1. Preventing and Treating C.difficile Lisa Casey, M.D. Assistant Professor, UT Southwestern Medical Center TSGE / SGNA Annual Scientific Meeting September 20. 2015

2. Clostridium difficile – the organism First described in 1935 (PCN first used 1943 by comparison) Best known for infectious, antibiotic associated diarrhea “pseudomembranous colitis” Anaerobic, gram positive, not invasive Forms heat, acid and antibiotic resistant spores

3. The Impact – morbidity: In 2011 there were an estimated 453,000 cases of c. difficile infection in the U.S. Estimated 159,700 cases were community acquired 293,000 were healthcare associated specifically 107,600 hospital acquired 83,000 were first recurrence 29,300 people died Dutch study with patients 2006-2009 – CDI was associated with a 2.5- fold increase in 30 day mortality

4. The Impact – financial burden CDC data compared CDI to other items we monitor – SSI, CLABSI,VAP, CAUTI Nosocomial CDI more than quadruples the cost of hospitalizations, increasing costs upward of $1.5 billion dollars a year in the U.S.

5. “Community” versus “healthcare” acquired Healthcare associated Community acquired The grey area in between

6. Transmission: Transmitted fecal oral by spores Spores are widely found in healthcare facilities and low level in the environment and food supply Normally colonization prevented by barrier properties of fecal microbiome Not everyone colonized develops infection – > infants

7. Pathogenesis – how it causes the damage In susceptible persons, colonizes the large intestine and releases two protein exotoxins that cause colitis Toxin A - enterotoxin Toxin B – cytotoxin, essential for the virulence Two very important factors impacting damage Virulence of the infecting strain Host immune response

8. Why are some infections worse than others? Between 2003 and 2006 CDI seemed to be more frequent, severe, refractory to standard therapy and more likely to relapse Meet BI/NAP1/027 – More virulent Increased toxin production Thought associated with FQ use

9. What are the risk factors? Antimicrobial exposure Acquisition of c.difficile Advanced age >65 years old Underlying illness Immunosuppression Tube feeds ?gastric acid suppression

10. Clinical predictors – what to look for: Significant diarrhea – new onset >3 loose stools in 24 hours Recent antibiotic exposure Abdominal pain Fever Distinctive foul odor to the stool

11. Prevention strategies – core strategies: Implement antibiotic stewardship Contact precautions for duration of diarrhea Hand hygiene in compliance with CDC / WHO Cleaning and disinfection of equipment and environment Laboratory-based alert system for immediate notification of positive test results Educate about CDI: HCP, housekeeping, administration, patients, families

12. Prevention strategies – supplemental: Extend use of contact precautions beyond duration of diarrhea (e.g.48 hours) (skin and environmental contamination w spores) Presumptive isolation of symptomatic patients pending confirmation of CDI Evaluate and optimize testing for CDI

13. Prevention strategies – supplemental: Implement soap and water hand hygiene before exiting a room of patient with CDI Implement universal glove use on units with high CDI rates Use sodium hypochlorite (bleach) – containing agent for environmental cleaning

14. Diagnosis In the past – Toxin A/B enzyme immunoassays - low sensitivities (70- 80%) leading to low predictive value. Poor test ordering practices. Formed stool Colonization

15. Limitations of testing - Colonization CDI is only responsible for 30-40% of hospital onset diarrhea. Carrier rate among healthy adults is about 3% C. difficile carrier rates in healthcare facilities ( hospitals, long term care facilities) are 20-50% May be a reservoir for environmental contamination /shedding spores

16. Hand hygiene: soap and water versus alcohol Alcohol is not effective in eradicating C. difficile spores Spores may be difficult to remove even with hand washing so adherence to glove use and contact precautions should be emphasized to reduce transmission Glove use – asymptomatic carriers have a role in transmission though not clear the extent

17. How to clean the environment Bleach can kill spores. Most other standard disinfectants do not. Must carefully investigate new products before implementation.

18. Treatment options Metronidazole Vancomycin New antibiotics Fecal microbial transplant

19. Metronidazole (Flagyl) Used since the 1970’s bacteriostatic Can be used oral or IV 500mg TID More recent treatment failures – strain related Lots of side effects – disulfiram reaction, carcinogenesis Can be associated with CDI infection or colonization Felt equivalent to Vanco for mild to moderate infection inexpensive

20. Oral Vancomycin Only oral dosing 125mg four times daily bacteriostatic Not absorbed systemically and reaches high levels in colon Cost improving with generic formulations Safer in pregnancy and breast feeding Believed better in moderate to severe disease, recurrence, taper

21. Newer antibiotic options - fidaximicin Approved for CDI in 2011 Macrocyclic, bacteriocidal Expensive Believed to have a lower incidence of recurrence than vancomycin Frequently need ID approval

22. Other possibilities for treatment Monoclonal antibodies Against toxins A and B along with ABX In clinical trials reduce recurrence Not clinically available Vaccination Probiotics – equivocal data Fecal transplant

23. Summary prevention points: Prescribe antibiotics carefully Test if more than 3 loose stools in 24 hours. Isolate patients with CDI or suspected immediately Wear gown and gloves and wash hands with soap and water Clean room surfaces thoroughly with bleach When patient transfers, notify the new facility patient has a CDI

24. Selected resources: ACG guidelines last updated February 2013 www.GI.org Centers for Disease Control – www.CDC.gov NEJM review article CDI April 16, 2015 – www.NEJM.org