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Clostridium difficile

Clostridium difficile. David B. Blossom, MD MS Division of Healthcare Quality Promotion Coordinating Center for Infectious Diseases Centers for Disease Control and Prevention. Objectives. Review of Clostridium difficile Discuss the transmission and virulence of C. difficile

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Clostridium difficile

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  1. Clostridium difficile David B. Blossom, MD MS Division of Healthcare Quality Promotion Coordinating Center for Infectious Diseases Centers for Disease Control and Prevention

  2. Objectives • Review of Clostridium difficile • Discuss the transmission and virulence of C. difficile • Describe briefly the clinical manifestations, evaluation and treatment of C. difficile-associated disease (CDAD) • Identify the changing epidemiology of CDAD • Define surveillance strategies • Clarify preventive measures

  3. Clostridium difficile • Anaerobic spore-forming bacillus • Ubiquitous in nature • Prevalent in soil • Isolated also from river, lake, sea, and swimming pool water as well as from farm animals, dogs, and cats1 • 1935 - First described by Hall and O'Toole2 • Known colonizer of neonates (50% to 60%) • 1978 - recognized as cause of antimicrobial- associated pseudomembranous colitis3 • Now regarded as most common cause of antimicrobial-associated diarrhea (20-30% of cases) 1. Brazier JS, al Saif. J Med Microbiol 1996; 45: 133-7 2. Hall I; O'Toole E. Am J Dis Child 1935; 49: 390 3. Larson HE et al. Lancet 1978; 8073: 1063–1066.

  4. Clostridium difficile :Pathogenesis • Fecal oral transmission • Survive gastric acidity • Small intestine – spores germinate into vegetative forms • Large intestine – normal flora disrupted by antibiotics Diagram: Sunenshine et al Clev Clin J Med 2006 73(2) 187-197

  5. C. difficile : Pathogenesis (cont) • C. difficile can produce 3 toxins • Toxin A – enterotoxin • Toxin B – cytotoxin • (Binary toxin) • Toxins cause the disease • Some strains only produce one toxin • (A-, B+) 1% in a recent study from Chicago1 Diagram: Sunenshine, et al. Clev Clin J Med 2006 73: 187-197 1.Geric B, et al. J Med Micro 2004;53:887-94

  6. C. difficile-Associated Disease (CDAD) • Incubation period – not known • Diarrhea • Pseudomembranous colitis - Has become the hallmark of CDAD1 - Bloody diarrhea - Raised whitish-yellow plaques - Unexplained leukocytosis (>10,000/cubic mm ) Healthy colon Pseudo-membranous colitis 1.Bartlett JG, et al. Gastroenterology 1978; 75:778-82

  7. Toxic megacolon • Life-threatening acute dilation • Characterized by - a dilated colon (megacolon) - Diameter : ≥ 5.5 cm - Fever, abdominal pain, abdominal distension - Radiograph: apparent edema of bowel wall • Complications - Perforation of colon - Sepsis, Shock - Death Diagram: http://www.nlm.nih.gov/medlineplus/ency/imagepages/17189.htm

  8. Summary: Pathogenesis of C. difficile Exposed to C. difficile Antibiotic therapy Disturbed colonic microflora Toxin A & Toxin B Diarrhea & colitis

  9. Biggest Risks C. difficile : Risk Factors • Increasing age1 • Exposure to antimicrobials • Length of stay in hospital2 • Infected patients/CDAD pressure • Immune response – IgG or local IgA against toxin A3 • Severe underlying gastrointestinal diseases • GI procedures or GI surgery • PPI/H2 blockers? 1.Brown E et al. Infect Control Hosp Epi 1990;11: 283-90 2. Johnson S, et al Lancet 1990;336:97-100 3. M. Delmee Clin Microbiol Infect 2001; 7: 411-416

  10. Increasing Age • Population based study in Sweden • Rate in those over 65 y.o = 20 times higher than those under 20 y.o • Quebec 2002 to 2003 • Rates in >65 y.o increased from 120 to 800 per 100,000 • Rates in under 65 y.o stayed stable (<100 per 100,000 1.Karlstrom et al. Clin Infect Dis 1998;26:141-5 2.Pepin et al. CMAJ 2004;171:466-72

  11. Antimicrobial Exposure • Major risk factor for disease • Acquisition and growth of C. difficile • Suppression of normal flora of the colon • The risk doubles with longer than three days of antibiotic therapy (risk ratio: 2.28) 1 • Clindamycin, penicillins, cephalosporins • Fluroquinolones2 1.WistromJ et al. J Antimicrob Chemother 2001;47:43-50 2. Pepin J. Clin Infect Dis. 2005 Nov 1;41(9):1254-60

  12. Flouroquinolones • Quebec1 • 12 hospitals in 2004, OR for quinolones was 3.9 (95%CI 2.3-6.6) • Ciprofloxacin, gatifloxacin and moxifloxacin associated, levofloxacin was not • Pittsburgh2 • Formulary change: ciprofloxacin to levofloxacin • C. diff rate = 2.7/1000 d/c increased to 6.8/1000 d/c • OR 2.0 (95% CI 1.2-3.3) 1 Loo VG, et al. NEJM 2005; 353:2442-9 2 Muto CA et al. Infect Control Hosp Epidemiol 1005; 26:273-80

  13. Length of Hospitalization • Related to rates of colonization1,2 • Rates increase from <5% at admission to 26% after hospitalization 1.McFarland et al. N Engl J Med 1989;320:204-10 2. Clabots et al. JID 1992;166:561-67

  14. Other Risk Factors:CDAD Pressure • Number of concurrent inpatients with CDAD on the same ward increases a patient’s risk of developing CDAD = daily exposure to CDAD patients Length of stay at risk

  15. CDAD Pressure Dubberke et al. Arch Int Med 2007; 167: 1092-7

  16. C. difficile : Laboratory Tests • Stool culture: Most sensitive - Requiring 2-3 days for growth - Unable to distinguish between the presence of toxin positive strains or toxin negative strains • Cell cytotoxin test – most specific - Cytotoxin B • Direct Enzyme immunoassay (EIA)– most common - May detect Toxin A only or Toxin A and B C difficile colonies on agar plate: http://en.wikipedia.org/wiki/Clostridium_difficile

  17. C. difficile: Resolution and Recurrence • Resolution: 15 to 23% of patients - Within 2 to 3 days after discontinuation - But most patients require specific treatment • C. difficile diarrhea recurs after treatment in ~20% of cases • Historically mortality rate was 1 to 2.5 percent

  18. Treatment • Initial Course of Antibiotics • At least 10 days • Metronidazole (mild/moderate disease) • Oral vancomycin (severe disease)1 • Treatment of Recurrence • Longer course of metronidazole • Vancomycin with a taper • Rifaximin • Nitazoxanide • Vancomycin and rifaximin2 1. Zar FA, et al. CID 2007; 45: 302-7 2. Johnson S, et al. CID 2007; 44: 846-8

  19. Costs • Responsible for more than $1 billion annually in excess healthcare costs* - Average of $3,600 excess costs per case - Average of 3.6 extra hospital days * Kyne L, et al. Clin Infect Dis. 2002;34:346-353

  20. Increasing Rates of C. difficile-associated Disease (CDAD) in US Hospitals McDonald et al. 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004

  21. National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed or Any Diagnosis McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

  22. Rates of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Age McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

  23. Increasing Severity of CDAD United Kingdom, 1994-51 • Comparing well-matched C difficile patients and controls – no difference in mortality at d/c, 3 mos. and 6 mos. Pittsburgh, 20002 • “Life-threatening disease” from 1.6% to 3.2% from 1989 to 2000 • Colectomies increased from 0.48% to 2.6% • In hospital deaths (attr. to C. difficile) increased from 0.21-1.4% Quebec, Canada, 20043 • Attributable mortality of 16.7% in 2005 epidemic in Quebec (in one hospital) • Attributable 30 day mortality 6.9% in 12 Quebec hospital prospective study 1. MacGowan AP, et al. J Antimicrob Chemother 1997;39:537-41 2. Dallal RM, et al. Ann Surg. 2002;235:363-372. Loo VG, et al. NEJM 2005;353:2442-2449 3. Pepin J et al. CMAJ. 2005;173(23):1037-42.

  24. Potential reasons for increased CDAD incidence and severity • Changes in underlying host susceptibility • Changes in antimicrobial prescribing • Changes in infection control practice • New strain with increased virulence

  25. Hypothesis: Change in underlying host susceptibility • Increase in the average age of the population - Increase in exposure to healthcare facilities - Increase exposure to antimicrobials • Possible, but probably not the whole story

  26. Hypothesis: Use of alcohol-based hand rubs • Hand hygiene - Important prevention strategy - HCWs can transmit C. difficile • Traditional: Soap and water hand washing • Increased use of alcohol-based hand rub over the last several years

  27. No relationship between alcohol-based hand rubs and increasing rates of CDAD Boyce et al. Infect Control Hosp Epidemiol 2006; 27:479-483

  28. Hypothesis: Change in antimicrobial prescribing • Quinolones • Popular for the management of CAP 1 • Most common treatment for uncomplicated UTI in women4 • Increased use by >50% from 2000– 2002 (p<0.001) 2 • Multiple antimicrobials and longer course of therapy - Increases risk for C. difficile3 1. Jones RN, Mandell LA. Diagn Microbiol Infect Dis. 2002;44:69–76 2. MacDougall C et al Emerg Infect Dis . 2005 ; 11(3):380-4 3. Bignardi GE. J Hosp Infect 1998; 40:1–15. 4. Kallen et al.Arch Int Med. 2005

  29. Fact: Epidemic C. difficile Strain • Characteristics • North American Pulsed Field Type 1 (NAP1) by PFGE • PCR ribotype 027 • Toxinotype III or “BI” by REA • Distinct from “J” strain of 1989-19921 • Binary toxin as a possible virulence factor • In addition to Toxin A&B containing • 18 bp deletion in tcdC gene • May allow increased toxin production2 • Increased resistance to fluoroquinolones • No resistance to metronidazole 1 Johnson S, et al. N Engl J Med 1999;341:1645-51 2 Warny M, et al. Lancet 2005; 366: 1079-84

  30. 2 1 2 1 1 1 Acute Care Hospitals with CDAD Outbreaks* Between 2001-2004 *Detected by increases in the number of positive routine clinical laboratory tests for C. difficile. McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

  31. Maine, Hospital A Pennsylvania Pennsylvania Maine, Hospital B Maine, Hospital B Illinois Illinois Georgia Maine, Hospital A New Jersey New Jersey Oregon Historic, 1988-1991 Historic, 1993 Historic, 1993-2000 Oregon Historic, 1990-1991 Historic, 1984-1991 Common (Epidemic) Strain by PFGE

  32. Toxinotype and Potential Virulence Factors of Isolates 1 Includes 5 historic “BI” isolates 2 32 (89%) were toxinotype 0 or wild type

  33. Increased Toxin A Production invitro In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations. Warny M, et al. Lancet. 2005;366:1079-1084.

  34. Increased Toxin B Production in vitro In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations. Warny M, et al. Lancet. 2005;366:1079-1084.

  35. Increased Resistance in Epidemic Strain Isolates (After 2000)

  36. States with the Epidemic Strain of C. difficile Confirmed byCDCandHines VA labs(N=27),Updated 4/3/2007 DC HI PR AK

  37. Lethal hospital bug cases rocket, United Kingdom • Potentially lethal cases of C. difficile “rocketed” from 1990s to 2004 • Cases had increased from 1,000 in 1990 to over 35,000 in 2003 • 44,488 cases of C. difficile in > 65 year olds in 2004. BBC News. http://news.bbc.co.uk/2/hi/health/4186834.stm

  38. NAP1/BI/027 in the Netherlands, 2006 1.Kuiper EJ et al. Emerg Infect Dis 2006;12(5):827-830. 2. Goorhuis A et al. CID 2007; 45: 695-703

  39. Other Places… • Canada • France • Poland • Austria • Japan Eurosurveillance Weekly Release. http://www.eurosurveillance.org/index.asp

  40. Community-associated CDAD: Sentinel Cases of Severe Disease • 23 cases of severe community-associated CDAD (CA-CDAD) • Generally young and healthy • Approximately 1/3 without precedent antimicrobial use

  41. Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (1) • Recent reports to the Pennsylvania Department of Health and CDC • Young patients without serious underlying disease • C.difficile toxin-positive by routine diagnostic testing • Responded to CDAD-specific therapy • Peripartum • Within 4 weeks of delivery • Reports from PA, NJ, OH, and NH • Community-associated • No hospital exposure in prior 3 months • Reports from Philadelphia and 4 surrounding counties CDC. MMWR. 2005;54:1201-1205.

  42. Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (2) CDC. MMWR. 2005;54:1201-1205.

  43. Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (3) • Recent onset dates • February 26, 2003 – June 28, 2005 • Only 1 case in 2003 • Transmission to close contacts in 4 cases • 8 cases without antimicrobial exposure • 5 children; 3 required hospitalization • 3 had close contact with diarrheal illness • Another 3 cases with < 3 doses of antimicrobials • Clindamycin most common exposure (10 cases) CDC. MMWR. 2005;54:1201-1205.

  44. Community-associated CDAD may be Increasing, Atlanta VA Hospital 67 total cases* 99 total cases 93 total cases 73 total cases • Through July 31, 2006 • Chi-square for trend: P<0.05 Gaynes, R et al. ICAAC 2006, San Francisco

  45. Gaynes, R et al. ICAAC 2006, San Francisco

  46. Many Patients Develop CDAD without Recent Hospital or Antimicrobial Exposure, Atlanta VA Hospital, 2003-2006 Gaynes, R et al. ICAAC 2006, San Francisco

  47. What is the Source? • Is it in the food supply? • Pathogen of food animals1 • C. difficile has been found in retail meat (beef and veal)2 • 20% of Canadian convenience sample • Only 3 of the 12 isolates found had corresponding isolated that had caused disease in humans • C difficile reported to live after being exposed to 71 degrees Celsius for 120 min. • Potential for interspecies transmission3 • Turkey fed to dogs 1Songer JG, et al. Anaerobe 2006; 12: 1-4 2Rodriguez-Palacios A, et al. EID 2007; 13: 485-7 3Arroyo LG, et al. J Med Microbiol 2005; 54: 163-6

  48. Defining CDAD Below the Waterline Dramatic, Severe Disease In Healthy, Young Persons Antibiotic-associated Inpatient Disease ? Diarrhea in older ambulatory patients +/- chronic conditions Antibiotics? NSAIDS? PPIs? H2 blockers? Source: Human-to-Human and ?

  49. C. difficile Surveillance • Potential Role • Detect disease trends • Detect outbreaks • Compare CDAD rates between institutions • Guide interventions to control CDAD • Monitor the impact of these interventions

  50. CDAD Definitions • CDAD • Diarrhea in a patient with a • Positive C. difficile laboratory assay or 2. Pseudomembranous colitis on endoscopy or surgery or 3. Pseudomembranous colitis seen on histopathology • Recurrent CDAD • An episode of CDAD that occurs 8 weeks or less after the onset of a previous episode • As long as the earlier episode resolved

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