1. Clostridium difficile Infection Fellow 이시내

2. Clostridium difficile  An anaerobic gram-positive, spore-forming, toxin-producing bacillus.  Transmitted among humans through the fecal–oral route.  In the United States, C. difficile is the most frequently reported nosocomial pathogen.  In 2011, 453,000 cases of C. difficile infection and 29,000 deaths associated with C. difficile infection.

3. Pathogenesis and Epidemiology  C. difficile colonizes the large intestine and releases two protein exotoxins (TcdA and TcdB) that cause colitis in susceptible persons.  Transmitted by spores that are resistant to heat, acid, and antibiotics.  C. difficile diarrhea is mediated by TcdA and TcdB, which inactivate members of the Rho family of guanosine triphosphatases (Rho GTPases), leading to colonocyte death, loss of intestinal barrier function, and neutrophilic colitis.

4.  The two factors that exert a major influence on clinical expression of disease are the virulence of the infecting strain and the host immune response.  The BI/NAP1/027 strain is characterized by high-level fluoroquinolone resistance, efficient sporulation, markedly high, toxin production and a mortality rate three times as high as that associated with less virulent strains, such as the 001 or 014 ribotypes.

8. Risk factors  Antibiotic use; the most important risk factor Ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are the antibiotics that are most frequently associated with the disease, but almost all antibiotics have been associated with infection.  Age: The risk of C. difficile infection and the severity of infection increases as age increases.  Inflammatory bowel disease  Organ transplantation  Chemotherapy  Chronic kidney disease  Immunodeficiency

10. Clinical manifestations

11. Unusual manifestations  Protein-losing enteropathy with ascites  Clostridium difficile and inflammatory bowel disease : - Account for about 10 percent of symptomatic relapses in patients with IBD - Rarely, C. difficile can trigger an initial bout of IBD - Endoscopy is usually not helpful because IBD patients generally do not develop pseudomembranes.  Extracolonic involvement : rare - appendicitis, small bowel enteritis, C. difficile appendicitis, small bowel enteritis, bacteremia, and reactive arthritis

12. Diagnosis  Diagnostic stool evaluation for the presence of C. difficile toxins should be pursued in the setting of clinically significant diarrhea (usually defined as 3≤loose stools per day for at least two days)  Suspicion is warranted if many stools (10 to 15) occur with fever or nocturnal diarrhea even if only one day in duration.  In general, only loose, watery, or semiformed stool should be tested for C. difficile.  C. difficile toxin degrades at room temperature and may be undetectable within two hours after collection; specimens should be kept at 4ºC if delay is anticipated.

13. Laboratory diagnosis  Polymerase chain reaction (PCR): -Detection of toxin A and B genes -Highly sensitive and specific -↑ The risk of false positive result -Can be available within as little as one hour.  Enzyme immunoassay (EIA) for C. difficile glutamate dehydrogenase (GDH): -An essential enzyme produced constitutively by all C. difficile isolates -Cannot distinguish between toxigenic and nontoxigenic strains. -Useful as an initial screening step in a multistep approach -Highly sensitive, and results are available in less than one hour.

14.  Enzyme immunoassay (EIA) for C. difficile toxins A&B: -Relatively low Sensitivity (75%) -High specificity (up to 99%) -Relatively high false negative rate -Results are available within hours.  Cell culture cytotoxicity assay: -The 'gold standard' test for diagnosis of C. difficile -More sensitive than enzyme immunoassays but is labor intensive and takes approximately two days.  Selective anaerobic culture: -the most sensitive diagnostic method -culture alone cannot distinguish toxin-producing strains from non- toxin–producing strains -generally too slow and labor-intensive for clinical use

17.  Stool testing for C. difficile toxins should be confined to patients with diarrhea.  The testing and treatment of persons with solid stools is not recommended.  Posttreatment testing has no role in confirming eradication.  Stool testing can be helpful in differentiating recurrent C. difficile infection from postinfectious irritable bowel syndrome or inflammatory bowel disease that can be triggered by acute enteric infections.

18. Endoscopic diagnosis  Indications: - High clinical suspicion for C. difficile with negative laboratory assays - Prompt C. difficile diagnosis needed before laboratory results can be obtained - Failure of C. difficile infection to respond to antibiotic therapy - Atypical presentation with ileus or minimal diarrhea

19. Endoscopic findings (PMC vs Normal)

21. Treatment  General management principles: −Cessation of the inciting antibiotic as soon as possible. −Patients with suspected or proven C. difficile infection should be placed on contact precautions −Healthcare workers should wash hands before and after patient contact. −Hygiene with soap and water may be more effective than alcohol -based hand sanitizers in removing C. difficile spore,since C. difficile spores are resistant to killing by alcohol. −Patients may have regular diet as tolerated, unless surgery or other procedure is planned.

24. Fecal microbial transplantation  Has been employed in patients with severe and recurrent C. difficile infection who have failed multiple attempts at conventional antibiotic therapy.  Route of administration: - Enema, Colonoscopy, Nasogastric/jejunal tube, Oral  Safety: -No known reports of serious infectious complications resulting from fecal microbial transplantation that was performed with appropriate donor screening. -In 2013, the results of a RCT of fecal microbial transplantation showed that the administration of vancomycin followed by an infusion of donor feces delivered by nasoduodenal tube was safe and superior to vancomycin alone for recurrent C. difficile infection.

27. References 1.Longo DL, Leffler DA, Lamont JT. Clostridium difficile In fection. New England Journal of Medicine. 2015 Apr 16; 372(16):1539–48. 2.www.uptodate.com