Clostridium difficile infection

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The genus Clostridium is a group of gram positive rod shaped bacteria with the ability to form spores. Most of the genus, are obligate anaerobes however some are aerotolerant (Clostridium perfringens). Some of the notable pathogens in the group are Clostridium tetani, Clostridium botulinum, Clostridium perfringens and Clostridium difficile; the causes of tetanus, botulism, gas gangrene and nonsocomial diarrhoea respectively.

Recently Clostridium difficile (CDF) has come into the spotlight due to an increasing occurrence and severity in CDF associated disease in hospitals (Gerding, 2009) and it has been estimated that infection with the organism can cost the NHS up to £4,000 in extended hospital stays per patient(Spencer, 1998).

CDF is a gram positive, obligatory anaerobic, motile, spore forming rod with the ability to produce toxins which damage the gut wall leading to disease. CDF was first isolated in 1935 from the stool of healthy newborn babies (Hall et al., 1935), it wasn't until 1978 that this organism was identified as being the cause of antibiotic induced pseudomembranous colitis (Bartlett et al., 1978) currently it is thought to be the cause of 15%-20% of all cases of antibiotic associated diarrhoea (Bartlett, 2002) and in 2006 its genome was fully sequenced (Sebaihia et al., 2006). This sequence should help us to further our understand of the organisms pathogenesis and so to develop new ways to diagnose and characterise CDF, current methods for which are still found to be lacking.

When this organism infects can be rapidly fatal in especially in an immunocompromised patient. However the presence of this organism does not automatically mean that the patient is infected as it also has the ability to colonise a host without producing toxin.

Clinical presentation of infection with toxin producing CDF can range from mild self limiting diarrhoea to the life-threatening condition of pseudomembranous colitis (Monaghan et al., 2009):

Typical clinical features include anorexia, nausea, lower abdominal pain, general discomfort accompanied by watery diarrhoea and sometimes a fever (Bauer et al., 2009).

There are three main risks associated with Clostridium difficile infection (CDI):

  1. Disruption of intestinal flora
  2. Age
  3. Hospitalisation

Disruption of intestinal flora by broad spectrum antibiotics is the most common predisposing factor to CDI although this is also possible via other methods e.g. gastrointestinal surgery. Clindamycin, cephalosporins and fluroquinolines have the highest occurence of subsequent infection however all antibiotics carry an associated risk (Denève et al., 2009) as they all have the potential to cause dysbacteriosis which disrupts the essential protective barrier of the normal gastrointestinal flora. The length of antimicrobial chemotherapy also appears to be a factor in the case of fluroquinoline and ciprofloxacin use (Pepin et al., 2005). It is now obvious that antibiotic treatment has a much bigger impact on the gut flora than what we previously thought (Dethlefsen et al., 2008) this is now a recognised as a risk factor in CDI re-occurrence (Chang et al., 2008)

Age is a factor in CDI and 80% of all reported cases from England, Wales and Northern Ireland in 2008 were in the 65 and over age range (HPA, 2008)it is thought that the high incidence in the elderly is due to their inability to produce a serum immunoglobulin G (IgG) immune response to CDF Toxin A (TcdA) when first exposed to CDF toxins (Rupnik et al., 2009). In contrast to the elderly, colonisation of healthy newborns with CDF is extremely common (up to 80%) and rarely associated with illness (Spencer et al., 2009). Due to a rabbit model it has been speculated that this is due to a lack of CDF toxin receptors in the child's intestines at birth (Eglow et al., 1992) and that these receptors do not develop until the child is a year or so old when they become susceptible (Kelly et al., 1992). However the lack of CDF toxin receptors expression in babies has not been proved on a human model (Spencer et al., 2009)

Hospitalisation increases risk as it increases the amount of CDI risks that a patient is exposed to including antibiotic use, a contaminated environment, poor hand hygiene by healthcare workers, other patients who are colonised and often the patient themselves could be part of a susceptible population (e.g. Elderly or immunosuppressed)(Rupnik et al., 2009). During hospitalisation it has been reported that 15-21% of patients become infected and that 66% of these may not be symptomatic (McFarland et al., 1989). Hospital colonisation rates are thought to be 20-40% compared with 2-3% in the healthy adult population (Bartlett, 2006). Colonisation rates in elderly patients residing in long term care facilities and hospitals have been reported as high as 73% (Denève et al., 2009). Taking into consideration that elderly patients make up the bulk of those in long term care it is not surprising then that they are considered an at risk group.

Other risks for CDI include irradiation, renal failure, obstructive pulmonary disease, malignancies (especially heamatologic), mechanical bowel cleansing, enteric infections that change colonic microflora, enteral feedings, intensive care and high dependency units, immunosupression including HIV/AIDS or post organ transplant medications, chemotherapy, proton pump inhibitor and H2 blockers, gastrointestianal surgery and procedures and inflammatory bowel diseases (Spencer et al., 2009; Rupnik et al., 2009; Monaghan et al., 2009; Denève et al., 2009; Bartlett, 2006)


For CDF to cause a person to become ill certain criteria have to be met. This can be described as a three hit model as shown in Figure 2. Firstly the patient's intestinal flora must be disrupted commonly due to antimicrobial therapy. This disruption in the barrier that commonly protects against infection makes the patient susceptible. Next the patient must be exposed to CDF spores. These are common in the healthcare setting as the spores can survive for weeks and months on inanimate objects being carried between patients by healthcare workers (Cleary, 1998). At this point if the patient acquires a toxin producing strain and fails to mount a anamnestic IgG response to TcdA the patient will be symptomatic i.e. infected. If the patient is able to mount a sufficient immune response or they acquire a non toxin producing strain they are asymptomatically colonised (Kyne et al., 2000). Asymptomatic patients can act as reservoirs of the disease (Hookman et al., 2009) but they are protected against CDF colonisation (Shim et al., 1998).

When a toxic form of CDF enters the body it penetrates to the mucus layer of the enterocytes by with the use of its flagella and proteases. Once through the mucus it can then attach itself to an enterocyte via adhesions (Denève et al., 2009).

Once the organism has attached itself to an enterocyte toxin production can begin. CDF has two main toxins involved in pathogenicity; Toxin A and Toxin B (TcdA and TcdB respectively). These are large potent cytotoxic enzymes which are classed as glucosyltrans-ferases (Hookman et al., 2009). These are coded for in a ˜19.6kb section of the CDF genome termed the pathogenicity locus or paLoc (Voth et al., 2005). Also found at this locus are three other genes, coding for TcdD, TcdC and TcdE. These are thought to each play a role in toxin production. Current evidence suggests that TcdD acts as a positive regulator of TcdA and TcdB production (Mani et al., 2001) whereas TcdC acts as a negative regulator of toxin production (Hundsberger et al., 1997). TcdE due to its similarity to holins is believed to assist TcdA and TcdB in leaving the cell via permeabilisation of the CDF cell wall (Tan et al., 2001).

CDF produces the toxins on the inside of the lumen. The cells then internalise TcdA via a glycoprotein receptor (Cleary, 1998). Once inside the cell TcdA glycosolates members of the Rho GTPase family which essentially inactivates them, this inactivation then leads to the breaking down of the cells actin cytoskeleton which results in loosening of cell junctions, the release of neutrophil attractants and ultimately cell death (Hookman et al., 2009).

Due to the increase of space between cells TcdB is able then to attach to the basal membrane of the cells and initiate its cytotoxic pathway (Monaghan et al., 2009), TcdB is also thought to mediate cell death via a similar pathway to TcdA however it is five times more active than TcdA and is able to exert this cytotoxic effect in more types of cells. The latter suggests that although the receptor for TcdB has not been elicited, its' expression is ubiquitous (Voth et al., 2005). The death of the cells in the intestinal lining increases the immune mediated response and the production and release of cytokines in response to TcdA resulting in the inflammatory diarrhoea and accumulation of neutrophils and dead intestinal cells which form the visible pseudomembrane seen in CDF associated colitis (Rupnik et al., 2006).