Review of Clostridium Difficile

Running Head: REVIEW OF CLOSTRIDIUM DIFFICILE

Review of Clostridium Difficile

Maria Kometer

2 December 2014

Liberty University

REVIEW OF CLOSTRIDIUM DIFFICILE 2

As the healthcare system develops, the science of cures continues to impress and astound

humans. Things that used to mean death can now be cured with a few simple steps done by an

incredibly well-educated physician. As the years go on, doctors are required to spend more and

more time in school, training to become a part of a system that every human in the United States

is affected by. Everyone has spent at least a small amount of time in a hospital, and everyone

knows someone whose life was dramatically helped or saved by the treatment they received.

However, the hospitals and healthcare system come with their own problems. With so much

sickness in one place, invisible agents of disease can cultivate and infect those who are most

susceptible—and who is more susceptible than a sick and recovering patient? These agents of

disease are microorganisms that are accidentally spread from patient to patient, whether as a

result of carelessness in cleanliness, or as a result of factors outside of the hospitals control.

Some of the microorganisms may not be life-threatening, but often these new infections can

cause a bigger problem than the original problem that put the patient in the hospital. Many kinds

of these agents exist, but one of the most prevalent and most common bacteria to pervade a

hospital is clostridium difficile.

Clostridium difficile or C. Diff is recognized as one of the most common bacterial

infection-causing agents in healthcare facilities in the United States, with a ten percent infection

rate with symptoms (1). The bacteria is incredibly potent, and can be fatal if the infection is

allowed to persist. C. diff is a gram-positive bacillus shaped bacteria that was very difficult to

initially colonize—hence its name, “difficult clostridia” (1). The infection and bacteria were first

identified and characterized by Hall and O’Toole in 1935 as found in new born infants bacterial

flora. While fatal to animals into which it was injected, C. diff was believed to be harmless to

humans because of its occurrence in the flora of babies. However, it was only in the 1970s that


this same bacteria was found in patients suffering from colitis associated with antibiotics. C. diff

is now identified as a major nosocomial bacterial infection, claiming much of hospital patient’s

recovery strength and even lives. (1)

Perhaps the most obvious reason that this pathogen is able to permeate such a large

quantity of hospital rooms is the simple fact that it is largely associated with antibiotics. Most

patients that are admitted to the hospital are put on some form of antibiotics, and because of the

association, a little carelessness in the sterile environment opens wide the door for C. diff to

enter. When a patient is taking antibiotics, the normal bacterial flora of the patients intestines is

being disturbed, simply by the nature of an antibiotic. (2) An antibiotics main role is to target

and kill bacteria. However, human’s bodies, especially the gastrointestinal tract, are filled with

normal bacteria—constituting the normal flora. Therefore, antibiotics can greatly disturb the

normal order of the flora, weakening the barrier effect that would usually protect the microbiome

from infection.(2) Recent studies show, also, that not only do drugs like ampicillin and

clindamycin disturb the microbiota of the intestinal tract, but they also enhance the environment

for colonization through triggering the release of certain colonization factors necessary for the

infection of C. diff. (2) In a certain study performed Gabriel Birgand, PharmD and associates,

hospitals in France that were affected by a certain potent strand of C. diff used significantly more

beta-lactams in the treatment of the patients than the hospitals that remained unaffected by the

infection. (3) From this information alone, it is clear that antibiotics remain very responsible for

most of the outbreaks of this nosocomial pathogen.

The pathology of this bacteria is particularly interesting. As mentioned earlier, the first

step in the process is the disturbance of the flora in the colon or large intestines. The antibiotics

first break down the barrier effect formed by the normal flora, opening the door for C. diff to


begin colonization. Researchers speculate that because this infection does not easily occur in

patients that have not had their intestinal microbiome disturbed, there is a good chance that

certain natural bacteria that are attacked by the antibiotics are actually responsible for preventing

the disease. Castagliuolo and LaMont speculate that Bacteroides, which make up about ninety

percent of the flora found in feces, may be responsible for the prevention of the infection, as they

are no longer present in patients suffering from a C. diff infection. (1)

The bacteria first adheres to the epithelial cells of the intestines, allowing it to invade the

microbiome of the colon. From here, the bacteria releases two toxins: toxin A and toxin B. It is

the detection of these two toxins in the fecal specimens of patients that allows the physician to

make a diagnosis of C. diff. (4) Both toxins seem to play a role in inflammation, and they set off

a cascade of events that is not fully understood. Recent studies show that these two toxins

trigger certain gene translation that proves harmful to the human colon, while the toxins also

trigger other necessary factors in regards to the inflammatory process. (5) An interaction is also

seen between the lamina propria neural cells and the epithelial cells of the intestines, causing the

inflammation known as colitis. (6) This colitis is not simply inflammation, however, and toxin A

seems to be primarily responsible for the diarrhea and the defining physical characteristic of C.

diff—the pseudomembrane. (1)

The pseudomembrane can be identified in the lumen of the intestines as a discolored

over-lying layer of infection. The infection is diverse in regard to severity, and the

pseudomembrane can be very “patchy”, varying throughout the lumen. (1) This is one of the

causes of diarrhea—one of the main functions of the colon is to absorb water. If the

pseudomembrance is covering the membrane of the lumen, the lumen is no longer able to absorb

water necessary to supply the body. Water is therefore released with the waster, causing the


stool to become watery. This is the reason that most of those infected suffer from diarrhea, and

the reason that this infection can become lethal through dehydration. (1)

A second characteristic of the disease is discoloration and compromise of the mucosa of

the colon. Studies have shown that when toxin A affects the epithelial layer of the intestines, the

mucosa is changed and increased in permeability. Interestingly enough, this was noticed in the

mucosa of the ileum—a segment of the small intestines that leads into the colon or large

intestines, giving rise to the speculation that the enterotoxin A may affect more than simply the

colon. (7) It is this mucosa that protects the lamina propria (neural immune cells) underneath,

and when the toxin is able to permeate the mucosa it can reach the neural immune cells and

trigger the inflammatory process. The compromise of the mucosa physically shows itself as

discoloration, and this increase in permeability shows yet again the strength of the toxins

produced by C. diff.

While both the pseudomembrance and the mucosa provide internal signs of the infection,

there are many other symptoms associated with C. diff that are important to pay close attention

to. These include symptoms such as fever, decline in appetite, nausea, and pain in the lower

abdomen. It is important to monitor these symptoms, especially if the patient is aware of having

been on antibiotics recently. If the infections is not caught and treated, it can lead to much more

severe complications than the characteristic diarrhea such as perforations in the colon, kidney

failure, low blood pressure, and occasionally can prove to be lethal. (8)

As mentioned before, while the defining sign of a C. diff infection is the

pseudomembrane, the defining symptom of the infection is diarrhea. Diarrhea that is present

without the formation of a pseudomembrane—C. diff in the early stages—is often easily treated

by simply stopping the initial antibiotic that began the problem. The infection is less systemic


and is confined to the lower part of the abdomen (near the sigmoid colon). (1) However,

diarrhea that is present in the full onset of C. diff—including the pseudomembranous colitis—is

much more severe. Here, not only does diarrhea occur, but the colon can also dilate. While

procedures such as a sigmoidoscopy are helpful after this diarrhea has begun in order to

determine the actual damage of the C. diff, puncturing the colon at this point could be dangerous

to the body, and is not recommended. (1)

In understanding diseases, not only must the path of the bacteria be understood,

but also the most frequently targeted victims. Often, it is simple ignorance on certain matters

that causes something that could have otherwise have been avoided to become not only

detrimental, but even lethal. Understanding not only what, but also who, enables health care

workers to better guard against these invisible agents that can seem like unstoppable forces

otherwise. Many studies have been done in an attempt to better understand the path of C. diff.

However, simply from looking at the information available it is easy to see which people may be

affected by the disease.

The most commonly targeted people groups range significantly in age and situation. The

first and most unusual people group to be affected was a completely asymptomatic group—

newborns. As mentioned earlier, the bacteria were already a natural part of their normal flora,

and therefore this group cannot really be considered a target for the disease. However, the fact

that bacteria was present and not harmful in newborns does raise room for speculation: is C. diff

actually a beneficial bacteria when part of its original host? While it seems that this must be the

answer, it does not necessarily makes sense in regards to the incredibly harmful information that

has been researched in regards to the potency and severity of the bacteria.


Another and already mentioned people group are hospitalized patients—and this group is

most certainly a targeted victim. Because these individuals are exposed to antibiotics, their

normal microbiome has been disrupted and they become the perfect environment for the

infection to set in. These patients receive the infection through a variety of different ways: an

unsterile environment, exposure to a patient who has the infection, and many other routes.

Studies have been implemented in order to determine which group of hospitalized patients have

the largest risk of catching the infection, and those hospitalized patients older than eighty years

old had the highest odds ratio for the infections. (9) An important statistic for surgical teams to

take into account, however, is that patients who undergo an abdominal surgery have an increased

risk of infection by six to nine times—and incredibly high increase of risk.(10)

A third and not already mentioned people group that is very likely to be affected by this

bacteria are the elderly. Whether these victims are hospitalized or in the care of a nursing home,

they are incredibly susceptible to infection by C. diff. Many obvious reasons for this exist, such

as a weaker immune system, less efficiently functioning digestive system, and just weaker body

in general. Care-takers and nurses working in these assisted living or nursing homes must take

extra precautions in order to ensure that a sterile environment is maintained where necessary and

to prevent an epidemic of C. diff from taking over their facility.

Finally, a large percentage of affected victims of C. diff are children from one to four

years old. Also very susceptible to infections of many kinds, children often pick up the disease

after being exposed to certain antibiotics or having been on chemotherapy. (8) Because children,

especially young children in the age group already specified, are constantly touching and putting

objects in their mouth, they are much more likely to pick up this disease if their hospital

environment has not already been sterilized. Once again, this is simply another warning to those


responsible for providing a sterile environment—dehydration and diarrhea can be truly lethal in a

child whose body is already less weak and in need of serious nurturing.

The epidemiology of C. diff across the world can be difficult to assess. In certain areas of

the world, not only can every incidence of the infection be recorded, but also the specific strain

number, duration, severity, and infection path. In other areas of the world, however, it is

incredibly difficult to receive any information regarding occurrences whatsoever. First, because

C. diff is primarily a nosocomial disease to begin with, it will naturally be less common in areas

with no healthcare facilities. While in certain places in in the world it is not uncommon for

every city to have multiple places where an abdominal surgery could be being performed, there

are places in the world without any surgical facilities within incredibly large distances. Naturally,

epidemics are less likely to begin. However, even if an epidemic of C. diff were to break out in

one of these places, most would have no way to record the outbreak, much less the specific strain

infecting the patients. The health care systems of these more primitive and underdeveloped

countries or continents are also not nearly organized or communicative enough to hold records

and conduct research on every individual outbreak of occurrence of the infection, causing yet

another obstacle in receiving information from these countries regarding incidences of C. diff.

Finally, there is a chance that the people who would experience an outbreak may not even know

what they were dealing with. There still exist very remote places in the world that are mostly

unreached by trained healthcare professionals, and if, somehow, an outbreak were to occur in

one of these areas, it may not even be identified. Therefore, it is difficult to receive very

conclusive epidemiological data concerning the occurrence and location of C. diff, and the

information that is found makes it seem as if North American and Europe are the only continents


that ever are infected by C. diff. While this may in actuality be the case, it is important to

understand the preceding rationale as to why the results may appear as they do.

In the United States, the increase rate from the years 2000 to 2005 was around as high as

23%. (11) This is an incredibly high increase rate; however, it seems that the years following

immediately after this time period were significantly smaller increase rates, showing that while

the incidence were still increasing, the actually rate of increase was beginning to decline. For a

while, it was difficult to form any conclusive correlations between data because of the different

forms of recording used nationally; however, over time this has improved. Studies from about

four years ago seem to say that the previously understood epidemiology as far as the not at risk

was changing. People previously deemed not at risk prior to these studies began to be recorded

as infected. Infants and very young children had been thought to be totally asymptomatic until

this point, and a shift took place that made them actually become largely at risk for the infection.

(11)

In Europe in the early 2000’s C. diff infections were slowly on the rise until Europe

began to implement ribotyping: a way that hospitals could immediately detect the strain of the

disease that had been discovered and contain it. This had an excellent effect, and began to

decrease the incidence rate across Europe. The decrease was very small and slow, however, and

when a new study was taken a few years later it showed that the incidences had made a turn in

the other direction and were beginning to increase once again. Countries such as Finland at first

seemed to never experience outbreaks of C. diff, but soon outbreaks were reported in these

countries as well. (11)

In Australia, Japan, South Korea, and China, few reports have been made of the

occurrence of C. diff. In Australia and Japan quite a few cases of C. diff have appeared,


however, exact information regarding the amount of cases is difficult to find until a very specific

strain of C. diff was identified in the past ten years. In South Korea and China very few cases of

C. diff have been reported whatsoever, and while studies have been done on the few cases that

have shown up, it does not seem to be a major concern. (11)

In Latin America and parts of the Middle East almost no reports have been received, and

in Africa no reports whatsoever have surfaced. It is for these places that the rationale mentioned

earlier must be implemented. These continents simply may not have the ability to identify this

infection when it appears, or they simply do not have a problem with it because of a general lack

of hospital facilities in certain areas. It is uncertain as to why exactly no incidences have been

reported, however, and could be further researched. (11)

The last and perhaps most perplexing problem when discussing C. diff are the methods

used in treatment of the disease. Because the disease is in most cases initiated by the very drugs

that would be used to treat most infections, the normal line of treatment cannot be applied. This

has resulted in some very interesting research that has revealed the usefulness of certain

techniques and treatments that are often looked at as being less effective. These treatments take

a more natural turn, and deal with restoring the normal flora to its original state. While most

treatment deals with attacking the infectious agent, C. diff treatments tend to rebuild the body’s

homeostasis so that the infection no longer is effective. In this case, that involves restoring the

helpful bacteria that is necessary in the colon in order for it to not only function properly, but

also to replenish what the original antibiotics took away. (12)

The first and more commonly known treatment is the use of probiotics. As opposed to

antibiotics, which are aimed toward killing bacteria, probiotics are filled with useful bacteria that

they body needs, and have been shown useful in restoring the microbiome of C. diff patients to


its functional state. Many people dispute the theory of probiotics and debate that results are

inconclusive, however multiple studies have proved just the opposite. In one study, the specific

probiotic S. boulardii showed significant reductions in patients with C. diff induced diarrhea.

(13) Certain studies have even tested and created special drinks that match directly to the patients

specific probiotic needs. (14) The usefulness of the correct strain of probiotics have made them

an acceptable and effective way to restore the body to its healthy state. (15)

Last and most interestingly of all is the untraditional use of the fecal transplant. While

cases do exist where the fecal transplant may be taken as a pill, the more common procedure is to

insert the healthy feces of a near relative into the colon by way of a colonoscopy or nasogastric

tube. The feces is then passed through the colon of the infected individual, and the healthy and

helpful bacteria from the healthy stool restores the normal flora of the infected colon to its

original and functional state. This procedure actually has an incredibly high success rate of 90%

according to the Mayo clinic, and is natural and cost effective. (16) Another study reported in

2012, however, used the same two fecal donors for all of their patients, as opposed to specific

relatives of the patients, and performed their procedures with edemas with a success rate of over

90%. (17) While this procedure may seem strange and primitive to many people, it is incredible

successful—and a strange infection sometimes requires a creative cure.


Works Cited

1. I. Castagliuolo, J. T. LaMont, Pathophysiology, diagnosis and treatment of Clostridium

difficile infection. The Keio journal of medicine 48, 169 (Dec, 1999).

2. C. Deneve, C. Delomenie, M. C. Barc, A. Collignon, C. Janoir, Antibiotics involved in

Clostridium difficile-associated disease increase colonization factor gene expression.

Journal of medical microbiology 57, 732 (Jun, 2008).

3. G. Birgand, K. Miliani, A. Carbonne, P. Astagneau, Is high consumption of antibiotics

associated with Clostridium difficile polymerase chain reaction-ribotype 027 infections in

France? Infection control and hospital epidemiology : the official journal of the Society of

Hospital Epidemiologists of America 31, 302 (Mar, 2010).

4. C. M. Surawicz, Antibiotics and Clostridium difficile: cause and cure. Journal of clinical

gastroenterology 41, 1 (Jan, 2007).

5. D. Q. S. Hon Wai Koon, Tressia C. Hing, Jun Hwan Yoo, Samantha Ho, Xinhua Chen,

Ciarán P. Kelly, Stephan R. Targan, and Charalabos Pothoulakis, Human Monoclonal

Antibodies against Clostridium difficile Toxins A and B Inhibit Inflammatory and

Histologic Responses to the Toxins in Human Colon and Peripheral Blood Monocytes.

Antimicrobial agents and chemotherapy 57, 3214 (Jul 2103, 2013).

6. C. Pothoulakis, Pathogenesis of Clostridium difficile-associated diarrhoea. European

journal of gastroenterology & hepatology 8, 1041 (Nov, 1996).

7. I. C. Andrew C. Keates , Bosheng Qiu , Sigfus Nikulasson , Ashok Sengupta , Charalabos

Pothoulakis, CGRP upregulation in dorsal root ganglia and ileal mucosa during

Clostridium difficile toxin A-induced enteritis. American journal of physiology.

Gastrointestinal and liver physiology 274, G196 (1 January 1998, 1998).


8. M. Megan A. Moreno, MSEd, MPH; Fred Furtner; Frederick P. Rivara, MD, MPH,

Clostridium difficile: A Cause of Diarrhea in Children. JAMA pediatrics 167, 592 (June

2013, 2013).

9. K. W. Garey et al., A clinical risk index for Clostridium difficile infection in hospitalised

patients receiving broad-spectrum antibiotics. The Journal of hospital infection 70, 142

(Oct, 2008).

10. A. Keshava, M. H. Collie, D. N. Anderson, Nosocomial Clostridium difficile infection:

possible cause of anastomotic leakage after anterior resection of the rectum. Journal of

gastroenterology and hepatology 22, 764 (May, 2007).

11. J. Freeman et al., The changing epidemiology of Clostridium difficile infections. Clinical

microbiology reviews 23, 529 (Jul, 2010).

12. S. M. Vindigni, E. K. Broussard, C. M. Surawicz, Alteration of the intestinal

microbiome: fecal microbiota transplant and probiotics for Clostridium difficile and

beyond. Expert review of gastroenterology & hepatology 7, 615 (Sep, 2013).

13. M. Guslandi, Are probiotics effective for treating Clostridium difficile disease and

antibiotic-associated diarrhea? Nature clinical practice. Gastroenterology & hepatology

3, 606 (Nov, 2006).

14. M. Miller, A probiotic drink prevented diarrhoea and Clostridium difficile infection in

older patients taking antibiotics. Evidence-based medicine 13, 46 (Apr, 2008).

15. L. V. McFarland, Deciphering meta-analytic results: a mini-review of probiotics for the

prevention of paediatric antibiotic-associated diarrhoea and Clostridium difficile

infections. Beneficial microbes, 1 (Jun 2, 2014).


16. M. Clinic, Quick, inexpensive and a 90 percent cure rate. Mayo Clinic proceedings,

(2014).

17. N. Stollman, C. Surawicz, Fecal transplant for Clostridium difficile. Archives of internal

medicine 172, 825; author reply 825 (May 28, 2012).

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Review of Clostridium Difficile