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Clostridium difficile

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Updated January 2011 by Charles Gomersall

Clostridium difficile-associated diarrhoea

  • 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.

Incidence

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

Pathogenesis

  • 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 3rd 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.

Diagnosis

Risk factors

  • 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

Clinical features

  • 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
  • mucus or occult blood per rectum. Melaena and frank blood rare.

Investigation

  • ± marked peripheral leucocytosis
  • Faecal leukocytes when present, suggest infection, ischaemia or mucosal inflammation
  • C. difficile toxin assay (in unformed stool, except when ileus is present) 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 more sensitive, 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%.  Same day result can be available, widely used
    • Testing stool from asymptomatic patients not useful
    • Repeat testing during the same episode of diarrhoea of limited use and should be discouraged
  • 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.

Management

General

  • 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
  • discontinue precipitating antibiotic as soon as possible
  • avoid anti-peristaltic agents if possible  - may obscure symptoms and precipitate toxic megacolon

Specific

  • 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
  • mild/moderate colitis: metronidazole 500 mg three times daily for 10-14 days
    • do not use metronidazole beyond first recurrence in view of potential neurotoxicity
  • severe or complicated colitis
    • start treatment as soon as diagnosis suspected without waiting for results of toxin assay
    • initial treatment is vancomycin 125 mg orally 4 times per day for 10–14 days for severe colitis
    • severe complicated colitis: vancomycin orally and per rectum (if ileus is present) ± metronidazole
      • vancomycin 500 mg four times daily orally
      • vancomycin 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema
      • metronidazole 500 mg IV 8 hourly
    • Severely ill patients who fail to respond to antibiotics warrant colectomy
  • 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
  • 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

Infection control

  • Limit use of antimicrobials, particularly cephalosporins and clindamycin
  • Handwashing between all patients, their body substances or environmental surfaces
    • alcohol does not eradicate C. difficile spores. Need proper handwashing with soap (or disinfectant) and water, vigorous mechanical scrubbing and rinsing to remove the spores from hands
  • Enteric (stool) isolation precautions.
  • Isolation room if possible
  • Contact 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

Further reading.

Cohen SH, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infection Control and Hospital Epidemiology, 2010; 31(5):431-55

© Claudia Cheng August 2009, Charles Gomersall January 2011


 

©Charles Gomersall, April, 2014 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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