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Title: PharmaNote
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Language: English
Creator: College of Pharmacy, University of Florida
Publisher: College of Pharmacy, University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008
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Volume ID: VID00069
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THE ROLE OF PROBIOTICS IN
THE PREVENTION OF
ANTIBIOTIC-ASSOCIATED
DIARRHEA

Erica Ratanothayanon, Pharm.D. Candidate


Diarrhea is a common complication of antibiotic
therapy occurring within several days of starting
therapy to weeks after the antibiotic has been discon-
tinued. Any antibiotic can induce diarrhea but broad
spectrum antibiotics such as ampicillin, amoxicillin,
cephalosporins, and clindamycin are the major cul-
prits.1 Several mechanisms have been proposed for
antibiotic-associated diarrhea (AAD). With the re-
duction in anaerobe concentration after antibiotic
administration, carbohydrate metabolism is de-
creased resulting in an osmotic diarrhea. Addition-
ally, some antibiotics such as erythromycin and cla-
vulanate have prokinetic effects. Lastly, antibiotics
create an environment in the GI tract that allows
pathogenic bacteria to overpopulate.1 Clostridium
difficile (C. difficile), a gram positive, spore-forming
anaerobe is the most predominant infectious agent
isolated accounting for 15% to 25% of all cases of
antibiotic-associated diarrhea.2 Symptoms of Clos-
tridium difficile-associated diarrhea (CDAD) range
from nuisance diarrhea to life threatening pseu-
domembranous colitis or toxic megacolon.
Antibiotics are the key predisposing players in
the pathogenesis of CDAD. The normal GI flora is
eradicated by antibiotics leading to an imbalance in
the enteric ecosystem and loss of protection by the
normal microflora. This unstable environment al-
lows colonization of pathogenic microbes such as C.


difficile. C. difficile exerts its injurious actions with
the production of two toxins, enterotoxin A and cyto-
toxin B. Enterotoxin A is responsible for activating
and recruiting inflammatory mediators, while cyto-
toxin B is responsible for cytotoxic effects.
Over the past several years, the incidence of
CDAD has risen dramatically.4 Both the number of
CDAD hospitalizations and CDAD-related age-
adjusted case-fatality have doubled in the US as re-
ported by the National Inpatient Sample data from
2000 to 2005 (Table 1). The number of deaths asso-
ciated with CDAD exceeds that of all other intestinal
infections combined.5 Health care expenditures for
CDAD have escalated to over 1 billion dollars/year
in the US.2 With the emergence of the hypervirulent
strain, NAP1/BI/027, CDAD is increasingly display-
ing a more complex clinical course and higher mor-
tality rate.6 The NAP1/BI/027 strain accounts for a
binary toxin that produces 16 times more enterotoxin
A and 23 times more cytotoxin B than control
strains.7
Current treatment options for CDAD include
metronidazole for mild to moderate cases and vanco-
mycin for more severe cases. Unfortunately, there
have been reports of decreased response rates and
increased recurrence rates with metronidazole treat-
ment.8Approximately 20% of patients will have re-
Fi,. .,i]


mm


PharmaNote


VOLUME 24, ISSUE 2 NOVEMBER 2008

tl I


INSIDE THIS ISSUE:
THE ROLE OF PROBIOTICS IN THE PREVENTION OF
ANTIBIOTIC-ASSOCIATED DIARRHEA


L.m mj


PharmaNote


Volume 24, Issue 2 November 2008







Table 1. Adult hospitalizations with C. difficile, by age group, in the United States, 2000-20055

Hospitalizations 2000 2001 2002 2003 2004 2005

18-44 y 14,738 15,001 18,747 19,393 22,168 25,662

45-64 y 28,280 29,527 39,421 43,290 50,898 61,757

65-84 y 69,018 74,010 98,148 105,404 122,875 147,675

>85y 22,325 25,194 31,899 35,363 43,341 56,209

All adults 134,361 143,732 188,215 203,450 239,282 291,303

Adapted from Zilberberg5


currency of CDAD despite initial treatment.9 These one strain cannot be applied to another strain.12 Pro-
patients are more prone to have repeated episodes of biotics, in general, exert antimicrobial actions by de-
CDAD that can last up to 4 years. There is a growing creasing luminal pH (Lactobacilli and bifidobacteria
interest in the potential benefits of alternative thera- belong to a group of bacteria that produces lactic
pies, such as probiotics, to prevent further spread of acid), secreting antimicrobial peptides, inhibiting
this clinical problem. bacterial invasion, and blocking bacterial adhesion to
Probiotics are live microorganisms that bestow a epithelial cells. They also augment barrier integrity
health benefit to the host when provided in adequate by increasing mucus production.13 In addition to
amounts.10 The word probiotic translates as "for these mechanisms, probiotics are also theorized to
life."11 The rationale for using probiotics in AAD and boost immune function by stimulating local macro-
CDAD is to restore normal GI microflora. Probiotics phages to amplify antigen presentation to B lympho-
can be classified into three main groups: Lactoba- cytes and enhancing secretary IgA production both
cilli, Bifidobacteria, and miscellaneous as shown in locally and systemically.2 Probiotics may also play a
Table 2. Saccharomyces boulardii and the Lactoba- role in modifying cytokine profiles.2
cilli species have been the most extensively studied
in AAD and CDAD.2 Sacchromyces boulardii
Not all probiotics are bacteria. S. boulardii is a
MECHANISM OF ACTION non-pathogenic yeast derived from lychee and man-
The precise mechanisms of action of probiotics gosteen fruits. It was first discovered in 1939 by a
remain unclear. Current evidence indicates that each French scientist named Henri Boulard who noticed
probiotic strain is unique and the effects vary from the natives of Southeast Asia chewing on the skins of
one strain to another. Even if the strain belongs to the these fruits to control cholera-induced diarrhea.14 S.
same species, the beneficial effect characterized by boulardii is commercially available in the US under



Table 2. Microorganisms that are considered to be probiotics11

Lactobacillus spp. Bifidobacterium spp. Others
L. acidophilus B. bifidum Saccharomyces boulardii
L. plantarum B. breve Escherichia coli Nissle
L. rhamnosus B. infants Streptococcus thermophilusa
L. gasseri B. longum Enterococcus faeciumb
L. fermentum B. adolescents
L. case B. lactis
L. crispatus
L. delbrueckii
L. johnsonii
L. paracasei
L. reuteri

Phrm~oe olme24 sse Nvebe 20


PharmaNote


Volume 24, Issue 2 November 2008







Table 3. Summary of six randomized placebo-controlled trials of probiotics for prevention of RCDAD4

Patient
Source N t Probiotic Antibiotic Results Comments
population


Initial CDAD
124 Recurrent
CDAD


S. boulardii Vancomycin or
1 g daily metronidazole


High dose van-
comycin or low
Recurrent S. boulardii dose
168
CDAD 1 g daily vancomycin
or metronida-
zole


Initial CDAD
25 Recurrent
CDAD


L. rhamnosus
GG


S Recurrent L. plantarum
CDAD 299v
5 x 1010 CFU


Recurrent L. rhamnosus
CDAD GG


Inpatient
elderly
138 receiving
antibiotics
for any
cause


L. acidophilus
and
Bifidobacte-
rium
Bifidum


Vancomycin or
metronidazole


Metronidazole


Varied
(chosen
by primary
clinician)



Varied
(chosen by
primary
clinician)


McFarland
et al16


p= 0.04
Dose, duration, and choice of
antibiotic were not controlled



p = 0.05
Decreased recurrence in high
dose vancomycin treated
patients only
(n=32)


26% in the probiotic
group had RCDD
compared to 44.8%
in the placebo group


16.7% in the probiotic
group had RCDD
compared to 50% in
the placebo group



36.4% in the probiotic
group had RCDD
compared to 35.7%
in the placebo group



36% in the probiotic
group had RCDD
compared to 67% in
the placebo group



37.5% in the probiotic
group had RCDD
compared to 14.3%
in the placebo group


CDD developed in
2.9% in the probiotic
group compared with
7.25% in the placebo
group


Not clinically significant;
Study underpowered


Not clinically significant;
Study underpowered


Study underpowered to detect
a clinically significant
difference


CDAD= Clostnrdzum .


S. .., .I diarrhea; RCDAD = Recurrent Clostrdzum . -- ~-I.I diarrhea.


the trade name, Florastor. Clinical trials have shown
S. boulardii to be advantageous in AAD. S. boulardii
was significantly better than placebo in preventing
AAD in several clinical trials. Recommendations re-
garding S. boulardii use were developed based on
evidence presented at the Advances in Clinical Use
of Probiotics Workshop held at Yale University. S.
boulardii received a grade "A" recommendation in
prevention of AAD in outpatient and inpatient adults.
An "A" recommendation is based on strong, posi-
tive, well-conducted, controlled studies in the pri-
mary literature.15
There is currently no evidence to support prophy-
lactic probiotic use for prevention of an initial epi-


sode of CDAD. Many of the clinical trials for AAD
do not identify the cause of diarrhea so it is very dif-
ficult to determine how much diarrhea is attributable
to C. difficile and how effectively probiotics reduce
the occurrence of CDAD. Most of the clinical trials
failed to draw cultures, C. difficile toxin assays, and
viral identification studies.14 Some trials have ana-
lyzed CDAD as a secondary outcome but the differ-
ences were insignificant due to the small amount of
individuals who had C. difficile infection.
However, there is some evidence to support S.
boulardii in decreasing the incidence of recurrent
CDAD (RCDAD). The beneficial effects of S. bou-
lardii in RCDAD may be attributed to its ability to


PharmaNote Volume 24, Issue 2 November 2008


No significant difference


Surawicz
et a117


Pochapin
et al0


Wullt
et a121


Lawrence
et a122


Plummer
et al19


PharmaNote


Volume 24, Issue 2 November 2008







Table 4. Selected Commercially Available Probiotic Products15

Product Probiotic Species Dose Cost


1-2 capsules per day $20.99 for 30 capsules. Price ob-
Culturelle Lactobacillus rhamnosus GG (35 billion microo $20.99 for 30 capsules. Price ob-
tained from Walgreens.
ganisms per capsule)


Bifidobacterium breve, Bifidobacte-
rium longum, Bifidobacterium infants, 0.5-8 packets per day $79.50 for 30 packets. Price ob-
VSL#3 Lactobacillus acidophilus, Lactobacil- (450 billion live lactic tainted from naturespharmaceuti-
lus plantarum,Lactobacillus case, acid bacteria per calscom
Lactobacillus bulgaricus, Streptococ- packet)
cus thermophilu

Activia y t B s r s # of bacteria not $3.50 for a pack of 4. Price ob-
Activia yogurt Bifidus regulars Pi.
stated tained from Publix.

1 capsule BID (5 bil-
Florastor Saccharomyces boulardicapsule BID (5 bil- $37.50 for 50 capsules. Price ob-
Florastor Saccharomyces boulardii lion live cells per 250 taied from newtimrx.com
mg capsule)

Acidophilus Pearls L # of bacteria not $12.99 for 30 pearls. Price ob-
Acidophilus Pearls Lactobacillus acidophilus stated tainted from GNC.com
stated tained from GNC.com

1 capsule every other
G48 Lactobacillus fermentum day (up to 2 billion $32.00 for 30 capsules. Price ob-
CFU per 100 mg cap- tained from evitamins.com
sule)



secrete a protease that neutralizes C. difficile toxins A follow-up study was conducted to substantiate
A and B. McFarland et al. conducted a multi-center, the results produced in the Mcfarland study.
double-blind, randomized, placebo-controlled study Surawicz et al. analyzed the efficacy of S. boulardii
in 124 adult patients with active or recurrent C. diffi- in combination with antibiotics for the prevention of
cile disease.16 The study included 64 patients with an recurrent CDAD in a double blind, placebo-
initial episode of CDAD and 60 patients with at least controlled trial.17 Patients were randomized to re-
1 previous episode of CDAD. All patients received ceive 10 days of high dose vancomycin, low dose
metronidazole, oral vancomycin, or both antibiotics vancomycin or metronidazole along with placebo or
along with a 1 month supply of S. boulardii (Igm/ S. boulardii at a dose of 1 g/day (two 250-mg cap-
day) or placebo. Patients were followed-up in 1 sules b.i.d.) for 4 weeks. Standardized culture meth-
month. Patients who were given S. boulardii had a ods were used to test for presence of C. difficile and
significantly lower relative risk of C. difficile diar- ELISA kits were used to detect toxin A. Standard
rhea when compared with those given placebo (RR, cytopathic cell cultures were used to detect toxin B.
0.43; 95% CI 0.20-0.97) as concluded by multivari- Results showed that the frequency of recurrence of
ate analysis. S. boulardii was not shown to be effec- CDAD was significantly reduced when S. boulardii
tive in patients with an initial episode of CDAD but was combined with high-dose vancomycin, but had
was effective in patients with a prior history of no effect in combination with low-dose vancomycin
CDAD. Patients with a prior history of CDAD who or metronidazole. In the high dose vancomycin and
were started on S. boulardii had a significantly de- S. boulardii group, 16.7% of patients had a recur-
creased recurrence of CDAD, from 64.7% to 34.6% rence of CDAD compared to 50% of patients in the
(P=0.04). group receiving high-dose vancomycin and placebo
(P = 0.5). In preventing further recurrences of

PharmaNote Volume 24, Issue 2 November 2008







CDAD, S. boulardii and vancomycin was 67% more
effective than treatment with vancomycin alone.

Lactobacillus rhamnosus GG (LGG)
LGG, marketed as Culturelle, comes from the
normal human microflora. LGG has been extensively
studied for the prevention of AAD. Most studies
have shown efficacy in children for the prevention
and treatment of AAD. However, in adults, LGG has
not demonstrated any beneficial effects. Some au-
thors criticize that the LGG dose used in the clinical
trials were too low. Thomas et al. conducted a ran-
domized, placebo controlled study with LGG at a
dose of 20 x 109CFU daily in 302 hospitalized adults
and concluded that LGG was no more effective than
placebo in preventing AAD.18 There is insufficient
data to support using LGG for prevention of CDAD.
Almost all of the data on LGG and CDAD are de-
rived from case reports.
However, there has been a study conducted on
the combination of Lactobacillus and Bifidobacte-
rium. In a double-blind, placebo controlled study,
Plummer and colleagues analyzed the effect of probi-
otics on the incidence of CDAD in hospitalized eld-
erly patients placed on antibiotic therapy.19 One-
hundred and fifty patients receiving antibiotic ther-
apy were randomized to receive either Lactobacillus
and Bifidobacterium or placebo for 20 days. Only
138 completed the study, 69 with the combination of
antibiotics and probiotics and 69 with only antibiot-
ics. In the probiotic group, the incidence of samples
positive for C. difficile-associated toxins was 2.9%


compared with 7.25% in the placebo group. There
was not enough power in the study to detect a clini-
cally significant difference.

DOSING
Table 4 indicates the recommended dosing on the
package label for maintenance of normal GI health.
There are no established dosing recommendations
for probiotics in AAD and CDAD but Katz et al. has
provided dosing guidelines for LGG and S. boulardii
based on clinical trial data (Table 5).

QUALITY CONTROL OF PROBIOTICS
Probiotics are considered dietary supplements
and therefore not strictly regulated by the FDA. The
manufacturer determines much of the efficacy and
safety of probiotics. Some probiotic products are in-
activated or nonviable after being manufactured. The
number of viable bacteria at the time of use deter-
mines the effectiveness of the probiotic.5 Many of
the products contain less bacteria than stated on the
label. Some contain unknown organisms or other
types of contaminates.19 Universal standard testing
procedures must be implemented to guarantee the
quality and safety of the probiotic.

SAFETY
Probiotics are generally considered safe and are
well tolerated. Side effects include flatulence or
changes in bowel habit.23 Cases of bacteremia and
fungemia have been documented but are rare and
seen most often in the severely ill or immunocom-


Table 5. Guidelines for Probiotic use in Antibiotic-associated Diarrhea and C. difficile Diarrhea9


Prevention of antibiotic-associated diarrhea
Adults: S. boulardii 1 g daily
Strength of evidence: good
Children: LGG 1-2 x 1010 CFU daily
Strength of evidence: good
Avoid in immunocompromised patients
Prevention of C. difficile diarrhea
No evidence to support efficacy in primary prevention of C. difficile
Recurrent C. difficile diarrhea
Adults: S. boulardii 1 g daily
Strenth of evidence: moderate
Children: not enough data to make a recommendation
Avoid in immunocompromised patients


Adapted from Katz9


PharmaNote Volume 24, Issue 2 November 2008


PharmaNote


Volume 24, Issue 2 November 2008







promised. There have been reports of LGG-
associated bacteremia in children with short gut syn-
drome and in children who have central venous
catheters. Endocarditis in an elderly patient with mi-
tral regurgitation after a dental extraction and liver
abscess in an elderly diabetic patient have also been
reported with LGG.24 In addition, there have been
reports of isolated candidemia with S. boulardii.25

SUMMARY
Lactobacillus GG and S. boulardii have shown
positive results in preventing AAD. As for other pro-
biotics, little evidence exists to conclude whether
they are efficacious in preventing AAD. With the
increasing outbreaks of CDAD, more clinical trials
are needed to evaluate probiotics for the primary pre-
vention of CDAD. There is scarce evidence to sup-
port routine clinical use of probiotics for RCDAD. S.
boulardii may have a positive impact in RCDAD;
however, better designed, well executed clinical tri-
als need to be conducted to validate proof of effi-
cacy.

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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D., FCCP

R. Whit Curry, M.D. Associate Editor

Steven M. Smith Assistant Editor
Pharm.D.


PharmaNote Volume 24, Issue 2 November 2008


PharmaNote


Volume 24, Issue 2 November 2008




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