1. Clostridium difficile Infections: Diagnosis, Treatment, and Prevention Theresa Cuoco, MD

2. Outline Introduction Risk Factors for Disease Methods for Detection Antibiotic Therapy Nonstandard Adjunctive Interventions Infection Control and Prevention

3. Introduction Gram positive, spore forming, toxin producing 1935: “difficult clostridium” (isolation on conventional media) Obligate anaerobic bacterium Survives 10-15 minutes following exposure to air Hardy spore Resistant to heat, acid, alcohol, and abx; ingested, and germinates Transmitted via fecal-oral route Causes disease by production of toxins that bind to receptors on colonic epithelium A enterotoxin: attracts neutrophils and monocytes B cytotoxin: mediates mucosal damage (10x more potent)

4. Definition The presence of symptoms Usually diarrhea (at least 3 unformed stools in 24hrs) <1% of cases: no diarrhea; ileus and colonic distention AND EITHER Stool test positive or Colonoscopic or histopathologic findings of pseudomembranous colitis 96% of patients received abx within 14 days prior to onset of diarrhea; nearly all within past 3 months Median time to onset 2-3 days after colonization

5. Spectrum of Clostridium difficile Infection (CDI) Asymptomatic carrier Colonization with nontoxigenic strain affords protection High circulating titers of IgG antitoxin Mild diarrhea (≥ 3 stools in 24hr) Fever, cramping, abdominal pain, leukocytosis Severe diarrhea (≥ 10 stools in 24hr) Pseudomembranous colitis Fulminant colitis Severe pain, distention, fever, shock, lactic acidosis,  WBC Toxic megacolon with paralytic ileus

6. Increasing Severity Age-adjusted Death Rate Due to Enterocolitis from C. difficile 1999 to 2006 Per 100,000 Population [From: Heron 2009 (http://www.cdphe.state.co.us/hf/patientsafety/CDItoolkit.pdf)

7. Hypervirulent Strain: NAP1/B1/027 “North American Pulsed-field Type” Deletion in gene that down regulates toxin production Produces 16-23 times more toxin Produces a binary toxin Resistance to fluoroquinolones Increased sporulation

8. Risk Factors for Development of CDI Antibiotic use: disruption of colonic flora Broad spectrum, multiple abx, and duration of therapy Host immune status Advanced age, duration of hospitalization, & female gender Comorbidities GI procedures and enteral feeding Gastric acid suppression (risk 1.4-2.75 times higher with PPI) Chemotherapeutic agents (antimicrobial/immunosuppressive) Hematopoietic stem cell transplantation

9. Antibiotics Implicated Frequently Associated Occasionally Associated Rarely Associated FluoroquinolonesMacrolidesAminoglycosides ClindamycinTrimethoprimTetracyclines PCN (broad spectrum)SulfonamidesChloramphenicol Cephalosporins (broad spectrum) Metronidazole Vancomycin

10. Diagnosis and Detection of CDI Only performed on unformed stool unless ileus suspected Testing asymptomatic patients, including use as a test of cure NOT recommended Repeat testing during same diarrheal episode discouraged

11. Detection of CDI 1.Cytotoxicity Assay 2.Culture 3.Immunoassays 4.Toxin Gene Detection 5.Endoscopic evidence

12. Cytotoxicity Assay Stool mixed with cultured test cells Monitored for toxin effects (cell rounding) Requires up to 48 hours Often used as reference test in the evaluation of other diagnostic tests Highly sensitive; not practical

13. Culture Cycloserine, cefoxitin, fructose agar (CCFA) Most sensitive Can take 2 to 9 days Colonies with specific odor and fluoresce with Woods lamp

14. Immunoassays – “EIA” Majority of labs use this technique – quick, inexpensive Some only detect toxin A and strains emerging with only toxin B Moderate and variable sensitivity 63-94% Frequent false negatives Specificity 75-100% Alternative 2 step process: high negative predict value EIA detection of Glutamate Dehydrogenase (GDH): enzyme produced by C diff toxin testing

15. Toxin Gene Detection: PCR Detects presence of gene involved in toxin production Rapid, sensitive and specific Used at MUSC

16. Pseudomembranes Endoscopic appearanceGross appearance Raised yellow or off-white plaques up to 2 cm in diameter scattered or confluent edema, erythema, friability, and inflammation

17. Treatment 1.Discontinue inciting antibiotic Implement infection control measures 2.Confirm with testing Empiric therapy may be warranted based on severity of symptoms 3.Avoid antiperistaltic agents – precipitates megacolon 4.Determine clinical severity Mild-moderate, severe, severe-complicated

18. Mild to Moderate Disease Metronidazole vs Vancomycin equivocal Metronidazole – first line 500 mg po q8 or 250 mg po q6 500 mg IV q8 if oral therapy not feasible Limitations: peripheral neuropathy, nausea, metallic Vancomycin 125 mg po Q6 **must be given orally Duration: 10-14 days If underlying infection requiring prolonged abx, continue CDI treatment throughout abx course + 1 additional week

19. Initial Recurrent Disease “Recurrence of symptoms within 8-10 weeks after cessation of specific antibiotic therapy” Up to 20-25% of patients adequately treated Confirm diagnosis Up to ½ of recurrent episodes are reinfections rather than relapses with original strain Most present 1-3 weeks after discontinuing abx therapy (but up to 2-3 months) Why? Persistent spores, impaired host immune response Treatment with same regimen as initial but stratify based on disease severity

20. Second Recurrence Confirm diagnosis Subset with high rate of repeat recurrence Avoid metronidazole due to cumulative neurotoxicity Vancomycin: tapered and/or pulsed dosing – allows spores to germinate 125 mg po QID for 7-14 days 125 mg po BID for 7 days 125 mg po QD for 7 days 125 mg QOD for 7 days 125 mg po q 3 days for 14 days Fidaxomicin 200 mg po BID for 10 days

21. Subsequent recurrence Confirm diagnosis Vancomycin 125 mg po QID for 14 days followed by rifaximin 400 mg BID for 14 days Based on small case series Fidaxomicin 200 mg po BID for 10 days

23. Fidaxomicin (Dificid) Macrocyclic macrolide antibiotic Bactericidal Narrower antimicrobial spectrum = less disruption of normal flora FDA approved in 2011 What’s the hype?

24. Fidaxomicin Limited to non-NAP1 strains

25. Severe CDI: markers Severe diarrhea >10 bowel movements/day Leukocytosis >15K – severe >25 increased fatality High or rising serum Cr (50% increase) Low serum albumin (<2.5 mg/dL) Severe abdominal distention, pain Ileus or toxic megacolon Colonic thickening on CT Ascites on CT Pseudomembranes on endoscopy Hemodynamic instability Organ Failure Pepin J, et al. Can Med J Assoc 2004: 171:466-472. Bartlett JG, Gerding DN. Clin Infect Dis 2008: 46(Suppl):S12-S18

26. Severe CDI No consensus definition Zar et al Clin Infect Dis 2007: ≥2 points = severe Treatment: Vancomycin 125 mg po QID for 10-14days No supportive evidence for higher dosing Improved rates of cure with vanc vs metronidazole but not significant when using strict intention to treat analysis 1 point2 points Age > 60Endoscopic pseudomembranes Temp > 38.3CTreatment in ICU Albumin < 2.5 mg/dL WBC > 15,000

27. Severe, Complicated CDI Hypotension, shock, ileus, or megacolon Vancomycin 500 mg po or per NGT ± metronidazole 500 mg IV q8 If complete ileus: add vancomycin 500 mg in 100cc NS as retention enema q6 Surgery considered if age ≥ 65 and WBC ≥20, lactate > 2.2, peritoneal signs, severe ileus, toxic megacolon Increased periop mortality with lactate > 5 and WBC > 50 Subtotal colectomy with ileostomy and rectum spared

28. Nonstandard Adjunctive Interventions Why explored? Standard antibiotics ineffective in 8-36% NO current antibiotics kill spores Rates of infection and relapse are increasing Specific therapies: Probiotics/Prebiotics Anion binding resins Fecal flora reconstitution C diff immune whey (antibody) IVIG

29. Prevention Strategies Low level evidence for link of prevention to outcomes “People” measures Environmental Measures Antimicrobial restrictions “Bundled prevention strategies”

30. Person measures Immediate infection control measures once CDI is suspected Gowns/gloves Hand washing with soap and water Friction and detergent action Private room with contact precautions If single room not possible, cohort patients with separate commodes

31. Environmental Cleaning and Disinfection Disposable rectal thermometers In place of electronic Inadequately cleaned commodes or bedpans Chlorine/hypochlorite containing cleaners

32. Antimicrobial Stewardship Minimize frequency, duration of therapy, and number of antibiotic agents Reduce use of “high risk” antimicrobials Stewardship programs based on local epidemiology Restriction of cephalosporins and clindamycin

33. Bibliography Butler M, Bliss D, Drekonja D, Filice G, Rector T, MacDonald R, Wilt T. Effectiveness of Early Diagnosis, Prevention, and Treatment of Clostridium difficile Infection. Comparative Effectiveness Review prepared for Agency for Healthcare Research and Quality. December 2001. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infection Control and Hospital Epidemiology. May 2010, Vol 31, No 5. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. Dial S, Alrasadi K, Manoukian C, Huang A, Menzies D. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ; July 6, 2004: 171 (1). Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK. Fidaxomicin versus Vancomycin for Clostridium difficile Infection.Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK. Fidaxomicin versus Vancomycin for Clostridium difficile Infection. N Engl J Med 2011; 364:422-31. Zar, FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatemtn of Clostridium difficile-associated diarrhea, stratified by disease severity.Zar, FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatemtn of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Ds 2007; 45: 302