1. Clostridium difficile infection (CDI) 소화기내과 R4 신아리 1

2. 45 세 남자환자가 내원 5 일 동안 지속되는 점액성 수양성 설사를 주소로 내원하였다, 환자는 내원 2 주 전 Community Acquired Pneumonia 로 입원하여 Cephalosporin 정맥투여 및 Clarithromycin 경구투여 받고 증상 호전되어 내원 1 주 전에 퇴원하였으나, 내원 5 일전부터 점액성 수양성 설사를 보이고, 발열이 동반되어 내원 하였다. 2 Case

3. Why are we Concerned about C.difficile infection ?? 1) Increasing numbers of infection 2) Potential for severe disease 3) Emergence of hypervirulent strains that may be more transmissible and/or cause more severe disease e.g. ribotype NAP1/BI/027 4) Concerns over possible antibiotic resistance 5) Increasingly recognized as a major nosocomial pathogen capable of causing outbreaks 3 Introduction

4. Clostridium difficile infection (CDI) - Unique colonic disease that is acquired almost exclusively in association with antimicrobial use and consequent disruption of the normal colonic flora - Most commonly diagnosed diarrheal illness acquired in hospital - Ingestion of spores of C.difficile that vegetate, multiply, and secrete toxins, causing diarrhea and pseudomembranous colitis (PMC) 4 Introduction Harrison 18th Ch129, page 1091-1094

5. Epidemiology 5 N Engl J Med (2008) 359, 1932~-1940 Arch Surg (2007) 142, 624~631

6. Epidemiology 6 대한소화기학회지 (2010) 55, 169-174 대한소화기학회지 (2010) 55, 175-182

7. Epidemiology 7 Arch Surg (2007) 142, 624~631

8. Risk Factors 8 Risk factors 1) Age > 65 yrs 2) Severe underlying disease 3) Antimicrobial therapy 4) Nasogastric intubation 5) Chemotherapy 6) Anti-ulcer medications : PPIs (proton-pump inhibitors) 7) Long hospital stay or long-term care residency FrequentOccasionalRare Cephalosporins Penicillins Clindamycin Fluoroquinolones Macrolides Trimethoprim Sulfonamides Aminoglycosides Tetracyclines Chloramphenicol Metronidazole Vancomycin Gastroenterology (2009) 136, 1899-1912

9. Introduction 9

10. 10

11. Pathogenesis 11 Gastroenterology (2009) 136, 1899-1912

12. Microbiology 12 Clostridium difficile : Anaerobe, Gram (+), Spore forming bacillus Pathogenicity of C.difficile 1) Toxin A (enterotoxin) - causes outpouring of fluid and watery diarrhea 2) Toxin B (cytotoxin) - damages colonic mucosa leading to pseudomemb. formation 3) Pathogenicity in a pathogenicity locus (PaLoc) of five genes J Clin Microbiol (2002) 40, 3470-3475

13. Microbiology 13 J Clin Microbiol. (2008) 46, 1530–1533 Current epidemic strain of C.difficile 1) BI/NAP1/027, toxinotype III 2) Historically uncommon – epidemic since 2000 3) More virulent : Increased toxin A and B production More resistant to fluoroquinolones : higher MICs Increased sporulation

14. Microbiology 14 In vitro production of toxins in epidemic strain Lancet. (2005) 366,1079-1084 x16 x23

15. Microbiology 15

16. 16 Factors appear to influence clinical expression of disease - Virulence of the infecting strain - Host immune response Onset of Symptoms - > 80% : During antibiotic treatment (typically after 4-5 d of Tx) - < 20% : After inciting antibiotic discontinued (most within 4 wks, almost all within 12 wks) Clinical Manifestations Harrison 18th Ch129, page 1091-1094

17. 17 Clinical Manifestations TypeDiarrheaOther SxP/Ex ASx. carrier Absent NL C.difficile associated diarrhea with colitis Diarrhea Fecal leukocyte (+) Occult bleeding (±) Hematochezia (rare) Anorexia, nausea, fever, leukocytosis Abd distention, tenderness Pseudo- membranous colitis Diarrhea more profuse than in colitis without pseudomemb. Fecal leukocyte (+) Occult bleeding (±) Hematochezia (rare) Anorexia, nausea, fever, leukocytosis ; more severe than in colitis without pseudomemb Marked abdominal tenderness, distention Fulminent colitis Diarrhea may be severe or diminished (d/t paralytic ileus & colonic dilatation) Lethargy, fever, tachycardia, abd pain; dilated colon/paralytic ileus may be demonstrated on plain abdomen film May present as acute abdomen; peritoneal signs suggest perforation Harrison 18th Ch129, page 1091-1094

18. 18 Diagnosis History taking : Sx, Hx of antibiotics use Laboratory test - Cell culture cytotoxin test on stool - Enzyme immunoassay toxin test (toxin A or toxin A&B) in stool - Stool culture for C.difficile - PCR for C.difficile toxin B gene in stool Endoscopy : Sigmoidoscopy Harrison 18th Ch129, page 1091-1094

19. 19 Diagnosis Laboratory tests CMAJ, (2004) 171, 51-58

20. Sigmoidoscopy Diagnosis 대한내과학회지, (2010) 78, 318-324 AB C D

21. Diagnosis

23. Gross Finding Diagnosis NEJM (2005) 353, 2491 Histologic Finding (H&E,x400) At autopsy, the colon showed evidence of pseudomembranous colitis with multiple yellow plaques. Mushroom-shaped pseudomembrane “Volcano” lesion, H&E, x400

24. Treatment Gastroenterology (2009) 136, 1899-1912

25. Treatment Gastroenterology (2009) 136, 1899-1912

26. Treatment Gastroenterology (2009) 136, 1899-1912

27. Treatment Gastroenterology (2009) 136, 1899-1912

28. Treatment Gastroenterology (2009) 136, 1899-1912

29. Treatment Infect Control Hsp Epidemiol; SHEA-IDSA guideline (2010) 31, 431-455

30. Treatment N Engl J Med (2010) 362, 197~205

31. Treatment N Engl J Med (2011) 364, 422~431

32. Prevention Gastroenterology (2009) 136, 1899-1912