A large proportion of nosocomial and antibiotic-associated diarrhoea is caused by Clostridium difficile. This anaerobic bacterium is capable of producing toxins that may precipitate diarrhoea and colitis in susceptible individuals. C. difficile is implicated in 10% to 25% of cases of antibiotic-associated diarrhoea and 50% to 75% of antibiotic-associated colitis. Less commonly, infection with C. difficile may result in colonic perforation, toxic megacolon, and even death.

C. difficile can be found in the gastrointestinal tract of approximately 2% to 5% of the population, particularly children less than two years of age, without causing infection. In healthy individuals, this resistance to infection is thought to be partly attributed to antibody-mediated immunity and commensal flora in the bowel. Colonisation of C. difficile in the gastrointestinal tract may originate from impairment of the body’s normal resistance mechanisms. This may arise as a result of disruption of the host flora by antibiotics, cancer chemotherapies, immunosuppression, or gastric acid suppression. For reasons yet to be fully understood, some of these colonised individuals then progress to clinical infection following overgrowth of toxin-producing strains of C. difficile.

Toxin A and toxin B are the two major virulence factors involved in C. difficile infection. These structurally related toxins are pro-inflammatory, cytotoxic, and enterotoxic in the human colon. While most strains produce both toxins, approximately 3% of Australian strains only produce toxin B.

Control of C. difficile often presents a challenge to healthcare facilities due to the ability of this bacterium to form spores. These resilient spores are resistant to heat, desiccation, and many common disinfectants. Spores can survive routine cleaning with detergents and alcohol-based gels and may survive for up to five months on hard surfaces. Hydrogen peroxide and sodium hypochlorite have sporicidal activity and have been shown to be superior to quaternary ammonium-based disinfectants in reducing environmental contamination with C. difficile.

Risk Factors
Healthy individuals usually do not develop C. difficile infections. The majority of cases are seen in hospitals and nursing homes. However, the incidence is rising within the community and outpatient setting.

There are a number of factors that may increase the risk of developing a C. difficile infection, including:

  • Current or recent antibiotic use. Any antibiotic may contribute to C. difficile infection. However, broad-spectrum antibiotics such as ampicillin, amoxicillin, clindamycin, and third and fourth-generation cephalosporins are more commonly implicated.
  • Older individuals. People aged 65 years and older are ten times more likely to become infected with C. difficile than someone younger.
  • Severe illness. Immunocompromised patients are at increased risk of being infected with C. difficile, particularly during a hospital stay.
  • Current or recent hospital stay. Up to 20% of hospitalised patients and up to 50% of individuals in long-term care facilities are asymptomatic carriers of C. difficile and may expose others to infection.
  • Recent infection with C. difficile.
  • Renal impairment.
  • Prior gastrointestinal surgery.
  • Prolonged hospital stay.
  • Gastric acid-suppressive therapy.

Signs and Symptoms:
C. difficile infections normally manifest five to ten days after the commencement of antibiotic therapy. However, it may occur as late as ten weeks following antibiotic treatment. Symptoms may vary between individuals, depending on the severity of the infection. The most common symptoms include:

  • Watery diarrhoea (occasionally bloody)
  • Stomach bloating, pain and tenderness
  • Fever
  • Loss of appetite
  • Nausea

An elevated white cell count is observed in approximately 40% of patients and hypoalbuminaemia in 76% of patients; life-threatening complications may arise in a small number of cases. Development of toxic megacolon and ileus in patients who present without diarrhoea are important clinical signs of the severity of infection. In rare cases, the bowels may rupture and lead to sepsis, organ failure, and even death.

It is also important to remember that some patients may present as asymptomatic carriers. These patients can shed bacteria in their faeces and contribute to the spread of infection within the facility.

Differential Diagnoses:
The typical symptoms of a C. difficile infection are fairly generalised, often making accurate diagnosis difficult. Common differential diagnoses of antibiotic-associated diarrhoea include:

  • Other bacterial pathogens (e.g. Campylobacter species)
  • Norovirus (often associated with significant vomiting, a self-limiting course, and a typical serial interval in outbreaks)
  • Ischaemic colitis
  • Inflammatory bowel disease
  • Use of laxatives or enteral feeds

Diagnosis:
Diagnostic tests are essential to ensure appropriate treatment is prescribed. Faecal samples are sent to the laboratory to determine if C.difficile toxins are present. A single positive faecal immunoassay for the toxin establishes the diagnosis of C. difficile-associated disease in patients presenting with signs and symptoms of the infection. Testing should only be performed on unformed stools as positive results from formed stools merely indicate colonisation. Rectal swabs are appropriate to use as specimens if the patient has ileus.

Treatment:
Discontinuation of the implicated antibiotics may results in symptom resolution in up to 23% of patients. The likelihood of relapse is also reduced. If the causative antibiotic cannot be discontinued, specialist advice should be sought. An antibiotic that is less likely to precipitate further growth of C. difficile may be appropriate.

Metronidazole is currently the antibiotic of choice for mild to moderate C. difficile infection. It should be administered orally or via a nasogastric tube, but may be given intravenously to patients intolerant of the oral formulation. Colonic concentrations of metronidazole are similar following oral and intravenous administration in patients with colitis. In most clinical trials, a ten-day course of treatment was used. A longer treatment period may be required if there is an ongoing need for the antibiotics suspected to have caused the infection. However, metronidazole should not be continued longer than four to six weeks due to the risk of developing peripheral neuropathy.

Vancomycin, either orally or via a nasogastric tube, is preferred for the treatment of severe infections. It is considered more effective and is associated with lower rates of relapse or treatment failure in comparison to metronidazole. In non-severe disease, a randomised comparative study reported that 90% of patients were cured with metronidazole and 98% with oral vancomycin. Higher gastrointestinal concentrations of vancomycin are achieved following oral administration compared to intravenous administration as it has poor penetration into the lumen of the colon. A capsule formulation is available, however it is significantly more expensive than the intravenous preparation. Therefore, the intravenous formulation is commonly used for oral administration. In severe infections with ileus, vancomycin may be administered as a retention enema (500mg in 100mL of normal saline administered rectally every six hours) in addition to oral vancomycin and intravenous metronidazole.

For patients who fail to respond after a few days of initial therapy, prescribers may choose to increase the dose of vancomycin or begin oral vancomycin therapy if metronidazole has been used.

Surgical intervention may be required for patients with severe disease, particularly if toxic megacolon, bowel perforation, or severe ongoing sepsis develop despite appropriate therapy. Early surgical referral is imperative as poor outcomes will arise if organ dysfunction is established prior to surgery.

There are other treatment options that may be considered, such as fidaxomicin. This relatively new antibiotic has been associated with lower rates of recurrence in comparison to vancomycin. However, it is quite expensive and the data for its use in severe disease is currently lacking.

In patients who have recurrent C. difficile infections, specialist advice should be sought. Repeat treatment with either metronidazole, or in severe cases vancomycin, has been shown to be effective. Other antibiotics that have been successfully used include bacitracin (as an extemporaneous preparation), rifaximin, tigecycline, sodium fusidate, and nitazoxanide (available through the Special Access Scheme). Faecal microbiota transplantation is another option for recurrent infections. However, there are currently few reports of its use in severe acute disease outside of specialist centres.

References:

  1. Antibiotic Expert Group. Antibiotic-associated diarrhoea [revised Mar 2015]. In: eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited; 2015.
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  3. Cheng AC, Ferguson JK, Richards MJ, Robson JM, Gilbert GL, McGregor A, et al. Australasian Society for Infectious Diseases guidelines for the diagnosis and treatment of Clostridium difficile infection. Med J Aust. 2011; 194(7): 353-8.
  4. Kelly CP, Lamont JT. Patient information: antibiotic-associated diarrhea caused by Clostridium difficile (beyond the basics). Alphen aan den Rijn: Wolters Kluwer; 2015.
  5. Knoop FC, Owens M, Crocker IC. Clostridium difficile: clinical disease and diagnosis. Clin Microbiol Rev. 1993; 6(3): 251-65.
  6. McFarlane M, Hajkowicz K. Controlling Clostridium difficile. Aust Prescr. 2013; 36(12): 121-4.
  7. Queensland Government – Queensland Health. Fact sheet: Clostridium difficile infection (CDI) [Internet]. Brisbane: Queensland Health; 2013.
  8. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007; 45(3): 302-7.

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