Clostridium difficile infection (CDI) 소화기내과 R4 신아리 1

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

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

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

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

Epidemiology 6 대한소화기학회지 (2010) 55, 대한소화기학회지 (2010) 55,

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

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,

Introduction 9

10

Pathogenesis 11 Gastroenterology (2009) 136,

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,

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 ) More virulent : Increased toxin A and B production More resistant to fluoroquinolones : higher MICs Increased sporulation

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

Microbiology 15

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

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

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

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

Sigmoidoscopy Diagnosis 대한내과학회지, (2010) 78, AB C D

Diagnosis

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

Treatment Gastroenterology (2009) 136,

Treatment Gastroenterology (2009) 136,

Treatment Gastroenterology (2009) 136,

Treatment Gastroenterology (2009) 136,

Treatment Gastroenterology (2009) 136,

Treatment Infect Control Hsp Epidemiol; SHEA-IDSA guideline (2010) 31,

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

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

Prevention Gastroenterology (2009) 136,