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Tres Difficile

Tres Difficile. Stephen M. Brecher PhD Director of Microbiology VA Boston Health Care System West Roxbury, Massachusetts. The opinions expressed in this presentation are those of the presenter and do not necessarily represent the views of the Veterans Affairs Health-Care System.

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Tres Difficile

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  1. Tres Difficile Stephen M. Brecher PhDDirector of Microbiology VA Boston Health Care SystemWest Roxbury, Massachusetts

  2. The opinions expressed in this presentation are those of the presenter and do not necessarily represent the views of the Veterans Affairs Health-Care System

  3. The Dominant Species The human body has 1013 human cells and a minimum of 1014bacterial cells

  4. Case reports Historical perspective Organism & key properties Changing epidemiology Disease Diagnosis Treatment Infection control Overview

  5. Case Study 1 • 60 yo male admitted to hospital for community acquired pneumonia, treated with levofloxacin and discharged • 7 days later, seen at another hospital because of 12-15 pound weight gain over last few days (“my abdomen has never been so big”) and hypertension (213/106) • Afebrile, WBC of 8.5, albumin 3.1, creatinine 0.9, no diarrhea noted • Admitted, treated for hypertension and ciprofloxacin given to complete treatment for CAP; discharged 3 days later

  6. Case Study 1 (cont’d)

  7. Case Study 1 (cont’d)

  8. Historical Perspective • In the 1960s it was noted that patients on antibiotics developed diarrhea1 • “staphylococcal colitis” • Originally thought to be caused by S. aureus and treated with oral bacitracin • Stool cultures routinely ordered for S. aureus • Early 1970s, a new explanation • “clindamycin colitis” • Severe diarrhea, pseudomembranous colitis, and occasional deaths documented in patients on clindamycin 1. Gorbach SL. NEJM. 1999;341:1689-1691.

  9. “Antibiotic Associated Pseudomembranous Colitis Due to Toxin-Producing Bacteria” • Bartlett and co-workers1 demonstrated cytotoxicity in tissue culture and enterocolitis in hamsters from stool isolates from patients with pseudomembranous colitis • Isolate was C. difficile • Bacillus difficilis (now confirmed as C. difficile) was cultured from healthy neonates (with difficulty, hence the name) in 19352 1. Bartlett JG, et al. NEJM. 1978;298: 531-534. 2. Hall JC and O’Toole E. Am J Dis Child. 1935;49:390-402.

  10. Quiz Time Q. Why did it take so long to associate the organism C. difficile with the disease? A. Organism was (is) found in healthy infants Q. Why do antibiotics sometimes cause diarrhea (unrelated to C. difficile)? A. Disrupt the intestinal flora which plays a major role in digestion of food

  11. Clostridium difficile • Gram-positive, anaerobic, spore-forming bacillus • Vegetative cells die quickly in an aerobic environment • Spores are a survival form and live for a very long time in the environment • Grows on selective media in 2 days and smells like horse manure (p-cresol)

  12. Importance of Spores • Resistant to heat, drying, pressure, and many disinfectants • Resistant to all antibiotics because antibiotics only kill or inhibit actively growing bacteria • Spores survive well in hospital environment • Spores are not a reproductive form, they represent a survival strategy

  13. Source of Infections • Spores in hospital, nursing home, or long-term care environment associated with ill patients • Large numbers of spores on beds, bed-rails, chairs, curtains, medical instruments, ceiling, etc. • Asymptomatic carriers in those same environments • Low risk compared to patients with active disease • False negative lab tests (low sensitivity) • Unknown in community based infections, but food has been implicated1 1. Jhung MA, et al. Emerg Infect Dis. 2008;14:1039-1045.

  14. Risk Factors for Infection • Hospitalization or long-term care facility • Antibiotics (some more than others) • Increasing age (>65, >>80) • Co-morbidity • Surgery • ? Proton-pump inhibitors • Community-associated cases • Peri-partum • Close contact of CDI (C. difficile infection) case • Food

  15. Case Study 2 • 31 yo pregnant female (14 weeks, twins) seen at a local ER with history of • 3 weeks intermittent diarrhea • 3 days cramping and watery diarrhea • Stool + for C. difficile toxin • Received T/S for UTI 3 months prior to ER visit • Admitted, treated with metronidazole and discharged • Readmitted next day with severe colitis • Treated in hospital for 18 days with metronidazole, oral vancomycin and cholestyramine, discharged

  16. Case Study 2 (cont’d) • Readmitted 4 days later • Diarrhea and hypotension • Spontaneously aborted her fetuses • Subtotal colectomy, aggressive therapy • Died on 3rd day • Post-mortem showed toxic megacolon with evidence of pseudomembranous colitis MMWR 54:(47);1201-1205.

  17. What Can We Learn From Case 2? • We know nearly nothing about community based CDI • Testing for C. difficile is now both an in-patient and out-patient test • Risk factors other than colonic imbalance mediated by antibiotics must be considered

  18. Role of Antibiotics • All antibiotics (including metronidazole and vancomycin) are associated with CDI • High-risk group • Clindamycin • Cephalosporins/penicillins/beta-lactams • Fluoroquinolones • Alteration of normal colonic flora thought to favor growth of C. difficile • Antibiotics do not know they are suppose to kill/inhibit only the “bad guys”

  19. PathogenesisHistorical Perspective • Most CDI were mild • Diarrhea was main symptom • Pseudomembranous colitis and toxic megacolon were rare • Discontinuing antibiotics worked in many cases • High response rate to metronidazole and vancomycin

  20. Incidence of CDI • United States • CDI is not a reportable disease so exact number of cases and deaths remain unknown • Based on discharge diagnoses, CDI cases have tripled over last 5 years • United Kingdom • Deaths in UK ~ 9,000/year CDI = C. difficile infection.

  21. Pathogenesis • Toxigenic strains produce 2 large protein exotoxins that are associated with virulence • Toxins A and B • Mutants strains that do not make toxins A and B are not virulent • Some strains make a third toxin known as Binary Toxin • By itself, not pathogenic • May act synergistically with toxins A and B in severe colitis • More common in animal strains

  22. Pathogenesis of CDI Asymptomatic C. difficile colonization Antimicrobial C. difficile exposure C. difficile infection Hospitalization From Johnson S, Gerding DN. Clin Infect Dis. 1998;26:1027-1036; with permission.

  23. PathogenesisChanging Epidemiology • Increasing morbidity and mortality noted beginning in 2000 • Outbreaks in US & Canada (>200 deaths) • Was this due to poor infection control, emergence of antibiotic resistance, or something else? • A new, hypervirulent strain was detected

  24. Epidemic Strain Strain typed BI/NAP1/0271,2 Is highly resistant to fluoroquinolones2,4 Binary toxin genes are present Produces large quantities of toxins A and B1,3 Has a tcdC gene deletion1 • Warny M, et al. Lancet. 2005;366:1079-1084. • Hubert B, et al. Clin Infect Dis. 2007;44:238-244. • CDC Fact Sheet. July 2005. • McDonald LC, et al. N Engl J Med. 2005;353:2433-2441. Adapted from McDonald LC, et al. N Engl J Med. 2005;353:2433-2441; with permission.

  25. In Vitro Production of Toxins in Epidemic Strain From Warny M, et al. Lancet. 2005;366:1079-1084, with permission.

  26. Not So Fast • 2 recent papers questioned whether this strain is more virulent • NAP-1 strain was detected around 25% of time in their hospital (BID in Boston) but was not associated with increased severity of disease (non-epidemic setting)1 • 18 and 39 bp deletion containing strains were not associated with increased severity of CDI at the Mayo Clinic2 • Age >65 and prior NH stay implicated 1. Cloud, J. et al. 2009. Cl Gastro and Hept. 7:868-873 2. Verdoorn, B. P. et al. Diag Micro and ID. 10.1016/j.diagmicrobio.2009.0815

  27. Should You Treat the Patient or Treat the Strain? • Routine diagnostics laboratory tests do not provide strain type • Routine tests not always reliable • Always treat the patient based symptoms, history, risk factors and markers of severe disease

  28. Symptoms of CDI • Asymptomatic colonization • Diarrhea mild  moderate  severe • Abdominal pain and distension • Fever • Pseudomembranous colitis • Toxic megacolon • Perforated colon  sepsis  death

  29. Markers of Severe Disease • Leukocytosis • Prominent feature of severe disease • Rapidly elevating WBC • Up to >100 K • >10 BM/day • Albumin < 2.5 • Creatinine 2x baseline • Hypertension • Pseudomembranous colitis • Toxic megacolon • Severe distension and abdominal pain

  30. Laboratory Diagnosis of C. difficile Infection (CDI)

  31. Which Test Should I Use? • Considerations • Accuracy • Time to detection • Prevalence in your population • Screening tests followed by confirmatory tests • In a low prevalence population, a screening test with a high sensitivity is useful (no/few false negatives) • Cost • Ease of use • At this time, there is no perfect test for the diagnosis of CDI

  32. What Should I do First? Make some rules • Rule 1: Accept only liquid stools or soft stools • Why? Any Exceptions? • Rule 2: Limit repeat testing once a patient is positive • Why? Any exceptions

  33. The Specimen • Fresh is best (test within 2 hours) • Liquid or loose, not solid • If unable to test within 2 hours, refrigerate at 4°C for up to 3 days • Freeze at -70°C (not -20°C) if testing will be delayed • Specimen quality will influence test results In: Manual Clin Micro. 9th ed. 2007;p. 897.

  34. Laboratory Diagnosis of CDI Enzyme Immunoassay (EIA) Glutamate Dehydrogenase (GDH) Cell Culture Neutralization Assay (CCNA) Laboratory Diagnosis Toxigenic Culture (Culture and CCNA) Stool Culture Molecular Based (PCR Or LAMP)

  35. Conflicting Results with EIA • Stamper PD, et al. J Clin Microbiol. 2009;47:373-378. • Musher DM, et al. J Clin Microbiol. 2007;45:2737-2739. • Sloan LM, et al. J Clin Microbiol. 2008;46:1996-2001. • Gilligan PH. J Clin Microbiol. 2008;46:1523-1525. • Ticehurst JR. J Clin Microbiol. 2006;44:1145-1149. • Nice review by Planche T, et al. 2008. www.thelancet.com/infection

  36. Advantages Rapid Inexpensive Relatively easy No costly equipment Batch or single test formats Disadvantages Great variations in published sensitivity and specificity Technologist error Contamination EIA Testing

  37. Screening Tests Glutamate dehydrogenase (GDH) Detects nearly all true positives as well as false positives Low PPV High sensitivity Very few false negatives Works best in a low-prevalence population EIA: Is it accurate enough to use as a screening test? Confirmatory test? Confirmatory Tests CCNA Add 1-2 days CX followed by CCNA Add 3-4 days PCR Possibility of false positives due to colonization Two-Step Tests1-3 • Gilligan PH. J Clin Microbiol. 2008;46:1523-1525. • Ticehurst JR. J Clin Microbiol. 2006;44:1145-1149. • Planche T, et al. 2008. www.thelancet.com/infection

  38. Most Recent Studies • CdiffQuikChek Complete (GDH and EIA on one test card)1 • Both + = + • Both - = - • 13.2% discrepant, re-test. Use PCR • PCR had very high S,S, PPV and NPV2 • PCR resolved low false positive EIA3 • Quinn, C. D. 2010. J Clin Microbiol. 48: 603-605 • Novak-Weekley, S. et al. 2010. J. Clin Microbiol.doi:10.1128/JCM.01801-09 • Brecher, S. et al. 2009. ICAAC Abstract D-1422

  39. Molecular-Based Assays • Polymerase Chain Reaction (PCR) • 3 FDA Approved test kits • 2 of them are less expensive but more labor intensive • 1 is easy enough to do that even I can do it, but is expensive • I recently switched from an EIA to the expensive PCR • The cost of a misdiagnosed patient is too great, especially for our Veterans

  40. Treatment

  41. Treatment ofMild to Moderate Disease • Stop antibiotic(s) if medically reasonable • Metronidazole • Oral or IV, 500 mg TID for 10-14 days is standard therapy • 5–20% failure rate • 20% relapse rate • Can use a full 2nd course for failure/relapse but beyond 2 courses, switch to vancomycin • Failures not due to metronidazole resistance

  42. Initial Treatment Options for CDI • Historical response (96%) and relapse rates (20%) similar between metronidazole and vancomycin1 • More recently, efficacy of metronidazole for severe disease called into question2-4 • Recent prospective trials report vancomycin to be superior to metronidazole in severe CDI5-7 1. Aslam S, et al. Lancet Infect Dis. 2005;5:549-557. 2. Fernandez A, et al. J Clin Gastroenterol. 2004;38:414-418. 3. Gerding DN. Clin Infect Dis. 2005;40:1598-1600. 4. Musher DM, et al. Clin Infect Dis. 2005;40:1586-1590. 5. Lahue BJ, Davidson DM. The 17th ECCMID Meeting, March 31 to April 4, 2007; Munich, Germany. Abstract 1732_215. 6. Zar FA, et al. Clin Infect Dis 2007;45:302-307. 7. Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a.

  43. Initial Treatment Options for CDI IV=intravenously; PO=orally. Fekety R. Am J Gastroenterol. 1997;92:739-750. Gerding DN, et al. InfectControl Hosp Epidemiol. 1995;16:459-477. American Society of Health-System Pharmacists. Am J Health-Syst Pharm. 1998;55:1407-1411.

  44. Metronidazole vs Vancomycin • Zar et al1 classified patients as mild or severe CDI • In mild disease, vancomycin was slightly better than metronidazole (98% vs 90%) • Not statistically significant • In severe disease, vancomycin was significantly better than metronidazole (97% cure vs 76% cure) 1. Zar FA, et al. CID. 2007;45: 302-307.

  45. Clinical Success by Disease Severity: Tolevamer Phase III Results Defining CDI Disease Severity Any one of the 3 defining characteristics assigns a patient to the more severe category. Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a.

  46. Metronidazole vs Vancomycin vs Tolevamer Patients stratified as mild, moderate, or severe Original goal of study was to evaluate tolevamer as a treatment for CDI Louie et al. ICAAC AbstractK-425-9 2007

  47. C. difficile Infection: Case 3 • 79-year-old woman with multiple medical problems admitted to hospital for treatment of community-acquired pneumonia • Responds slowly to levofloxacin 750 mg daily • After 6 days • Develops diarrhea (9 loose BMs) • WBC count: 11,500/mm3 • Day 7–14 loose BMs, WBC count rises to 19,500/mm3 • Stool testing for C. difficile toxins A and B is requested • Continued antibiotic therapy for pneumonia is deemed necessary • How would you manage her care? • Await stool test results and monitor her progress • Empirically start metronidazole PO • Empirically start metronidazole IV • Empirically start vancomycin PO

  48. C. difficile Infection: Case 3 • 79-year-old woman with multiple medical problems admitted to hospital for treatment of community-acquired pneumonia • Responds slowly to levofloxacin 750 mg daily • After 6 days • Develops diarrhea (9 loose BMs) • WBC count: 11,500/mm3 • Day 7–14 loose BMs, WBC count rises to 19,500/mm3 • Stool testing for C. difficile toxins A&B is requested • Continued antibiotic therapy for pneumonia is deemed necessary • How would you manage her care? • Await stool test results and monitor her progress • Empirically start metronidazole PO • Empirically start metronidazole IV • Empirically start vancomycin PO

  49. Treatment of Severe Disease • Follow definition of severe disease • >10 BM/day, high WBC, low albumin • This is a life-threatening infection • Surgical consultation recommended as patient may require a colectomy • Oral vancomycin drug of choice • Dose varies based on severity • Can add metronidazole (oral or IV)

  50. Management of Severe CDI Early recognition is critical Initiate therapy as soon as diagnosis is suspected Manage as for mild CDI plus: Oral vancomycin (125 mg QID for 10 to 14 days) as initial treatment If patient is unable to tolerate oral medication, consider intracolonic vancomycin instillation (by enema) 0.5–1 g vancomycin (IV formulation) in 0.1 to 0.5 L of normal saline via rectal (or Foley) catheter Clamp for 60 minutes Repeat every 4–12 hours Gerding DN, et al. InfectControl Hosp Epidemiol. 1995;16:459-477. Zar FA, et al. Clin Infect Dis. 2007;45:302-307. Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a. Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:690-696.

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