Clostridium difficile infection

1. Clostridium difficileinfection Kelly Strine FNP-S NUR 652

2. Definition • Clostridium difficile (C-diff) is a gram-positive, spore-forming anaerobic bacillus. • C-diff was initially detected in 1935 in the stool of newborns and was considered nonpathogenic. • It is spread by ingesting the spore through the fecal oral route. • Infection and colonization is usually linked to the use of broad-spectrum antibiotic within 12 weeks, proton pump inhibitors, H2 antagonists, chemotherapy, increasing age and hospitalization. • It is characterized by the presence of 3 or more unformed, diarrheal stools in 24 or fewer consecutive hours, a stool test result positive for the presence of toxigenic C-diff or its toxins, pseudomembranous colitis. • Reinfection is common and is seen in 25% of cases treated with oral antibiotics. Once a relapse has occurred, second relapse is 45%. (Lessa, Gould, and McDonald, 2012), (Kelly & LaMont, 2013)

3. Etiology • C difficile colitis results from a disruption of the normal bacterial flora of the colon, ingestion of a C-Diff causing spore, colonization with C difficile, and release of toxins that cause mucosal inflammation, mucosal damage, and diarrhea. • It is the only bacteria noted to be caused by the use of antibiotics. (Aberra & Katz, 2013)

4. Pathophysiology • Colonization occurs from ingestion of C-diff spores via fecal oral route. Colonization can occur and patients can remain asymptomatic (Carriers). As many as 2-3% of healthy adults and 70% of healthy infants are carriers. • During a disruption in the intestinal microbiota, such as the use of broad spectrum antibiotics, the bacteria has an opportunity to proliferate. • Toxins are produced during this time of proliferation causing colitis, diarrhea, and abdominal pain. (Aberra & Katz, 2013)

5. Pathophysiology • Two distinct toxins have been seen in C-diff infections (CDI), toxin A and toxin B. These toxins are associated with approximately 75% of C-diff strains. • Both toxins are proteins capable of binding to specific receptors on the intestinal mucosal cells where they gain entry to the cells. The toxins produce inflammation of the mucosa and secrete a protein rich exudate that contains neutrophils, monocytes and slough enterocytes. They are responsible for activating cytokine release from the monocytes. (Hamm, 2000) • A hypervirulent strain of C-diff, NAP1 is the most serious strain. This strain produces 16 fold higher concentrations of toxin A and 23 fold higher concentrations of toxin B. This strain is also characterized by a binary toxin. The pathogenesis of the binary toxin is unclear but it is thought that the synergistic effect of these toxins is what produces more severe symptoms. (Aberra & Katz, 2013)

6. Pathogenesis of CDI 1. Ingestion of spores transmitted from other patients via the hands of healthcare personnel and environment 3. Altered lower intestine flora (due to antimicrobial use) allows proliferation of C. difficile in colon 4. Toxin A & B Production leads to colon damage +/- pseudomembrane 2. Germination into growing (vegetative) form (Sunenshineet al, 2006)

7. Risk Factors • Recent hospitalization • Recent use of broad spectrum antibiotics • Age greater than 65 • Gastrointestinal surgery • Nasogastric tube feeding • Reduced gastric acid secretion • Concurrent disease such as Inflammatory Bowel Syndrome • Impaired immunity • Comorbidities that cause use of additional antibiotics (Henrich, Krakower, Bitton & Yokoe, 2009), (Stuart, Cohen, Dale, Gerding, Johnson, Kelly, Loo & McDonald, 2013)

8. Incidence • The incidence of C-diff has increased across the United States, Canada and Europe. In 2008 it was reported that 8.75 per 1000 discharges in 28 southern United States community hospitals had C-diff listed as a diagnosis. • It accounts for 20-30% of cases of antibiotic-associated diarrhea and is the most commonly associated cause of infectious diarrhea in the healthcare setting. • In 2008 the incidence of C-diff in a survey of US health-care facility inpatients was 13.1/10,000. Of those individuals, 70% was older than 60. • According to the Center for Disease Control and Prevention, approximately 337,000 cases of CDI are reported each year, causing 14,000 deaths. • In the out patient setting the rate is approximately 7.7 cases per 100,000 person-years. (Lessa, Gould & McDonald, 2012)

9. Clinical Findings • Mild to moderate infection • Watery diarrhea three or more times a day for two or more days • Mild abdominal cramping and tenderness • Severe infection • Watery diarrhea 10 to 15 times a day • Abdominal cramping and pain, which may be severe • Fever • Blood or pus in the stool • Nausea • Dehydration • Loss of appetite • Weight loss • Swollen abdomen • Kidney failure • Increased white blood cell count Pseudomembranous Colitis (Aberra & Katz, 2013) (Stuart, Cohen, Dale, Gerding, Johnson, Kelly, Loo & McDonald, 2013)

10. Differentiation of Disease Severity • Possible severe disease criteria • WBC > 15,000 cells/microL • Creatinine level > or =1.5 times the premorbid level • More than 10 bowel movements per day • Severe abdominal pain • Scoring System • 1 point given for age >60, temp > 38.3 degrees Celsius, serum albumin <2.5 mg/dL, or WBC count >15,000 cells/microL. • 2 points for endoscopic evidence of pseudomenbranous colitis or treatment in the ICU. • If 2 or more points, consider severe disease (Kelly & LaMont, 2013)

11. Complications • Dehydration • Electrolyte Imbalances • Kidney Failure • Toxic Megacolon • Bowel Perforation • Death (Aberra & Katz, 2013)

12. Differential Diagnosis • Food poisoning • Enteric infections • Antibiotic-associated diarrhea • Crohn’s Disease • Diverticulitis • Viral Gastroenteritis • Intra-abdominal Sepsis • Irritable Bowel Syndrome • Malabsorption • Salmonellosis • Shigellosis • Ulcerative Colitis • Vibrio Infections (Domino, 2013)

13. Screening • Screening is not recommended for asymptomatic individuals • Individuals should only be tested for C-Diff if they have 3 or more watery, unformed stools per day or are have a suspected ileus due to C-diff. (Stuart, Cohen, Dale, Gerding, Johnson, Kelly, Loo & McDonald, 2013) (Surawicz, .Brandt, Binion, Ananthakrishnan, Curry, Gilligan, McFarland & Mellow, 2013)

14. Laboratory Tests • Stool Culture for toxin-producing C-diff (*Gold Standard*) • Most accurate for diagnosis but due to slow turn around times of up to 3 days, it is not clinically feasible. • Nucleic Acid Amplified Tests (NAAT) including Polymerase Chain Reaction (PCR) • PCR testing has high sensitivity and high specificity. This may lead to false-positive results. This test is only recommended in patients with acute disease. • Enzyme Immunoassay (EIA) • Rapid results but low sensitivity with high specificity. • Glutamate Dehydrogenase (GDH) • GDH is an enzyme for produced by C-diff in large amounts with toxins A and B. It is sensitive in detecting but is not specific for C-diff. (Bartlett, 2010), (Belanger, Boissinot & Clairoux, 2003), (Carroll, 2011), (Humphries, Uslan & Rubin, 2012), (Su, Mercer, Van Hal & Maley, 2013)

15. Laboratory Tests (Surawicz, Brandt, Binion, Ananthakrishnan, Curry, Gilligan, McFarland & Mellow, 2013)

16. Environmental Considerations • C-diff can remain on surfaces for months or years and can be found in multiple surfaces in the healthcare setting • Chlorine-containing cleaning agents or other sporicidal agents should be used to clean any equipment, beds, and rooms that patient becomes in contact with. • Equipment used in the care of individuals with C-diff should be disposable such as blood pressure cuffs, thermometers, stethoscopes. Other non-disposable equipment should be cleansed with a chlorine containing solution. (Stuart, Cohen, Dale, Gerding, Johnson, Kelly, Loo & McDonald, 2013) (Surawicz, .Brandt, Binion, Ananthakrishnan, Curry, Gilligan, McFarland & Mellow, 2013)

17. Management/ Treatment Guidelines • Discontinue the current antimicrobial therapy as soon as possible. This may influence the risk of CDI recurrence. • Discontinue use of any antiperistalsis agents such as Imodium as they my precipitate toxic megacolon. • Probiotics use during infection is conflicting. • If the patient is hospitalized isolation Room for Enteric Pathogen until laboratory confirmation. • Gown and glove for ANY person, nurse or visitor entering the patient’s room. • Hand washing! Hand washing! Hand washing! No alcohol based hand sanitizers. This is important for the patient as well as nurses, other members of the health care team and visitors. (Stuart, Cohen, Dale, Gerding, Johnson, Kelly, Loo & McDonald, 2013) (Surawicz, .Brandt, Binion, Ananthakrishnan, Curry, Gilligan, McFarland & Mellow, 2013)

18. pharmacological • Initial Treatment for Mild to Moderate Infection • Flagyl 250 mg PO Q 6h for 10-14 days or • Flagyl 500 mg PO Q 8h for 10-14 days • If Symptoms persist after 5-7 days of treatment • Vancomycin 125-500 mg PO Q 6h for 10-14 days or • Dificid 200 mg PO BID for 10-14 days (Kelly & LaMont, 2013), (Tannock, Munro, Taylor , Lawley, Young, Byrne, Emergy & Louie, 2010)

19. Pharmacological • Treatment for Initial Recurrence of Mild to Moderate Infection • New course of Flagyl for 10-14 days, may give Vanco or Dificid • For a Second Recurrence of Mild to Moderate Infection • Vancomycin pulse therapy: 125 – 500 mg PO Q 2-3 days for 3 weeks • Vancomycin taper • Week 1: 125 mg PO Q6 hours • Week 2: 125 mg PO Q12 hours • Week 3: 125 mg PO QD • Week 4: 125 mg PO QOD • Week 5 and 6: 125 mg PO Q3 days • For Subsequent Recurrences • Vanco or Dificid for 10-14 days follow by • Rifaximin 200 mg PO TID x 3 days (McFarland, Elmer & Surawicz, 2002)

20. Pharmacological • Initial Treatment for Severe Infection • Vanco 125 mg PO Q 6h for 10- 14 days • If no improvement of diarrhea in 3 days, • Vanco 500 mg PO Q 6h for 10-14 days • Dificid 200 mg PO BID may be substituted for Vanco if the patient cannot tolerate Vanco • If Critically Ill • Vanco 500 mg PO Q 6h and Flagyl 500 mg IV Q 8h • If toxic megacolon, ileus, or no improvement with PO meds • Vanco Retention Enema 500 mg in 100 mL of NS Q 6h • Continue with IV Flagyl in conjunction with retention enemas (Kelly & LaMont, 2013), (Tannock, Munro, Taylor , Lawley, Young, Byrne, Emergy & Louie, 2010)

21. Non-Pharmacological • Surgical Consultation Complicated CDI • Hypotension requiring vasopressors • Sepsis and Organ dysfunction • Mental Status Changes • WBC > 50,000 • Failure to improve with therapy after 5 day • Surgical Procedures • Subtotal Colectomy • Diverting Loop Ileostomy with colonic lavage • Intestinal Microbiota Transplantation (IMT) • Otherwise known as a Fecal Transplant (Kelly & LaMont, 2013), (Stuart, Cohen, Dale, Gerding, Johnson, Kelly, Loo & McDonald, 2013)

22. Intestinal Microbiota Transplants • Fecal transplants can be delivered via Nasojejunal Tube, duodenal infusion, gastroscope, colonoscope, enema, or rectal catheter. • Several studies have revealed a high success rate with up to 93% success rate after 1 treatment. Cure rates after a second infusion were 94% of remaining patients. • Continued use of antibiotics, such as those use to treat C-Diff suppresses the natural flora found in the intestines. • Eradication of C-diff after fecal transplants is thought to occur due to the natural flora present in stool that wards off the C-diff infection. (Brandt, Aroniadis, Mellow, Kanatzar, Kelly, Park, Stollman & Rohlke, 2012),(Gough, Shaikh & Manges, 2011), (Nood, Vrieze, Nieuwdorp, Fuentes, Zoetendal, de Vos, Visser & Kuijper, 2013)

23. Pediatric considerations • In children less than 3 years of age, testing for C-diff is not recommended unless the child has an accompanying diagnosis of Hirschsprung disease or other motility disorder. • In children who are age 3 and older who are symptomatic, a positive test result is indicative of CDI. • Pseudomembranous colitis seen on endoscopy is indicative of CDI. • Test of cure is not recommended. • In moderate disease Flagyl 30mg/kg/day is recommended in 4 divided doses orally with a max of 2g per day. • In severe disease Vanco 40mg/kg/day is recommended in 4 divided doses orally with a max of 2g per day • Contact isolation with glove and gown recommended until diarrhea has resolved. (Committee on Infections Diseases, 2013)

24. Follow-up • In non-severe cases, patient can be managed as outpatients. • Patients should be seen 5-7 days after the initiation of therapy to evaluate for treatment effectiveness. If initial treatment is not effective, alternate antibiotic should be considered. • Due to the high rate of relapse, patients should be reevaluated 2-10 days after discontinuing antibiotics. • In severe cases, patients will need to be admitted to the hospital for IV antibiotic therapy and for monitoring of serum electrolytes, treatment effectiveness, and disease complications such as toxic megacolon, paralytic ileus, septic shock, and perforation. • Post hospitalization patients should be again reevaluated in 1 week upon discharge and then 2-10 days after discontinuing antibiotic therapy for relapse. (Domino, 2013)

25. Counseling/Education • Good Hand Hygiene • Encourage patients and families to use 10% bleach products to clean their home bathrooms after each bowel movement for two weeks. • Use only paper towels (no cloth towels) and dispose of used paper towels after each use.

26. Consultation/ReferraL • Gastroenterologist • Infectious Disease Specialist • Surgical Consult • If patients are unresponsive to initial therapy in Mild to Moderate disease or patients who have recurrent disease, Referral to either specialty is indicated.

27. Ten Multiple Choice Questions C-Diff is spread by • Fecal-Oral Route • Droplet • Contact • Air-borne People can be colonized and not have any symptoms • True • False Risk Factors for C-Diff include • Recent antibiotic use, recent hospitalization, age greater than 65. • Eating at a restaurant, taking antibiotics, age 25. • Upper respiratory infection, recent doctors appointment, age 40 • Mild Crohn’s disease without flare up in 1 year, no healthcare in the last 2 years, age 35.

28. Multiple choice questions A 56 year old male patient comes into the office with complaints of watery diarrhea 3-5 times per day and slight cramping abdominal pain for the past 3 days. He was recently treated in the Emergency Department with Bactrim for an abscess but has finished the antibiotic. Blood pressure is 110/65, pulse 92, RR 18, temp 99.1 orally. What tests would you consider for this patient? • CBC, CMP, Amylase, Lipase • CBC, CMP, CT scan • CBC, CMP, Stool Culture • CBC, CMP, Stool Culture, Stool PCR for C-diff,

29. Multiple choice questions What medication is recommended for treatment of mild C-diff in the adult. • Loperamide 4 mg PO x1 then 2 mg PO after each loose stool • Flagyl 250 mg PO Q 6 hours for 10 days • Flagyl 500 mg IV Q 6 hours • No medication is required to treat mild C-diff What medication is can be given if a patient has moderate C-diff and has an allergy to Vanco. a) Erythromycin b) Penicillin c) Dificid d) Immodium

30. Multiple choice questions • All of the following are true except • Nurses need to gown and glove each time she crosses the threshold of a patient who is suspected of having C-diff or has a positive diagnosis of C-Diff. • Bleach and other sporicidals are necessary to clean all non-disposable equipment that has been utilized with a patient with C-diff. • Patients family members who live in the same house as the patient do not need to gown and glove when entering their family members room because they have already been exposed. • C-diff can live on surfaces in the hospital environment for months.

31. Multiple Choice Questions • All children under the age of 12 months should be tested for C-diff because the rate of colonization is high. • True • False • Possible complications of C-diff include • Toxic Megacolon • Dehydration • Bowel Perforation • Death • All of the above

32. Multiple Choice Questions • Treatment by which of the following has been shown to significantly improve the recurrence of C-diff • Colon Transplants • Continued use of clindamycin • Colon lavage • Fecal Transplants

33. Questions?

34. References • Aberra, F. N., & Katz, J. (2013). Clostridium difficile colitis. Medscape Reference Drugs, Disease & Procedures, Retrieved from http://emedicine.medscape.com/article/186458-overview • Bartlett, J. G. (2010). Recent developments in testing and the changing epidemiology of clostridium difficile infection. Infectious Diease Special Edition, 72-77. • Belanger, S. D., Boissinot, M., & Clairoux, N. (2003). Rapid detection of clostridium difficile in feces by real-time pcr. Journal of Clinical Microbiology, 41(2), 730-734. • Brandt, L. J., Aroniadis, O. C., Mellow, M., Kanatzar, A., Kelly, C., Park, T., Stollman, N., & Rohlke, F. (2012). Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent clostridium difficile infection. The American Journal of Gastroenterology, 107, 1079-7087. doi: 10.1038/ajg.2012.60 • Carroll, K. C. (2011). Tests for the diagnosis of clostridium difficile infection: the next generation. Anaeorbe, 17, 170-174. doi: 10.1016/j.anaerobe.2011.002 • Centers for Disease Control, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID). (2013). Clostridium difficile infection. Retrieved from website: http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_infect.html • Committee on Infections Diseases. (2013). Clostridium difficile infection in infants and children. Official Journal of the American Academy of Pediatrics, 131, 196-200. doi: 10.1542/peds.2012-2992 • Domino, F. (2013). The five minute clinical consult. (21 ed.). Philadephia, PA: Lippincott Williams & Wilkins. • Gough, E., Shaikh, H., & Manges, A. R. (2011). Systematic review of intestinal microbiotatransplation (fecal bacteriotherapy) for recurrent clostridium difficile infection. Clinical Infectious Disease, 53, 994-1002. doi: 10.1093/cid/cir632 • Gould, C. V., & McDonald, L. C. (2008). Bench-to-bedside review: Clostridium difficile colitis. Critical Care, 12(1), Retrieved from http://ccforum.com/content/12/1/203 • Hamm, L. (2000). Clostridium difficile. Pediatric Pharmacology, 6(6), • Henrich, T. J., Krakower, D., Bitton, A., & Yokoe, D. S. (2009). Clinical risk factors for severe clostridium difficile-associated disease. Emerging Infection Diseases, 15(3), 415-421. doi: 10.3201/eid1503.080312 • Humphries, R. M., Uslan, D. Z., & Rubin, Z. (2012). Performance of clostridium difficile toxin enzyme immunoassay and nucleic acid amplification tests stratified by patient disease severity. Journal of Clinical Microbiology, 51(3), 869-873q10.1128/JCM.02970-12. • Johnston, B. C., Ma, S. Y., Goldenberg, J. Z., Thorlund, K., Vandvik, P. O., Loeb, M., & Guyatt, G. H. (2012). Probiotics for the prevention of clostridium difficile-associated diarrhea. Annals of Internal Medicine, 157, 878-888. • Kelly, C. P., & LaMont, J. T. (2013). Clostridium difficile in adults: Treatment. UpToDate,

35. Referebces • Lessa, F. C., Gould, C. V., & McDonald, L. C. (2012). Current status of clostridium difficile infection epidemiology. Clinical Infectious Disease, 55, s65-s70. • Loo, C., Bourgault, A., Poirier, L., Lamothe, F., Michaud, S., Turgeon, N., & …Dascal, A. (2011). Host and pathogen factors for Clostridium difficile infection and colonization. The new England Journal of Medicine, 365(18), 1693-1703. doi:10.1056/MEJMoa1012413 • McElwain, L., & Owens, R. (2005). C.difficile clinical practice guidline- third or more episode within one year. The Barbara Bush Children's Hospital, Retrieved from http://www.mmc.org/workfiles/mmc_bush/C Diff Clinical Guideline 3rd episode.pdf • McDonald, L. C., Lessa, F., Sievert, D., Wise, M., Herrera, R., Gould, C., Malpiedi, P., & Dudeck, M. (2012). Vital signs: Preventing clostridium difficile infections. Morbidity & Mortality Weekly Report, 61(9), 157-162. • McFarland, L. V., Elmer, G. W., & Surawicz, C. M. (2002). Breaking the cycle: Treatment strategies for 163 cases of recurrent clostridium difficile disease. The American Journal of Gastroenterology, 97(7), 1769-1775.   • McKinney, M. (2013). FDA slaps regs on fecal transplants, Increased steops for C. diff treatment draw mixed reactions from providers. Modern Healthcare, 43(21), 10. • Nood, E. V., Vrieze, A., Nieuwdorp, M., Fuentes, S., Zoetendal, E. G., de Vos, W. M., Visser, C. E., & Kuijper, E. J. (2013). Duodenal infusion of doner feces for recurrent clostridium difficile. The New England Journal of Medicine, 368(5), 407-415. • Stuart, H., Cohen, M. D., Dale, N., Gerding, M. D., Johnson, S., Kelly, C. P., Loo, V. G., & McDonald, L. C. (2013). Clinical practice guidelines for clostridium difficile infections in adults: 2010 update by the society for healthcare epidemiology of american and the infection diseases society of america. Infection Control and Hospital Epidemiology, 31(5), 431-455. • Surawicz, C. M., .Brandt, L. J., Binion, D. G., Ananthakrishnan, A. N., Curry, S. R., Gilligan, P. H., McFarland, L. V., & Mellow, M. (2013). Guildelines for diagnosis, treatment, and prevention of clostridium difficile infections. The American Journal of Gastroenterology, 108, 478-798. doi: 10.1038/ajg.2013.4 • Su, W. Y., Mercer, J., Van Hal, S. J., & Maley, M. (2013). Clostridium difficile testing: Have we got it right?. Journal of Clinical Microbiology, 51(1), 377-378. doi: 10.1128/JCM.02189-12 • Tannock, G. W., Munro, K., Taylor , C., Lawley, B., Young, W., Byrne, B., Emergy, J., & Louie, T. (2010). A new macrocyclic antibiotic, fidaxomicin (opt-80), causes less alteration to the bowel microbiota of clostridium difficile-infected patients than does vancomycin. Society of General Microbiology Journals, 156, 3354-3359. doi: 10.1099/mic.0.042010-0