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Running head: PROBIOTIC THERAPY TO PREVENT C.

DIFF
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Probiotic Therapy to Reduce the Occurrence of C. diff Associated Diarrhea


PICO Paper Assignment
Shannon M. Murphy
NURS 612 Medical Surgical Nursing
University of New Hampshire

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Abstract
Clostridium difficile associated diarrhea is an all too common complication of antibiotic
therapy that can cause prolonged hospitalization, life-threatening symptoms, and if
untreated or serious enough it can lead to death. It is thought that if patients who are
receiving antibiotics prophylactically use probiotics such as Lactobacillus will be at a
decreased risk of developing a C. difficile infection. In this paper I will explore three
studies that examine the use of prophylactic Lactobacillus probiotic therapy with adults
patients receiving antibiotics.
Keywords: Clostridium difficile, C. diff, probiotic, Lactobacillus, antibiotic

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In adult patients being treated with antibiotics, how does the prophylactic use of
Lactobacillus probiotic therapy compare to the lack of probiotic therapy in preventing the
development of Clostridium difficile associated diarrhea.

Every day patients are prescribed antibiotics to treat various infections and
unfortunately diarrhea is a common side effect of the treatment. In most cases, the
diarrhea is self-limiting but in others a more serious infection might be to blame. When a
patient receives an antibiotic the goal is to kill a certain bacteria that is present in the
body, however occasionally the antibiotic can eradicate more than the culprit bacteria that
it was intended for such as those in the human intestines. When the normal and healthy
bacteria in the intestines are killed, more room is made for dangerous bacteria to multiply.
Naturally found in soil, Clostridium difficile is a spore forming bacteria that is
sometimes found in the intestines of a healthy person who has come into contact with it.
The bacteria commonly referred to as C. diff is generally transmitted through a fecal oral
route, however because it is spore forming the bacteria can live on objects for months and
it can lay dormant in the intestines of a person for a lifetime. In instances where a patient
takes an antibiotic that wipes out all the healthy bacteria, or normal flora, then the C. diff
will begin to multiply and take over the intestine. As it begins to take over, the bacteria
release toxins that cause irritation to the intestines that can cause diarrhea and in extreme
cases, a perforated bowel (Walters & Zuckerbraun, 2014).
In a recent study, Walters and Zuckerbraun (2014) estimate that C. diff infections
occur in 500,000 patients treated with antibiotics annually with a 9% mortality rate
among the cases. At this point in time, the patients are treated with a new antibiotic,

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generally Flagyl or Vancomycin and although the efforts are usually successful, C. diff
infections are notoriously resistant and often require long hospital stays and costly
interventions.
In an effort to prevent the development of a C. diff infection from taking place,
prophylaxis probiotic therapy has been incorporated into to treatment for many patients
who are set to begin treatment with antibiotics. Probiotics are living microscopic
organisms such as bacteria and yeast that are either the same as or very similar to the
normal flora found in the intestines. Probiotic treatment can be administered in the form
of pills or a drink and generally contains actual or replicated Lactobacillus, a bacteria that
is populated in the human intestine through the breakdown of dairy products. Although
its actually benefits on the digestive system are not known, it is thought to aid in food
digestion and prevent other bacteria such as C. diff from becoming over populated.
Probiotic therapy is generally started when the patient begins antibiotic therapy and is
continued past the stop date of the antibiotic regime in an effort to replace any of the
normal flora that the antibiotics might inadvertently kill through the treatment thus
preventing space for C. diff to take over (Probiotics, 2008). With this new prophylactic
intervention being used, one must then question its effectiveness. Through a review of
the literature published I will evaluate whether or not the use of prophylactic lactobacillus
based probiotics lessen the occurrence of Clostridium difficile associated diarrhea in adult
patients being treated with antibiotics compared to those who are not receiving
probiotics.
In order to obtain the articles that I referenced in this paper, I utilized
EBSCOhosts advanced search feature. This tool allowed me to search through many

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databases provided by the library at the University of New Hampshire including
CINHAL, MEDLINE, PubMed, and the Cochrane Database of Systematic Reviews. In
order to generate my search I used keywords Clostridium difficile, C. diff, C. difficile,
probiotics, Lactobacillus, and treatment. Originally my search yielded 182 articles so in
an effort to find more specific sources I limited my search to only include articles
published between 2005 and 2015, those that were written in English, as well as only
ones that included a full text or included a link to one. With the new limitations set only
37 articles remained. At this point I further limited the sources by excluding those that
concentrated on pediatric patients, cancer patients or neonates and those that studied
probiotics that did not contain Lactobacillus. At the end of my search I was left with three
articles that met the qualifications for inclusion.
In the first article, researchers Ziakas and Mylonaks (2014) performed a
randomized, double blind, placebo controlled trial study using 2,981 patients in five
different UK hospitals. Their study included only patients who were over 65 and received
antibiotics in the last 7 days or were about to start treatment. Patients who had
experienced diarrhea in the past 24 hours, had been treated for a C. diff infection in the
past 3 months, were immunocompromised, or had previous adverse reactions to
probiotics were excluded from the study.
Participating patients were randomly divided into two groups and given either one
probiotic capsule containing Lactobacilus acidophilus or a placebo pill once a day for 21
days. The patients were all followed for 12 weeks after their completion of the probiotic
therapy. At the conclusion of the study the results stated that the in the group receiving
the probiotic 0.8% of the patients developed a C. diff infection compared to 1.2% of the

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patients in the placebo group. The results conclude that the probiotics did not produce a
significant decrease in the occurrence of C. difficile associated diarrhea.
Although this study did contain a relatively large sample size, there are many
issues to consider when evaluating its execution. Because this study includes patients
who have started antibiotic therapy within the past seven days, there is the possibility for
a large gap between the start of antibiotic therapy and the probiotic therapy. It could be
argued that the development of C. diff in the patients receiving the probiotics could be a
result of therapy being initiated too late. Another consideration is the fact that the study
took place in five different hospitals. This could potentially lead to discrepancies in the
way that the administration of the probiotic is carried out and the risks that the patients
may have been at. It is hard to say whether or not one hospital had more exposure to the
C. difficile bacteria and a difference in exposure between hospitals could alter the results.
Another factor to consider with this study is the rigid length of time that the probiotic is
given for. All the patients receive the probiotic for 21 days regardless of how long they
are on antibiotic therapy. This can present as both good and bad. In some ways, the
regimented time frame allows for a greater sense of unison between the patient
treatments. On the other hand, it can also present as a problem because if a patient
receives antibiotics for a longer period of time such as 14 days, they will receive less
probiotic treatment after the antibiotic therapy is over than the patient who only receives
seven days of antibiotics.
In a second study performed by Gao, Mubasher, Fang, Reifer, and Miller (2010)
the effects of a Lactobacillus probiotic is again examined with respect to the development
of a C. diff infection. A randomized double blind placebo controlled trial was used and

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255 patients in one hospital were involved. In order to be included in the study the
patients must have started antibiotic therapy within the last 36 hours and had to have been
free of diarrhea for the past 48 hours. Patients with a history of a C. diff infection were
excluded as well as those who were immunocompromised, had a disease that affected the
bowel, or those who were NPO. This study also compared the doses of probiotics so
therefore the participants were broken up into three groups. The first group received two
probiotic pills, the second received one probiotic pill and one placebo pill, and the third
received two placebo pills. The pills were continued 5 days after therapy ended and the
patients were followed for 21 days after completion. The results of the study reported that
the patients who received two probiotic pills had a 1.2% occurrence of C. diff associated
diarrhea, the group that received one pill had a 9.4% occurrence, and the group that
received two placebo pills had a 23.8% occurrence. As a result, the study supports that
the probiotic pills, regardless of the dosing, did cause a decreased incidence of C. diff
associated diarrhea.
In this particular study, the experiment was performed all within one hospital.
This allowed for a more controlled environment of all the participants because they were
all exposed to the same factors in the same facility. In contrast to the previous study, the
probiotic treatment was initiated within 36 hours of the antibiotic treatment thus
narrowing the gap between the two and lessening the risk of developing the infection
before the probiotic therapy is initiated. The placebo pills were also continued for five
days after the end of the antibiotic therapy regardless of the length of time that the
antibiotics were administered for unlike the Ziakas and Mylonaks (2014) study. Again,
this can present itself as a good or a bad aspect. Positively, all the patients receive the

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same amount of probiotic therapy after the conclusion of their antibiotic therapy, however
if one patient receives 14 days of antibiotics he or she will receive more probiotic therapy
overall than a patient that receives seven days of antibiotics.
In a final study performed by Hickson et al. (2007) a randomized, double blind,
placebo controlled trial was carried out. The study involved 135 patients in three London
hospitals who were all over the age of 50 and started receiving antibiotics within the past
48 hours. Patients who were immunocompromised, had recently undergone bowel
surgery, had artificial heart valves, had a history of rheumatic heart disease or infective
endocarditis, had used probiotics prior to admission, had received two or more antibiotics
in the past four weeks, were NPO, had any sign of diarrhea on admission, had a history of
of reoccurring diarrhea, had a bowel pathology, or were sensitive to lactose or dairy were
excluded from the study.
The participating patients were randomly divided into two groups and given either
100g of a Lactobacillus probiotic drink or a sterile milkshake containing no probiotics
twice a day 30 minutes before meals or 1-2 hours after meals. The drinks were all
discontinued one week after completion. At the end of the study the results reported that
0% of the patients who received the probiotic drink developed C. diff associated diarrhea
compared to 12% of those who received the placebo sterile milkshake thus producing
significant results.
In this study, the sample size was slightly smaller than the others, however it the
exclusion factors included were very thorough and eliminated any patients that could
have presented with outlying results. Similar to the Ziakas and Mylonaks (2014) study,
the trials performed by Hickson et al. (2007) also took place in three different hospitals,

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which could cause discrepancies in the delivery of the drinks as well as presented the
participants with different environmental risks. This study also continued the probiotic a
set number of days after completion of the antibiotic therapy as opposed to a set number
of days overall which might have created varying treatment times but it also allowed for a
consistent treatment time after discontinuation of antibiotics between patients. A window
of 48 hours after antibiotic therapy initiation for the start of the probiotics reduces the
chance of development of a C. diff infection before the probiotics have been started just
like in the Gao, Mubasher, Fang, Reifer, and Miller (2010) study, which reflects
positively on the results, presented.
After evaluating the three studies presented in this paper, I can conclude that
probiotics do seem to be linked to a decreased occurrence of C. difficile associated
diarrhea in adult patients being treated with antibiotics. Although the Ziakas and
Mylonaks (2014) states that their results showed insignificant results, I would argue that
this study is somewhat questionable because of the large window of time they allowed to
occur between the start of the antibiotic therapy and the probiotic therapy. Walters and
Zuckerbraun (2014) declare that the majority of C. difficile infections occur within the
first week of antibiotic treatment, and therefore starting prophylactic treatment up to
seven days after the antibiotics are started puts the patient at risk for developing the
infection before the probiotics can be started. I feel that the statistically significant results
obtained from the Hickson et al. (2007) and the Gao, Mubasher, Fang, Reifer, and Miller
(2010) studies are more relevant because the start of probiotic therapy was more
consistent and within a closer proximity to the start of antibiotic therapy thus creating
more reliable results.

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With the results of the two more reliable study supporting the use of Lactobacillus
probiotic therapy to decrease the occurrence of C. difficile associated diarrhea in adults
receiving antibiotic therapy I would suggest that probiotics be initiated into the care plan
of all patients receiving antibiotic therapy. McGlone et al. (2014) estimate that treating
one patient with C. diff associated diarrhea costs the hospital around $9,179-$11,456
adding up to an annual cost of over $496 million. This cost is monumental and when
compared to the cost of treating patients prophylactically with Lactobacillus antibiotics is
obscene. Hickson et al. (2007) claim that prophylactic treatment with a probiotic drink
costs about $120. The comparison between $120 and $11,456 creates an obvious need for
change and a movement towards proactive treatment strategies. That being said, with
Walters and Zuckerbraun (2014) claiming that on average C. diff causes 45,000 deaths a
year it is obvious that changes need to be made in order to battle this notoriously difficult
bacteria.
Moving forward, I feel that there is a need for more studies that examine possible
negative effects of probiotic therapy in patients receiving antibiotics. I feel that if
negative effects can be ruled out, probiotic therapy should be seriously considered for
high-risk patients regardless of whether or not all studies display significant results
supporting the use. I also think that more studies that examine the doses and therapeutic
range of probiotics as well as the best probiotics to use would be beneficial.
References Cited
Gao, X. W., Mubasher, M., Fang, C. Y., Reifer, C., & Miller, L. E. (2010). Dose response
efficacy of a proprietary probiotic Lactobacillus acidophilus CL1285 and
Lactobacillus casei LBC80R for antibiotic associated diarrhea and clostridium

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difficile-associated diarrhea prophylaxis in adult patients. American Journal of
Gastroenterology, 105(7). doi:10.1038/adg.2010.11
Hickson, M., DSouza, A. L., Muthu, N., Rogers, T. R., Want, S., Rajkumar, C., &
Bulpitt, C. (2007). Use of probiotic Lactobacillus preparation to prevent diarrhoea
associated with antibiotics: Randomised double blind placebo controlled trial.
BBJ, 335(80).
McGlone, S. M., Bailey, R. R., Zimmer, S. M., Popovich, M. J., Tian, Y., Ufberg, P.,
Muder, R. R., & Lee, B. Y. (2012). The economic burden of clostridium difficile.
Clinical Microbiology and Infection, 18(3), 282-289.
Probiotics: What they are and what they can do for you. (2008). American
Gastroenterological Association. Retrieved from: www.gastro.org/patientcenter/diet-medications/probiotics
Walters, P. R., & Zuckerbraun, B. S. (2014). Clostridium difficile infection: Clinical
challenges and management strategies. Critical Care Nursing, 34(4), 24-35.
Ziakas, P. D., & Mylonakis, E. (2014). Probiotics did not prevent antibiotic associated or
C. difficile diarrhea in hospitalized older patients. Annals of International
Medicine, 160(12).