Clostridium difficile (CD) is a Gram-positive anaerobic bacillus, and approximately 1 in 5 antibiotic-associated diarrhea is caused by CD infection, which is defined as the presence of at least 3 unformed stools within 24 hours and the presence of Clostridium difficile confirmed by stool, endoscopic or histopathological findings. The following is a brief description of risk factors, clinical presentation, diagnostic tests, treatment and prevention. Risk factors The major risk factors for CD infection include hospitalization, advanced age, and antibiotic use. Studies have shown that the risk of CD infection increases with increasing hospitalization days, with a 13% CD colonization rate in patients who have been hospitalized for 1-2 weeks and a 50% CD colonization rate in patients who have been hospitalized for more than 4 weeks; an increased risk of CD infection in those aged >65 years, and a 2% increase in the risk of medically acquired CD infection for each year of age; and an increased risk of CD infection with the use of almost all antibiotics, especially carbapenems Almost all antibiotic applications increase the risk of CD infection, especially carbapenems and new generation fluoroquinolones. Other risk factors include: the use of antacids, especially proton pump inhibitors, which have a dose-dependent effect on the risk of CD infection; inflammatory bowel disease and immunosuppressive states, tube feeding, chronic liver disease, and end-stage renal disease, which also increase the risk of CD infection. Clinical presentation Approximately 15-25% of antibiotic-associated diarrhea is caused by CD infection, and its clinical presentation varies. In mild cases, the diarrhea is mild and resolves with the discontinuation of antibiotics; in severe cases, the disease presents as fulminant colitis, which accounts for about 10% of CD infections and has a high mortality rate; in some patients, the symptoms tend to recur. Mild-moderate CD infection: The typical manifestation of CD infection is watery diarrhea (bloody stools are rare), which may be accompanied by colitis symptoms such as fever, lower abdominal cramps, and fecal leukocytosis. Routine laboratory tests may show blood leukocytosis and hypoalbuminemia, with an average leukocyte level around 15,000/ul, and in some patients a marked increase in leukocytes, manifesting as a leukemia-like reaction. How to identify people at risk for CD infection is crucial. Severe CD infection: There is no uniform definition of severe CD infection. The Society for Healthcare Epidemiology of America/Infectious Diseases Society of America (SHEA/IDSA) guidelines define leukocytes above 15,000/ul or creatinine levels 1.5 times higher than basal levels as severe CD infection. Other factors suggestive of severe CD infection include advanced age, albumin <2.5 mg/dL, admission to an ICU unit and endoscopic findings of pseudomembrane formation, and comorbid chronic kidney disease, chronic lung disease, or diabetes mellitus as independent risk factors for severe CD infection. Fulminant CD infections: accounting for <5% of all CD infections, patients are critically ill and the associated mortality rate can reach 50%, and timely diagnosis is critical. The clinical presentation is massive diarrhea, intestinal obstruction or toxic megacolon. Colonoscopy may show extensive colonic inflammation and pseudomembrane formation. Leukocytes >50,000/uL or lactate levels >5 mmol/L suggest a poor prognosis. A retrospective study showed that age >70 years, leukocytes >35,000/uL, leukocytes <4000/uL, neutrophil granulocytosis, and respiratory and circulatory failure were predictors of mortality in fulminant CD infections. Recurrent CD infections: account for approximately 20% of all CD infections. After experiencing 1 recurrence, the chance of another recurrence is 40%, and the chance of a third recurrence after another recurrence is 60%. The mechanisms leading to CD relapse are unclear and may be related to both host factors (lack of antibodies against CD toxin) and environmental factors. A meta-analysis showed that risk factors for recurrence included continued antibiotic use, antacid use, and advanced age. Another retrospective study showed that diabetes mellitus was also a risk factor for recurrence. Other manifestations of CD infection: Extracolonic manifestations of CD infection are uncommon and include bacteremia, wound and joint infections, and abdominal abscesses. reactive or post-infectious syndromes, including reactive arthritis and irritable bowel syndrome, can occur after CD infection. Diagnostic tests There are several tests for CD infection, each with its own characteristics. Notably, only 15-25% of antibiotic-associated diarrhea is caused by CD infection; therefore, it is recommended that treatment be initiated only after a positive test result is obtained, unless the patient is rapidly deteriorating or the CD infection test used is known to be of low sensitivity. Since no therapeutic measures are required for asymptomatic CD colonization, testing for CD should only be considered when patients present with symptomatic diarrhea (3 > times/day) or unformed stools. Retesting is not recommended for those whose symptoms have resolved after treatment. In the United States, detection of CD toxin A or A+B by enzyme immunoassay is the most commonly used test, which has the advantage of being inexpensive, simple, and specific for the detection of toxin-producing strains, but not very sensitive (31%-99%), so many laboratories have begun to apply other screening methods. Cytotoxicity tests and toxin-producing culture tests were previously used as diagnostic criteria for CD infection, but are not suitable for clinical application. The detection of the CD co-antigen glutamate dehydrogenase (GDH) is highly sensitive and can be used as a screening test for the diagnosis of CD infection. The nucleic acid amplification test (NAAT) for the detection of genes encoding toxins (usually toxin B) is rapid and sensitive but has a high false-positive rate and is costly. When a rapid diagnosis and differential diagnosis is needed, consider colonoscopy, which shows a 2-10 mm sized, bulging yellow pseudomembrane involving the entire colon as a characteristic sign of CD. Treatment In the 2010 U.S. SHEA/IDSA guidelines, it is stated that current antibiotics should be discontinued if possible and metronidazole or oral vancomycin should be given to patients with CD infection, as shown in Table 2. In May 2011, the US FDA approved fidaxomicin (DIFICID) for the treatment of CD infection again. In addition, several other antibiotic and non-antibiotic treatment options are under investigation. Fidaxomicin: A macrolide antibiotic with little oral absorption that selectively eradicates Clostridium perfringens with little effect on normal intestinal flora. Randomized controlled studies have shown that the efficacy of fidaxomicin 200 mg Bid is comparable to oral vancomycin (88.2% vs 85.8%), while the recurrence rate of CD infection is lower than in the vancomycin-treated group (15.4% vs 25.3%), and fidaxomicin has fewer side effects, fewer drug interactions, and a lower risk of resistance. Fidaxomicin is more effective in patients who require continued treatment with other antibiotics. The disadvantage is that it is expensive. Nitrothiazide: Originally an antiparasitic drug used to treat Giardia lamblia and Cryptosporidium infections. Two randomized controlled studies with small samples comparing nitrothiazide with vancomycin and metronidazole showed that although it was therapeutic for CD, it was not superior to the other drugs and had no cost advantage. It has also been reported as a remedial treatment for the failure of metronidazole treatment. Rifaximin: A rifamycin derivative for travelers’ diarrhea with little oral absorption. Case series have shown that rifaximin is effective in preventing relapse as an adjunct to standard CD infection treatment regimens, and its efficacy in recurrent CD infections remains to be further investigated. Monoclonal antibodies: The host immune response to CD infection is mediated by antibodies to toxins A and B. Therefore, monoclonal antibodies against toxins have the potential to be a new therapeutic approach. In a phase II clinical trial, 200 patients with CD infection were given a single injection of monoclonal antibodies to toxins A and B or placebo along with a standard treatment regimen, and the results showed a lower relapse rate in the monoclonal antibody group compared to the placebo control group (7% vs 25%). Fecal transplantation: Disruption of the intestinal microbiota is the initiating factor in CD infection, so re-establishing normal colonic flora should be therapeutic. The steps of fecal transplantation include screening of the donor (including HIV, hepatitis virus, etc.) and transplantation (transplantation of feces from the donor into the recipient via nasogastric tube, enema, or colonoscopy), which has the advantage of being simple, inexpensive, and effective. A systematic review study that included 317 patients with recurrent CD infection showed an overall 92% effectiveness of fecal transplantation with few adverse events. Probiotics: Probiotics aim to re-establish normal intestinal flora and therefore have a preventive effect on antibiotic-associated diarrhea, but their efficacy in CD infections is inconclusive and they are not included in the 2010 SHEA/IDSA guidelines. A randomized controlled trial completed in 1994 in which Saccharomyces cerevisiae was given daily in addition to standard therapy for 4 weeks in patients with CD infection showed a lower relapse rate than the placebo group (26% vs 45%). However, the potential of probiotics to cause systemic infection is one of the concerns in choosing this treatment. Vaccine: There is no vaccine available for CD, but several studies are underway. Prevention of CD infection CD bacilli persist in the body for months to years and are difficult to eradicate; the key to prevention is how to reduce bacilli colonization. Prevention methods include: improving hand hygiene, such as applying soap containing chlorhexidine; isolating CD-infected patients in a single room; screening diarrhea patients for CD multiple times to identify infected patients early; applying appropriate disinfection methods to the environment and medical equipment, applying antibiotics appropriately, and reducing the use of high-risk antibiotics (including clindamycin, fluoroquinolones, and cephalosporins).