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Introduction to Clostridium difficile infection

Introduction to Clostridium difficile infection. Slide resource set. Introduction to Clostridium difficile. Vegetative form. Spores surrounding a vegetative cell. C. difficile is a Gram-positive, spore-forming, anaerobic bacillus that was first identified in 1935 1

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Introduction to Clostridium difficile infection

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  1. Introduction to Clostridium difficile infection Slide resource set

  2. Introduction to Clostridium difficile Vegetative form Spores surrounding a vegetative cell C. difficile is a Gram-positive, spore-forming, anaerobic bacillus that was first identified in 19351 C. difficile is the leading cause of infective nosocomial diarrhoea in industrialised countries2 C. difficile passes through a life cycle where it exists in two forms; as vegetative cells and as spores3 Hall IC, O’Toole E. Am J Dis Child 1935;49:390–402; Crobach MJT, et al. Clin Microbiol Infect 2009;15:1053–66; Poutanen S, Simor AE. CMAJ 2004;171:51–8. FDX/12/0076/EUa| MW101

  3. Clinical presentation of C. difficile infection (CDI) Normal, healthy colon Pseudomembranous colitis Increasing severity Asymptomatic colonisation Diarrhoea without colitis Watery Mucus but no blood Colitis without pseudomembrane formation Pseudomembranous colitis Fulminant colitis Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79; Bartlett JD, Gerding DN. Clin Infect Dis 2008;46:S12–8. FDX/12/0076/EUb| SJ103

  4. Other signs and symptoms of CDI, including severe colitis Vomiting Abdominal tenderness Fever (rigors) Dehydration Leucocytosis Hypoalbuminaemia Exhaustion Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79. AI/12/0055/EUg| DM104

  5. Broad-spectrum antibacterials1 Risk factors for CDI There are numerous reported risk factors for CDI Immuno-compromised2 PPIs2 Nasogastric tube/GI surgery2 Older age2 ICU stay2 Severity of underlying diseases2 Prolonged stay in hospital/care home2 GI, gastrointestinal;ICU, intensive care unit; PPI, proton pump inhibitor Cohen SH, et al. Infect Control Hosp Epidemiol 2010;31:431–55; Bignardi GE. J Hosp Infect 1998;40:1–15. FDX/12/0076/EUb | SJ108

  6. Key steps in the pathogenesis of CDI Antibacterial therapy Alteration of colonic microflora C. difficileexposure and colonisation Release of toxins A and B Colonic mucosal injury and inflammation Kelly CP, LaMont JT. Annu Rev Med 1998;49:375–90. FDX/13/0038/EUb | VA002

  7. The infectious cycle of transmission and recurrence of CDI 1. Ingestion of spores transmitted from other patients, via hands of healthcare personnel and the environment 4.Toxin production leads to inflammation and damage to intestinal cells 3. Disruption of normal colonic microflora allows colonisationand overgrowth of C. difficile in the colon C. difficile 2. Germination into growing (vegetative) cells Toxins 5. Transmissionof spores via thefaecal–oral route Adapted from Sunenshine RH, et al. Cleve Clin J Med 2006;73:187–97. FDX/12/0076/EUb| SJ101

  8. Cycle of infection with C. difficile Spores Vegetative cells C. difficilespores andvegetative cellsare ingested C. difficilemultiplies inthe colon Stomach Colon Most vegetative cells are killed in the stomach,but spores can survivethe acid environment Small bowel Gut mucosafacilitatesadherenceto thecolonicepithelium C. difficile spores germinate in the small bowel uponexposure to bile acids Flagellae facilitateC. difficile movement Adapted from Poutanen SM, Simor AE. CMAJ 2004;171:51–8. FDX/13/0038/EUb | VA001

  9. CDIis toxin mediated *Large, single-unit, glucosylatingtoxins; BI/NAP1, characterised as group BI by restriction endonuclease analysis and North American pulse-field type 1 by gel electrophoresis Toxin A*1 Referred to as the ‘enterotoxin’ because of the easily demonstrated effects of purified toxin in animal intestinal models Likely to be intimately involved in CDI pathogenesis Toxin B*1 Potent cytotoxin Structurally similar to toxin A but effects in animal intestinal models have not been easy to demonstrate Likely to be intimately involved in CDI pathogenesis Binary toxin Unrelated to toxins A and B1 Present in the epidemic BI/NAP1/027 strain2 Role in pathogenesis uncertain2 Rupnik M, et al. Nat Rev Microbiol 2009;7:526–36; Warny M, et al. Lancet 2005;366:1079–84. FDX/12/0076/EUb | SJ134

  10. Role of host antibody-mediated responses in CDI pathogenesis Asymptomatically colonised Exposure to non-toxigenic C. difficile Patients with risk factors for CDI,including antibacterialuse in hospital setting Exposure to toxigenicC. difficile accompanied byIgG response to toxin A Asymptomatically colonised Exposure to toxigenicC. difficile without an IgG response to toxin A C. difficile negative Symptomatic CDI IgG, Immunoglobulin G antibody Adapted from Rupnik M, et al. Nat Rev Microbiol 2009;7:526–36. FDX/12/0076/EUb | SJ102

  11. Impact of CDI on short- and long-term patient management CDI may necessitate treatments for underlying diseases to be reduced in intensity or suspended Alterations to treatment plans may irreversibly affect long-term outcomes1 Episodes of CDI arising in the ICU may prolong ICU stay and overall hospitalisation2 Excess ICU length of stay: 2.2 days (p=0.069) Excess hospital length of stay: 4.5 days (p=0.030) Hautmann MG, et al. Radiat Oncol 2011;6:89; Kenneally C, et al. Chest 2007;132:418–24. FDX/12/0076/EUb| SJ119

  12. Length of hospital stay among patients with CDI by country 50 45 40 37 35 30 27 25 Length of stay (days) 21 20 18 17 17 16 15 15 12 10 5 0 UK EU Spain Ireland France Belgium Germany Switzerland Netherlands EU, European Union Wiegand PN, et al. J Hosp Infect 2012;81:1–14. FDX/12/0076/EUd|DN139

  13. Association of CDI with hospital readmissions Kaplan–Meier estimates of time until hospital readmission for matched pairs (N=580) in patients with and without CDI 1.0 No CDI 0.8 CDI 0.6 Proportion without readmission 0.4 Log-rank p<0.001 0.2 0.0 0 30 60 90 120 150 180 Time since hospital discharge (days) • In this study, CDI patients were significantly more likely to be readmitted to hospital than controls; the readmission rate attributable to CDI was 19.3% Dubberke ER, et al. Emerg Infect Dis 2008;14:1031–8. FDX/12/0076/EUd|DN149

  14. Association of CDI with mortality Kaplan–Meier survival estimates for cohort (N=18,050) in patients with and without CDI 1.0 No CDI 0.8 CDI 0.6 Cumulative survival 0.4 Log-rank p<0.001 0.2 0.0 0 30 60 90 120 150 180 Time since hospital discharge (days) • 38% of patients with CDI died within 180 days after hospital admission vs12% of patients without CDI Dubberke ER, et al. Emerg Infect Dis 2008;14:1031–8. FDX/12/0076/EUd|DN150

  15. Mortality rates in studies of CDI In a recent pan-European hospital-based survey:1 ~2% of patients with CDI died as a result of the infection CDI contributed to mortality in a further 7% of cases In a case-control study in Canada:2 ~7% of patients with CDI died as a result of the infection CDI contributed to mortality in a further 8% of cases Bauer MP, et al. Lancet 2011;377:63–73; Loo VG, et al. N Engl J Med 2005;353:2442–9. FDX/12/0087/EUu| slide 013

  16. Mortality rates associated with CDI across Europe Weighted average 30-day mortality in patients with healthcare facility-acquired CDI by country 45 40 35 30 30% 25 22% 30-day mortality (%) 20% 20 16% 16% 15 15% 14% 14% 10 9% 7% 5 3% 0 UK Spain Ireland Austria France Finland Germany Denmark Switzerland Luxembourg The Netherlands • Data from a systematic review found the weighted average 30-day mortality from CDI ranged from 3–30% Wiegand PN, et al. J Hosp Infect 2012;81:1–14. FDX/12/0076/EUd |DN108

  17. Age-specific incidence of CDI and attributable mortality Loo VG, et al. N Engl J Med 2005;353:442–9. FDX/12/0076/EUb | SJ113

  18. Factors contributing to risk of mortality from CDI Dubberke ER, et al. Infect Con Hosp Epidemiol 2007;28:208–11; Ananthakrishnan AN, et al. Gut 2008;57:205–10; Bajaj JS, et al. Am J Gastroenterol 2010;105:106–13. Advancing age1,2 Older age and severity associated with the epidemic 027/NAP1 strain3 Use of metronidazole for severe disease4 Haematological malignancy and severe disease5 Comorbidity Renal disease4 Ischaemic heart disease4 Inflammatory bowel disease6 Liver disease (cirrhosis)7 Loo VG, et al. N Engl J Med 2005;353:2442–9; Bauer MP, et al. Lancet 2011;377:63–73; Miller M, et al. Clin Infect Dis 2010;50:194–201; Wilson V, et al. Clin Infect Dis 2010;50:e77–81; FDX/12/0076/EUb | SJ110

  19. Increased mortality: a result ofCDI severity Toxic megacolon • Up to 8% of patients develop fulminant CDI1 • Fulminant colitis accounts for serious complications including toxic megacolon2 • Many patients with toxic megacolon require emergency surgery (colectomy) to remove dead sections of the colon2–4 • Approximately half of all patients who undergo colectomy die3,4 Jaber MR, et al. Am J Gastroenterol 2008;103:3195–203; Longo WE, et al. Dis Colon Rectum 2004;47:1620–6; Berman L, et al. J Clin Gastroenterol 2008;42:476–80; Dallal RM, et al. Ann Surg 2002;235:363–72. FDX/12/0076/EUb | SJ111

  20. Recurrence of CDI Recurrence of CDI has been identified by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) as the most important problem in the treatment of CDI1 CDI recurrence is common, occurring in up to 25% of cases within 30 days following treatment2–4 Recurrence appears to be related to a combination of:5 A failure to re-establish the colonic microflora The presence in the intestines of spores of C. difficile A sub-optimal host immune response to the infecting organism and its toxins Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79; Louie TJ, et al. N Engl J Med 2011;364:422–31; Lowy I, et al. N Engl J Med 2010;362:197–205; Bouza E, et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4; DuPont HL. N Engl J Med 2011;364:473–4. FDX/12/0076/EUb | SJ121

  21. The incidence of recurrent CDI 1st recurrence of CDI Recurrence(s) of CDI ~45–65% of patients have further recurrences4,5 Up to 25% of patients have recurrent CDI1–3 Initial episode of CDI Louie TJ, et al. N Engl J Med 2011;364:422–31; Lowy I, et al. N Engl J Med 2010;362:197–205; Bouza E, et al. Clin Microbiol Infect 2008;4(Suppl 7):S103–4; McFarland LV, et al. Am J Gastroenterol 2002;97:1969–75; McFarland LV, et al. JAMA 1994;271:1913–8. FDX/12/0076/EUb | SJ122

  22. Risk factors for a recurrence of CDI Hu MY, et al. Gastroenterology 2009;136:1206–14; Do AN, et al. Clin Infect Dis 1998;26:954–9; Bauer MP, et al. Clin Microbiol Infect 2011;17(Suppl 4):A1–4; Pépin J, et al. Clin Infect Dis 2005;40:1591–7. Immunocompromised state1 Exposure to other antibacterial agents that disrupt the normal colonic microflora2–5 Renal impairment6,7 Aged 65 years or over2,4,8 Impaired immune response to C. difficile toxin A2 Severe underlying disease2 Prolonged hospitalisation8 ICU stay5 Cohen MB. J Pediatr Gastroenterol Nutr 2009;48(Suppl 2):S63–5; Kyne L, et al. Lancet 2001;357:189–93; Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79; Bauer MP, et al. Lancet 2011;377:63–73; FDX/12/0076/EUr| SJ204

  23. Laboratory detection of CDI EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; PCR, polymerase chain reaction The recommended approach is to demonstrate:1,2 Organism in stool GDH or culture: do not distinguish toxigenic vs non-toxigenic Need confirmatory test for toxigenicity Toxin in stool Cell culture toxin cytotoxicity EIA to detect toxins A and/or B Toxin from organism Culture cytotoxicity Toxin genes in organism PCR for toxin B gene Crobach MJT, et al. Clin Microbiol Infect 2009;15:1053–66; Kelly CP, LaMont JT. Annu Rev Med 1998;49:375–90. FDX/12/0087/EUu| slide 018

  24. ESCMID recommended diagnostic algorithm for CDI Toxin detection or bacterial detection EIA to detect GDH, or real-time PCR to detect TcdB EIA to detectTcdA and TcdB No CDI − + − + EIA to detect GDH,or real-time PCR to detect TcdB, or cytotoxicity assay EIA to detect TcdA,and TcdB, or cytotoxicity assay High clinical suspicion:toxigenic culture + − − + CDI isdiagnosed No CDI CDI isdiagnosed C. difficile toxins are not detectable in faeces but C. difficile is present; CDI cannot be excluded EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; PCR, polymerase chain reaction Adapted from Crobach MJT, et al. Clin Microbiol Infect 2009;15:1053–66. FDX/12/0076/EUo|CS209

  25. CDI imposes a significant burden on hospitals Infection control and environmental decontamination1 Patient isolation and ward closures1 Monitoring and surveillance2 Laboratory tests3 Surgical costs1,3 ICU length of stay4 Hospital length of stay2,4,5 Kuijper EJ, et al. Clin Microbiol Infect 2006;12:2–18; Wiegand PN, et al. J Hosp Infect 2012;81:1–14; Ghantoji SS, et al. J Hosp Infect 2010;74:309–18; Kenneally C, et al. Chest 2007;132:418–24; Vonberg RP, et al. J Hosp Infect 2008;70:15–20. FDX/12/0076/EUb | SJ120

  26. CDI: a public health challenge Søes L, et al. Euro Surveill 2009;14:1–4; CDC. MMWR Morb Mortal Wkly Rep 2005;54:1201–5; Kuijper EJ, et al. Clin Microbiol Infect 2006;12:2–18; Wilcox M, et al. J Hosp Infect 1996;34:23–30. The recorded incidence and severity of CDI have increased in many settings in recent years, including in people previously thought to be at lower risk1–6 Clusters/outbreaks of CDI cause ward closures and disruption of hospital activity7 There is a considerable burden of morbidity and mortality due to CDI7 The resultant effect is an erosion of public confidence concerning the risk of healthcare-associated infection Also, the financial burden of disease is high8 Bauer MP, et al. Lancet 2011;377:63–73; Vonberg RP, et al. Emerg Infect Dis 2007;13:179–80; Soler P, et al. Infect Control HospEpidemiol 2008;29:887–9; Lyytikäinen O, et al. Emerg Infect Dis 2009;15:761–5; FDX/12/0076/EUa| MW103

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