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Clostridium difficile

Microbiology > Bacteriology > Anaerobic bacteria > Clostridium
• Anaerobic, spore-forming, Gram positive rod that produces 2 exotoxins, toxin A (enterotoxin) and toxin B (cytotoxin).

• In 1978, C. difficile was identified as the causative agent of antibiotic-associated diarrhea (AAD) and pseudomembranous colitis (PMC).
• It is one of the most common hospital-associated infections (HAI), particularly in older adults.
• If C. difficile enters the intestinal tract, it is generally kept in check by the normal colonic flora.  However, if the normal flora has been altered, for example, by antibiotic therapy, C. difficile is able to quickly overgrow and cause disease.
• In the early 2000’s, a strain of C. difficile designated NAP1/B1/027 (depending on the typing method) was isolated in association with outbreaks and  appeared to be more virulent than previous strains.  This strain was characterized by increased toxins A and B production, an additional  binary toxin (which has been reported to facilitate adherence of the organism to intestinal epithelial cells) and fluoroquinolone resistance (providing a selection advantage).
• Transmission of C. difficile occurs via the fecal-oral route by ingestion of spores.  Persons with   C. difficile carriage (whether they have clinical disease or not) serve as a reservoir for environmental contamination.
• Antibiotics most often associated with AAD are penicillins, cephalosporins, fluoroquinolones and clindamycin.

• Produces 2 exotoxins capable of binding to intestinal epithelial cells leading to inflammation and diarrhea.  Toxin A is an enterotoxin which attracts neutrophils and stimulates the release of cytokines and Toxin B is a cytotoxin which causes mucosal damage, increasing the permeability of the intestinal wall with subsequent diarrhea.
• Toxin B seems to be essential for disease, so that strains that are A (-), B (+) cause disease, but   A (+), B (-) strains do not.
• Spore formation allows the organism to persist in the environment and resist non-bleach disinfection efforts.

Disease Manifestations:
• A small percentage of persons with C. difficile are asymptomatic.
• A spectrum of clinical manifestations is observed from mild diarrhea to life-threatening inflammation of the colon.  
o Symptoms generally develop 4-10 days following antibiotic therapy, but ranges from 1 day to 2 months.
o Non-severe:  watery diarrhea (>3 stools/day) and abdominal cramping.
o Severe: profuse, watery diarrhea (10-15 stools/day), blood and/or pus in the stool, abdominal cramping, fever and dehydration.
o Complications may include: dehydration, kidney failure, toxic megacolon, bowel perforation and death.
• Infants (<2 years of age) colonized with C. difficile are not symptomatic, most likely due to the lack of specific receptors on intestinal epithelial cells.

Laboratory diagnosis:
• Rapid PCR detection of C. difficile toxin genes, either alone or as part of an algorithm including initial screening by immunoassay for glutamate dehydrogenase (GHD) antigen and toxins A and B.
• Immunoassays for toxins A + B are less sensitive than PCR.
• Detection of cytotoxin B using tissue cell culture and specific neutralizing antibody, although sensitive, requires 1-2 days and is technically cumbersome.
• Only patients with clinically significant diarrhea should be tested as test methods do not distinguish between disease and colonization.
• For patients with ileus, submit a perirectal swab for testing.
• Radiographic imaging is warranted in patients with severe illness to evaluate for the presence of toxic megacolon, bowel perforation or other findings warranting surgical intervention.

Differential diagnosis:  other bacterial and viral causes of diarrhea, noninfectious causes of diarrhea

• For mild disease, discontinue the implicated antibiotic when possible.
• Oral metronidazole or oral vancomycin: vancomycin has a slightly higher initial cure rate, but the recurrence rate is the same for both.
• Fidaxomycin:  considerably more expensive, the initial cure rate is the same as vancomycin, but the recurrence rate is lower.
• Recently, the FDA has approved bezlotoxumab, a human monoclonal antibody directed against toxin B, as an adjunct to antibiotic therapy.
• Approximately 20-25% of patients will relapse, generally within 1-2 weeks post-therapy (but up to several months after therapy) as the antibiotic does not kill the spore form.  Treatment of the relapse is generally with vancomycin and may involve a pulsed regimen.  Relapse due to true antibiotic resistance is rare.
• After multiple relapses, fecal microbiota transplantation (via colonoscopy or nasogastric tube) may be required.  Success rates of >90% have been reported.

Prevention and control:
• Judicious use of antibiotics (antibiotic stewardship).
• Strict hand hygiene with soap and water (alcohol based hand sanitizers do not kill spores).
• Thorough room cleaning protocols that involve using bleach as a disinfectant in order to kill the spores.

Related concepts
antibiotic associated diarrhea, pseudomembranous colitis, toxic megacolon, anaerobic spore-forming Gram positive rod, enterotoxin, cytotoxin
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