Clostridium difficile - From Colonization to Infection

Abstract

Clostridium difficile is the most frequent cause of nosocomial antibiotic-associated diarrhea. The incidence of C. difficile infection (CDI) has been rising worldwide with subsequent increases in morbidity, mortality, and health care costs. Asymptomatic colonization with C. difficile is common and a high prevalence has been found in specific cohorts, e.g., hospitalized patients, adults in nursing homes and in infants. However, the risk of infection with C. difficile differs significantly between these cohorts. While CDI is a clear indication for therapy, colonization with C. difficile is not believed to be a direct precursor for CDI and therefore does not require treatment. Antibiotic therapy causes alterations of the intestinal microbial composition, enabling C. difficile colonization and consecutive toxin production leading to disruption of the colonic epithelial cells. Clinical symptoms of CDI range from mild diarrhea to potentially life-threatening conditions like pseudomembranous colitis or toxic megacolon. While antibiotics are still the treatment of choice for CDI, new therapies have emerged in recent years such as antibodies against C. difficile toxin B and fecal microbial transfer (FMT). This specific therapy for CDI underscores the role of the indigenous bacterial composition in the prevention of the disease in healthy individuals and its role in the pathogenesis after alteration by antibiotic treatment. In addition to the pathogenesis of CDI, this review focuses on the colonization of C. difficile in the human gut and factors promoting CDI.

Keywords: CDI; Clostridium difficile; Clostridium difficile infection; asymptomatic colonization; microbiota.

FIGURE 1

Processes leading from asymptomatic C. difficile colonization to CDI. Different factors can prevent an asymptomatic individual from the development of CDI. Gastric acid production within the stomach prevents further spreading of the spores. A healthy indigenous intestinal microbial composition serves as a colonization resistance, can produce bacteriocins limiting C. difficile expansion and compete with nutritional contents. Additionally, a change in the bile acid composition can also have effects on the expansion of C. difficile. Increased exposure to C. difficile, e.g., contact with HCF or via oral ingestion with food, predisposes an individual at risk for asymptomatic colonization. In case of underlying risk factors, an asymptomatic colonization can progress to CDI. After application of antibiotics, a depletion of the commensal bacterial composition can occur leading to a reduced colonization resistance favoring the development of CDI. Other risk factors are increased age, comorbidities and the application of drugs which reduce the gastric acid, e.g., proton pump inhibitors (PPIs). Abbreviations: CDI, C. difficile infection; HCF, health care facilities; IgA, Immunoglobulin A; PPI, proton pump inhibitor; TcdA, C. difficile toxin A; TcdB, C. difficile toxin B.