Clostridium difficileBy Kimberly Bowman,

Katie Lee, Michelle Shim

Objectives

Clostridium difficile • Epidemiology • Causes & Diagnosis • Treatment & Prevention

EpidemiologyKatie Lee

Morphology

• Rod shaped• Gram positive• Anaerobic bacillus bacteria • Spore-forming

Habitats

• Soils• Marine Sediments • GI tract of Humans and other animals• Spores survive harsh conditions such as:

- Acid human stomach - Disinfectant-treated hospital surfaces - Endoscopy equipment

Spore Survival

Pathogenesis• Produces two exotoxins, A and B, which

activate cytokines• Toxin A: Attracts the immune cells neutrophils

and monocytes • Toxin B: Degrades the epithelial cells of the

colon; cause necrosis and inflammation of intestinal cells.

Outbreak Strain

• New virulence factors in NAP1 strain (NAP1/B1/027)1. Binary toxin

2. Fluoroquinolone resistance 3. Deletion of tcdC gene

Genetic Arrangement of Toxins

 Voth, D.E. & Ballard, J.D. Clostridium difficile toxins: mechanism of action and role in disease. Clin. Microbiol. Rev. 18, 247–263 

Spore Germination

Agents that trigger spore germination:

• Taurocholate (Bile salt)• Glycine • Lysozyme • Thioglycolate

Comparative Phylogenomics

• Multi-locus Sequence Typing (MLST) - Mutation found to be 8x higher than recombination events

• Microarray comparison among various strains - Genetic exchange readily available - Only 19.7% of DNA shared among strains

Associated Diseases

• C. difficile associated infection (CDI) • C. difficile associated disease (CDAD)• Pseudomembranous colitis (PMC)

Causes & Diagnosis Michelle Shim

Causes

• Contact with contaminated surfaces/items, then contact with mouth or nose

• Nosocomially infected hospitals, long-term care institutions

• Broad range of antibiotic use

Symptoms & Recurrence

• Watery diarrhea (at least 3 bowel movements per day for 2 or more days)

• Fever• Loss of appetite• Nausea• Abdominal pain or tenderness• Recurrance diarrhea – 5% to 40% of patients

receiving treatment for C. difficile diarrhea

Diagnosis

• Significant diarrhea (new onset of 3 or more partially formed or watery stool per 24 hour period)

• Foul stool odour• Colitis• Recent antibiotic exposure

Diagnosis

• Generally based on detection of toxin A or BLaboratory Test Advantages Disadvantages

Cytotoxin assay Excellent specificity Reduced sensitivity; 48h for results; requires special facility; detects only toxin B

Immunoassay Good specificity; < 4h for results; simple technique

Decreased sensitivity

Stool culture (with subsequent cytotoxin assay)

Excellent specificity and sensitivity

72-96h for results; labour intensive; requires special facility

Outbreak

• 2003: 2 outbreaks of highly virulent strain in Montreal and Calgary with deaths up to 89 people

• 2005: spread into Toronto and hospitalized 10, killing 1

• 2006: 21 deaths in Quebec; C. difficile mentioned on 6,480 death certificates in UK

• 2007: 4 killed and 14 cases in Mississauga

Incidence

Poutanen, S. M. “Clostridium difficile-associated diarrhea in adults”. CMAJ. 2004. Canadian Medical Association. 10 Jan 2010. <http://www.cmaj.ca/cgi/content/full/171/1/51>

Risk factors

• Age: > 65 years• Gender: female• Gastrointestinal surgery• Less than 1 year since admission to long-term

care facility, hospital admission within 3 months of diagnosis

• Serious underlying disease• Broad use of antibiotics (>3), esp. PPI, H2RA

Treatment & Prevention

Kimberly Bowman

Treatment for CDI

• Asymptomatic Carriage– Treatment discouraged

• Symptomatic Infection (CDAD & Colitis)– Depending on severity, treat with antibiotics

• Pseudomembranous Colitis– Antibiotics and surgery

• Recurrent CDAD

Metronidazole vs VancomycinMetronidazole Vancomycin

Cost/Course $20 $800

Response > 95% > 95%

Route Oral or IV Oral only

Acts on Anaerobes Gram positives

Negatives Systemic side effects, some resistant strains of C diff

Promotes vancomycin-resistant bacteria [VRE], $$

Treatment for Symptomatic CDI

• Stop Afflicting antibiotics• 1st line: Metronidazole (Flagyl)• 2nd line: Vancomycin • Others: Bacitracin, Fusidic Acid, Teicoplanin• Probiotics• Surgical: Colectomy• Fecal Bacteriotherapy

Infection Control Measures

• Isolation:– Full enteric precautions

• Disinfection:– Hypocholrite substances

• Hand Hygiene:– Soap and water recommended by CDC for CDAD

• Education

**The persistence of C diff spores is the biggest challenge in eradicating C diff from the hospital environment!

Image from: Rupnik M, Wilcox MH and Gerding DN. Clostridium difficile Infection: new developments in epidemiology and pathogenesis. Nature: July 2009: 7;526-536.

CDAD & Antibiotics

• Almost all antibiotics have been correlated with increased incidence of C diff infection

• Those of greatest concern– Clindamycin– Cephalosporins (3rd and 4th generation)– Fluroquinolones– Broad Spectrum -lactams

Antimicrobial Stewardship Programs

• Goals: Reduce C diff incidence by monitoring usage of antibiotics esp. broad-spectrum antibiotics

• After 2005 NAP1 outbreak in Quebec, antimicrobial stewardship program saw 54% reduction in antibiotics, 60% decrease in incidence

• Implementing a program: key personnel– ID specialists– Multi professional team

Questions ?