1. CLOSTRIDIUM DIFFICILE ASSOCIATED DIARRHEA VALERIE FLETCHER, M.D. INFECTIOUS DISEASES SOUTHERN OHIO MEDICAL CENTER August 2006

2. Introduction Clostridium difficile is a Gram-positive, spore-forming anaerobic bacillus. Most common cause of nosocomial diarrhea. Rate and severity of C. difficile-associated diarrhea (CDAD) increasing. New strain of C.difficile with increased resistance and virulence identified.

3. History 1893 – first case of pseudomembraneous colitis reported as diphtheritic colitis. 1935 – “Bacillus difficile” isolated. 1970s – antibiotic-asociated colitis identified. 1978 – C. difficile toxins identified in humans. 1979 – therapy with vancomycin or metronidazole 2000 – increased incidence and virulence

4. Annual CDAD rates for hospitals with >500 beds (NNIS 1987 – 2001)

5. Adapted from McDonald LC, et al. Annual Meeting of IDSA, 2005

6. Epidemiology Present in environment. Hospital is major reservoir. Spores can be recovered from surfaces for months. Spread primarily on hands of HCW. Fecal-oral transmission. Transmission may occur from asymptomatic colonized persons.

7. Epidemiology Colonizes the colon of up to 3% of healthy adults. 15 – 25% of debilitated and antibiotic-treated hospitalized adults colonized. Toxigenic strains may cause disease in colonized patients. Implicated in approx. 25% of cases of antibiotic- associated diarrhea

8. Clinical features Mild disease – mild abdominal cramping pain. - endoscopic findings of diffuse or patchy, nonspecific colitis. Moderate disease – fever, dehydration, nausea, anorexia, malaise, profuse diarrhea, abdominal distention and cramping pain. - moderate leukocytosis, fecal leukocytes. - diffuse, patchy colitis on endoscopy

9. Severe disease – usually profuse diarrhea, may be little or no diarrhea. - abdominal pain - fever - volume depletion - marked leukocytosis - peritoneal signs - radiologic signs include ileus, dilated colon and edematous colonic mucosa - endoscopic findings of adherent yellow plaques

10. Complications of CDAD Pseudomembraneous colitis Toxic megacolon Perforation of the colon Sepsis Death

11. Patients at increased risk for disease ANTIBIOTIC EXPOSURE Gastrointestinal surgery or manipulation Long length of stay in healthcare setting Infected roommate Co-morbid illnesses Immunosuppression Advanced age Proton-pump inhibitors and H2-blockers?

12. Predictors of Severe Disease Leukocytosis > 20,000 Increased creatinine above the baseline

13. Traditional list of Antibiotics associated with CDAD MORE FREQUENT LESS FREQUENT Cephalosporins (3 rd and 4 th generation)Ticarcillin-clavulanate Ampicillin/AmoxicillinMetronidazole ClindamycinFluoroquinolones Other penicillinsRifampin Macrolides5-Fluorouracil TetracyclinesMethotrexate Trimethoprim-SulfamethoxazoleCyclophosphamide

14. Laboratory Diagnosis Stool culture Latex agglutination to detect antigen in stools Tissue culture assay for cytotoxicity of toxin B Enzyme-linked immunosorbent assay (ELISA) for toxins A and B

15. A new strain of C. difficile (NAP-1) Toxinotype III Unsuppressed production of toxins A and B Associated with presence of binary toxin. Increased resistance to clindamycin and fluoroquinolones. Potential for increased complications and adverse outcome.

16. Adapted from L.C. McDonald, MD, CDC DC PR AK HI States with the North American Pulsed Field Type 1 strain of C. difficile confirmed by CDC as of May 15, 2006 (N=17)

17. Muto CA, et al. Infect Control Hosp Epidemiol 2005;26:273-280 Rate of antibiotic resistance in 91 C. difficile isolates from a Pittsburg hospital that experienced a large CDAD outbreak beginning January 2000

18. Loo VG, et al. NEJM 2005;353:2442-2449. The risk of CDAD and antibiotic use in a study of 1,703 patients from 12 Canadian hospitals

19. Dr. T. Cassity, SOMC Number of inpatients tested and percentage of stools positive for Clostridium difficile toxin at SOMC 2004 - 2006

20. Dr. T. Cassity, SOMC Number of positive Clostridium difficile toxin tests SOMC laboratory 2003 -2006

21. Data from Marcie Malone, PharmD candidate CDAD - SOMC 2006 114 patients had C. difficile toxin detected in stools between Jan 2006 – June 2006. 46 charts were available for review. 31 (67%) patients were female. 2 (4%) patients had recurrent CDAD. 13 (28%) patients did not receive a fluoroquinolone during or immediately before admission.

22. Data from Marcie Malone, PharmD candidate Antibiotics associated with CDAD - SOMC 2006

23. Ceftriaxone and Levofloxacin use – SOMC, Jan – Aug 2006

24. Data from Marcie Malone. PharmD candidate Proton Pump Inhibitors, H2-blockers and C.difficile toxin detection – SOMC 2006

25. Management Enhanced infection control measures. Targeted antibiotic restriction Appropriate antibiotic therapy Adjunctive therapy – probiotics, IVIG, toxin binders

26. Surgery Avoid antiperistaltic and opiate drugs. Experimental therapy – rifaximin, tolevamar, corticosteroids, vaccine, monoclonal antibodies to toxins A and B, non-toxigenic C,difficile

27. Antibiotic Therapy Oral therapy – vancomycin, metronidazole Unable to tolerate oral therapy – IV metronidazole, vancomycin via NG tube or enema. Vancomycin + rifampin Less frequently used – Bacitracin, fusidic acid

28. Antibiotic therapy for CDAD MetronidazoleVancomycin RouteOral or IVOral only Dose250 – 500 mg q8h or q6h125 – 500 mg q6h Response rate94% Duration10 – 14 days Cost$20$200 - $800 Recurrence rate20%19%

29. Indications for Vancomycin therapy No response to metronidazole Metronidazole intolerance Pregnancy and child < 10 yrs Severe/fulminant CDAD

30. Conclusion Increasing numbers and severity of CDAD. Active surveillance recommended. Early diagnosis and treatment are important for reducing severe outcome. Judicious use of antibiotics may reduce incidence of CDAD Strict infection control practices essential.