Clostridium difficile

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• Major (? only) important infectious cause of diarrhoea that develops in patients after hospitalization in developed countries
• Clostridium difficile infection may present in a variety of ways: uncomplicated diarrhoea, moderate to severe colitis ± pseudomembranes, fulminant colitis (uncm).
• Toxic megacolon is most serious complication. May present in the absence of diarrhoea.

Clostridium difficile related disease occurs in 5-21% of hospitalized patients, especially in ICU. Causes up to 50% of cases of diarrhoea in ICU

• Unclear. Probably result of disruption of normal gut flora by antibiotics and subsequent colonization/infection by oro-faecal route. Host’s normal flora is a less likely route. Some additional factor(s) also involved: determines whether patient becomes an asymptomatic carrier or develops symptomatic disease
• Clindamycin, ampicillin and cephalosporins most frequently associated with pseudomembranous colitis. Parenteral aminoglycosides, vancomycin and metronidazole infrequently implicated.
• Currently 3^rd generation cephalosporins most frequently implicated. Appear more prone to cause Clostridium difficile associated diarrhoea than other broad spectrum agents eg ticarcillin/clavulanate
• Pathogenic strains produce toxins that result in colitis and diarrhoea. Toxin A and possibly toxin B appear to be responsible for disease.
• Asymptomatic carriage does not appear to predispose patient to disease.

• Advanced age (persons > 65 years have a 10 fold higher risk)
• Hospitalisation and  ICU stay
• Exposure to antibiotics
  • particularly those with activity against anaerobic organisms
  • duration of antibiotics is also important, with risk becoming significant after 10 days of therapy
  • antibiotics most frequently implicated in diarrhoea associated with C. difficile infection are:
    • clindamycin
    • expanded-spectrum penicillins
    • cephalosporins
      However, virtually any antibiotic may be implicated, including brief courses of antibiotics that are given prophylactically before surgery, with the exception of parenteral vancomycin. Metronidazole is both a cause and the cure for C. difficile diarrhoea/colitis.
• Certain chemotherapeutic agents (methotrexate, paclitaxel)
• Preexisting carriage, or more commonly, exposure to environmentally-acquired C. difficile (eg. hand-carriage among hospital personnel, roommate exposure and environmental contamination) results in subsequent colonisation, overgrowth, and infection with the toxin-producing organism in susceptible patients.
• The role of gastric acid suppression as a risk factor for C. difficile infection remains controversial. There are conflicting reports whether proton pump inhibitors are associated with an increased in C. difficile infection rates

• asymptomatic carriage
• diarrhoea
  • usually is watery and moderate, but may be profuse in severe cases
• colitis with or without pseudomembranes
• fulminant colitis (rare)
• abdominal tenderness and cramps with or without diarrhoea
• fever

• ± marked leucocytosis
• Faecal leukocytes when present, suggest infection, ischaemia or mucosal inflammation
• C. difficile toxin assay should always be obtained. C. difficile produces 2 potent exotoxins that mediate diarrhoea and colitis, toxins A and B. C. difficile toxin A is an ‘enterotoxin”; toxin B is a “cytotoxin”. In vivo, stool toxin levels correlate with disease severity; however, it is not entirely clear what the relative importance of each toxin is in the pathogenesis of C. difficile diarrhoea and/or colitis
  • Tissue culture cytotoxin assay is the gold standard for diagnosis. It is the most sensitive test, detecting as little as 10 pg of toxin B. Slow turnaround time (>48h needed)
  • Enzyme immunoassays to detect toxin A alone or toxin A and B. Detection of both A and B toxin recommended as A-B+ strains increasingly recognized. Good specificity, but 100 to 1000 pg of either toxin A or toxin B must be present for the test to be positive. Hence there is a false negative rate of 10 to 20%. Testing 2 or 3 samples for toxins improves the diagnostic yield by 5-10%. Same day result can be available, widely used
• normal stool osmolar gap
• culture of the organism is technically demanding, requiring 2-3 days for growth, and is not useful for distinguishing between the presence of toxin positive strains or toxin negative strains. May be useful in the setting of nosocomial outbreaks for epidemiological purposes.
• direct visualisation of pseudomembranes is highly specific for the diagnosis of C. difficile colitis. Sensitivity in one study was around 71%. Not a first line investigation, however a role for direct visualisation may exist in cases requiring rapid diagnosis if laboratory results will be delayed or if false negative assays are suspected. Many clinicians would treat such patients empirically rather than do sigmoidoscopy or colonoscopy.

• monitor serum electrolytes especially sodium, potassium, magnesium and phosphorus
• fluid resuscitate
• monitor leucocytosis - sign of worsening condition eg ischaemia, bowel perforation
• AXR for toxic megacolon

• Indications for treatment include evidence of colitis (fever, leukocytosis and characteristic findings on CT or endoscopy), severe diarrhoea or persistent diarrhoea despite discontinuation of the implicated agent
• Vancomycin PO 125 mg qds or metronidazole PO 250 mg qds or metronidazole IV (for those unable to tolerate oral medication) for 10 days.
  • Oral vancomycin and metronidazole previously thought to be equally effective but the latter is cheaper and there are concerns regarding the emergence of vancomycin resistant enterococci. Recent reports suggest that metronidazole may be less effective
  • Anticipated response to treatment is resolution of fever within 24 to 48 hours and resolution of diarrhoea in 4 to 5 days. Lack of response should prompt a search for an alternative diagnosis, or an assessment for ileus or toxic megacolon, since these conditions may prevent the drug from reaching the target site
  • For patients with ileus, transport of antibiotic to the colonic lumen may be increased by using high doses of oral vancomycin (500 mg qid) or changing to intravenous metronidazole, or by instilling vancomycin through long tubes inserted orally or administering vancomycin enemas rectally
  • Severely ill patients who fail to respond to antibiotics warrant colectomy
• Faecal metronidazole concentrations are markedly reduced in the absence of diarrhoea. This may be because metronidazole is secreted across inflammed mucosa or because absorption is decreased due to decreased transit time in patients with diarrhoea.
• Treatment of recurrence:
  • occurs in 20-25% of cases
  • suspect if there is a return of symptoms, usually 3 to 21 days after metronidazole or vancomycin is discontinued. Assays for C. difficile toxin are usually unnecessary immediately after the completion of treatment and the results may be misleading, since about one third of patients have positive assays despite successful therapy.
  • most recurrences respond to another course of antibiotics in standard doses for 10 days
  • 33% of patients with a first recurrence have a second recurrence. Recurrence rate correlates with age and length of stay
• New antimicrobial and non-antimicrobial therapeutic options
  • Rifaximin and nitazoxanide (off-label)
  • Faecal transplant or faecal reconstitution (eg from spouse) – effective but aesthetically not appealing!
  • Probiotics eg Lactobacillus plantarum and the yeast Saccharomyces boulardii
    • Makes good sense – alter intestinal flora, intestinal barrier protection, antimicrobial activity, immunomodulation
    • But not shown to work in humans, works in hamsters
    • Risk of Saccharomyces fungaemia
• Fulminant colitis may require surgical intervention

• Limit use of antimicrobials
• Handwashing between all patients, their body substances or environmental surfaces
  • alcohol does not eradicate C. difficile spores. Need proper handwashing with disinfectant and water, vigorous mechanical scrubbing and rinsing to remove the spores from hands
• Enteric (stool) isolation precautions.
• Isolation room if possible
• Wear gloves when in contact with patients who have Clostridium difficile-associated diarrhoea or with their environmental surfaces
• C. difficile spores can survive dry surfaces for up to several months. Disinfect objects contaminated with C. difficile with sodium hypochlorite, akaline glutaraldehyde or ethylene oxide

Complications - specific

• develop in 11% with the first recurrence
• ischaemia
• partial obstruction
• perforation
• toxic megacolon associated with colitis.

© Claudia Cheng August 2009

©Charles Gomersall, October, 2009 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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