Clostridium difficile infection

Introduction

The genus Clostridium is a group of gm positive rod shaped bacteriums with the ability to organize spores. Most of the genus, are obligate anaerobes nevertheless some are aerotolerant ( Clostridium perfringens ) . Some of the noteworthy pathogens in the group are Clostridium tetani, Clostridium botulinus, Clostridium perfringens and Clostridium difficile ; the causes of lockjaw, botulism, gas sphacelus and nonsocomial diarrhea severally.

Recently Clostridium difficile ( CDF ) has come into the limelight due to an increasing happening and badness in CDF associated disease in infirmaries ( Gerding, 2009 ) and it has been estimated that infection with the being can be the NHS up to & A ; lb ; 4,000 in extended infirmary corsets per patient ( Spencer, 1998 ) .

CDF is a gram positive, obligatory anaerobic, motile, spore organizing rod with the ability to bring forth toxins which damage the intestine wall taking to disease. CDF was foremost isolated in 1935 from the stool of healthy newborn babes ( Hall et al. , 1935 ) , it was n’t until 1978 that this being was identified as being the cause of antibiotic induced pseudomembranous inflammatory bowel disease ( Bartlett et al. , 1978 ) presently it is thought to be the cause of 15 % -20 % of all instances of antibiotic associated diarrhea ( Bartlett, 2002 ) and in 2006 its genome was to the full sequenced ( Sebaihia et al. , 2006 ) . This sequence should assist us to foster our understand of the organisms pathogenesis and so to develop new ways to name and characterize CDF, current methods for which are still found to be missing.

When this being infects can be quickly fatal in particularly in an immunocompromised patient. However the presence of this being does non automatically intend that the patient is infected as it besides has the ability to colonize a host without bring forthing toxin.

Clinical presentation of infection with toxin bring forthing CDF can run from mild ego restricting diarrhea to the dangerous status of pseudomembranous inflammatory bowel disease ( Monaghan et al. , 2009 ) :

Typical clinical characteristics include anorexia, sickness, lower abdominal hurting, general uncomfortableness accompanied by watery diarrhea and sometimes a febrility ( Bauer et al. , 2009 ) .

There are three chief hazards associated with Clostridium difficile infection ( CDI ) :

  1. Break of enteric vegetations
  2. Age
  3. Hospitalization

Break of enteric vegetations by wide spectrum antibiotics is the most common predisposing factor to CDI although this is besides possible via other methods e.g. GI surgery. Clindamycin, Mefoxins and fluroquinolines have the highest occurence of subsequent infection nevertheless all antibiotics carry an associated hazard ( Den & A ; egrave ; ve et al. , 2009 ) as they all have the possible to do dysbacteriosis which disrupts the indispensable protective barrier of the normal GI vegetation. The length of antimicrobic chemotherapy besides appears to be a factor in the instance of fluroquinoline and Cipro usage ( Pepin et al. , 2005 ) . It is now obvious that antibiotic intervention has a much bigger impact on the intestine vegetation than what we antecedently thought ( Dethlefsen et al. , 2008 ) this is now a recognised as a hazard factor in CDI re-occurrence ( Chang et al. , 2008 )

Age is a factor in CDI and 80 % of all reported instances from England, Wales and Northern Ireland in 2008 were in the 65 and over age scope ( HPA, 2008 ) it is thought that the high incidence in the aged is due to their inability to bring forth a serum Ig G ( IgG ) immune response to CDF Toxin A ( TcdA ) when foremost exposed to CDF toxins ( Rupnik et al. , 2009 ) . In contrast to the aged, colonization of healthy neonates with CDF is highly common ( up to 80 % ) and seldom associated with unwellness ( Spencer et al. , 2009 ) . Due to a coney theoretical account it has been speculated that this is due to a deficiency of CDF toxin receptors in the kid ‘s bowels at birth ( Eglow et al. , 1992 ) and that these receptors do non develop until the kid is a twelvemonth or so old when they become susceptible ( Kelly et al. , 1992 ) . However the deficiency of CDF toxin receptors expression in babes has non been proved on a human theoretical account ( Spencer et al. , 2009 )

Hospitalization additions risk as it increases the sum of CDI hazards that a patient is exposed to including antibiotic usage, a contaminated environment, hapless manus hygiene by healthcare workers, other patients who are colonised and frequently the patient themselves could be portion of a susceptible population ( e.g. Aged or immunosuppressed ) ( Rupnik et al. , 2009 ) . During hospitalization it has been reported that 15-21 % of patients become septic and that 66 % of these may non be diagnostic ( McFarland et al. , 1989 ) . Hospital colonization rates are thought to be 20-40 % compared with 2-3 % in the healthy grownup population ( Bartlett, 2006 ) . Colonization rates in aged patients shacking in long term attention installations and infirmaries have been reported every bit high as 73 % ( Den & A ; egrave ; ve et al. , 2009 ) . Taking into consideration that aged patients make up the majority of those in long term attention it is non surprising so that they are considered an at hazard group.

Other hazards for CDI include irradiation, nephritic failure, clogging pneumonic disease, malignances ( particularly heamatologic ) , mechanical intestine cleaning, enteral infections that change colonic microflora, enteric eatings, intensive attention and high dependence units, immunosupression including HIV/AIDS or station organ graft medicines, chemotherapy, proton pump inhibitor and H2 blockers, gastrointestianal surgery and processs and inflammatory intestine diseases ( Spencer et al. , 2009 ; Rupnik et al. , 2009 ; Monaghan et al. , 2009 ; Den & A ; egrave ; ve et al. , 2009 ; Bartlett, 2006 )

Pathogenesis

For CDF to do a individual to go sick certain standards have to be met. This can be described as a three hit theoretical account as shown in Figure 2. First the patient ‘s enteric vegetation must be disrupted normally due to antimicrobic therapy. This break 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 health care puting as the spores can last for hebdomads and months on inanimate objects being carried between patients by healthcare workers ( Cleary, 1998 ) . At this point if the patient acquires a toxin bring forthing strain and fails to mount a anamnestic IgG response to TcdA the patient will be diagnostic i.e. infected. If the patient is able to mount a sufficient immune response or they get a non toxin bring forthing strain they are asymptomatically colonised ( Kyne et al. , 2000 ) . Asymptomatic patients can move as reservoirs of the disease ( Hookman et al. , 2009 ) but they are protected against CDF colonization ( Shim et al. , 1998 ) .

When a toxic signifier of CDF enters the organic structure it penetrates to the mucous secretion bed of the enterocytes by with the usage of its scourge and peptidases. Once through the mucous secretion it can so attach itself to an enterocyte via adhesions ( Den & A ; egrave ; ve et al. , 2009 ) .

Once the being has attached itself to an enterocyte toxin production can get down. CDF has two chief toxins involved in pathogenicity ; Toxin A and Toxin B ( TcdA and TcdB severally ) . These are big powerful cytotoxic enzymes which are classed as glucosyltrans-ferases ( Hookman et al. , 2009 ) . These are coded for in a & A ; tilde ; 19.6kb subdivision of the CDF genome termed the pathogenicity venue or paLoc ( Voth et al. , 2005 ) . Besides found at this venue are three other cistrons, coding for TcdD, TcdC and TcdE. These are thought to each play a function in toxin production. Current grounds 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 help TcdA and TcdB in go forthing the cell via permeabilisation of the CDF cell wall ( Tan et al. , 2001 ) .

CDF produces the toxins on the interior of the lms. The cells so internalize TcdA via a glycoprotein receptor ( Cleary, 1998 ) . Once inside the cell TcdA glycosolates members of the Rho GTPase household which basically inactivates them, this inactivation so leads to the interrupting down of the cells actin cytoskeleton which consequences in relaxation of cell junctions, the release of neutrophil attractants and finally cell decease ( Hookman et al. , 2009 ) .

Due to the addition of infinite between cells TcdB is able so to attach to the basal membrane of the cells and originate its cytotoxic tract ( Monaghan et al. , 2009 ) , TcdB is besides thought to intercede cell decease via a similar tract to TcdA nevertheless it is five times more active than TcdA and is able to exercise this cytotoxic consequence in more types of cells. The latter suggests that although the receptor for TcdB has non been elicited, its ‘ look is omnipresent ( Voth et al. , 2005 ) . The decease of the cells in the enteric liner increases the immune mediated response and the production and release of cytokines in response to TcdA ensuing in the inflammatory diarrhea and accretion of neutrophils and dead intestinal cells which form the seeable pseudomembrane seen in CDF associated inflammatory bowel disease ( Rupnik et al. , 2006 ) .