1. 1
Is Clostridium Difficile still a
problem in UK hospitals?
Carl A P Aston
Clostridium Difficile is the most common cause of antibiotic resistant
diarrhoea but can also cause more severe pseudomembranous colitis.
It is a gram-positive anaerobe and is capable of forming spores which
further enhance its pathogenicity.
C. difficile is commonly found as a normal component of the gut flora
in about 5% of the adult population and usually only causes disease if
the rest of the flora is disrupted, for example, when taking certain
kinds of antibiotics. Nosocomial (hospital acquired) infections are
much more common than community acquired infections. This is due
to a combination of factors. Hospital patients are often exposed to
antimicrobials and therefore experience changes in their natural flora,
allowing C. difficile infections (CDIs) to take hold. As patients are often
kept in the same environment for long periods of time the possibility
of ingestion of bacterial spores present in their environment is much
more likely.
Between 1990-2004, the UK saw a sharp rise in the number of CDIs
being reported. Significantly, 20% of these infections were in younger
age groups which were not considered at risk. CDI was also indicated
as an underlying cause of death on 4,056 death certificates in 2007 and
it is thought that this figure was under-reported. In light of this, the
government issued new guidelines in an attempt to combat the rate
of infection and reduce its associated risk factors. This review will
attempt to assess whether CDI is still an issue in UK hospitals today,
looking at C. difficile as the causative organism and its pathology, the
guidelines issued by the government, their intended purpose, and
figures from the NHS detailing the frequency of infection over time and
their possible implications.
Clostridium Difficile
Clostridium difficile is a member of the genus Clostridia, which, along
with the genus bacillus, are the only two gram positive, bacterial
genera capable of producing spores. Spores can survive in the
environment for several months allowing them to infect new hosts
long after an initial infection has passed. Spores are also antibiotic,
heat, and acid resistant meaning they can survive conventional,
bleach-free cleaning methods as well as stomach acids. Different
strains of C. difficile produce spores at different rates [1], more detail
will be given on this later.
Trends
The NHS routinely deals with
cases of nosocomial C. difficile
infection and has recently
recovered from a serious
epidemic.
Epidemic strain ribotype 027
was thought to be the major
cause of this epidemic along
with poor adherence to
prevention and treatment
guidelines.
New guidelines were issued in
2008 in an attempt to control
and prevent further
outbreaks and subsequent
deaths.

2. 2
Figure 1 shows the basic structure of a bacterial spore. The
exosporium is the outermost layer but is not always present. Its role
is unclear but is thought to be one of adherence. Below this, the
spore coat forms the main protective layer and is comprised of many
layers of proteins and dipicolonic acid. This, combined with a very
low water content, conveys great resistance to the elements,
antibiotics, lytic enzymes, and noxious chemicals2 making spores the
ideal vehicles for environmental transmission and infection.
Figure 1 main structural components of a bacterial spore.
Bacterial spores possess a spore coat made of many layers of protein providing resistance to the environment,
enzymes, antibiotics and noxious chemicals. Combined with a low water content this makes them extremely
hardy and able to survive in many environments for long periods of time.
Pathology
As per Figure 2, once inside the host, spores travel to the colon and
become vegetative cells after exposure to bile salts [2]. In a healthy
gut, these would be competed for by other bacteria, thereby inhibiting
germination. This is the primary reason why antibiotic treatment is the
leading contributing factor to CDI, lack of competition in the gut for
both space and resources allows spores to germinate, attach, and
flourish within the now colonised individual. Once active, infective C.
difficile releases two exotoxins, A and B, which contribute to the death
of colonocytes by inhibiting the function of intracellular signalling Rho
proteins via glycosylation of the Thr37 residue [3,4]. This results in
effects such as cytoplasmic contraction, inflammation of the mucosa,
and cellular necrosis [5].

3. 3
Figure 2. Life cycle of Clostridium difficile [6]. Spores are ingested via the faecal-oral route. Germination
occurs in the colon upon exposure to bile salts. Vegetative cells colonise the colon and secrete exotoxins A and
B causing disease. Spores are shed in faeces.
Clinically this can present in a number of ways, from self-limiting, mild
diarrhoea, to colitis, pseudomembranous colitis, and toxic megacolon.
Mild CDI is characterised by watery diarrhoea, malaise, abdominal
cramps and nausea. More severe conditions are characterised by the
appearance of pseudomembranes in the colon. Risk factors associated
with CDIs include: severe dehydration and subsequent kidney damage;
the colon becoming perforated due to inflammation and resulting in
peritonitis which can lead to multiple organ failure if untreated, and
the development of toxic megacolon where gasses become trapped in
the colon which can send the body into shock and risks perforation of
the colon [7]. In severe cases a colectomy is required to remove the
damaged colon.
It is thought the recent epidemic in the UK was caused by the
emergence of a new strain of C. difficile which originated in Canada
and the USA [8] named BI/NAP1/027 (Restriction endonuclease
analysis group BI, North American pulsed-field gel electrophoresis type
NAP1 and PCR ribotype type 027 [9,10]) based on different
identification methods. Virulence of this new strain is enhanced by
production of an additional binary toxin named CDT which causes a
massive disruption of the cytoskeleton4; a deletion in the tcdC gene
which causes an increased

4. 4
production of toxins A and B [11]; altered surface proteins; and a
heightened ability to bind to human intestinal epithelial cells [8]. It also
produces spores at a much higher rate than more common strains of
C. difficile and that sporulation can be promoted further with exposure
to non-chlorinated cleaning agents [1]. Furthermore, evidence shows
that changes in its peptidoglycan provide greater antibiotic resistance
[2]. Gene transfer between enterococci and C. difficile may have also
conferred resistance to vancomycin and fluoroquinolone [8].
There is some contention over the extent of the strains virulence [12]
stating that, whilst certainly a problem, presence of ribotype 027 is not
necessarily an indicator of severe CDI and a more well-rounded
diagnostic approach should be taken rather than relying on the
presence of this strain. Other strains are equally or more capable of
causing severe infection so diagnosis through toxin assay and presence
of diarrhoea is the preferred method.
Dealing with the problem
As mentioned previously, the response of the UK government to the
dramatic increase of CDI was the release of new guidelines relating to
both treatment and infection control published in December 2008 [11]
and a subsequent review in 2012 [13]. This was an update to guidelines
released in 1994 taking into account new evidence, techniques, and
infrastructure in an attempt to improve aspects of both prevention
and control practices as well as the monitoring of outbreaks.
The report advises use of the SIGHT protocol [11] (Box 1) It encourages
the treatment of CDI as a specific diagnosis rather than a symptom of
another condition. This has led to CDI acquiring its own set of specific
treatments and handling procedures which has resulted in the
reduction of infection rates as we will see.
Box 1. The SIGHT Protocol
S Suspect that a case may be infective where there is no clear alternative cause for
diarrhoea
I Isolate the patient and consult with the infection control team (ICT) while
determining the cause of the diarrhoea.
G Gloves and aprons must be used for all contacts with the patient and their
environment.
H Hand washing with soap and water should be carried out before and after each
contact with the patient and the patient’s environment.
T Test the stool for toxin, by sending a specimen immediately.

5. 5
Prevention through Isolation
Suspicion of infective diarrhoea when there is no other apparent cause
means that treatment and protective measures can be taken as soon
as possible without the need for further symptoms or confirmatory
testing. The patient can then be isolated, ideally this would be to an
individual room until tests confirming the presence of CDI can be
performed. This measure reduces the risk of infection to other patients
by physically quarantining an individual with suspected CDI until
confirmation and treatment can begin. It also allows the patient and
the severity of their diarrhoea to be monitored on a daily basis. This
greatly reduces the number of infective spores released into the
environment. These measures were also present in the 1994
guidelines, though a survey by The Healthcare Commission found that
40% of trusts did not isolate patients with CDI as they should have
been [11]. It seems likely that this was a contributing factor to the
rising rate of infection.
Prevention through environmental cleaning
Once the patient is isolated, interactions with them need to be as
controlled as possible to prevent further contamination of the
environment and healthcare personnel. Disposable gloves and aprons
are advised when interacting with the patient and their environment.
As CDI incidence is dependent on the transmission of spores, proper
sanitation and cleaning of the environment is crucial. C. difficile spores
have been shown to be resistant to normal cleaning practices in
hospitals which commonly use detergent-based cleaners [1]. However
it has been shown that cleaning with chlorine-containing cleaning
agents, or hypochlorites, is a much more effective method of
decontamination [14]. There are also more extreme methods such as
the use of hydrogen peroxide vapour, whereby hydrogen peroxide is
heated to the point of evaporation and pumped into the atmosphere
to sterilise a whole room at once [15]. There is much debate over
which methods are the most effective[14,16], as there are so many
variables to take into account and no guarantee that hospital staff are
following guidelines or manufacturer’s instructions. Reduction in the
number of environmental spores is proportional to the reduction of
CDI transmission and infection.

6. 6
Prevention through hand hygiene
Hands must be washed using soap and water before and after each
interaction with patients. C. difficile spores are resistant to alcohol-
based hand sanitisers which have become commonplace but can still
be removed with conventional soap and water. A study by Wilcox, M
et al [14] found there was a direct correlation between CDI and
presence of C. difficile in the environment and a direct correlation
between spores on environmental sites and on healthcare worker’s
hands, indicating that improper personal hygiene is one of the main
forms of transmission. Commodes, toilet floors and bed rails were
found to be the most common environmental sites where spores were
found. This is likely due to direct contact with faecal matter,
aerosolised faecal matter and improper hand cleaning from patients
respectively. Again, this shows how important elimination of
environmental spores is to the reduction of CDI.
Prevention through control of antibiotics
All non-vital treatment with antibiotics or other drugs which could
cause diarrhoea are stopped to limit suppression of the normal flora
and to eliminate more possible causes of diarrhoea.
Limiting antibiotic use is also encouraged. Specifically the use of
clindamycin, 2nd and 3rd generation cephalosporins and
fluoroquinolones, carbapenems and aminopenicillins [11]. This is to
prevent selection of C. difficile which has gained resistance to these
drugs but also to prevent excessive disturbance of the gut flora which
may provide C. difficile a foothold to begin colonisation. The guidelines
from 1994 did suggest restrictions in the use of broad spectrum
antibiotics, especially cephalosporins. Again, the Healthcare
Commission survey in 2005 found that 38% of NHS trusts had placed
no such restrictions, despite 87% of trusts having written guidelines to
follow [11].
Prevention through Diagnosis
Diagnostic test guidelines for C. difficile currently state that an episode
of diarrhoea which is not attributable to any other cause and is
accompanied by a positive toxin assay is to be considered a CDI [13].
Toxin enzyme immunoassays (EIA) must be for both A and B as strains
exist which are not positive for toxin A. It has historically been thought
that toxin B was incapable of causing disease without the presence of
toxin A. However, as mentioned above, pathogenic samples have been
clinically isolated which do not produce A, thereby casting doubt on
this assertion. Indeed, studies have even found toxin B to be the more
effective cytotoxin [17] and a significant enterotoxin [18].

7. 7
Repeat tests are encouraged if the first is negative but there is still a
strong case to suspect CDI because the sensitivity and specificity of
these tests can be variable [8, 11, 19, 20].
Tissue culture and cytotoxic assay are considered the gold standard of
toxicity testing. The assay tests whether the cytopathic effects of C.
difficile toxins can be neutralised with a C. sordelli antitoxin [20].
Although the most reliable, this test is labour intensive and time
consuming, needing up to 48 hours in some cases to complete.
These methods have mostly replaced older methods of diagnosis such
as colonoscopy and sigmoidoscopy, which directly look for the
presence of pseudomembranes in the colon. These procedures can
often be time consuming and uncomfortable for the patient whereas
EIA can be performed quickly with an easily obtained stool sample.
Stool culture is performed alongside toxin detection in cases of
outbreak. It is highly sensitive but does take time for the organism to
grow; cultures are read after 48 hours [19] in normal diagnostic
situations. Where rapid identification is needed, this is unsuitable.
Culture is combined with PCR ribotyping to monitor epidemiology of
existing strains for future reference and identify any new strains which
appear in order to better combat rates of infection. PCR is also used as
a diagnostic method, though somewhat rarely. Although it is highly
sensitive and can easily identify the presence of C. difficile, it cannot
determine if the strain is infective [10] so must be combined with a
toxin assay for confirmation. This may change in the future with the
introduction of 2nd generation PCR which identifies all genomic data in
a sample and, combined with mass spectrometry, can provide a rapid
identification of all microbes present in a sample.
Treatment
Mild cases of CDI can be self-limiting, and as such no treatment may
be required [13]. However, in cases where it is, oral metronidazole is
prescribed. Although it is less effective than vancomycin, it is also less
expensive [8,10,11] and less toxic. The doses of vancomycin
prescribed orally for severe and life-threatening infections have been
shown to be nephrotoxic [21] so tight controls are necessary and
prescribed only when absolutely essential. Vancomycin may be
combined with IV metronidazole and oral rifampicin in severe cases
[11]. Oral fidaxomicin has also been approved as a treatment for CDI
as of 2012. It has been found to be better at preventing recurrence of
CDI than vancomycin but is unfortunately more expensive [13]

8. 8
Stool transplant are considered in very severe cases. This is an infusion
of intestinal bacterial flora from a healthy donor as an attempt to
restore balance of the patient’s natural flora [22]. Donor faeces is
administered via colonoscopy, enema, or nasogastric tube. These
measures have been found to be mostly successful with few long-
lasting side effects [13, 23]. The downsides of this treatment are
mainly aesthetic in nature but there is also some risk regarding the
transfer of infectious agents from donor to recipient. This could be
difficult to screen and prevent as identifying infectious agents in full
stool samples is often difficult due to the sheer number of microbes
present. There are studies underway determining the effects of a
synthetic mixture [24] which may seem more appealing than the use
of donor faecal matter and would be easier to keep free of infectious
contaminants.
The use of probiotics is also gaining favour as a method of prophylaxis
on the basis they would help to bolster the balance of a person’s gut
flora whilst they were undergoing antibiotic treatment. However, few
studies have been done that have stood up to peer review and Public
Health England does not currently recommend their use [13].
Infection rates
Since 2007 the UK has seen a dramatic decrease in the number of CDIs
reported on a yearly basis. In 2014/15 a total of 5,213 CDIs were
reported compared to 33,442 in 2007/2008 [25].
Figure 3. Trends in rates of C. difficile infection 2007/2008 to 2014/2015 [25]
A large decline was seen between 2007 and 2010. This continued to decrease year on year until 2014/2015
where a slight rise has now been seen in infection rates.

9. 9
As shown in Figure 3 an initially large decrease between 2007-2010
eventually began to level off. It is likely that this was due to a
combination of factors, mostly driven by the new guidelines and SIGHT
scheme. Between April 2014 and March 2015 the UK saw its first
increase in the reported number of CDIs in a year since 2007 [25].
Figure 4 shows that not only have infection rates drastically reduced
between 2007 and 2015, it has reduced proportionately in terms of
age groups and highlights that women have overtaken men in number
of infections.
0
200
400
600
800
1000
1200
1400
1600
02-14 15-44 45-64 65-74 75-84 85 +
Numberofdeathsattributedto
C.difficileinfection
AgeM F
0
200
400
600
800
1000
1200
1400
1600
02-14 15-44 45–64 65–74 75–84 85 +
Numberofdeathsattributedto
C.difficileinfection
AgeM F
Fig 4a 2007/2008 Fig 4b 2014/2015
Fig 4 Age and sex specific C. difficile infections rates per 100, 000 population [25]. Infection
rates have drastically fallen over all age groups between 2007 and 2015. In 2015, more women were infected
than men.
Fig 5a [26] Number of deaths attributed to C.
difficile infection 2007
Fig 5b [27] number of deaths attributed to C.
difficile infection 2014
Fig 5. Comparison of total deaths attributed to CDI on death certificates between 2007 (5a) and
2014 (5b)

10. 10
Figure 5 shows the drastic reduction in the number of deaths which
have been attributed to CDI between 2007 and 2014 from a total of
4056 to 522 respectively. The decrease is directly proportional to the
rate infection and the largest difference is seen in patients above 85
years of age.
Conclusion
The emergence of an epidemic strain and lack of adherence to
government guidelines in the 1990s and early 2000s were dually
responsible for the rapidly rising increase in CDI and CDI related
deaths. 2008 saw the government take action on information received
from a survey performed by the Healthcare Commission and publish a
new report building on the old guidelines originally issued in 1994
restating isolation, antibiotic control, and environmental cleansing
would be key to containing the epidemic. Strict supervision and the
introduction of sanctions helped ensure the guidelines would be
followed to their fullest extent. In the years that followed, CDI and CDI
related deaths rapidly declined and the problem currently seems to be
under control.
That being said, the UK has seen a slight increase in the number of CDIs
in the past year which may need to be investigated further in order to
prevent a recurrence in the lapse of practice and vigilance which was
partly responsible for the past outbreak. Antibiotic resistance is also
an ever-present factor which needs to be monitored closely due to the
few remaining antibiotic options left to us.
With new treatments, improved diagnostic methods, and a greater
understanding of the dangers of environmental transmission, it seems
hopeful that the decline in CDI will continue. Although due to the
ubiquity of the organism, it is unlikely that it will ever be fully
eradicated.
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Outstanding Questions
Will the recent increase in CDI
continue?
Should 2nd
generation PCR
become a more prevalent
diagnostic tool?
What treatments can we turn to
in the event C. difficile becomes
resistant to metronidazole and
vancomycin?
Are there even more efficient
ways of removing infective
spores from the environment?

11. 11
7. NHS. Complications of clostridium difficile
infection.
http://www.nhs.uk/Conditions/Clostridium-
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12. 12
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