Clostridium Difficile Associated Diarrhea Biology Essay


Clostridium difficile-associated diarrhea (CDAD) is caused by a colon infection that results from the ingestion of C. difficile spores. It is recognized as the most important cause of nosocomial diarrhea in adults, ranging from mild diarrhea to pseudomembranous colitis, sepsis, and sometimes death (Hookman & Barkin, 2009). In 2002 several hospitals in Quebec experienced a dramatic increase in outbreaks of CDAD, with mean rates of 25 cases per 1000 hospital admissions. It was decided that new the new emergent strain, NAP1/BI/027, was responsible (Pepin et al., 2005). Reports of the Canadian Nosocomial Infection Surveillance Program (CNISP) determined that the mortality rate for CDAD was four times higher in a Canadian study conducted in 2004­­-2005 than it was in study conducted in 1997 (Gravel et al., 2009). The epidemiology of C. difficile has been changing, with reports of illness in people in low risk group: people who have not taken antibiotics, children, and pregnant women (Hookman & Barkin, 2009). As a result, CDAD has become an important public health concern and a costly, leading cause of gastrointestinal disease (McFarland, 2009).

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The responsible pathogen for CDAD, C. difficile, is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus, whose spores are found widely in nature, particularly in the environments of hospitals and chronic care facilities. C. difficile can exist in spore and vegetative forms. Outside the colon, C. difficile survives in a spore form that is resistant to heat, acid, and antibiotics. These spores are resistant to disinfectants and can persist for months on surfaces such as beds, commodes, or the hands of caregivers (Pelleschi, 2008). The identified risk factors for development of CDAD include antibiotic therapy, advanced age, multiple and severe underlying disease, immunosuppressive therapy, recent surgery, and prolonged hospital stay (Hookman & Barkin, 2009; Kyne et al., 2001; Pelleschi, 2008). According to Dial et al. (2004), uses of medications that reduce stomach acidity, such as proton pump inhibitors, may lead to proliferation of C. difficile bacteria. In healthy individuals, growth of C. difficile is regulated by protective normal flora and the acid of the stomach (Pelleschi, 2008).

Three major events must occur in the pathogenesis of CDAD: (1) alteration of normal colonic flora; (2) acquisition of and colonization by C. difficile; and (3) toxin production and toxin-mediated intestinal injury and inflammation (Kyne et al., 2001; Poutanen & Simor, 2004). Loss of protective normal colonic flora normally occurs due to antibiotic exposure and/or decreased stomach acidity. The protective effect of the normal stable intestinal flora frequently is referred to as colonization resistance. Disruption of this barrier by antibiotics provides a niche for C. difficile to multiply and produce toxins. In addition, the development of C. difficile antibiotic resistance plays an important role in increased virulence (Kyne et al., 2001; Poutanen & Simor, 2004). Transmission of spores and vegetative cells occurs via the fecal-oral route. Most vegetative cells are killed in the stomach, but spores can survive the acidic environment. C. difficile spores then germinate in the small bowel upon exposure to bile acids; flagellae facilitate C. difficile movement through the colon where C. difficile multiplies and adheres to the colonic epithelium. Once inside the colon, C. difficile converts to fully functional vegetative, toxin-producing forms that are difficult to kill by antibiotics (Poutanen & Simor, 2004). C. difficile vegetative cells produce two toxins: enterotoxin A (TcdA) and cytotoxin B (TcdB). Both toxins induce the production and release of pro-inflammatory cytokines (interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, interleukin (IL)-8) that lead to increased vascular permeability, neutrophil and monocyte recruitment, opening up of the tight epithelial cell junctions, and epithelial cell death by apoptosis, thus allowing fluid release (diarrhea). The production of (TNF)-alpha and pro-inflammatory interleukins contributes to the acute colonic inflammatory response and pseudomembrane formation. Pseudomembrane, also referred to as volcano lesion, is an inflamed mucosa covered with adherent elevated white and yellow patches that are composed of neutrophils, fibrin, mucin, and cellular debris (Gould & McDonald, 2008; Hookman & Barkin, 2009; Kyne et al., 2001; Poutanen & Simor, 2004). Toxin B is more potent than toxin A and is essential for the virulence of C. difficile; it is ten times more potent than toxin A when mediating colonic mucosal damage (Lyras et al., 2009). In addition, there are reports of the isolation of toxin A­-negative/toxin B-positive strains of C. difficile, suggesting that toxin B may be pathogenic in humans (Kyne et al., 2001). A minority of C. difficile strains do not produce toxins; these strains can colonize the gastrointestinal tract and grow normally in culture media but are not pathogenic (Kyne et al., 2001).

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A new hypervirulent strain, NAP1/BI/027, has been implicated in recent C. difficile outbreaks in Canada. This strain is more virulent and produces larger quantities of toxin A (16 times more) and toxin B (23 times more) than the other C. difficile strains (Hookman & Barkin, 2009; Sunenshine & McDonald, 2006). Moreover, this strain produces a third toxin, binary toxin (CDT), and is associated with more severe diarrhea. Binary toxin is not present in other C. difficile strains and its role in C. difficile is not fully known (Hookman & Barkin, 2009).

According to Hookman & Barkin (2009), some patients are colonized with C. difficile, but they have no symptoms due to the fact that C. difficile remains in the small intestine where its toxic effects are neutralized. Authors suggest that colonization with C. difficile actually protects against symptomatic disease due to increased serum levels of IgG antibody to toxin A than in those who develop CDAD (due to poor antibody response they could be predisposed to severe, prolonged, or recurrent CDAD); this promotes the development of the asymptomatic carrier state. These individuals may act as reservoir for nosocomial spread of C. difficile.

Changing epidemiology and increased virulence of C. difficile strains require a shift toward effective treatment for severe and relapsing CDAD. A variety of new and exciting therapeutic ideas and options are currently under investigation in determining disease outcomes, and they are directed toward biological and immunological approaches to CDAD treatment (Hookman & Barkin, 2009). Therapies for CDAD include efforts to rebuild colonic flora with the use of probiotics (living nonpathogenic microbes), usually Lactobacillus species or Saccharomyces boulardii. One mechanism of probiotic action relates to the idea that probiotics can colonize the gut, produce bactericidal acids, and promote "competition" among microbes by competing for nutrients and epithelial adhesion. This action would reduce the favorability of the environment for C. difficile (Hookman & Barkin, 2009; Leffler & Lamont, 2009). However, to date, there is insufficient evidence to support the routine use of probiotics to prevent or treat CDAD, especially because of the emergence of concerns over the safety of probiotics in severely ill or immunocompromised patients after reports of sepsis and fungemia (Leffler & Lamont, 2009). Although it is aesthetically not very pleasing, an alternative approach to restoration of gut flora involves administration of the entire fecal flora (via enema or nasogastric tube) from a healthy individual, which is referred as fecal bacteriotherapy (fecal transplantation). In vitro studies suggest that fecal transplantation may stop the proliferation of toxinogenic C. difficile strains (Hookman & Barkin, 2009). This method has been used successfully for severe cases of relapsing or recurrent C. difficile infection for which conventional treatments failed, and researchers reported a 94% cure rate in return of normal bowel function (Aas et al., 2003). Immunoglobin therapy also offers promising results in the management of recurrent CDAD (Hookman & Barkin, 2009). According to Kyne et al. (2001), serum antibody levels against C. difficile toxins are low in patients with recurrent CDAD. Therefore treatment with pooled intravenous gamma globulin, which contains IgG anti-toxin A, could be associated with a marked increase in serum antitoxin antibody levels and resolution for severe and recurrent CDAD. Another immune therapy approach, the use of human monoclonal antibodies against C. difficile toxin A and B, promises the reduction in reoccurrence of CDAD and offers a non-antibiotic, parenteral approach that targets both toxins specifically in battling CDAD infection (Lowy et al., 2010). This novel, recently reported treatment showed a 72% reduction in recurrence of C. difficile infection and supports the concept that inadequate antibody levels against C. difficile predispose patients to symptomatic and recurrent CDAD. Perhaps innovative approaches show promise for treating CDAD, but traditional hand washing to interrupt the route of transmission should be strictly applied together with patient isolation, contact precautions, and cleaning of the physical environment (Hookman & Barkin, 2009).

As the most common cause of nosocomial infection in the past decade, CDAD has proven to be an immense public crisis. It is clear that despite the best attempts to control and prevent this disease, CDAD is more widespread than ever before. Over the last decade, a more virulent and transmissible C. difficile strain emerged that was associated with outbreaks in Canada. Recognition of risk factors for CDAD is important for prompt diagnosis and treatment of this condition to prevent new outbreaks. The roles of alternative therapies for CDAD should be further investigated and applied in the clinical setting as they hold great promise for future management. The growing prevalence of C. difficile emphasizes the need for early recognition, improved methods to manage this severe disease, and greater attention to infection control and antibiotic restraint. The educational activities that address these issues, ensuring all health-care providers remain current on the transmission, clinical features, prevention, and treatment of C. difficile, are needed.

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