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Conventional Treatment options

Conventional Treatment options. Slide resource set. Snapshot of treatment for initial episodes of Clostridium difficile infection (CDI). Treatments used in an initial episode of CDI in a 2008 European survey. Bauer MP, et al. Lancet 2011;377:63–73. FDX/12/0076/ EUf | EK206.

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Conventional Treatment options

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  1. Conventional Treatment options Slide resource set

  2. Snapshot of treatment for initial episodes of Clostridium difficile infection (CDI) Treatments used in an initial episode of CDI in a 2008 European survey Bauer MP, et al. Lancet 2011;377:63–73. FDX/12/0076/EUf| EK206

  3. Rates of clinical cure for metronidazole and vancomycin p=0.36 p=0.02 p=0.006 37/41 28/38 30/31 66/79 39/40 69/71 Note: patients were stratified by mild or severe disease based on a severity assessment score developed for this study. Patients received one point each for age >60 years, temperature >38.3°C, albumin level <2.5 mg/dL, or peripheral white blood cell count >15,000 cells/mm3 within 48 hours of enrolment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in an intensive care unit. Patients with ≥2 points were considered to have severe CDI Zar FA, et al. Clin Infect Dis 2007;45:302–7. FDX/12/0076/EUf  EK205

  4. Rates of clinical success for metronidazole and vancomycin Rates of clinical success in two identical, multicentre, randomised, double-blind, parallel-group trials p<0.05 p=NS p=NS Johnson S, et al. Poster presented at IDWeek 2012; 818. Clinical success was defined as diarrhoea resolution and absence of severe abdominal discomfort due to CDI on Day 10; NS, not significant; qid, four times daily FDX/12/0076/Euj | OC104

  5. Clinical limitations associated with current treatments for CDI Although metronidazole and vancomycin are effective in a first episode of CDI, therapy remains suboptimal Among the most significant drawbacks of current therapy for CDI are: Rates of treatment failure with metronidazole of up to 18%1 Rates of recurrent infection following treatment with metronidazole and vancomycin of up to 25% within 30 days following treatment2–4 Risk of overgrowth of vancomycin-resistant enterococci (VRE) in patients who are already colonised with VRE5 Aslam S, et al. Lancet Infect Dis 2005;5:549–57; Louie TL, 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; Al-Nassir WN, et al. Antimicrob Agents Chemother 2008;52:2403–6. FDX/12/0087/EUu|slide 041

  6. Is there an increasing treatment failure rate with metronidazole? Average rate of treatment failure in patients receiving metronidazole Note: the dates relate to the year of publication not the year of the study Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57. FDX/12/0076/EUf| EK213

  7. 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

  8. Rates of disease recurrence with metronidazole and vancomycin (1) Note: the dates relate to the year of publication not the year of the study Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57. FDX/12/0076/EUa  MW303

  9. Rates of disease recurrence with metronidazole and vancomycin (2) Rates of recurrence in two identical, multicentre, randomised, double-blind, parallel-group trials p=NS p=NS p=NS Johnson S, et al. Poster presented at IDWeek 2012; 818. NS, not significant FDX/12/0076/Euj | OC105

  10. Rates of recurrence for metronidazole and vancomycin grouped by age CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials p=NS p=NS p=NS *Subset of subjects aged >65 years; NS, not significant Johnson S, et al. Poster presented at IDWeek 2012; 818. Recurrence increased with increasing age in metronidazole-treated subjects but remained relatively stable in vancomycin-treated subjects FDX/12/0076/EUq| EB113

  11. Rates of recurrence for metronidazole and vancomycin grouped by sex CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials p<0.05 p=NS Johnson S, et al. Poster presented at IDWeek 2012; 818. Male subjects treated with vancomycin had significantly fewer (p<0.05) recurrences vs males treated with metronidazole NS, not significant FDX/12/0076/EUq|EB112

  12. Rates of recurrence for metronidazole and vancomycin grouped by C. difficile strain CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials p=NS p=NS BI, restriction-endonuclease analysis group BI strain of C. difficile (also known as NAP1/027);NS, not significant Johnson S, et al. Poster presented at IDWeek 2012; 818. FDX/12/0076/EUq| EB115

  13. Differences in estimates of CDI recurrence and its definition across Europe Wiegand PN, et al. J Hosp Infect 2012;81:1–14. *Ribotypes 001, 014 and 078; †Ribotype 027 FDX/12/0076/EUq| EB107

  14. Vancomycin regimens for recurrent CDIpost hoc analysis from two trials (n=163) *p<0.05 compared with vancomycin 1 g/day * * McFarland LV, et al. Am J Gastroenterol 2002;97:1769–75. FDX/12/0076/EUr|SJ230

  15. Rationale for a new treatment CDI remains a disease for which there are significant unmet needs e.g.: Therapy to provide sustained clinical cure (defined as clinical cure without recurrence)1 Therapy to reduce recurrence (relapse and/or reinfection)1 Better identification of patients at risk of recurrence or those for whom the impact of recurrence would be most dramatic2 New approaches under investigation but data from large-scale randomised controlled trials are lacking3 Management strategies to treat acute episodes of CDI effectively and markedly reduce the risk of recurrence would represent a significant therapeutic advance4 Cornely OA. ClinMicrobiol Infect 2012;18(Suppl 6):28­–35; Kelly CP. ClinMicrobiol Infect 2012;18(Suppl 6):21­–7; Bauer MP, et al. ClinMicrobiol Infect 2009;15:1067–79; Bouza E. ClinMicrobiol Infect 2012;18(Suppl 6):5–12. FDX/12/0076/EUk|MB145

  16. Faecal microbiota therapy for CDI NG, nasogastric;PMC, pseudomembranous colitis Borody TJ, Khoruts A. Nat Rev Gastroenterol Hepatol 2012;9:88–96. FDX/12/0100/EUk | JC129

  17. Faecal microbiota therapy for recurrent CDI: study design • Endpoints1,2 • Diarrhoea (≥3×/day) and C. difficile toxin on Days 35 and 70 • Quality of life, days spent in isolation, days admitted to the hospital, attributable costs • Psychological analysis of effect of faecal transplant • Follow-up 10 weeks, cross-over if failure in antibiotic group van Nood E, et al. N Engl J Med 2013;368:407–15; Protocol to: van Nood E, et al. N Engl J Med 2013;368:407–15. qid, four-times daily FDX/12/0100/EUk | JC132

  18. Duodenal faecal microbiota transplantation vs vancomycin plus lavage p<0.001 p<0.001 p=0.008 p=0.003 Rates of cure without relapse (%) van Nood E, et al. N Engl J Med 2013;368:407–15. Study stopped after interim analysis No significant differences in adverse events among study groups, except for mild diarrhoea and abdominal cramping in the infusion group on the day of infusion FDX/12/0076/EUf| EK242

  19. Microbiota diversity in patients before and after faecal infusion versus healthy donors 250 200 150 Simpson’s reciprocal index 100 50 0 Donors Patients beforeinfusion Patients afterinfusion van Nood E et al. N Engl J Med 2013;368:407-415 van Nood E, et al. N Engl J Med 2013;368:407–15. FDX/12/0100/EUk | JC135

  20. Faecal bacteriotherapy: limitations No supporting data from prospective, randomised controlled trials1–3 Very limited data on long-term safety Administration via colonoscopy, nasogastric tube or retention enema associated with some risk4 Potential transmission of infectious agents contained in the donor stool may also carry inherent risks4 Acceptability of the procedure may be an issue5 Patients and physicians reluctant to choose donor-faeces infusion at an early stage6 Gough E, et al. Clin Infect Dis 2011;53:994–1002; Anderson JL, et al. Aliment PharmacolTher 2012;36:503–16; Guo B, et al. Aliment PharmacolTher 2012;35:865–75; Aas J, et al. Clin Infect Dis 2003;36:580–5; Hedge DD, et al. TherClin Risk Manag 2008;4:949–64; van Nood E, et al. N Engl J Med 2013;368:407–15. FDX/12/0076/EUk|MB137

  21. Issues surrounding the clinical application of faecal transplantation Acceptability1–3 Patient selection Immunocompromised3,4 Concomitant antibiotic therapy5 Allergens (e.g. nuts)4 Donor screening Epstein–Barr virus,5 cytomegalovirus,5 HIV,4–6 hepatitis A/B/C4–7 Syphilis,7C. difficile5–7 Enteric pathogens including parasites5–7 No antibiotics in previous 3 months4 Cost Screening6 Procedure-related6 Yoon SS, Brandt LJ. J ClinGastroenterol 2010;44:562–6; Hedge DD, et al. TherClin Risk Manag 2008;4:949–64; Borody TJ, Khoruts A. Nat Rev GastroenterolHepatol 2012;9:88–96; Bakken JS, et al. ClinGastroenterolHepatol 2011;9:1044–9; van Nood E, et al. N Engl J Med 2013;368:407–15; Rohlke F, Stollman N. TherapAdvGastroenterol 2012;5:403–20; Aas J, et al. Clin Infect Dis 2003;36:580–5. FDX/12/0100/EUk | JC136

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