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Clostridioides difficile (formerly known as Clostridium difficile) infection (CDI) has emerged as a pathogen of major importance among hospitalized and ambulatory patients. It now rivals methicillin-resistant Staphylococcus aureus (MRSA) as the leading cause of nosocomial infections,1 and is increasingly encountered among ambulatory patients,2 often with little to no prior contact with the healthcare system. Because of increased incidence and severity, and the high likelihood of recurrent disease after initial successful treatment, CDI has imposed a large burden on healthcare systems across the world. This burden is manifested by a high rate of morbidity and mortality, financial costs, and a high consumption of healthcare time and effort devoted to testing, infection control, cleaning, and reporting.3 Because of this substantial impact on the healthcare system, the United States Centers for Diseases Control and Prevention (CDC) designated C. difficile as one of five “urgent” threats in its 2019 Antimicrobial Resistance Threat Report,4 joining drug-resistant Neisseria gonorrhoeae, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Acinetobacter, and Candida auris in this top tier. Challenges and controversies regarding epidemiology, testing, treatment, prevention, and transmission of C. difficile have emerged (and sometimes re-emerged) over the past two decades, creating difficulties for clinicians and persisting questions for researchers studying CDI.


Originally deemed a harmless colonizer of human neonatal intestinal flora when first isolated by Hall and O’Toole in 1934,5 there was a hint of the potential virulence of C. difficile when they described themselves as “surprised to find the new bacillus highly pathogenic for guinea-pigs and rabbits.” However, the change in perspective about C. difficile as a neonatal colonizer to one of the most important causes of healthcare-associated gastrointestinal infection took several decades. With the advent of antimicrobial therapy, there was an increase in pseudomembranous colitis, a severe gastrointestinal condition that had no clear etiology. The introduction of clindamycin and lincomycin was noted to be associated with pseudomembranous colitis, and several groups worked to determine a specific microbial cause. Several lines of research eventually led to the discovery of C. difficile as the offending agent. One group described a cytopathic effect of stool from patients with pseudomembranous colitis in tissue culture, and postulated the presence of an unidentified toxin.6 Another line of investigation demonstrated that clindamycin-induced overgrowth of Clostridium species in hamster colonic flora, and that enterocolitis could be induced by intracecal injection of a cell-free filtrate of this clostridial strain.7 Subsequently, stool from patients with pseudomembranous colitis or antibiotic-associated diarrhea was investigated, and C. difficile was isolated from the pseudomembranous colitis patients (and from one of the antibiotic-associated diarrhea patients) that produced cytotoxic changes on tissue culture and induced enterocolitis in a hamster model. Finally, both the cytotoxicity and enterocolitis were neutralized by gas-gangrene antitoxin, implicating toxin-producing C. difficile as the cause of illness.8

In the early 2000s, clinicians reported an increase in the incidence of fulminant ...

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