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Disclosure of Conflicts of Interest

Evolving Challenges in Clostridium difficile Infection (CDI): From Risk Assessment to Innovative Treatments. Disclosure of Conflicts of Interest. Linda M. Mundy, MD, Ph.D

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Disclosure of Conflicts of Interest

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  1. Evolving Challenges in Clostridium difficile Infection (CDI): From Risk Assessment to Innovative Treatments

  2. Disclosure of Conflicts of Interest Linda M. Mundy, MD, Ph.D • Dr. Linda M. Mundy, has affiliations with Genentech, Inc. (Patent holder - spouse) and GlaxoSmithKline (Consultant).

  3. Educational Objectives • Discuss the pathophysiology of Clostridium difficile infection (CDI) as it relates to clinical disease • Identify important risk factors for initial CDI and recurrence • Apply therapeutic strategies for improved patient outcomes • Implement methods to prevent CDI in high-risk patients

  4. CDI Overview: 60 Years of Research • Evolution of C. difficile knowledge over past 60 years • 1950: Staphylococcus enterocolitis • 1974: “Clindamycin” colitis • 1978: C. difficile as agent of pseudomembranous colitis • 1981: Vancomycin approved by FDA for CDI • 1982: Metronidazole introduced for CDI • 1984: Enzyme immunoassays for CDI • 2000: Outbreak in Pittsburgh, PA • 2003: Outbreak in Quebec • 2005: Outbreaks in United States and Europe

  5. CDI Overview • Spore-forming, anaerobic, gram-positive bacterium • Causes gastrointestinal infections resulting in diarrhea and colitis • Severity ranges from mild colitis to toxic megacolon and death • Leading cause of healthcare-associated infectious diarrhea in US • Rivals methicillin-resistant Staphylococcus aureus (MRSA) as the most common organism to cause healthcare-associated infections in US Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. CDC. Fact Sheet, August 2004 (updated 7/22/05). McDonald LC, et al. Emerg Infect Dis. 2006;12:409-415.

  6. CDI Epidemiology • Incidence of CDI appears to be increasing in the US 348,950 138,954 Healthcare Cost and Utilization Project (HCUP). http://hcupnet.ahrq.gov.

  7. CDI Epidemiology • Severity of CDI appears to be increasing1-2 • Increased morbidity and mortality • Increased infection in “low-risk” populations1-3 • Emergence of novel, hypervirulent strain now reported across the US, Canada, and Europe • Increased toxin production and sporulation may contribute to widespread disease4,5 1. McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-415. 2. Loo VG, et al. N Engl J Med. 2005;353:2442-2449. 3. Kuijper EJ, et al. Euro Surveill. 2007;12(6):E1-E2. 4. Tucker ME. http://www.ehospitalistnews.com/news/infectious-diseases/single-article/ic-difficilei-epidemic-still-poses-clinical-challenges/01e37c081f.html 5. Merrigan M, et al. J Bacteriol. 2010;192:4904-4911.

  8. CDI Epidemiology • Characteristics of novel epidemic strain: • Typed BI/NAP1/027 • Highly virulent • Produces 16-fold higher levels of Toxin A and 23-fold higher levels of Toxin B • Produces binary toxin CDT • Highly resistant to fluoroquinolones • Denève C, et al. Int J Antimicrob Agents. 2009;33:S24-S28.

  9. CDI Pathophysiology • Primary virulence factors: • Toxin A (TcdA) • Toxin B (TcdB) • Toxins A and B are potent cytotoxic enzymes that damage the human colonic mucosa • Binary toxin (CDT) was previouslyidentified in ~6% of C. difficile isolates, but is present in all isolates of the hypervirulent strain • May potentiate toxicity of TcdA and TcdB and lead to more severe disease • Denève C, et al. Int J Antimicrob Agents. 2009;33:S24-S28.

  10. Economic Burden of CDI 1. Kyne L, et al. Clin Infect Dis. 2002;34:346-353. 2. O’Brien JA, et al. Infect Control Hosp Epidemiol. 2007;28:1219-1227. 3. Dubberke ER, et al. Clin Infect Dis. 2008;46:497-504.

  11. Economic Burden of CDI • Limitations of current data • Primarily hospitalized patients with CDI • Few studies determined costs associated with treatment of CDI complications • Most data obtained prior to outbreak of epidemic strain • Difficult to extrapolate and apply to current epidemiology and management • Economic burden expected to accumulate 1. Dubberke ER, Wertheimer AI. Infect Control Hosp Epidemiol. 2009;30:57-66. 2. Ghantoji SS, et al. J Hosp Infect. 2010;74:309-318.

  12. Pathogenesis of CDI From Poutanen SM, Simor AE. Can Med Assoc J. 2004;171(1):51-58; with permission.

  13. Risk Factors for Initial CDI • Classic risk factors: • Antibiotic therapy • Advanced age • Prolonged stay in healthcare facility • High severity of illness • Additional risk factors • Inflammatory bowel disease • Gastrointestinal surgery • Gastric acid suppression (PPIs) • Immunosuppression 1. Hookman P, Barkin, JS. World J Gastroenterol. 2009;15:1554-1580. 2. APIC. Guide to the Elimination of Clostridium difficile in Healthcare Settings. November 2008. 3. Makris AT, Gelone S. J Am Med Dir Assoc. 2007;8:290-299. 4. Cohen SH, et al. Infection Control and Hospital Epidemiology. 2010;31(5):431-455. 5. Goodhand JR, et al. Ailment Pharmacol Ther. 2011;33:428-441. 6. Aseeri M, et al. Am J Gastroenterol. 2008;103:2308-2313. 7. Schaier M, et al. Nephrol Dial Transplant. 2004;19:2432-2436.

  14. Identifying Patients at Risk for Recurrence and Poor Outcomes • Elderly • Administration of antibiotics after initial treatment of CDI • Prolonged hospitalization or stay in long-term care facility (LTCF) • Defective immune response to toxin A • Gastric acid suppression 1. Johnson S. J Infect. 2009;58:403-410. 2. Hookman P, Barkin JS. World J Gastroenterol. 2009;15(13):1554-1580. 3. Zilberberg M, et al. Crit Care Med. 2009;37:2583-2589. 4. Garey KW, et al. J Hosp Infect. 2008;70:298-304.

  15. Elderly 20.4/1,000 discharges 15.2/1,000 discharges 8.29/1,000 discharges 2.97/1,000 discharges Healthcare Cost and Utilization Project (HCUP). http://hcupnet.ahrq.gov.

  16. Administration of Antibiotics After Initial CDI Therapy • Continued use of non-C. difficile antibiotic after diagnosis of CDI associated with an odds ratio of 4.23 (P<0.001) for recurrent disease1 • Phase 3 study of fidaxomicin and vancomycin linked concomitant antibiotics with lower rates of global cure (initial cure without recurrence at 30d):2 P<0.001 Patients, % GLOBAL CURE FDX VAN Total FDX VAN Total 1. Garey KW, et al. J Hosp Infect. 2008;70:298-304. 2. Johnson S, et al. DDW 2010; Abstract 711c.

  17. Prolonged Hospitalization or Stay in LTCF • Risk related to transmission of C. difficilespores • Primary source from healthcare workers • Staff may carry C. difficilespores on their hands (not likely fecal carriers) • Environmental contamination important secondary source • Up to 50% of LTCF residents and 40% of hospitalized patients have been found to be colonized with C. difficile or its toxin • Infection control and preventions strategies (ie, hand hygiene, isolation precautions) can reduce this risk 1. McFarland LV, et al. N Engl J Med. 1989;320:204-210. 2. Bartlett JG, Gerding DN. Clin Infect Dis. 2008;46(Suppl 1):S12-S18. 3. Simor AE, et al. Infect Control Hosp Epidemiol. 2002;23:696-703. 4. Hookman P, Barkin JS. World J Gastroenterol. 2009;15:1554-1580.

  18. Defective immune response to toxin A Median serum concentrations of antibody against toxin A • Generation of antibody responses to toxin A associated with protection from disease and asymptomatic carriage of C. difficile. • Following symptomatic infection, many individuals develop anti-toxin A and B antibodies • Inability to acquire immunity to toxin A increases risk for recurrent disease • Individuals with recurrent CDI mount poor anti-toxin responses Serum IgM Serum IgG 1. Giannasca PJ, Warny M. Vaccine. 2004;22:848-856. 2. Kyne L, et al. Lancet. 2001;357:189-193; with permission

  19. CDI Diagnostic Challenges

  20. CDI Diagnostic Challenges • Two- and three-step testing algorithms have been proposed • Initial screen: EIA for glutamate dehydrogenase • Confirmatory: Cell cytotoxicity assay (or culture) or polymerase chain reaction (PCR) • Results appear to differ based on the GDH kit used • Optimal universal strategy remains continuous source of debate 1. Hansen G, et al. Clin Laboratory News. 2010 July:10-13. 2. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  21. SHEA/IDSA 2010 Guidelines for Diagnosis • Testing for C. difficile or its toxins should be performed only on unformed stool (unless ileus is suspected) • Testing asymptomatic patients not clinically useful and not recommended outside of epidemiological studies • Stool culture with confirmation of isolate toxigenicity (“toxigenic culture”) provides the standard against which other clinical test results should be compared Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  22. SHEA/IDSA 2010 Guidelines for Diagnosis (Cont.) • EIA considered a suboptimal alternative approach for diagnosis • 2-step testing can help to overcome low sensitivity of toxin testing; this approach remains an interim recommendation • More data on the utility of PCR testing is necessary before it can be recommended for routine testing • Repeat testing during same episode of diarrhea is discouraged Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  23. Basic Principles of CDI Therapy • Discontinue offending antimicrobial agent (if possible) • Send stool specimen for C. difficiletesting • Initiate CDI therapy either empirically or following confirmation of diagnosis (depending on clinical urgency) • Pharmacotherapy • Vancomycin (only FDA-approved treatment for CDI) • Metronidazole • Other • Supportive treatment • Monitor for symptom resolution and be aware of recurrence after treatment discontinuation Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  24. SHEA/IDSA Treatment Recommendations • Severity-based management • SHEA/IDSA recommends stratification of treatment based on disease severity • Risk-stratification method has not yet been validated • Criteria based on expert opinion and/or retrospective data Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  25. SHEA/IDSA Treatment Recommendations Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  26. Additional Management of Severe, Complicated CDI • Prompt recognition of severe, complicated CDI and early surgical evaluation is critical* • Indications of severe, complicated disease course: • Elevated and rising white blood cell count (WBC) • Elevated serum creatinine (SCr) level • Elevated serum lactate • Clinical and/or radiographic evidence of severe ileus, impending toxic megacolon • Consider vancomycin per rectum if ileus is severe *Colectomy may be lifesaving, but is associated with increased risk of mortality if WBC is > 50,000 and lactate is >5 mg/dL 1. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455. 2. Pepin J, et al. Dis Colon Rectum. 2009;52:400-405.

  27. Management of Recurrent CDI • CDI recurrence is a significant challenge • Rates of recurrent CDI: • 20% after first episode • 45% after first recurrence • 65% after two or more recurrences 1. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455. 2. Johnson S. J Infect. 2009;58(6):403-410.

  28. Multiple Recurrent CDI Several empirical approaches have been advocated but most have no controlled data1-3 Metronidazole should not be used beyond first recurrence or for prolonged course, ie, >14 days (concerns for hepatotoxicity and polyneuropathy)1-3 Best data with vancomycin taper regimen4,5 Oral Vancomycin Taper 125 mg QID x 10-14 days 125 mg BID x 7 days 125 mg daily x 7 days 125 mg once every 2 days x 8 days 125 mg once every 3 days x 15 days 1. Aslam S, et al. Lancet Infect Dis. 2005;5:549-557. 2. McFarland LV, et al. Am J Gastroenterol. 2002:97:1769-1775. 3. McFarland LV, et al. JAMA. 1994;271:1913-1918. 4. Kyne L, Kelly CP. Gut. 2001;49:152-153. 5. Tedesco FJ, et al.Am J Gastroenterol. 1985;80:867-868.

  29. Alternative CDI Therapies: Probiotics • Adjunctive treatment for recurrent CDI • Randomized trials of Lactobacillus species have failed to demonstrate benefit to prevent recurrent CDI • Saccharomyces boulardii for secondary prophylaxis once promising2,3 • “Confirmatory” trial failed to confirm • Overall no effect: 44% vs 47% recurrence (RR 0.91; 95% confidence interval 0.66 to 1.27)3 • subgroup analysis showed borderline benefit with S. boulardii and high dose vancomycin (p=0.05) • Reports of fungemia have been reported • More study needed for probiotics in primary prevention 1. Dendukuri N, et al. CMAJ. 2005;173:167-170. 2. Tung JM, et al. Can J Gastroenterol. 2009;23:817-821. 3. Surawicz CM, et al. Clin Infect Dis. 2000;31:1012-1017.

  30. Alternative CDI Therapies: Rifaximin • Rifaximin “chaser” therapy for multiple recurrent CDI1 • Rifaximin 400 mg BID for 14 days immediately following last course of vancomycin • Seven of eight patients had no further diarrhea recurrence • Single case of rifaximin resistance with recurrent CDI after a second course of rifaxmin • Follow up experience with 6 patients • 2 recurred, rifaximin resistance identified in one • Issues with resistance2 • Rifampin resistance observed in 36.8% of 470 recovered isolates and 81.5% of 205 epidemic clone isolates 1. Johnson S, et al. Clin Infect Dis. 2007;44:846-848. 2. Curry SR, et al. Clin Infect Dis. 2009;48:425-429. 3. Johnson S, et al. Anaerobe. 2009; 15:290-1

  31. Alternative CDI Therapies: Nitazoxanide Time to resolution of symptoms • May be effective in patients who failed treatment with metronidazole1 • 66% cure rate in 35 patients who failed treatment with metronidazole • Non-inferior to vancomycin in small study of 50 patients (Figure)2 • Initial response: • Vancomycin: 87% • Nitazoxanide: 94% • Similar time to complete resolution of symptoms P=0.55 1. Musher DM, et al. J Antimicrob Chemother. 2007;59:705-710. 2. Musher DM, et al. Clin Infec Dis. 2009;48:e41-e46; with permission.

  32. Alternative CDI Therapies: Tigecycline • Adjunctive treatment for severe CDI • Lu CL, et al. Int J Antimicrob Agents. 2010;35:311-312. • Single case study • CDI refractory to metronidazole and vancomycin successfully treated with IV tigecycline • Herpers BL, et al. Clin Infect Dis. 2009;48:1732-1735. • 4 pts with severe, refractory CDI • Successful treatment with IV tigecycline therapy • Kopterides P, et al. Anaesth Intensive Care. 2010;38:755-758. • Single case study • Treatment failure with tigecycline combined with vancomycin, metronidazole, and intravenous immunoglobulin (IVIG)

  33. Alternative CDI Therapies: IVIG • Inconclusive evidence regarding the benefit of intravenous immunoglobulin (IVIG) in CDI 1. McPherson S, et al. Dis Colon Rectum. 2006;49:640-645. 2. Abougergi MS, et al. J Hosp Med. 2010;5:E1-E9. 3. Wilcox MH. J Antimicrob Chemother. 2004;53:882-884. 4. O’Horo J, Safdar N. Int J Infect Dis. 2009;13:663-667. 5. Hassoun A, Ibrahim F. Am J Geriatr Pharmacother. 2007;5:48-51.

  34. Fecal Flora Restoration • Theory: Restoration of fecal flora and colonization resistance • Data: • 1958 to 2000: 9 reports (68 patients); cure rate ~90%. • 2003: 18 patients; fecal filtrate (stool transplant); 1 of 16 survivors had a single subsequent recurrence; pre-treated with vancomycin and omeprazole; instilled through nasogastric tube. • Test donor: enteric pathogens, C. difficile, ova and parasites, HAV, HBV, HCV, HIV, RPR 1. Persky SE, Brandt LJ. Am J Gastroenterol. 2000;95:3283-3285. 2. Borody TJ. Am J Gastroenterol. 2000;95:3028-3029. 3. Palmer R. Nat Med. 2011;17:150-152.

  35. Potential Future CDI Therapies: Fidaxomicin • Rate of clinical cure with fidaxomicin non-inferior to that of vancomycin (phase 3 trial results) • Fidaxomicin associated with significantly lower rate of CDI recurrence • Similar adverse event profile Louie TJ, et al. N Engl J Med. 2011;364:422-431; with permission.

  36. Potential Future CDI Therapies: Fidaxomicin * • Similar conclusions reached in second phase 3 study • Equivalent cure rates were achieved withFDX and VAN • Significantly fewer recurrences were seen after FDX (50% less than VAN) resulting in higher global cures † † † 46 182 198 216 411 451 213 235 172 216 154 235 326 451 FDX, fidaxomicin; VAN, vancomycin; *P = NS; †P = .002; ‡P < .001 23 180 69 362 FDX VAN Total FDX VAN Total FDX VAN Total Johnson S, et al. DDW 2010; Abstract 711c.

  37. Potential Future CDI Therapies: Nontoxigenic C. difficile Non-toxigenic C. difficile prevented CDI in 87%-97% of hamsters • NontoxigenicC. difficile strains occur naturally • Natural asymptomatic C. difficile colonization (toxigenic or nontoxigenic) decreases risk of infection • NontoxigenicC. difficile can be administered orally as spores to provide protection against CDI • Mechanism by which nontoxigenicC. difficile prevents colonization by toxigenic strains not yet elucidated • Human Phase I trials completed in early 2010 1. Gerding DN, Johnson S. Clin Infect Dis. 2010;51:1306-1313. 2. Sambol SP, et al. J Infect Dis. 2002;186:1781-1789; with permission

  38. Prevention of Fatal Infection with ToxigenicC. difficile (J9) by Prior Colonization of Hamsters with Non-toxigenicC. difficile(M3) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day.. Clindamycin M3 J9 J9 XX -dead Control

  39. Potential Future CDI Therapies: C. difficile Toxoid Vaccine • Seroconversion rates in young vs elderly healthy subjects (50 μg dose) Study 008 18–55 yrs; median age = 26 Study 009 ≥65 yrs; median age = 70 100% 100% 100 100 75% 80 75 75% 60 Seroconversion Rate (%) Seroconversion Rate (%) 50 42% 40 25 25% 20 0 0 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80 Day Day Both toxins Toxin B Toxin A Foglia G, et al. Anarobe Society of Americas 2010; Abstract CD 1093.

  40. Potential Future CDI Therapies: Monoclonal Antibodies(mAbs) • Recent study of mAbs in 200 CDI patients receiving metronidazole or vancomycin • Recurrence rates: • 7% in mAb group vs. 25% in placebo group Time to CDI recurrence Lowy I, et al. N Engl J Med. 2010;362:197-205.

  41. Prevention of CDI • Transmission between patients and healthcare professionals within hospitals represents major source of C. difficileacquisition • Survey reports inconsistencies among infection control measures • Hand hygiene policies • Duration of isolation • Environmental cleaning practices • Antimicrobial stewardship programs APIC 2010 Clostridium difficile Pace of Progress Survey. Available at: http://www.apic.org/Content/NavigationMenu/ResearchFoundation/NationalCDiffPrevalanceStudy/CDI_Pace_of_Progress_Survey_Report.pdf. Accessed January 31, 2011.

  42. Minimize Transmission among Healthcare Personnel: Hand Hygiene • Appropriate hand hygiene – area of controversy • In routine settings, alcohol-based hand hygiene in conjunction with isolation precautions using gloves may be acceptable • In setting of outbreak or increased rates, consider washing hands with soap and water after caring for patients with C. difficile HCWs = healthcare workers. 1. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31:431-455. 2. Dubberke ER, et al. Infect Control Hosp Epidemiol. 2008;29:S81-S92. 3. APIC Guide to the Elimination of Clostridium difficile in Healthcare Settings, Association for Professionals in Infection Control and Epidemiology, Inc. November 2008.

  43. WWS CWS WWA AHW AHR Efficacy of Hand Hygiene Methods for Removal of C. difficile Contamination from Hands AHR = alcohol hand rub AHW = alcohol hand wipe CFU = colony forming units CWS = cold water soap WWA = warm water and antibacterial WWS = warm water and soap Decrease in colony counts compared with no wash 2.5 2 1.5 1 1.8 1.8 Decrease in colony counts (log CFU/mL) 1.4 0.5 ** ** * * 0.6 0 -0.1 -0.5 -1 Hand hygiene method * Different from AHR (P<0.05). ** Different from AHR and AHW (P<0.05). Oughton M, et al. Infect Control Hosp Epidemiol. 2009;30(10):939-944.

  44. Minimize Transmission among Healthcare Personnel: Hand Hygiene • C. difficile spores generally resistant to bactericidal effects of alcohol • Clinical correlation of CDI and alcohol-based disinfectants? • Several studies have failed to demonstrate an increase in CDI rates with alcohol-based hand hygiene • No studies have found a decrease in CDI rates with soap and water Gordin FM, et al. Infect Control Hosp Epidemiol. 2005;26:650-653. Boyce JM, et al. Infect Control Hosp Epidemiol. 2006;27:479-483. Knight N, et al. Am J Infect Control 2010;38:523-528. Vernaz N, et al. J Antimicrob Chemother. 2008; 62:601-607. Kaier K, et al. Infect Control Hosp Epidemiol. 2009;30:346-353.

  45. Minimize Transmission Among Healthcare Personnel: Contact Precautions • Patients with CDI placed in private rooms when possible • Full barrier precautions (gown and gloves) for contact with CDI patient • Use of dedicated patient care items and equipment 1. Dubberke ER, et al. Infect Control Hosp Epidemiol. 2008;29:S81-S92. 2. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455.

  46. Minimize Transmission among Healthcare Personnel: Use of Gloves • Four wards randomized • Intervention • Education: gloves when handling body substances (stool) • Gloves placed at bedside • Reduction in CDI and colonization on glove wards P = 0.015 Johnson S, et al. Am J Med. 1990;88:137-140.

  47. Minimize Transmission from Environment: Disinfection • Use of sodium hypochlorite (at least 5,000 ppm available chlorine) for environmental contamination, during outbreak areas • Inconsistent efficacy in endemic settings • Areas in question: • Concentration of bleach? [Available chlorine: 5,000 ppm (1:10), 1,000 ppm, or 500ppm] • Where to clean? [CDI rooms only, all rooms, entire ward] • How frequent? [Daily or upon discharge] • How to implement? [Mix fresh daily, premixed, or prepackaged wipes; wipe or spray] Perez. J, et al. Am J Infect Control. 2005;33:320-325.

  48. Minimize Transmission by Environment: Bleach Disinfection Mayfield JL, et al. Clin Infect Dis. 2000;31:995-1000.

  49. Reduce Risk of CDI Acquisition: Antimicrobial Stewardship • Reduce use of “high risk” antimicrobials • Reduce unnecessary antimicrobial use • Effective in outbreak and non-outbreak settings 1. Valiquette L. Clin Infect Dis. 2007;45:S112-121; with permission. 2. Fowler S. J Antimicrob Chemother. 2007;59:990-995.

  50. Bundles for CDI • Prevention and treatment bundles • In response to increased CDI incidence and severity • Prevention bundle stressed adherence to existing policies Abbett SK, et al. Infect Control Hosp Epidemiol. 2009; 30:1062-1069.

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