Running Head: EFFECT OF PROPHYLACTIC PROBIOTICS ON CLOSTRIDIUM DIFFICILE

Kaitlyn Rutigliano
Effect of Prophylactic Probiotics on Clostridium Difficile in Hospitalized Patients
Nursing 612
University of New Hampshire
May 6, 2014













EFFECT OF PROPHYLACTIC PROBIOTICS ON CLOSTRIDIUM DIFFICILE 2


Abstract
Clostridium difficile (C-diff) infection in the hospitals is a problematic issue for patients on
antibiotic therapy and is rising exponentially. Probiotics may benefit patients in preventing or
decreasing the incidence of C-diff associated with antibiotic therapy through the restoration of
normal flora in the intestine. The focus of this review is to assess the effectiveness of probiotics
in the research literature. Four studies were critically reviewed to conclude whether probiotics in
addition to antibiotic therapy prevented or aided in the reduction of C-diff acquired in health care
facilities. Through extensive research these studies provide strong evidence to show that
probiotics can help prevent the incidence of C-diff in hospitalized patient taking antibiotics.














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Title
P: Hospitalized patients
I: Prophylactic probiotics in conjunction with antibiotics
C: Absence of probiotics
O: Reductions of Clostridium difficile incidences
Background
Clostridium difficile (C-diff) is an illness that is mainly caused by the use of antibiotics in the
clinical setting. According to the Centers of Disease Control and Prevention (CDC) 25 % of
hospitalized patients will develop C-diff while on antibiotics. Due to the increased rates of
antibiotic therapy in the United States, the statistics of C-diff within the clinical setting are rising
at alarming rates. In addition to the incidence of C-diff , mortality rates are steadily climbing due
to this detrimental intestinal manifestation. Studies have concluded that every patient who
develops C-diff as a result of antibiotic therapy in the hospital has an increase in length of stay
and a mean cost of $10,000 per patient stay (Pilli & Nelson, 2008). The average patient with C-
diff remains in the hospital 3.6 days longer than patients with similar diagnoses (Avadhani and
Miley, 2009). With more patients becoming infected with C-diff and hospital costs increasing,
additional therapies must be considered to treat this costly and deadly disease.
The main purpose of this PICO question is to determine whether probiotics are an effective
treatment option for antibiotic associated C-diff. While antibiotics treat harmful bacteria, they
also kill the normal bacteria or flora in the intestines. Once the normal bacteria are killed,
bacteria such as C-diff flourish inside the intestinal walls and symptoms of diarrhea and
abdominal discomfort develop. Other symptoms may include mucus, occult blood in the stool,
fever, cramping, and an increase in white blood cell count indicative of an infection. If not
treated, the C-diff pathogens can progress and lead to dehydration, severe electrolyte imbalance,
EFFECT OF PROPHYLACTIC PROBIOTICS ON CLOSTRIDIUM DIFFICILE 4

hypotension, hypoalbuminemia, toxic megacolon, bowel perforation, renal failure, sepsis, and
death (Cohen et al., 2010).
The diagnosis of C-diff infection is made based on testing diarrhea. A stool culture is the
most sensitive test for detecting C-diff, but the time needed to receive results may be lengthy.
Once a patient has a confirmed C-diff diagnosis, the patient must be placed on isolation
precautions in which gowns and gloves are required for patient contact. While the use of
antimicrobial agents is the primary cause of C-diff, the illness may also be transmitted to others
(Cohen et al., 2010).
The use of antimicrobial agents, even if used for a short period of time, increases the risk of
developing C-diff. Another risk factor is the use of chemotherapeutic agents. These agents kill
the normal flora and compromise the immune system. Gastrointestinal surgeries, GI tract
manipulation and even the use of tube feedings place patients at risk for developing C-diff.
Advancing age and duration of hospitalization are two other main risk factors that make patients
susceptible to contracting C-diff (Cohen et al., 2010).
Typical treatment for C-diff includes discontinuing current antimicrobial therapies and
addition of new antibiotics. Metronidazole is the preferred antimicrobial treatment for C-diff in
mild to moderate cases as well as Fidaxomicin. Oral Vancomycin is also a preferred treatment,
either with or without the use of intravenous Metronidazole (Cohen et al., 2010). Since the main
cause of C-diff is use of antimicrobials killing the normal flora in the intestines, an additional
therapy that may be considered is probiotics which can restore the normal flora. Probiotics are
seen to be beneficial due to their ability to suppress growth or invasion by pathogens, improve
intestinal barrier function and induce protective cytokines, and suppress intestinal inflammation
such as tumor necrosis factor thereby modulating the immune system (Avadhani & Miley, 2009).
EFFECT OF PROPHYLACTIC PROBIOTICS ON CLOSTRIDIUM DIFFICILE 5

Search Methods
The databases used to provide evidence-based research include CINAHL, PubMed and
Medline from years 2008-2014. Search engines also include UpToDate, Agency for Healthcare
Research and Quality and American Academy of Family Physicians. In order to obtain the most
specific research information for this PICO question, keywords such as c-diff, probiotics,
antiobiotics and effects were searched. Boolean terms such as and and or were also
implemented into these findings. The limitations of this research topic include English only, full-
text articles, and a six year time frame. These limitations allowed for a more up to date,
methodical and direct research process. Although there are multiple sources referenced in this
paper, four main citations were used to support the topic listed above. The student insisted on
keeping information the most relevant and as concise as possible. All material used is cited and
referenced in accordance to the 6
th
edition APA format.
Critical Appraisal of the Evidence
The first study reviewed was entitled Clostridium difficile and Probiotic. This study provided
a concise overview of the pathological components of how C-diff affects the internal organs and
how destructive antibiotics can be on the intestinal tract. In addition, the research provided an in
depth conclusion of how effective use of probiotics could aid in prevention and treatment of C-
diff. Probiotics work in four main mechanisms which include: alteration of intestinal flora,
antimicrobial activity, intestinal barrier protection and immunomodulation. The alteration of
intestinal flora correlates to the disruption of the healthful microorganisms within the
gastrointestinal tract. Antibiotics are a significant detriment to the intestinal flora and therefore
cause an imbalance in these organisms. When this occurs, pathogens of C-diff colonize and
diminish the good bacteria. In order to maintain homeostasis within the gut lining and reduce the
EFFECT OF PROPHYLACTIC PROBIOTICS ON CLOSTRIDIUM DIFFICILE 6

chances of C-diff growth, probiotics are implemented. Probiotics, such as lactobacilli and S.
boulardii, produce bacterial acids and peptides to help combat the harmful microbes contributed
by antibiotic exposure (Davidson, 2013). The use of probiotics lessens the likelihood of C-diff
presentation and promotes the restoration of intestinal flora.
The second study collected was entitled Probiotics in the prevention of antibiotic-associated
diarrhorea and Clostridium difficile. This study addressed the effectiveness of probiotics among
those who acquire C-diff secondary to antibiotic-associated diarrhea. Diarrhea is a known side
effect of antibiotics; however, when the intestinal flora is negatively altered, the result can lead
to C-diff. The study discussed the major risk factors of those who are affected with C-diff. These
include type and duration of antibiotic course, advanced age, illnesses severity, length of hospital
stay, presence of a nasogastric tube, and prescribed proton pump inhibitors. This population of
those at risk benefit from the use of probiotics to aid in the prevention and treatment of C-diff
and antibiotic-associated diarrhea. Research used in this study, showed that bacteria strains such
as S. Thermophilus, L. Bulgaricus, L. Acidophilus, Bifidus and L. Casei are the most common
and effective probiotics used to lessen the chances of developing C-diff (Hickson,2011). The
bacteria prefaced above are typically found in food items such as yogurt and fermented milk
(kefir). The active live cultures promote growth of healthy bacteria used to minimize poisonous
pathogens such as Clostridium difficile.
The third study reviewed was entitled Probiotics for the treatment of Clostridium difficile
associated disease. This study was similar to the second study above, however, this one
discussed both pharmacological and non-pharmological methods of treating C-diff. Although the
study mentioned pharmacological interventions such as fecal transplants, the study greatly
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supported more conservative measures: probiotic therapy. An in depth, pathological explanation
was given as to how c-diff inoculates the intestinal tract.
C. difficile associated toxins (particularly toxin A) result in the activation of three
transcription factors. Nuclear factor-kappa B (NF-B) is involved in chemokine production,
and also plays a role in colonocyte apoptosis Activator protein-1 (AP-1) also plays a role in
interleukin (IL)-8 production, in response to stimulation of colonocytes with toxin A. Cyclic-
AMP response binding protein (CREB) is critical for the production of Prostaglandin E
2
. This
prostaglandin plays an important role in the fluid secretion/diarrhea associated with CDAD.
There is also cross talk between the various pathways. For example, prostaglandin E
2
can
stimulate Fas ligand expression and apoptosis in colonic epithelial cell (Fitzpatrick, 2013).
From the explanation presented above, C-diff invades the intestinal flora and stimulates
prostaglandin production and festers with harmful bacteria. The bacteria form colonies and cause an
exacerbation of intestinal symptoms especially, diarrhea and abdominal cramping. With the help of
probiotics used alongside antibiotics, the possibility of developing C-diff drastically decreases.
The final study reviewed was entitled Probiotics for the prevention of Clostridium difficile. The
study addressed the benefits of supplementing with a probiotics agent in conjunction with antibiotic
therapy. Researchers discovered that the use of probiotics was more cost-effective for medical
facilities due to the decreased incidence of C-diff exposure. The probiotics aided in the maintenance
and restoration of healthy intestinal bacteria while also ensuring protection from the internal damage
of antibiotics. Although the study supported the use of probiotics, researchers found that probiotics
had little to no effect on elderly patients (Rainkie, 2013). The study was inconclusive as to why the
elderly population did not benefit from probiotics, however, did confirm that more investigative
research must be conducted. Overall, the study reported that probiotics therapy was a successful way
of preventing and treating C-diff associated with antibiotic use.

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Evidence Synthesis
The studies reviewed were both systematic reviews and meta-analysis. To ensure accuracy and
evidence-based research, it is crucial for the student to understand how to find the most supported
data. Reliable and factual sources are needed to ensure a high level of confidence. The studies used in
this paper were based off of the highest levels of research available which allows for an increased
reliability. With the support of evidence-based research, the student was able to formulate this paper
using the most up-to-date information on non-pharmological methods of preventing c-diff in
combination with antibiotic therapy.
Clinical and Research Recommendations
The evidence found in for this PICO paper supports the use of probiotics in conjunction with
antibiotic therapy. This prophylactic measure was heavily supported by research conducted within
the last six years. Although there are more invasive methods of preventing C-diff such as fecal
transplants, the research is showing that probiotics are proving to be the effective, non-
pharmacological method of preventing and treating c-diff associated with antibiotic use. With the
incidence of C-diff infections increasing in acute care facilities, additional interventions are
necessary. Although more studies are needed, eventually the use of probiotics in addition to
antibiotic therapy could become a policy used in hospitals. Patients who have had C-diff
understand the unfortunate experience of this illness; therefore, future treatment with probiotics
do decrease recurrence would be something most patients would be inclined to try. In addition,
the student hopes that more in depth reasoning can be gathered as to why elderly do not receive
the major benefits of probiotics therapy and what are the best methods to ensure appropriate
intestinal maintenance when prescribed these potent antibiotics. Health care facilities should
require the use of probiotics is any patient is taking antibiotics. The incidence of C-diff could
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significantly decline if preventative measures were implemented in the healthcare setting. The
research and knowledge is current and greatly supported; now it must be applied. As the student
advances on in the nursing field, there is a strong hope for prophylactic probiotic therapy to be
put into action by all medical institutions.













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References
Avadhani, A., Miley, H. (2009). Probiotics for prevention of antibiotic associated diarrhea and
clostridium difficile associated disease in hospitalized adults- a meta-analysis. Journal of
the American Academy of Nurse Practitioners, 23 (2011), 269-274.
Cohen, S., Gerding, D., Johnson, S., Kelly, C., Vivian, L., McDonald, C., Pepin, J., & Wilcox,
M. (2010). Clinical practice guidelines for clostridium difficile infection in adults: 2010
update by the society for healthcare epidemiology of America (SHEA) and the infectious
diseases society of America (IDSA). Infection Control and Hospital Epidemiology, 31
(5).
Davidson, L. E., & Hibberd, P. L. (2013, August 19). Clostridium difficile and
probiotics.Clostridium difficile and probiotics. Retrieved May 4, 2014, from
http://www.uptodate.com/contents/clostridium-difficile-and-probiotics
Fitzpatrick, L. R. (2013, August 15). Probiotics for the treatment of Clostridium difficile
associated disease. . Retrieved May 4, 2014, from
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740259/
Hickson, M. (2011, May 1). Probiotics in the prevention of antibiotic-associated diarrhoea and
Clostridium difficile infection. National Center for Biotechnology Information. Retrieved
May 4, 2014, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105609/
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Klarin, B., Wullt, M., Palmquist, I., Molin, G., Larsson, A., & Jeppsson, B. (2008). Lactobacillus
plantarum 299v reduces colonisation of clostridium difficile in critically ill patients
treated with antibiotics. The Acta Anaesthesiologica Scand, 52: 10961102. doi:
10.1111/j.1399-6576.2008.01748.
Pillai, A., & Nelson, R. (2008) Probiotics for treatment of Clostridium difficile-associated colitis
in adults. The Cochrane Collaboration, 3. Retrieved from Cochrane Library database.
Rainkie, D. (2013, September 1). Probiotics for the prevention of Clostridium difficile.Probiotics
for the prevention of Clostridium difficile. Retrieved May 4, 2014, from
http://www.cfp.ca/content/59/9/957.full.pdf+html