Case Presentation

Clostridium Difficile

Patient G.R.

- 88 yo WM- Previous hospital admission for pneumonia treated with piperacillin/tazobactam- Admitted to KMC on 1/17/02 for scrotal edema and diarrhea.

Physical Exam

WD thin, frail confused WM A & O to Person Only Mild Tenderness in RLQ Scrotal Edema Without erythema Ht: 152.4cm Wt: 40 Kg IBW: 52 Kg CrCl: 21ml/min

U/S Revealed Cysts in Scrotum W/o Testicular Involvement. No Evidence of Infection.

G.R.’S Meds:

Zosyn 2.5gm IV Q 6hTylenol 10gr Po Q 4 H prnPhenergan 12.5mg IV Q 6 H prnIV Fluids With KCl at 120ml/hrCoumadin 2.5mg Po qdLanoxin 0.25mg Po qdASA 81mg Po qd

G.R.’S Meds: (cont’d)

Atenolol 50mg Po qdCardizem(diltiazem) IV for HR > 100

Ensure Plus 1 can tid Vancomycin 125mg Po qid *Bacid 1 Capsule Po tid*Questran(cholestyramine) 1 scoopful*Lactinex 1 tablet po bid*Flagyl(metronidazole) 250mg po tid*

*= Treatment related therapy

Cultures/Studies

Stool Toxin Positive for C. difficile 1/19/02Urine Cx – negative 1/18/02

Treatment Changes

-Discontinue Zosyn-Change Flagyl to 250mg po qid-Discontinue Vancomycin po-Discontinue Questran-Discontinue Bacid

Summary

The patient’s diarrhea gradually improved over a period of several days and the patient was discharged to an ECF

Antibiotic-Associated Diarrhea

-AAD is defined as otherwise unexplained diarrhea that occurs in association with the administration of antibiotics.

AAD Frequency of Complication

•10-25% of pts treated with amoxicillin/clavulanate.

•15-20% of pts treated with cefixime.

•2-5% of those treated with other cephalosporins, quinolones, azithromycin, clarithromycin, erythromycin, and tetracycline.• 5-10% of pts treated with ampicillin.•1 in 10 to 1 in 10,000 treated w/ clindamycin- in hospital

Spectrum of Findings

• Nuisance diarrhea• Colitis– Abdominal cramping– Fever– Leukocytosis– Fecal leukocytosis– Hypoalbuminemia– Colonic thickening on CT and endoscopic changes

Colitis

www.gicare.com/pated/ eicnclcc.htm

Clostridium difficile

-Gm +, spore-forming anaerobic bacillus.

-accounts for approx. 25% of the cases of AAD

-accounts for the majority of cases of colitis associated with antibiotic therapy.

-Causes 300,000 to 3,000,000 cases of diarrhea and colitis in the U.S. every year

Bartlett J, Antibiotic-Associated Diarrhea, N Engl J Med, Vol. 346, No. 5, Jan. 31, 2002

Clostridium difficile

-Other Causes of AAD

-Other enteric pathogens

-Direct effects of antimicrobial agents

-Reduced fecal flora

-Other enteric pathogens

-salmonella,

-C. perfringens type A,

-Staphylococcus aureus, and possibly

-C. albicans overgrowth

Clostridium difficile

-Other Causes of AAD

-FQ-resistant disease

-Drug effects independent of motility

-Effects of non-antibiotic drugs

- Laxatives - Antacids

- Contrast Agents - Antiarrhythmics - NSAIDs - Cholinergic Agents

- Products containing lactose or sorbitol

Pathogenesis

Major Risk Factors for C. difficile infection:

1. Advanced age

2. Hospitalization

3. Exposure to antibiotics

Clostridium Difficile

- Antibiotics most frequently associated with the infection are:

- Clindamycin- Ampicillin- Amoxicillin- Cephalosporins

Clostridium difficile

Epidemiology:

-Most cases occur in hospitals or LTC (rate of 25-60 per 100,000 occupied bed-days)

-incidence in the OP setting is 7.7 cases per 100,000 person-years

Pathogenesis

-Toxinogenic C. difficile is isolated from stool specimens in only 0% to 3% of healthy adults.

-During hospitalization, colonization frequently occurs.

-C. difficile forms spores that persist in the environment for years and contamination by C. difficile is common in hospitals and LTC facilities

Pathogenesis

-Clinical symptoms develop in only about 1/3 of colonized patients, and

- asymptomatic colonization with C difficile may be associated with a decreased risk for development of C. difficile-associated diarrhea.

Pathogenesis

-Two factors have recently been shown to increase the probability of symptomatic disease in patients who acquire C difficile colonization in the hospital:•1. Severity of other illnesses•2. Reduced levels of serum IgG antibody to toxin A.

Pathogenesis

-Clinically significant strain of C. difficile that cause disease produce 2 protein exotoxins, toxin A, and toxin B.

-Full tissue damage requires the action of both toxins

Clinical Manifestations

-diarrhea -colitis without pseudomembranes -pseudomembranous colitis -fulminant colitis -hyperpyrexia

Clinical Manifestations

-Mild to moderate CDAD is usually accompanied by lower abdominal cramping pain but no systemic symptoms or physical findings.

-Moderate to severe colitis usually presents with profuse diarrhea, abdominal distention with pain, and, in some cases, occult colonic bleeding.

Clinical Manifestations

Fulminant Colitis- develops in approximately in 1% to 3% of patients

Others: hyperpyrexia, chronic diarrhea, and hypoalbuminemia with anasarca.

C difficile may occasionally complicate idiopathic inflammatory bowel disease. A reactive arthritis occurring 1-4 weeks after C.

difficile colitis develops in some patients.

Diagnosis

-Non-specific laboratory abnormalities: leukocytosis with left shift and fecal leukocytes in about 50-60 % of cases.

-Avg peripheral WBC is 12 x 109/L to 20 x 109/L.

- Gram staining of fecal specimens are no value

- Anaerobic culture of stool (takes 2-3 days and does not distinguish between toxinogenic from nontoxinogenic strains)

Diagnosis

-Most sensitive and specific test is a tissue culture assay for the cytotoxicity of toxin B (takes 1-3 days and requires tissue culture facilities)- GOLD STANDARD

-ELISA- detects toxin A and/or B in stool. Rapid turnaround.

-Stool samples- If results are negative, 1-2 additional samples should be sent. If first is positive, no further specimens are required.

Bartlett J, Antibiotic-Associated Diarrhea, N Engl J Med, Vol. 346, No. 5, Jan. 31, 2002

TreatmentTable 4. General Guidelines for the Managementof Clostridium difficile–Associated Diarrhea*

1. Isolate the patient.2. Educate personnel to use gloves when in contact with patient and for the handling of bodily substances.3. If possible, discontinue inciting antibiotic therapy and avoid anti-peristaltic and opiate drugs.

4. Confirm the diagnosis with a test for C difficile toxin. If the results of the first specimen are negative and diarrhea persists, 1 or 2 additional stool samples should be sent.

Treatment

5. If clinically indicated (moderate or severe diarrhea, systemic symptoms, significant leukocytosis, etc), consider antimicrobial treatment against C difficile. If the clinical suspicion is high and the patient is severely ill, empiric antimicrobial treatment may be started awaiting laboratory confirmation.

6. Oral metronidazole (250 mg 4 times per day or 500 mg 3 times per day) for 10-14 d is usually adequate.

7. Oral vancomycin hydrochloride (125 mg 4 times per day) for 10-14 d is indicated for those who cannot tolerate oral metronidazole, those in whom metronidazole therapy fails, pregnant patients, and, perhaps, severely ill patients.

Treatment

8. The first relapse/recurrence of C difficile colitis can be treated with another 10- to 14-d course of oral metronidazole or vancomycin

9. Therapy of patients with multiple relapses of C difficile colitis has not been examined by randomized, prospective, controlled clinical trials. A tapering course of metronidazole or vancomycin for 4-6 wk has been used.

* Adapted from Johnson and Gerding and Fekety.

Mylonakis E, et al, Clostridium difficile-Associated Diarrhea A Review. Archives of Internal Medicine, Vol. 161, No. 4, Feb. 26, 2001

TreatmentTapering Schedule

Week Vanco dose

1 125mg qid

2 125mg bid

3 125mg qd

4 125mg q.o.d.

5 & 6 125mg q 3 dMylonakis E, et al, Clostridium difficile-Associated Diarrhea A Review. Archives of Internal Medicine, Vol. 161, No. 4, Feb. 26, 2001

Treatment

Other Approaches

-Vancomycin with cholestyramine resin (4gm BID)

- Oral Vancomycin 125mg qid, oral rifampin 600mg bid x 7 days

- Saccharomyces cerevisiae (Brewer’s Yeast)_

- IgG infusion at dose of 200 to 300mg/kg