M.D.

Clostridium difficile is a bacterium that causes diarrhea and more serious intestinal conditions such as colitis. In the past few years there has been an increased incidence and severity of Clostridium difficile colitis, not just in the USA, but worldwide. A number of factors have likely contributed to this, including fluoroquinolone -resistant clone of C. difficile and decreasing effectiveness of the first-line agent metronidazole in treating this disease. Human infection with Clostridium difficile can take many forms. It can exist in many patients who are relatively well or who have symptoms similar to irritable bowel syndrome. It can also infect the patient in the acute care facility. These patients typically have received antibiotics for more than 3 days and begin to experience foul-smelling, watery stools within a few days of initiation of antibiotic coverage.
   Over the years, clostridium difficile has become more common, stronger and more resistant to antibiotics. This change could be caused by new strains of the bacteria, its increasing resistance to antibiotics or the increasing severity of illness and therefore susceptibility to infection among hospitalized patients

Clostridium Difficile Colitis risk factors
Clostridium difficile toxin -positive patients are older, more often come from nursing homes, have higher leukocyte counts , higher blood urea nitrogen, lower serum albumin and more often receive diuretics and antibiotics. Previous antibiotic-associated diarrhea is the most significant risk factor for toxin-positive diarrhea, followed by clindamycin treatment, diuretics and older age. The use of proton pump inhibitors increases the risk for C. difficile infection.

Natural Treatment for Clostridium difficile

Probiotics are living organisms which, when ingested, have a beneficial therapeutic effect. Controlled trials indicate a benefit of these bacteria in the prevention of antibiotic-associated diarrhoea. Early evidence suggests the use of probiotics may be helpful in C difficile inection. The addition of fiber, for instance in the form of psyllium, may reduce the severity of diarrhea since fiber is able to absorb fluids. It may be a good idea to avoid prune juice since prune juice accelerates peristalsis. Foods high in fiber are worth a try.

Antibiotic Treatment C Difficile
Treatment of C. difficile colitis includes correction of dehydration and electrolyte (mineral) deficiencies, discontinuing the antibiotic that caused the colitis, and using antibiotics to eradicate the C. difficile bacterium. Oral metronidazole and vancomycin are equally effective in treating diarrhea caused by C difficile infection.

C Difficile Infection - C Difficile Colitis
Clostridium difficile colitis occurs in about 20% of hospitalized patients taking antibiotics (1). Most patients treated for this infection improve, but about 20% relapse (2). Relapse is defined as recurrence of symptoms and documentation of infection within 2 months of successful standard therapy. Patients with relapsing C difficile colitis are prone to further relapses, each one making eradication more difficult.

C Difficile Symptom
Symptom of C difficile toxin and infection include watery diarrhea (at least three bowel movements per day for two or more days), fever, loss of appetite, nausea. Abdominal pain/tenderness can be another symptom of C difficile infection.

C Difficile infection research
Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease.
Am J Gastroenterol. 2006 Apr;101(4):812-22. McFarland LV. Department of Health Services Research and Development, Veterans Administration Puget Sound Health Care System, Seattle, Washington 98101, USA.
Antibiotic-associated diarrhea (AAD) is a common complication of most antibiotics and Clostridium difficile disease, which also is incited by antibiotics, is a leading cause of nosocomial outbreaks of diarrhea and colitis. The use of probiotics for these two related diseases remains controversial. OBJECTIVE: To compare the efficacy of probiotics for the prevention of AAD and the treatment of Clostridium difficile disease based on the published randomized, controlled clinical trials. Trials were included in which specific probiotics given to either prevent or treat the diseases of interest. Trials were required to be randomized, controlled, blinded efficacy trials in humans published in peer-reviewed journals. Trials that were excluded were pre-clinical, safety, DATA SYNTHESIS: From 25 randomized controlled trials (RCTs), probiotics significantly reduced the relative risk of AAD (RR = 0.43, 95% CI 0.31, 0.58, p < 0.001). From six randomized trials, probiotics had significant efficacy for Clostridium difficile disease. CONCLUSION: A variety of different types of probiotics show promise as effective therapies for these two diseases. Using meta-analyses, three types of probiotics (Saccharomyces boulardii, Lactobacillus rhamnosus GG, and probiotic mixtures) significantly reduced the development of antibiotic-associated diarrhea. Only S. boulardii was effective for Clostridium difficile disease.

Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhoea.
Int Microbiol. 2004 Mar;7(1):59-62. Cultech Ltd., York Chambers, York Street, Swansea, SA1 3NJ, United Kingdom.
Colonic infection with Clostridium difficile, leading to pseudomembranous colitis, is a common complication of antibiotic therapy, especially in elderly patients. It has been suggested that non-pathogenic probiotic bacteria might prevent the development and recurrence of C. difficile infection. This double-blind, placebo-controlled study examines the role of probiotic administration in the prevention of C. difficile -associated diarrhoea in elderly patients receiving antibiotic therapy. Consecutive patients (150) receiving antibiotic therapy were randomised to receive either a probiotic containing both Lactobacillus and Bifidobacterium or placebo for 20 days. Upon admission to hospital, bowel habit was recorded and a faecal sample taken. Trial probiotic or placebo was taken within 72 h of prescription of antibiotics, and a second stool sample was taken in the event of development of diarrhoea during hospitalisation or after discharge. Of the randomised patients, 138 completed the study, 69 with probiotics in conjunction with antibiotics and 69 with antibiotics alone. On the basis of development of diarrhoea, the incidence of samples positive for C. difficile -associated toxins was 2.9% in the probiotic group compared with 7.25% in the placebo-control group. When samples from all patients were tested (rather than just those developing diarrhoea) 46% of probiotic patients were c difficile toxin -positive compared with 78% of the placebo group.

Inhibition of Clostridium difficile growth and adhesion to enterocytes by Bifidobacterium supernatants.
Anaerobe. 2006 Jun 5; Centro de Investigacion y Desarrollo en Criotecnologia de Alimentos (CIDCA), 47 y 116 (1900). Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina.
The antimicrobial and anti-adhesive effects of extracellular factors from 27 strains of bifidobacteria isolated from healthy infants were tested against two reference strains of Clostridium difficile (ATCC 9689 and ATCC 43593). All bifidobacterial supernatants at pHs between 5.0 and 4.1 were able to produce strain-dependent growth inhibition of clostridia in the agar-diffusion assay. Six strains of Bifidobacterium produced during growth extracellular factors able to antagonize the adhesion of C. difficile ATCC 9689 and ATCC 43593 to cultured human enterocytes (Caco-2/TC7). Factors responsible for the anti-adhesive effect were thermolabile, active at neutral pH and unaffected by proteolytic cleavage (proteinase K and chymotrypsin). Results of the present paper show the potential of selected bifidobacteria to antagonize key mechanisms involved in the virulence of C. difficile.

Prophylactic Saccharomyces boulardii in the prevention of antibiotic-associated diarrhea: a prospective study.
Med Sci Monit. 2006 Apr;12(4):PI19-22.  Department of Infectious Diseases and Clinical Microbiology, Gulhane Military Medical Academy, Ankara, Turkey.
Interest to probiotics for the prevention and treatment of antibiotic-associated diarrhea is increasing gradually. The most promising seems to be Saccharomyces boulardii. Using a double-blind controlled study, we investigated the preventive effect of S. boulardii on the development of antibiotic-associated diarrhea in patients under antibiotherapy but not requiring intensive care therapy. S. boulardii was given twice daily during the course of antibiotic therapy and application was initiated in all patients as late as after 48 hours of antibiotic therapy. RESULTS: The antibiotic-associated diarrhea development ratio in placebo group was 9% (7/78) and in the study group 1.4% (1/73). Stool samples from the patients with antibiotic-associated diarrhea were stored at -70 degrees C and Clostiridium difficile toxin A assay was performed using Enzyme Immune Assay as late as in seven days. C. difficile toxin A assay yielded positive results in two (2/7) stool samples from the patients with antibiotic-associated diarrhea in the placebo group and a negative result in the only patient who developed antibiotic-associated diarrhea in the study group. CONCLUSIONS: The results implied that prophylactic use of Saccharomyces boulardii resulted in reduced, with no serious side effects, antibiotic-associated diarrhea in hospitalized patients.

Exopolysaccharides produced by probiotic strains modify the adhesion of probiotics and enteropathogens to human intestinal mucus.
J Food Prot. 2006 Aug;69(8):2011-5. Functional Foods Forum, University of Turku, Itainen Pitkakatu 4A, FIN 20014, Turku, Finland.
Exopolysaccharides (EPSs) are exocellular polymers present in the surface of many bacteria, including Lactobacillus and Bifidobacterium. The genome sequence of several strains revealed the presence of EPS-encoding genes. However, the physiological role that EPSs play in the bacterial ecology still remains uncertain. In this study, we have assessed the effect of EPSs produced by Lactobacillus rhamnosus GG, Bifidobacterium longum NB667, and Bifidobacterium animalis IPLA-R1 on the adhesion of probiotic and enteropathogen strains to human intestinal mucus. The EPS fraction GG had no significant effect on the adhesion of L. rhamnosus GG and B. animalis IPLA-R1. However, the EPS fractions NB667 and IPLA-R1 significantly reduced the adherence of both probiotic strains. In contrast, the three EPS fractions increased the adhesion of Enterobacter sakazakii ATCC 29544 and Escherichia coli NCTC 8603. Higher adherence of Salmonella enterica serovar Typhimurium ATCC 29631 and Clostridium difficile ATCC 9689 was detected in the presence of the EPS fractions GG and NB667. In general, these effects were obtained at EPS concentrations of up to 5 mg/ml, and they were EPS dose dependent. The competitive exclusion of probiotics in the presence of EPS could suggest the involvement of these biopolymers in the adhesion to mucus. The increase in the adherence of enteropathogens could be explained if components of the pathogen surface are able to bind to specific EPSs and the bound EPSs are able to adhere to mucus. To the best of our knowledge, this is the first work reporting the effect of EPSs from probiotics on bacterial adhesion properties.

Proton pump inhibitor therapy is a risk factor for Clostridium difficile -associated diarrhoea.
Aliment Pharmacol Ther. 2006 Aug 15;24(4):613-9. Department of Adult Medicine, Royal Gwent Hospital, Newport, South Wales, UK.
Inhibition of gastric acid removes a defence against ingested bacteria and spores, increasing the risk of some forms of gastroenteritis. Previous studies investigating a possible link between acid suppression therapy and Clostridium difficile -associated diarrhoea have reported conflicting results. Conclusion: The risk of C. difficile-associated diarrhea in hospitalized patients receiving antibiotics may be compounded by exposure to proton pump inhibitor therapy.

Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized, controlled study.
Clin Gastroenterol Hepatol. 2005 May;3(5):442-8. Department of Medicine, Derriford Hospital, Plymouth, UK
Ten percent to 20% of patients relapse after successful treatment of their Clostridium difficile -associated diarrhea. We set out to determine if the prebiotic oligofructose could alter the fecal bacterial flora and, in addition to antibiotic treatment, reduce the rate of relapse from C difficile infection. Consecutive inpatients with C difficile -associated diarrhea were randomly allocated to receive oligofructose or placebo for 30 days in addition to specific antibiotic treatment. Patients were followed up for an additional 30 days. The main end point was the development of further diarrhea. Stools were collected for bacterial culture and C difficile toxin measurement. CONCLUSIONS: Fecal cultures confirmed the prebiotic effect of oligofructose. Patients taking oligofructose were less likely to develop further diarrhea than those taking the placebo.