The Clostridium Difficile Toxins: Mechanism of Action and Immunopathogenesis

Clostridium difficile infection (CDI) is now the most common definable cause of hospital-acquired and antibiotic-associated diarrhea in the United States, with the total cost of treatment estimated between 1 to 4.8 billion U.S. dollars annually (Dubberke and Olsen, 2012; DuPont, 2011; Kyne et al., 2002; Magill et al., 2014; O'Brien et al., 2007; Wilkins and Lyerly, 2003). This bacterium is responsible for 10–25% of the cases of antibioticassociated diarrhea, 50–75% of antibiotic-associated colitis, and 90–100% of pseudomembranous colitis (Bartlett, 2002; Elliott et al., 2007). Morbidity and mortality resulting from CDI-associated diseases have also increased significantly over the past ten years, making C. difficile the most common emerging pathogen in the US (Ananthakrishnan, 2011; McDonald et al., 2005; O'Brien et al., 2007; Redelings et al., 2007). C. difficile overpopulates the colon after the normal gut microbiota has been altered by antibiotic therapy. Therefore, the highest risk factor for CDI is previous antibiotic therapy (Bartlett and Perl, 2005). Treatment of CDI has been hampered by increased virulence of the causative strains, sporulation, recurrence of the infection, and antibiotics used in treatment that further alter the composition and colonization resistance of the normal colonic microbiota. Moreover, treatment with antimicrobials is, in as many as 25% of cases, ineffective resulting in recurrence of the infection (Burke and Lamont, 2013; Hansen et al., 2013).