Clostridium difficile Colitis

C. diff.—Gram stain

Bacteriology• anaerobic gram-positive, spore-forming,

toxin-producing bacillus • first described in 1935• C. difficile can exist in spore and vegetative

forms.• releases two potent exotoxins that mediate

colitis and diarrhea– toxin A ("enterotoxin") – toxin B ("cytotoxin")

Bacteriology

• Toxin A causes inflammation leading to intestinal fluid secretion, mucosal injury and inflammation

Bacteriology

• Toxin B is essential for the virulence of C. difficile, and is approximately ten times more potent than toxin for mediating colonic mucosal damage

Epidemiology

• C. difficile colonizes the colon of about 2 percent of healthy adults.

• New colonization occurs predominantly by the fecal-oral route.

• Patients who become colonized are subsequently at risk for developing C. diff, primarily after treatment with antibiotics.

Pathophysiology

• Colonization of the intestinal tract occurs via the fecal-oral route.

• Facilitated by disruption of normal intestinal flora due to antimicrobial therapy.

• The organism is capable of elaborating exotoxins that bind to receptors on intestinal epithelial cells, leading to inflammation and diarrhea.

Pathophysiology

• Once intracellular, toxins A and B inactivate regulatory pathways mediated by proteins that are involved in cytoskeleton structure. This leads to shallow ulceration on the intestine mucosal surface.

• Both toxins also disrupt intercellular tight junctions.

Pathophysiology

• Toxin B is essential for the virulence of C. difficile, and is approximately ten times more potent than toxin A in mediating colonic mucosal damage.

• Strains lacking toxin A can be as virulent as strains with both toxins.

Hypervirulent Strain• A new, hypervirulent strain, NAP1/BI/027, has

been implicated as the responsible pathogen in selected Clostridium difficile outbreaks since the early 2000s.

• produces binary toxin related to the iota-toxin found in Clostridium perfringens.

• produces substantially larger quantities of toxins A and B in vitro than other C. difficile strains.

Clinical Manifestations

• Watery diarrhea• Abdominal pain and cramping• Low grade fever• Leukocytosis• Ileus• Abdominal tenderness

Extra-colonic Manifestations

• Protein-losing enteropathy with ascites• C. difficile infection in the setting of chronic

inflammatory bowel disease• Extracolonic involvement

--appendicitis--small bowel enteritis--extraintestinal involvement—cellulitis, arthritis

Diagnosis

• Anaerobic stool culture is the most sensitive test—impractical.

• Toxin assays--EIA– specificity (up to 99 percent)– variable sensitivity (60 to 95 percent)– relatively high false negative rate since 100 to

1000 pg of toxin must be present for the test to be positive

Diagnosis

• Stool WBCs

– Sensitive—fecal leukocytes never normal

– Low specificity—but clinical setting will help

– Cheap

– Readily available

Diagnosis

• Sigmoidoscopy or colonoscopy—findings variable.

• CT scan--not usually necessary– Non-specific– Expensive– Radiation exposure

Treatment

• Initial episode: Preferred: metronidazole 500 mg orally three times daily or 250 mg four times daily for 10 to 14 days.

• Alternative: vancomycin 125 mg orally four times daily for 10 to 14 days First relapse Confirm diagnosis (see text) If symptoms are mild, conservative management may be appropriate If antibiotics are needed, repeat treatment as in initial episode

Treatment

• Up to 50 percent of patients have positive stool assays for as long as six weeks after the completion of therapy. DON’T repeat C. diff toxin assay as routine.

Approach to Treatment Failure

• Recurrent disease often results from reinfection with the same or a different strain of C. difficile.

• Up to one-half of recurrent episodes are reinfections rather than relapses of infection with the original strain.

Treatment Failure

• Risk factors for recurrence – age >65 years– severe underlying medical disorders– ongoing therapy with concomitant antibiotics

Treatment Failure

• First relapse:

– If symptoms are mild, conservative management may be appropriate.

– If antibiotics are needed, repeat treatment as in initial episode above

Treatment Failure

• Second relapse: Tapering and pulsed oral vancomycin 125 mg orally four times daily for 7 to 14 days--125 mg orally twice daily for 7 days--125 mg orally once daily for 7 days--125 mg orally every other day for 7 days--125 mg orally every 3 days for 14 days.

• Alternative: fidaxomicin 200 mg orally twice daily for 10 days[4]

Treatment Failure

• Subsequent relapse: Vancomycin 125 mg orally four times daily for 14 days, followed by rifaximin 400 mg twice daily for 14 days.

• Alternative: Fidaxomicin 200 mg orally twice daily for 10 days.

Fecal Infusion

• Cure rates are high (up to 100 percent in small series), with a high level of patient acceptance.

• However, there is a concern about transmission of infectious agents to the stool recipient.

Fecal Infusion

• 200 to 300 g of donor stool suspended in 200 to 300 mL of sterile normal saline (homogenized briefly in kitchen blender to a liquid consistency).

• Administered via enema or NG or NE tube within 10 minutes of preparation, repeated daily for five days.

• Can also be given as an enema or injected thru a colonoscope.

Prevention--Goals

• Prevention of new colonization with the organism

• Prevention of C. diff colitis among patients already colonized by the organism

Prevention

• Surveillance — track rates of C. diff.• Contact precautions — patients should be

placed on contact precautions, including gloves and gowns.

• Hand hygiene — Alcohol-based hand rub (ABHR) does NOT eradicate C. difficile spores. Centers for Disease Control recommends soap and water hand hygiene when caring for patients with C. diff.

Prevention

• Stethoscope disinfection — alcohol wipes or gauze moistened with sterile water or alcohol.

• Environmental cleaning—bleach solution.• Restrict antibiotic usage—clindamycin,

fluroquinolones and cephalosporins• Home hygiene—clean surfaces with dilute

bleach

Summary• Clostridium difficile infection is one of the most

common hospital-acquired infections.• Recurrences frequently caused by reinfection.• Environmental hygiene is mandatory.• Diagnosis and treatment need not be expensive.• Antibiotic usage should be reduced.• Pulse-taper therapy is effective for complicated

recurrence.• Fecal infusion therapy useful in severe refractory

disease