Epidemiology, Diagnosis and Treatment of Clostridium Difficile Infection

Matteo Bassetti; Giovanni Villa; Davide Pecori; Alessandra Arzese; Mark Wilcox

Disclosures

Expert Rev Anti Infect Ther. 2012;10(12):1405-1423. 

In This Article

Pathogenesis

C. difficile spores are highly resistant to desiccation, chemicals and extreme temperature. Spores frequently contaminate the environment around patients with CDI, potentially persisting for months or even for years.

Best et al. demonstrated the possibility of airborne spread of C. difficile spores from patients with symptomatic CDI.[62] In addition, the same group of authors conducted a study to assess the risk of airborne dissemination following flushing a toilet; they demonstrated that C. difficile was recoverable from air sampled at heights up to 25 cm above the toilet seat, especially immediately following flushing, and discouraged the use of lidless conventional toilets in order to decrease the risk of C. difficile environmental contamination.[63]

When conditions are favorable, endogenous or exogenously acquired C. difficile spores germinate and vegetative cells multiply. These can then adhere and penetrate the mucus layer that covers the enterocytes via flagella and proteolytic enzyme activity. The bacteria then adhere to the cells through their adhesins and colonize the gut. The second phase of the pathogenesis of CDI is the production of toxins A and B, the two main virulence factors. These are potent cytotoxic enzymes that can damage the colonic mucosa by causing cell cytoskeleton disorganization.[64,65] This creates decreased transepithelial resistance, fluid accumulation and destruction of the intestinal epithelium. A third toxin is produced by certain strains, including C. difficile BI/NAP1/027; as mentioned above, it is a binary toxin called CDT, and it might increase the toxicity of TcdA and TcdB, leading to a more severe disease.[66]

C. difficile toxins can elicit the release of several inflammatory mediators (cytokines) that can perpetrate the vicious cycle of colonic inflammation, by attracting inflammatory cells and promoting fluid secretion.[67] Environmental factors influence the release of toxins: these include nutrients, such as biotin, glucose and amino acids, temperature and sub-inhibitory levels of certain antibiotics; toxin production also depends on the strain of C. difficile.[38,65,68]

The relative importance of toxins A and B to disease pathogenesis remains unclear. Since C. difficile was proven to be etiologically related to PMC, AAD and similar syndromes, enterotoxin A and cytotoxin B have been intensively studied, in order to establish their biological activities and role in the genesis of human infections. At the beginning of the C. difficile era it was established that clinically significant disease occurs only for toxigenic strains of C. difficile that produce both toxin A and toxin B.[69,70] Several reports indicate that there is a range of deletions, insertions and rearrangements in the PaLoc that codes for toxin production in strains of C. difficile isolated from humans; the C. difficile toxins coded by the region found so far are represented by toxin A, toxin B and CDT.[27,71–73] Deletions in the toxin A gene appear to be more common than deletions or insertions in the toxin B gene,[74,75] as already mentioned in the previous section. It was thought that C. difficile strains lacking toxin A production were not clinically significant;[76] however, clinically significant isolates of C. difficile that are missing large segments of the toxin A gene that code for the clostridial repetitive oligopeptide (CROP) region (responsible for binding to eukaryotic cells) were reported.[76] Although such isolates apparently do not produce biologically active toxin A, they do produce the full range of CDI.[71,78]

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