Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients

1. Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients Katelyn R Richards, PharmD University of Wisconsin Hospital and Clinics PGY-2 Solid Organ Transplant Pharmacy Resident

2. Objectives • Compare and contrast Clostridium difficile associated disease (CDAD) in solid organ transplant recipients with the general population • Evaluate guideline recommendations for pharmacologic therapy • Describe the role of probiotics • Explain secondary prevention of CDAD No conflicts of interest to disclose

3. Clostridium difficile http://textbookofbacteriology.net/normalflora_3.html • Spore-forming, anaerobic, gram-positive bacillus • Toxin producing – A & B • Inflammatory diarrhea, colonic mucosal injury • Pseudomembranous colitis • Less common in immunosuppressed patients • Fecal-oral route of transmission Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

4. http://www.humenhealth.com/clostridium-difficile-infection

5. History of New Strain • Higher incidence of CDAD • North American PFGE type 1 (NAP1) • PFGE: pulsed-field gel electrophoresis • More virulent • Higher severity of disease • Incidence is more highly related to fluoroquinolone use then previous existing strain Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

6. Epidemiology • Incidence in hospitalized patients: 1-2% • Incidence in transplant recipients • Liver: 3 – 7% • Kidney: 3.5 – 16% • Kidney-pancreas: 1.5 – 7.8% • Heart: 15% • Lung: 7 – 31% • Highest incidence within first 3 months • 40% risk if inpatient for >4 weeks Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

7. Risk Factors • Antimicrobial exposure • Any and all antibiotics – including surgical prophylaxis • Clindamycin – highest risk for original strain • Fluoroquinolones – highest risk for NAP1 strain • Sulfamethoxazole-trimethoprim prophylaxis has not been associated with CDAD • Reduced humoral response • Acid suppressant agents Dubberke ER et al. AJT 2009

8. Risk Factors • Age >65 • Severe underlying disease • Uremia • Surgery • Nasogastric or endotracheal tube • Prolonged hospitalization Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

9. Acid Suppression and CDAD Debate • Clostridium difficile spores are not killed by gastric acid • BUT, vegetative forms which germinates spore form are killed by gastric acid • Clinical trials differ • 2 x higher incidence of CDAD with proton pump inhibitors • Confounded by severity of disease and hospital length of stay Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009Cunningham R et al. J Hosp Infect 2003 Dubberke ER et al. Clin Infect Dis 2007 Loo VG et al. NEJM 2005

10. Typical presentation Watery diarrhea Up to 10-15 bowel movements per day Fever Abdominal cramping, discomfort Unexplained leukocytosis Atypical presentation Vitals: fever Physical exam: abdominal pain/distension Lab values: leukocytosis >30,000 cells/mm3 >50% transplant patients CT scan: severe colitis Clinical Manifestations Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

11. Diagnosis http://emedicine.medscape.com/article/226645-overview • Up to 50% of hospitalized patients are colonized • Only perform diagnostic tests if symptomatic • CDAD is a clinical diagnosis • Colonoscopy for the presence of pseudomembranes • definitive diagnosis • Test for C.difficile toxin in stool • Cytotoxicity cell assay (Gold Standard) • Expensive, 24 hour turn around time • ELISA • Inexpensive, rapid turn around time • 60-90% sensitive with a negative predictive value >95% • Repeat testing increases risk of false positive Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

12. Classifying Disease Severity Cohen SH et al. IDSA Guidelines 2010

13. Complications • Dehydration • Electrolyte disturbances • Hypoalbuminemia • Toxic megacolon • Bowel perforation • Sepsis • Renal failure • Total colectomy • Death http://www.hopkins-gi.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Cat_ID=AF793A59-B736-42CB-9E1F-E79D2B9FC358&GDL_Disease_ID=2A4995B2-DFA5-4954-B770-F1F5BAFED033 Cohen SH et al. IDSA Guidelines 2010

14. Prevention • Horizontal transmission (IDSA) • Hand washing with soap and water • Contact precautions: gloves and gown • Clean areas with sporicidal agents • Minimize risk factors Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

15. Contact Precautions http://www.medscape.org/viewarticle/558476

16. Treatment • Stop or narrow antibiotics • Metronidazole (PO, IV) • Vancomycin (PO, PR) • Fidaxomycin (PO) • Alternatives • IVIG • Rifaximin • Nitizoxanide

17. Metronidazole (Flagyl®) • Not FDA approved for CDAD • Mechanism: disrupts protein synthesis resulting in cell death in anaerobic bacteria • Dose: 500 mg PO Q8h, 500 mg IV Q6-8h • Pharmacokinetics: rapidly absorbed • Concentration in colon minimal Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

18. Metronidazole (Flagyl®) • Use: effective for mild to moderate disease and first recurrence • Adverse effects • Caution in liver failure • Higher risk for side effects as drug is hepatically metabolized • Neurotoxicity, primarily manifested as paraesthesias • Paraesthesias are more common with prolonged exposure Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

19. Vancomycin (Vancocin®) • FDA approved for CDAD • Mechanism: inhibits the growth of C.Difficile (bacteroistatic) • Dose: 125 – 500 mg PO Q6h; 500 mg PR • IV administration does not treat CDAD • Enema may lead to bacteremia from colonic flora • Administration: • Oral capsules (expensive) • IV product used orally (in hospital administration) • Retention enema Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

20. Vancomycin (Vancocin®) • Use: Initial episode of severe or complicated disease and for recurrence • Pharmacokinetics: poorly absorbed in gut • Concentrates in colon • Adverse effects • Compromised gastrointestinal tract may result in systemic absorption Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

21. Fidaxomicin (Dificid®) • FDA approved for CDAD in May 2011 • Mechanism: macrolide antibiotic • Kills C.difficile (bactericidal) • Postantibiotic effect • Dose: 200 mg PO BID x 10 days • Pharmacokinetics: poor absorption in gut Louie TJ et al. NEJM 2011

22. Fidaxomicin (Dificid®) http://www.idse.net/ViewArticle.aspx?d=Bacterial+Infections+/+MRSA&d_id=211&i=June+2011&i_id=733&a_id=17269 • Use: treatment of C.difficile infections • Non-inferior to oral vancomycin • Lower rate of recurrence of non-NAP1 strain • Less effect on normal colonic flora • Adverse effects: Nausea, vomiting • Minimal drug interactions • Significant cost: $2800 for 10 day course, poorly covered by insurance providers Louie TJ et al. NEJM 2011

23. Surgical Intervention • May be required in complicated or refractory cases • Total colectomy • 3% in immunocompetent • 13% in solid organ transplant recipients • May represent more severe disease • May reduce mortality if taken to the OR within 48 hours of medical therapy failure, bowel perforation or multi-organ failure Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

24. Recurrence • 6 – 25% of patients experience 1 episode of recurrence • Definition: relapse of same infection or re-infection from new strain • Risk factors • Age > 65 • Metronidazole (especially in patients > 65) • Use of other antibiotics during or after initial treatment • Impaired immune response to toxin A Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

25. Treatment of Recurrence • First recurrence: same as initial episode • Second recurrence: vancomycin taper and/or pulse therapy • Taper: slow taper over prolonged period of time • Pulse: high dose given fewer times over a prolonged period of time • Avoid metronidazole for cumulative neurotoxicity • >2 recurrences: • Alternative therapy Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

26. Alternative Therapies • Intravenous immune globulin (IVIG) • Rifaximin • Nitizoxanide • Fecal transplant

27. IVIG • Not FDA approved for CDAD • Mechanism: Antitoxin antibodies • Dose: 150 – 400 mg/kg • Use in combination with other antibiotic therapy • Efficacy controversial • Expensive • Not recommended by the American Society of Transplantation Dubberke ER et al. AJT 2009 Cohen SH et al. IDSA guidelines 2010

28. Rifaximin • Not FDA approved for CDAD • Mechanism: inhibits bacterial RNA synthesis (bacteriostatic) • Used following vancomycin therapy • Dose: 200-400 mg PO 2-3 times/day x 14d • High risk for development of C.difficile resistance • Effectiveness depends on the minimum inhibitory concentration (MIC) • Expensive Johnson S et al. Clin Infect Dis 2007 Cohen SH et al. IDSA guidelines 2010

29. Nitizoxanide • Not FDA approved for CDAD • Mechanism: interferes with aerobic metabolism of bacteria and protozoa • Dose: 500 mg PO Q12h x 10 days • Recent prospective, double-blind, randomized controlled trial suggests non-inferiority to vancomycin • Small sample size Musher DM et al. Clin Infect Dis. 2009

30. Fecal Transplant • Restore indigenous fecal flora • Disruption of flora is a risk factor for C.difficile • Factors to consider: • Screen donor for transmissible agents • Logistic issues (timing, collection, processing) • Transplant typically done via nasogastric tube or enema • Limited availability but high success rates Cohen SH et al. IDSA guidelines 2010

31. Infectious Diseases Society of America (IDSA) Guidelines Cohen SH et al. IDSA guidelines 2010

32. American Society of Transplantation Guidelines Dubberke ER et al. AJT 2009

33. Where dose fidaxomicin fit? • Non-inferior to vancomycin • Similar recurrence rate to vancomycin • Except non-NAP1 strains • Both products have minimal adverse effects • Fidaxomicin significantly more expensive • Clinical practice: • Typically used after vancomycin has failed Louie TJ et al. NEJM 2011

34. Role of Probiotics Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009 Hickson M et al. BMJ 2007 • Small randomized trial showed reduced the risk of C.difficile with yogurt • Lactobacillus casei, bulgaricus, and Streptococcus thermophilus • Excluded patients on high-risk antibiotics • Not recommended for primary prevention • Risk of bacteremia http://www.parade.com/health/2009/09/20-good-bacteria-probiotics.html

35. Secondary Prevention • If antibiotics are needed during C.difficile treatment: • Continue C.difficile treatment for the duration of the antibiotic regimen (and usually beyond course for anywhere from 3-10 days) • If prolonged, switch to vancomycin to avoid metronidazole toxicities • If broad-spectrum antibiotics are needed after C.difficile treatment is complete: • No empiric treatment of C.difficile without symptoms Dubberke ER et al. AJT 2009 Cohen SH et al. IDSA guidelines 2010

36. References Cohen SH, Gerding DN, Johnson S, et al. 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). Infect Control Hosp Epidemiol 2010;31(5):431-455. Dubberke ER, Riddle DJ, AST Infectious Disease Community of Practice. Clostridium difficile in solid organ transplant recipients. Am J Transpl 2009;9(s4):S35-S40. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoae. J Hosp Infect 2003;54:243-245. Dubberke ER, Reske KA, Olsen YY, et al. Clostridium difficile-associated disease in a setting of endemicity: identification of novel risk factors. Clin Infect Dis 2007;45:1543-1549 Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353:2442-2449. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-431. Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007;44:846-848 Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomized double blind placebo controlled trial. BMJ 2007;335:80

37. Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients Katelyn R Richards, PharmD University of Wisconsin Hospital and Clinics PGY-2 Solid Organ Transplant Pharmacy Resident