Clostridium Difficile Treatment and Prevention of Recurrence in Transplant Recipients

Katelyn R Richards, PharmDUniversity 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

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

http://textbookofbacteriology.net/normalflora_3.html

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

Cohen SH et al. IDSA Guidelines 2010Dubberke 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

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

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

Risk Factors

Age >65 Severe underlying disease Uremia Surgery Nasogastric or endotracheal tube Prolonged hospitalization

Cohen SH et al. IDSA Guidelines 2010Dubberke 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

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

Cunningham R et al. J Hosp Infect 2003Dubberke 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 2010Dubberke 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

http://emedicine.medscape.com/article/226645-overview

Cohen SH et al. IDSA Guidelines 2010Dubberke 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

OR

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

Cohen SH et al. IDSA Guidelines 2010

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

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 2010Dubberke 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 2010Dubberke 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 2010Dubberke 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 2010Dubberke 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

Cohen SH et al. IDSA Guidelines 2010Dubberke 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

Louie TJ et al. NEJM 2011

http://www.idse.net/ViewArticle.aspx?d=Bacterial+Infections+/+MRSA&d_id=211&i=June+2011&i_id=733&a_id=17269

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 2010Dubberke 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 2010Dubberke 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 2010Dubberke 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

Dubberke ER et al. AJT 2009Cohen 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

Johnson S et al. Clin Infect Dis 2007Cohen 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 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 2010Dubberke ER et al. AJT 2009

Hickson M et al. BMJ 2007http://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 2009Cohen SH et al. IDSA guidelines 2010

References1. 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.

2. 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.

3. 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.

4. 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

5. 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.

6. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-431.

7. 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

8. 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, PharmDUniversity of Wisconsin Hospital and Clinics

PGY-2 Solid Organ Transplant Pharmacy Resident