1. Photomicrograph courtesy of SL Gorbach C. difficile Screening and Identification Fact or Fiction Lisa E Davidson, MD Tufts Medical Center Boston, MA

2. Disclosures  None

3. Objectives: Fact or Fiction  Clinical Presentation You can only get C difficile in the hospital Colonization makes you more likely to develop active disease Diarrhea is required for the diagnosis of C difficile infection Nurses are very good at diagnosing C difficile by smell Only older antibiotics are associated with C difficile infection  Identification and testing I only need to send one loose, stool specimen to the micro lab  Treatment: Metronidazole is recommended initial treatment of mild to moderate CDI Metronidazole is recommended initial treatment of mild to moderate CDI Prompt initial treatment prevents recurrence Alternative therapies such as probiotics are well proven to treat/prevent C difficile infection

4. Fact or Fiction: You can only get C difficile in the hospital Fiction:  Most commonly acquired in the hospital  Risk factors include antibiotic exposure, immune function age, exposure to PPIs  Becoming increasingly common in outpatient UK: incidence rose from less than 1 case per 100,000 persons to 20 per 100,000 between 1994 and 2004 (1) UK: incidence rose from less than 1 case per 100,000 persons to 20 per 100,000 between 1994 and 2004 (1) Reports in peripartum women and healthy individuals with no known risk factors (2) Reports in peripartum women and healthy individuals with no known risk factors (2) ○ May-June 2005: 10 peripartum and 23 community acquired cases in 4 states -48% in children (11/33). ○ 8/33 had no exposure to antibiotics in 3 months prior to illness ○ 3/33 had minimal exposure (2 were given one dose of Clindamycin for elimination of Group B Strep carriage peripartum. 1) JAMA. 2005;294(23):2989-95 2) MMWR Morb Mortal Wkly Rep. 2005;54(47):1201-5.

5. Fact or Fiction: Colonization makes you more likely to develop active disease Fiction:  About 20% of non colonized patient become colonized during their hospitalization (1-3)  C. difficile carriage occurs in 20 to 50 percent of adults in long term care facilities (1-3)  Patients colonized with C. difficile are more likely to be asymptomatic Colonization ≠ toxin production  New acquisition of C. difficile is more likely to lead to CDAD (4) 1) N Engl J Med. 2000;342(6):390-7 2) N Engl J Med. 1989;320(4):204-10. 3) Clin Infect Dis. 2007;45(8):992-8 4) N Engl J Med. 1989;320:204-210

6. Fact or Fiction: Diarrhea is required for the diagnosis of C difficile infection Fact: SHEA/IDSA definition (1) presence of diarrhea (3 or more unformed stools) in 24 hrs (2) a stool test result positive for the presence of toxigenic C. difficile or its toxins or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.  Watery diarrhea up to 10 or 15 times daily  lower abdominal pain and cramping  Fever  Leukocytosis CDAD is reported to routinely be associated with a WBC on average of 15K Higher with colitis ICHE Vol. 31, No. 5 (May 2010), pp. 431-455

7. Fact or Fiction: Nurses are very good at diagnosing C difficile by smell

8. 80%!!

9. Fact or Fiction: Only older antibiotics are associated with C difficile infection Fiction: ALL antibiotics have been associated with CDI High risk antimicrobials Fluoroquinolones, especially gati, moxi, levo fluoroquinolone resistance of the NAP1/BI/027 strain is associated with increased virulence 2 nd & 3 rd generation cephalosporins Clindamycin Ampicillin, amoxicillin/clav, Pip/tazo, Ticar/clav Intermediate risk antimicrobials TMP/SMX Macrolides Low risk antimicrobials Aminoglycosides Vancomycin Metronidazole

10. Fact or fiction: I only need to send one, loose stool specimen to the micro lab  FACT: Testing for C. difficile or its toxins should be performed only on diarrheal (unformed) stool, unless ileus due to C. difficile is suspected  Because of the low increase in yield and the possibility of false-positive results, routine testing of multiple stool specimens is not supported as a cost-effective diagnostic practice (1) 1 ) J Clin Microbiol. 2008;46(11):3686-9

11. DIAGNOSTIC TESTS FOR CLOSTRIDIUM DIFFICILE Slide courtesy of SL Gorbach Mylonakis et al., 2001 MORE RECENT NUMBERS for ELISAs C. Diff ToxA/B II (TechLab, VA) Se/Sp: 88.3%/100% ProSpecT C. Diff tox A/B microplate (Remel) Se/Sp: 93.3%/100% Vs. “gold standard” = cytotoxin assay for B combined with tcdA and tcdB PCR Eur. J. Clin. Microbiol. Infect. Dis 2007;26:115-119.

12.  Enzyme immunoassay (EIA) allows direct detection of C difficile toxins in stool good specificity (up to 99%), variable sensitivity (60 to 95%) relatively high false negative rate because need a higher level of toxin present  Newer ELISA using C. difficile common antigen (GDH ) Step one: ELISA GDH antigen and toxin a/b Step two: (ag+ and toxin- ) amplification test for toxin loci  Real-time PCR assays for toxin B (Cepheid Gene Xpert), BD-GeneOhn C diff assay, and IVD RT-PCR (Pro-gastro, Prodesse).

13. Fact or fiction: Metronidazole is recommended initial treatment of mild to moderate CDI  FACT: current IDSA guidelines recommend metronidazole for initial therapy of mild- moderate CDI ICHE May 2010, vol. 31, no. 5 Clin Infect Dis. 2007;45(3):302-7.

14. Initial treatment: factors to consider  Age  Peak white blood cell count (leukocytosis)  Severity of illness – evidence of organ dysfunction or sepsis  Is the GI tract working?

15. ICHE Vol. 31, No. 5 (May 2010), pp. 431-455

16. Fact or fiction: Prompt initial treatment prevents recurrence FICTION: Relapse occurs in 6-30% of cases  Not related to severity of diarrhea, inciting antibiotic or length of diarrhea  Strain is usually the same, with identical antibiotic sensitivities as original isolate  In hospital, relapse can be confused with re-infection  Retreatment can use the original drug for a 14 day course  Two thirds of patients relapse again within 4 weeks of initial treatment  Risk of recurrence increases with each subsequent recurrence

17. Fact or Fiction: Alternative therapies such as probiotics are well proven to treat/prevent C difficile infection  Fiction: Probiotics have NOT been proven effective by rigorous clinical trials to prevent or treat CDI(1) Many small trials, not many placebo controlled Slightly better results on prevention of recurrence than treatment Lactobacillus GG 1 capsule po twice daily for 14 days Saccharyomyces boulardii 500 mg capsule twice daily for 4 weeks 1) Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev. 2008;

18. NEW PRODUCTS FOR C. DIFFICILE  Rifaximin  Nitazoxanide (comparator=Metronidazole),Tinidazole,  Ramoplanin,  OPT-80 (Difimicin)  Oral toxin binding agents: e.g., DiffGam, a bovine milk-derived anti-C. difficile IgG delivered to the colon using a proprietary delivery system, Tolevamer  Vaccines: active (toxoid A,B) and passive (monoclonal antibody to toxin A and toxin B) Babcock GJ et al I and I 2006;6339-6347.

19. OPT-80  Macrocyclic  Non-absorbed from GI tract, well- tolerated  VRE and C. diff, but NOT anaerobic and facultative GNR, or Strep, so may allow host to maintain colonization pressure.