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

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

Clostridium difficile 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 http://textbookofbacteriology.net/normalflora_3.html Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

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

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 Not necessarily drug resistant Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

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 20-30% of ABX-associated diarrhea Incidence not typically significantly higher than other surgical patients highest incidence within the first three months due to more frequent antimicrobial exposure intense immunosuppression and increased exposure to the healthcare setting Incidence is increasing Risk increases with prolonged length of stay: Up to 40% after 4 weeks 7 - 26% adult inpatients are colonized Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

Risk Factors Antimicrobial exposure Reduced humoral response 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 Antimicrobial exposure – suppresses normal flora of GI tract providing a niche for c.diff to flourish; broadspectrum and prolonged use inc risk Gastric acid kills vegetative forms of c.diff; PPI may disturb GI flora and allow C.difficile more easily colonize the bowel Clinda and FQ due to resistance patterns of each strain Dubberke ER et al. AJT 2009

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

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 Highly debatable Not expected to affect pathogenesis of infection but Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009 Cunningham R et al. J Hosp Infect 2003 Dubberke ER et al. Clin Infect Dis 2007 Loo VG et al. NEJM 2005

Clinical Manifestations 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 Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

Diagnosis 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 After negative toxin test, only test again based on clinical suspicion of disease; PCRs are newly available: advantage = enhanced sensitivity compared to ELISA but MUCH more expensive http://emedicine.medscape.com/article/226645-overview Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

Classifying Disease Severity Clinical Definition Supportive Clinical Data Initial episode, mild or moderate WBC < 15,000 cells/mcL OR Scr < 1.5 x above baseline Initial episode, severe WBC > 15,000 cells/mcL Scr > 1.5 x above baseline Initial episode, severe, complicated Hypotension or shock, ileus, megacolon Cohen SH et al. IDSA Guidelines 2010

Complications Dehydration Electrolyte disturbances Hypoalbuminemia Toxic megacolon Bowel perforation Sepsis Renal failure Total colectomy Death toxic megacolon is a rapid dilation of lg intestine within 1 to few days leading to perforation, sepsis, death Total colectomy more 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

Prevention Horizontal transmission (IDSA) Minimize risk factors Hand washing with soap and water Contact precautions: gloves and gown Clean areas with sporicidal agents Minimize risk factors The key to treatment is prevention since c.diff is highly contagious Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

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

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

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

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

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

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 No drug interactions Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

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

Fidaxomicin (Dificid®) 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 http://www.idse.net/ViewArticle.aspx?d=Bacterial+Infections+/+MRSA&d_id=211&i=June+2011&i_id=733&a_id=17269 Louie TJ et al. NEJM 2011

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 but these the bias to take these patients back to the OR quicker Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009

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

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

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

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 Based on case studies and retrospective data Dubberke ER et al. AJT 2009 Cohen SH et al. IDSA guidelines 2010

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 Use is based on recent uncontrolled case series Johnson S et al. Clin Infect Dis 2007 Cohen SH et al. IDSA guidelines 2010

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

Fecal Transplant Restore indigenous fecal flora Factors to consider: 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

Infectious Diseases Society of America (IDSA) Guidelines Clinical Definition Recommended Treatment Initial episode, mild or moderate Metronidazole 500 mg PO Q8h x 10-14 days Initial episode, severe Vancomycin 125 mg PO Q6h x 10-14 days Initial episode, complicated Vancomycin 500 mg PO Q6h PLUS Metronidazole 500 mg IV Q8h +/- Vancomycin 500 mg enema for ileus First recurrence Same as for initial episode Second recurrence Vancomycin taper or pulsed regimen Cohen SH et al. IDSA guidelines 2010

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

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

Role of Probiotics 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 Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009 Hickson M et al. BMJ 2007 http://www.parade.com/health/2009/09/20-good-bacteria-probiotics.html

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

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

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