Wageningen Academic

Beneficial Microbes, December 2013; 4(4): 329-334 P u b l i s h e r s

Prevention and treatment of diarrhoea with Saccharomyces boulardii in children with

acute lower respiratory tract infections

L.-S. Shan1, P. Hou1, Z.-J. Wang1, F.-R. Liu1, N. Chen1, L.-H. Shu1, H. Zhang1, X.-H. Han1, X.-X. Cai1, Y.-X. Shang1
and Y. Vandenplas2

1Department of Pediatric Pneumology, Shengjing Hospital of China Medical University, Shenyang 110004, China; 2UZ
Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium; shangyx@sj-hospital.org

Received: 17 January 2013 / Accepted: 23 July 2013

© 2013 Wageningen Academic Publishers

RESEARCH PAPER
Abstract

The aim of this study was to determine whether Saccharomyces boulardii prevents and treats diarrhoea and antibiotic-
associated diarrhoea (AAD) in children. A total of 333 hospitalised children with acute lower respiratory tract
infection were enrolled in a 2-phase open randomised controlled trial. During the 1st phase, all children received
intravenous antibiotics (AB). They were randomly allocated to group A (S. boulardii 500 mg/day + AB, n=167) or
group B (AB alone, n=166) and followed for 2 weeks. Diarrhoea was defined as ≥3 loose/watery stools/day during at
least 2 days, occurring during treatment and/or up to 2 weeks after AB therapy had stopped. AAD was considered
when diarrhoea was caused by Clostridium difficile or when stool cultures remained negative. In the 2nd phase of the
study, group B patients who developed diarrhoea were randomly allocated to two sub-groups: group B1 (S. boulardii
+ oral rehydration solution (ORS)) and group B2 (ORS alone). Data from 283 patients were available for analysis.
Diarrhoea prevalence was lower in group A than in group B (11/139 (7.9%) vs. 42/144 (29.2%); relative risk (RR):
0.27, 95% confidence interval (CI): 0.1-0.5). S. boulardii reduced the risk of AAD (6/139 (4.3%) vs. 28/144 (19.4%);
RR: 0.22; 95% CI: 0.1-0.5). When group B patients developed diarrhoea (n=42), S. boulardii treatment during 5
days (group B1) resulted in lower stool frequency (P<0.05) and higher recovery rate (91.3% in group B1 vs. 21.1%
in B2; P<0.001). The mean duration of diarrhoea in group B1 was shorter (2.31±0.95 vs. 8.97±1.07 days; P<0.001).
No adverse effects related to S. boulardii were observed. S. boulardii appeared to be effective in the prevention and
treatment of diarrhoea and AAD in children treated with intravenous antibiotics.

Keywords: antibiotic-associated diarrhoea, Clostridium difficile, Saccharomyces boulardii, acute lower respiratory tract
infection, hospitalised children

1. Introduction (Bartlett et al., 1978; McFarland, 1998; Ruszczyński et al.,

Antibiotic-associated diarrhoea (AAD) is an acute
inflammation of the intestinal mucosa caused by the
administration of antibiotics (Bartlett et al., 1978).
Clostridium difficile is the most commonly bacterial agent
associated with AAD. Almost all antibiotics can cause
AAD, especially broad-spectrum antibiotics (Elstner et
al., 1983; Turck et al., 2003), such as aminopenicillins,
clavulanate, cephalosporins and clindamycin (Barbut et al.,
1997; McFarland et al., 1990). The prevalence of AAD is
approximately 5-35%, depending on patients and antibiotics
2008; Turck et al., 2003; Wistrom et al., 2001).
Probiotics are defined as microorganisms that, when
administered in adequate amounts, confer a health benefit
to the host (Vandenplas et al., 2011). Saccharomyces
boulardii is a probiotic yeast isolated from the peel of
fruits growing in Indochina, such as lychees, and belonging
to a species closely related to Saccharomyces cerevisiae
(Hennequin et al., 2001). S. boulardii has shown to be
effective in the treatment of acute infectious diarrhoea,
the prevention of AAD and as an adjunctive eradication
therapy of Helicobacter pylori (Buts, 2009; Erdeve et al.,

ISSN 1876-2833 print, ISSN 1876-2891 online, DOI 10.3920/BM2013.0008329

L.-S. Shan et al.
2004; Guandalini, 2011; Kotowska et al., 2005; Szajewska
and Mrukowicz, 2005; Vandenplas et al., 2007, 2009, 2011).
Our study aimed to evaluate the efficacy of S. boulardii
in the prevention and treatment of diarrhoea and AAD in
hospitalised children with an acute lower respiratory tract
infection. This is the first study evaluating the efficacy of
S. boulardii in hospitalised children developing diarrhoea
during antibiotic treatment.
2. Materials and methods
Subjects
The study was performed between January and June 2012 in
children (age range from 6 months to 14 years) hospitalised
in the Department of Pediatric Pulmonology, Shengjing
Hospital of China Medical University, Shenyang, China
because of an acute lower respiratory infection and the
need of administration of intravenous antibiotics. Acute
lower respiratory infections included bronchitis, bronchial
pneumonia, extended lobar pneumonia, and asthma attacks
together with lower respiratory tract infections. Exclusion
criteria were obvious malnutrition, severe dehydration,
unconsciousness, gastrointestinal disease, a central line,
and use of antifungal drugs or probiotics. Participation in
this clinical study was voluntary. Informed consent was
obtained from the children’s guardian. The study protocol
was approved by the University Hospital Ethical Committee.
Sample size
It was assumed that the incidence rate of diarrhoea
development in the control groups would be equal to 25%.
Based on this, we estimated that a minimum sample size
of 129 children in each treatment group would show 15%
reduction in the proportion of children with AAD in the
intervention groups with a significance level of 5% and
power of 90%. It was assumed that the study withdrawal
rate would be at least 20-25% and, therefore, the sample
size was increased to compensate for the potential influence
of loss to follow-up.
Study design
This study was an open, randomised, controlled clinical
trial. All patients included were given the standard
intravenous antibiotic treatment according to the hospital
recommendations and were randomly allocated to two
groups. Group A received S. boulardii daily 2×250 mg
(Bioflor; CMS·Shenzhen Kangzhe Pharmaceutical Co.
Ltd., Shenzhen, China) for the duration of the antibiotic
treatment (n=167) and group B received no additional
therapy (n=166). Randomisation was done according to
a computer-determined allocation to group A or B. The
sequence was concealed in an envelope, and the next
330
neutral envelope was opened each time the next patient
was included in the study. To evaluate the role of S. boulardii
in prevention, the incidence of diarrhoea and AAD was
evaluated every day up to 2 weeks after the antibiotic
therapy had stopped.
The Bristol stool scale (BSS) classifying stool consistency
in seven categories was used to evaluate stool consistency
(Lewis and Heaton, 1997). The definition of diarrhoea was
≥3 loose or watery stools (BSS type 5, 6 and 7) per day
during at least 2 days, occurring during treatment and/
or up to 2 weeks after the antibiotic therapy had stopped.
AAD was defined as diarrhoea caused by C. difficile or
diarrhoea with negative stool cultures (Bartlett et al., 1978).
Recovery was defined as a decrease in stool frequency and
BSS type ≤4. The number of stools, stool consistency, and
any other symptom were recorded daily in a diary during
hospitalisation and during a two week follow-up period.
When diarrhoea occurred, stool samples were analysed
for rotavirus antigen using a colloidal gold test device
(Rotavirus Group A diagnostic kit; Beijing Wantai Biological
Pharmacy Enterprise Co., Beijing, China); standard stool
cultures (Salmonella, Shigella, Yersinia, Campylobacter,
Escherichia coli) were performed and C. difficile toxins A
and B were looked for using an enzyme immunoassay (C.
difficile TOX A/B Test; Tech Lab Inc., Blacksburg, VA,
USA). Treatment compliance was evaluated by returning
medication after the intervention period.
Children who developed diarrhoea were rehydrated with
oral or intravenous fluids, but antibiotic treatment was
continued. Children from group B who developed diarrhoea
were divided in two sub-groups: group B1, S. boulardii
(daily 2×250 mg for 5 days) + oral rehydration solution
(ORS), and group B2, ORS only. The enrolment method
for the second part of the study was identical to that of
the first part.
Outcome measures
The outcome measures were twofold. For the first part
of the study, the development of diarrhoea between the
start of antibiotic treatment up to two weeks later was
the primary outcome. The secondary outcome was AAD,
when all cultures were negative or when diarrhoea was
caused by C. difficile. For the second part of the study,
only groups B1 and B2 were considered. In those patients,
duration of diarrhoea was the primary endpoint. Duration
of diarrhoea was determined by the number of days of
continuous diarrhoea, from the first diarrheic stool until
the first normal stool.
Beneficial Microbes 4(4)
 S. boulardii in diarrhoea and antibiotic-associated diarrhoea

Statistical analysis Table 1. Baseline demographics of patients receiving

Saccharomyces boulardii during antibiotic treatment or
Continuous variables were presented as mean ± standard antibiotics alone.
deviation and analysed using the t-test, approximating a
normal distribution. Statistical analysis was performed Group A: Group B:
using ‘available case analysis’, i.e. analysis in which data S. boulardii iv AB1
are analysed for every participant for whom an outcome + iv AB1
was obtained. Categorical variables were expressed in
percentage and compared using a chi-square test. The Number of patients 167 166
relative risk (RR) and 95% confidence interval (CI) were Sex (male/female) 82/85 84/82
calculated. The difference was considered significant when Age (months, range) 49.8±36 48.7±34
the P-value was <0.05. Statistical analyses were performed (6.2-158) (6.1-161)
by SPSS version 13.0 (IBM, Armonk, NY, USA). Diagnosis
Bronchitis 36 (53.7%) 31 (46.3%)
3. Results Pneumonia 70 (48.6%) 74 (51.4%)
Asthma + LRT infection1 39 (48.1%) 42 (51.9%)
Clinical characteristics Others 22 (53.6%) 19 (46.3%)
Antibiotic
333 patients were included in the trial. The patients’ Cefepime 26 24
stool frequency and characteristics were normal prior to Cefoperazone + sulbactam 24 28
admission. 167 patients received S. boulardii (group A) Cefuroxime 37 34
shortly after the first dose of antibiotics; the other 166 Amoxicillin+ clavulanic acid 43 45
patients (group B) were not given S. boulardii (Figure 1). Erythromycin 22 24
Baseline demographics, clinical characteristics and Others 12 11
antibiotics did not differ significantly between both groups
(Table 1). In total, 50 (15%) patients were considered drop- 1 iv AB = intravenous antibiotics, LRT = lower respiratory tract.
outs (28 (16.7%) in group A and 22 (13.2%) in group B)
because of withdrawal of consent (n=12), antibiotic stop
within 48 h (n=8), non-compliance (n=10), and lost to Diarrhoea was diagnosed in 53/283 patients (18.7%)
follow-up (n=20). Data of 283/333 children were available: (Table 2): 11/139 (7.9%) in group A compared to 42/144
139/283 in group A and 144/283 in group B. (29%) in group B (RR=0.27; 95% CI = 0.13-0.55; P<0.01).

Acute lower respiratory

tract infections
(n=333)

Group A: SB + iv AB Group B: iv AB
(n=167) (n=166)

drop out drop out

n=28 (17 %) n=22 (13 %)

n=139 n=144

No diarrhoea Diarrhoea No diarrhoea Diarrhoea

n=128 n=11 n=102 n=42
(92%) (8%) (71%) (29%)

Group B1: Group B2:

SB + ORS ORS
n=23 (56%) n=19 (45%)

Figure 1. Study flow chart. Abbreviations used: iv AB = intravenous antibiotics, n = number of patients, ORS = oral rehydration
solution.

Beneficial Microbes 4(4) 331

L.-S. Shan et al.

Table 2. Primary and secondary outcomes in patients receiving Saccharomyces boulardii during antibiotic treatment or antibiotics
alone.

Group A: Group B: RR (95% CI)2

S. boulardii + iv AB1 (n=139) iv AB1 (n=144)

Diarrhoea 11/139 (7.9%) 42/144 (29.2%) 0.27 (0.13-0.55)

Cause of diarrhoea
Rotavirus 5 (3.6%) 14 (9.7%) 0.37 (0.13-1.06)
Clostridium difficile 1 (0.7%) 8 (5.6%) 0.13 (0.02-1.05)
Unexplained diarrhoea 5 (3.6%) 20 (13.9%) 0.26 (0.09-0.71)
AAD3 (C. difficile, unexplained diarrhoea) 6 (4.3%) 28 (19.4%) 0.22 (0.09-0.55)

1 iv AB = intravenous antibiotics.
2 RR = relative risk, CI = confidence interval.
3 AAD = antibiotic-associated diarrhoea.

AAD was diagnosed in 34/53 (64%) patients. The AAD
risk was lower in group A (RR=0.22; 95% CI = 0.09-0.56),
especially in patients treated with cefuroxime (1/30
(3.3%) vs. 8/31 (25.8%); RR=0.13; 95% CI = 0.02-0.97), or
amoxicillin/clavulanic acid (2/36 (5.6%) vs. 9/37 (24.3%);
RR=0.23; 95% CI = 0.05-0.99) (Table 3). The incidence
of rotavirus gastroenteritis was similar in both groups
(Table 2).
Therapeutic effect of Saccharomyces boulardii on
diarrhoea
For the second part of the study, the sample size calculation
was not performed. The 42 patients with diarrhoea in group
B were further randomly allocated: 23 to group B1 (ORS
+ S. boulardii) and 19 to group B2 (ORS). After 3 days of
administration of S. boulardii to patients in group B1, the
recovery rate was significantly higher than in group B2 (83
vs. 16%; χ2=18.62, P<0.001) (Table 4). The mean duration
of diarrhoea in group B1 was significantly shorter than in
group B2 (2.31±0.95 vs. 8.97±1.07 days, t=21.36, P<0.001).
Adverse reactions
No adverse reaction to S. boulardii and no case of drug
discontinuation (neither antibiotics nor S. boulardii) have
been reported.
4. Discussion
This study confirms the efficacy of S. boulardii in the
prevention of diarrhoea and AAD developing during or
short after antibiotic treatment. The administration of
S. boulardii during 5 days in the group of children that

Table 3. Features of patients with antibiotic-associated diarrhoea.

Group A: Group B: P-value RR (95% CI)2

S. boulardii + iv AB1 (n=6) iv AB1 (n=28)

Age (months±SD)3 (range) 16.5±14 (3.3-33.5) 18.8±19 (3.7-30.6) 0.69

Onset diarrhoea (days±SD) (range) 4.8±1.7 (3-8) 4.9±2.5 (2-10) 0.89 -
Antibiotics4
Cefepime 1/21 (4.5%) 3/21 (14.3%) 0.57 0.32 (0.04-2.82)
Cefoperazone + sulbactam 1/21 (4.5%) 2/23 (8.7%) 1.0 0.50 (0.05-5.14)
Cefuroxime 1/30 (3.3%) 8/31 (25.8%) 0.03 0.13 (0.02-0.97)
Amoxicillin + clavulanic acid 2/36 (5.6%) 9/37 (24.3%) 0.02 0.23 (0.05-0.98)
Erythromycin 0/18 (0%) 4/23 (17.4%) 0.12 0
Others 1/10 (10%) 2/9 (22.2%) 0.92 0.45 (0.05-4.16)

1 iv AB = intravenous antibiotics.
2 RR = relative risk, CI = confidence interval.
3 SD = standard deviation.
4 The difference in number of children with antibiotics between Tables 1 and 3 is due to the withdrawals.

332 Beneficial Microbes 4(4)

 S. boulardii in diarrhoea and antibiotic-associated diarrhoea
Table 4. Efficacy of Saccharomyces boulardii in children from the initial control group that developed diarrhoea.
Group B1 (n=23):
S. boulardii + ORS1
Day 0
Stool frequency (n/day) 4.03±0.61
Day 3
Stool frequency (n/day) 2.22±1.89
Recovery rate (%) 19/23 (82.6)
Day 5
Stool frequency (n/day) 1.01±0.85
Recovery rate (%) 21/23 (91.3)
1 ORS = oral rehydration solution..
developed diarrhoea during antibiotic treatment or
during the following two weeks, shortened the duration
of diarrhoea. After 3 days, diarrhoea had stopped in 83%
of the children in the S. boulardii group compared to
only 16% in the untreated group. There were no adverse
reactions. These results suggest that S. boulardii offers an
appropriate and safe therapeutic intervention to prevent
and treat diarrhoea and AAD.
Antibiotic use in children is three times higher than in
adults due to more frequent infections in that age group
(Szajewska et al., 2006). Besides being an effective treatment
for bacterial infections, antibiotics may also induce AAD
by disrupting the balance of the intestinal flora. Antibiotics
may cause direct damage to the intestinal mucosa and
atrophy of intestinal epithelium, and reduce the activity of
cellular enzymes (disaccharidases), which leads to diarrhoea
and abdominal pain (Johnston et al., 2011). Children may
be prone to AAD because of their still-developing immune
system. All antibiotics can cause AAD depending on type
and duration of administration (Bergogne-Berezin, 2000)
rather than dosage or administration route (McFarland,
1998). While AAD in children is estimated at 11-40%, it has
been reported that incidence for cephalosporin, penicillin,
and clindamycin may be higher (Kotowska et al., 2005).
Similar results were obtained in our study.
The yeast S. boulardii secretes proteins that lower the
cAMP activity of intestinal epithelium cells and, therefore,
reduces the secretory watery diarrhoea (Czerucka et al.,
1994). Moreover, S. boulardii increases production of
polyamines and activates mucosal enzymes (Buts et al.,
1999; Vandenplas et al., 2007). Furthermore, as it secretes
proteases, S. boulardii can directly hydrolyse the toxins
secreted by C. difficile, resulting in a reduction of the
occurrence of AAD. In addition, S. boulardii can stimulate
the gastrointestinal immune system, such as intestinal
phagocytosis, intestinal secretary IgA, and other non-
specific immunity functions (Czerucka et al., 2007). S.
Beneficial Microbes 4(4)
Group B2 (n=19): t-value or χ2 P-value
ORS1
3.98±0.52 0.28 0.779
4.01±2.15 2.87 0.006
3/19 (15.8) χ2=18.62 <0.001
3.98±1.89 6.766 <0.001
4/19 (21.1) χ2=21.31 <0.001
boulardii is not inactivated by gastric acid and antibiotics,
except for fungicides. These properties make S. boulardii an
attractive probiotic to test in the prevention and treatment
of AAD.
A major shortcoming of this trial is its ‘open’ design.
Because there is no placebo control group, a placebo effect
cannot be excluded. However, a previous placebo-controlled
trial reported similar results (Johnston et al., 2011). The
age-range of the patients included is quite wide, but other
studies used similar inclusion criteria (McFarland, 1998).
Another limitation of this study is the 2-week follow-up.
AAD may occur within 2 months after antibiotic treatment
had stopped, therefore, some AAD cases might not have
been included. In addition, we only tested for the major
stool pathogens; other pathogens may have been missed.
Therefore, AAD in this study was defined as diarrhoea
caused by C. difficile or as unexplained diarrhoea that
might be related to antibiotics (McFarland, 1998). Only
the children without acute or chronic diarrhoea and without
other chronic gastrointestinal diseases were enrolled in this
study to reduce interference.
5. Conclusions
The results of the present study confirm that prophylactic
use of oral S. boulardii reduces the risk to develop
(antibiotic-associated) diarrhoea during treatment or during
two weeks after antibiotic administration had stopped. It is
for the first time that the efficacy of S. boulardii is suggested
when diarrhoea occurs during antibiotic treatment or
the following two weeks. Future double-blind placebo-
controlled trials are needed to confirm these data.
Conflict of interest
Y. Vandenplas is consultant for Biocodex and United
Pharmaceuticals.
333
L.-S. Shan et al.
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