Systematic review with meta-analysis: Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea

Systematic review with meta-analysis: Saccharomyces boulardii
in the prevention of antibiotic-associated diarrhoea
H. Szajewska & M. Kołodziej
Department of Paediatrics, The
Medical University of Warsaw,
Warsaw, Poland.
Correspondence to:
Prof. H. Szajewska, Department of
Paediatrics, The Medical University
of Warsaw, Dzialdowska 1,
Warsaw 01-184, Poland.
E-mail: hania@ipgate.pl
Publication data
Submitted 1 June 2015
First decision 20 June 2015
Resubmitted 26 June 2015
Accepted 11 July 2015
EV Pub Online 27 July 2015
As part of AP&T’s peer-review process, a
technical check of this meta-analysis
was performed by Dr Y. Yuan. This
article was accepted for publication after
full peer-review.
SUMMARY
Background
Antibiotic-associated diarrhoea is a common complication of antibiotic use,
but it can be prevented with administration of probiotics.
Aim
To update our 2005 meta-analysis on the effectiveness of Saccharomyces bou-
lardii in preventing antibiotic-associated diarrhoea in children and adults.
Methods
The Cochrane Library, MEDLINE, and EMBASE databases were searched
up until May 2015, with no language restrictions, for randomised controlled
trials; additional references were obtained from reviewed articles. The qual-
ity of evidence was assessed using the Grading of Recommendations
Assessment, Development and Evaluation (GRADE) guidelines.
Results
Twenty-one randomised controlled trials (4780 participants), among which
16 were new trials, met the inclusion criteria for this updated systematic
review. Administration of S. boulardii compared with placebo or no treat-
ment reduced the risk of antibiotic-associated diarrhoea (as defined by the
study investigators) in patients treated with antibiotics from 18.7% to 8.5%
(risk ratio, RR: 0.47; 95% CI: 0.38–0.57, number needed to treat, NNT: 10;
95% CI: 9–13). In children, S. boulardii reduced the risk from 20.9% to 8.8%
(6 randomised controlled trials, n=1653, RR: 0.43, 95% CI: 0.3–0.6); in adults,
from 17.4% to 8.2% (15 randomised controlled trials, n=3114, RR: 0.49, 95%
CI: 0.38–0.63). Moreover, S. boulardii reduced the risk of Clostridium diffi-
cile-associated diarrhoea; however, this reduction was significant only in chil-
dren (2 randomised controlled trials, n = 579, RR: 0.25; 95% CI: 0.08–0.73)
and not in adults (9 randomised controlled trials, n = 1441, RR: 0.8, 95% CI:
0.47–1.34).
Conclusions
This meta-analysis confirms that S. boulardii is effective in reducing the
risk of antibiotic-associated diarrhoea in children and adults.
Aliment Pharmacol Ther 2015; 42: 793–801
ª 2015 John Wiley & Sons Ltd 793
doi:10.1111/apt.13344
Alimentary Pharmacology and Therapeutics

INTRODUCTION
Antibiotic-associated diarrhoea (AAD) is defined as diar-
rhoea which occurs in conjunction with antibiotic
administration and that cannot be explained by another
process.1
Essentially, any antibiotic can initiate AAD as
early as just a few hours following antibiotic administra-
tion up to several months after its discontinuation.2, 3
The prevalence of AAD depends on the definition of
AAD, the antimicrobial agents, host factors such as
extreme ages of life (<6 years and >65 years), or hospi-
talisation. In the paediatric population, it generally varies
from 5% to 30%, but exceptionally, has been reported to
be as high as 80% in very young hospitalised children.4
In adults, the prevalence ranges from 5% to 70%.5
The
clinical presentation of AAD varies from mild diarrhoea
to colitis or fulminant pseudomembranous colitis.5
The
two latter conditions manifest with abdominal pain, fever
and bloody diarrhoea.
Probiotics are ‘live microorganisms that, when admin-
istered in adequate amounts, confer a health benefit on
the host’.6
In humans, Saccharomyces boulardii, a non-
pathogenic yeast, is one of the most commonly used
probiotics. Previously, we investigated the effects of
S. boulardii in preventing AAD in children and adults.7
A meta-analysis of data from five randomised controlled
trials (RCTs) showed that S. boulardii is moderately
effective in preventing AAD in children and adults trea-
ted with antibiotics for any reason (mainly respiratory
tract infections). In the last few years, a number of new
relevant studies have been published. Here, our aim was
to update the 2005 assessment of the effects of
S. boulardii compared with placebo or no intervention
for preventing AAD in children and adults. This review
was initiated as part of the development of guidelines on
the use of probiotics for preventing AAD in children.
METHODS
As previously, this systematic review and meta-analysis
was conducted according to the guidelines from the
Cochrane Handbook for Systematic Reviews of Interven-
tions,8
with reporting following the PRISMA Statement.9
Electronic databases (see Search strategy) were system-
atically searched to identify studies appropriate for inclu-
sion in this systematic review. Only RCTs were eligible
for inclusion. Participants were adults and children who
received antibiotics for any reason, including Helicobac-
ter pylori eradication therapy. Patients in the experimen-
tal groups additionally received S. boulardii at any dose/
duration. Subjects in the control group received placebo
or no additional intervention. The primary outcome
measure was the incidence of diarrhoea or AAD (as
defined by the investigators). If both outcomes were
reported, a more conservative outcome has been chosen
for reporting in this meta-analysis. The secondary out-
come measures were the incidence of Clostridium difficile
diarrhoea; the need for discontinuation of the antibiotic
treatment; the need for hospitalisation to manage the
diarrhoea (in outpatients); the need for intravenous rehy-
dration in any of the study groups; and adverse events.
Search strategy
The Cochrane Central Register of Controlled Trials (CEN-
TRAL, the Cochrane Library), MEDLINE and EMBASE
databases were searched for relevant studies published up
until May 2015. The principal search text word terms and
MESH headings used were diarrhea/diarrhoea, antibiotic-
associated/antibiotic associated, Clostridium difficile, Heli-
cobacter pylori, probiotics and Saccharomyces boulardii.
Furthermore, reference lists from the original studies and
review articles identified were screened, and key experts in
the field were approached for unpublished material. No
limit was imposed regarding the language of publication.
Two registers for clinical trials (www.clinicaltrials.gov,
www.clinicaltrialsregister.eu) were screened. All poten-
tially relevant articles were retained, and the full text of
these studies examined to determine which studies met
the inclusion criteria. One reviewer (MK) carried out data
extraction, using standard data extraction forms, which
was then assessed by the second reviewer (HS). Data were
extracted as complete (available) case analyses. Studies
reported in languages other than those familiar to the
authors were translated. Disagreements were resolved by
discussion. The Cochrane Collaboration’s tool for assess-
ing risk of bias in the included trials was used. Use of the
following strategies associated with good quality studies
was assessed: adequacy of sequence generation; allocation
concealment; blinding of investigators, participants, out-
come assessors, and data analysts; incomplete outcome
data; and selective outcome reporting.10
For assessing the
quality of evidence for outcomes reported in the included
studies, we chose to use the GRADE methodology and
GRADEProfiler software (GRADEpro. [Computer pro-
gram on www.gradepro.org]. Version [3.6, 2011]. McMas-
ter University, 2011). The GRADE system offers four
categories of the quality of the evidence (i.e. high, moder-
ate, low and very low).11
Heterogeneity was quantified by v2
and I2
, which can
be interpreted as the percentage of the total variation
between studies that is attributable to heterogeneity
rather than to chance. For the v2
test, P < 0.15 indicates
794 Aliment Pharmacol Ther 2015; 42: 793–801
ª 2015 John Wiley & Sons Ltd
H. Szajewska and M. Kołodziej

significant heterogeneity, and for the I2
statistic, a value
>50% indicates substantial heterogeneity. All analyses
were based on the random effects model if it was still
considered appropriate to pool the data. To test for pub-
lication bias, a test for asymmetry of the funnel plot, as
proposed by Egger et al.,12
was used if sufficient (≥10)
eligible trials were available.
Statistical methods. The data were analysed using the
Review Manager (RevMan) [Computer program, Version
5.3.; Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2014] and StatsDirect version
3.0.146 (StatsDirect Ltd, Sale, Cheshire, England) to gen-
erate forests plots and funnel plots. The binary measure
(prevalence of diarrhoea or AAD) for individual studies
and pooled statistics is reported as the risk ratio (RR)
between the experimental and control groups with 95%
confidence intervals (95% CI). The number needed to
treat (NNT), with the 95% CI, was calculated, if there
was a significant difference in the dichotomous outcome
between the groups, using the formula recommended by
the Cochrane Handbook [NNT = 1/ACR 9 (1ÀRR)],
where ACR, assumed control risk, was an average con-
trol group risk.8
Two subgroup analyses were planned
based on the study population (children and adults), the
indication for the antibiotic therapy (common infections
and antibiotic therapy as part of H. pylori eradication
therapy), and the type of antibiotics administered or
the indication. However, only the first two analyses were
feasible.
RESULTS
Figure S1 documents the identification process for eligi-
ble trials. In addition to the previously identified five
RCTs,13–17
16 new trials were included.18–33
Except for
three trials published in Chinese,18
Portuguese19
and
Spanish20
for which the translation was obtained, all of
the remaining trials were published in English. Table S1
summarises characteristics of all the included RCTs, and
Table S2 summarises characteristics of the excluded tri-
als, including the reasons for exclusion. Moreover, three
registered trials were identified. Among them, one RCT
was completed but no publication was found (EU
Clinical Trials Register, 2008-001426-14); one RCT was
terminated but the results were not published (Clini-
calTrials.gov, NCT01143272, Germany) and one RCT is
not recruiting yet (ClinicalTrials.gov, NCT01463943,
Brazil).
The 21 selected studies recruited a total of 4780 par-
ticipants (2441 in the experimental group and 2339 in
the control group) treated as in-patients and/or out-pa-
tients. Sample size calculations were only available in 11
trials. Twelve studies were placebo-controlled; in the
remaining studies, there was no intervention in the con-
trol group. Fifteen trials were performed in adults, and
six trials were performed in children.
The daily dose of S. boulardii ranged from 50 mg to
1000 mg. There was high variability in the type of
antibiotics administered, which were administered as sin-
gle drugs or in combinations. In nine RCTs, antibiotics
were administered as part of H. pylori eradication ther-
apy consisting of proton pump inhibitors and two antibi-
otics. There was variability in the definition of outcome
measures. The most commonly used definition of the
diarrhoea was the presence of three or more loose (or
watery) stools per 24 h, but criteria for its duration var-
ied from 24 h to at least 48 h (Table S1). There were
also wide differences in the duration of follow-up, which
varied from 2 weeks to 1 year after the cessation of
antibiotic treatment, or it was not specified.
The risk of bias assessment is presented in Figure S2.
Only two trials were at low risk of bias.13, 24
In the
remaining trials, the limitations included unclear random
sequence generation (14 trials), unclear or no allocation
concealment (17 trials), unclear or no blinding of partici-
pants and personnel (14 trials), unclear or no blinding of
outcome assessment (9 trials), and selective or unclear
reporting (6 trials). Intention-to-treat analysis was per-
formed in 14 trials. The GRADE assessment for out-
comes related to S. boulardii administration and
diarrhoea is presented in Tables S3 and S4. Using the
GRADE, the overall quality of evidence for all assessed
outcomes was rated as moderate to low.
Effects of interventions
Treatment with S. boulardii compared with placebo or no
treatment reduced the risk of AAD (as defined by the
study investigators) in patients treated with antibiotics
from 18.7% to 8.5% (RR: 0.47, 95% CI: 0.38–0.57, random
effect model). No significant heterogeneity was found
(v2
= 28.44, P = 0.10, I2
= 30%; Figure 1). For every 10
patients receiving daily S. boulardii with antibiotics, one
fewer would develop diarrhoea (NNT: 10, 95% CI: 9–13).
A reduction in the risk of AAD was found both in
children and adults evaluated separately. In children,
compared with placebo or no treatment, S. boulardii
reduced the risk of diarrhoea from 20.9% to 8.8% (6
RCTs, n = 1653, RR: 0.43, 95% CI: 0.30–0.60, NNT: 9,
95% CI: 7–12; Figure S3); in adults, compared with pla-
cebo or no treatment, S. boulardii reduced the risk of
Aliment Pharmacol Ther 2015; 42: 793–801 795
Systematic review with meta-analysis: S. boulardii and preventing antibiotic-associated diarrhoea

Study or Subgroup
1.1.1 Antibotics for infections in children
Kotowska 500 mg
Erdeve 250 mg
Shan 500 mg
Casem 500 mg
Subtotal (95% CI)
Total events
Heterogeneity: Tau2 = 0.13; Chi2 = 5.60, df = 3 (P = 0.13); I2 = 46%
Test for overall effect: Z = 3.78 (P = 0.0002)
1.1.2 Antibotics as part of eradication therapy in children
Bin 250 mg
Zhao 250 mg
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.00; Chi2 = 0.50, df = 1 (P = 0.48); I2 = 0%
1.1.3 Antibotics for infections in adults
Can 500 mg
Adam 200 mg
Chu 250 mg
Zojaji 250 mg
Surawicz 1000 mg
McFarland 1000 mg
Monteiro ? mg
Bravo 500 mg
Pozzoni 500 mg
Lewis 226 mg
Subtotal (95% CI)
Total events
1.1.4 Antibotics as part of eradication therapy in adults
Kyriakos 50 mg
Cremonini 500 mg
Duman 1000 mg
Cindoruk 1000 mg
Song 750 mg
Subtotal (95% CI)
Total events
Test for overall effect: Z = 4.16 (P < 0.0001)
Total (95% CI)
Total events
Test for overall effect: Z = 7.69 (P < 0.00001)
Test for subgroup differences: Chi2 = 1.74, df = 3 (P = 0.63), I2 = 0%
Events
4
14
6
11
35
12
27
39
1
9
3
21
11
7
19
3
16
7
97
1
1
14
9
11
36
207
Total
132
244
167
69
612
105
120
225
73
199
50
80
116
97
121
41
141
33
951
36
21
196
62
330
645
2433
Events
22
42
18
16
98
26
47
73
7
33
8
55
14
14
33
5
13
5
187
7
6
28
19
20
80
438
Total
137
222
166
71
596
100
120
220
78
189
50
80
64
96
119
45
134
36
891
34
20
180
62
331
627
2334
Weight
2.9%
6.9%
3.7%
5.5%
19.1%
6.3%
10.2%
16.4%
0.8%
5.3%
2.1%
10.3%
5.1%
4.0%
8.1%
1.8%
5.5%
2.9%
45.8%
0.9%
0.9%
6.5%
5.3%
5.2%
18.7%
100.0%
M-H, Random, 95% CI
0.19 [0.07, 0.53]
0.30 [0.17, 0.54]
0.33 [0.13, 0.81]
0.71 [0.35, 1.41]
0.36 [0.21, 0.61]
0.44 [0.23, 0.82]
0.57 [0.39, 0.86]
0.53 [0.38, 0.74]
0.15 [0.02, 1.21]
0.26 [0.13, 0.53]
0.38 [0.11, 1.33]
0.38 [0.26, 0.57]
0.43 [0.21, 0.90]
0.49 [0.21, 1.17]
0.57 [0.34, 0.94]
0.66 [0.17, 2.58]
1.17 [0.59, 2.34]
1.53 [0.54, 4.35]
0.52 [0.36, 0.73]
0.13 [0.02, 1.04]
0.16 [0.02, 1.20]
0.46 [0.25, 0.84]
0.47 [0.23, 0.96]
0.55 [0.27, 1.13]
0.45 [0.31, 0.66]
0.47 [0.38, 0.57]
SB Control Risk Ratio
Risk of bias legend
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
+ + + + + +
? ? ? ? ? –
+ + – ? ? +
+ – – ? + +
? ? ? ? + –
? ? – – ? –
? ? + + + +
? ? ? ? ? +
? ? – + ? +
? ? – + ? +
? ? + + – ?
? ? ? ? ? +
? ? ? ? ? –
? ? + + + +
+ + + + + +
? ? ? ? + –
? ? – + ? +
+ + + + ? +
? ? – + ? +
+ ? + + ? +
+ ? – + – +
Risk of Bias
A B C D E F
Risk Ratio
M-H, Random, 95% CI
0.005 0.1 1 10 200
Favours S. boulardii Favours control
Figure 1 | Effect of Saccharomyces boulardii for preventing antibiotic-associated diarrhoea.

diarrhoea from 17.4% to 8.2% (15 RCTs, n = 3114, RR:
0.49, 95% CI: 0.38–0.63, NNT: 11, 95% CI: 9–15; Fig-
ure S4). Moreover, both in children and adults, pre-
planned subgroup analyses showed a reduction in the
risk of diarrhoea associated with antibiotic treatment,
regardless of the reason for which the antibiotics were
used (i.e. as part of H. pylori eradication or for other
reasons; Figure 1).
Eleven trials13, 15–17, 20, 21, 24, 25, 27, 29, 30
evaluated
the effect of S. boulardii in the prevention of C. difficile-
associated diarrhoea. Among them, two RCTs were per-
formed in children.13, 25
Overall, the risk of documented
C. difficile-associated diarrhoea was lower in the
S. boulardii group compared with the placebo group, but
the difference was not significant (n = 2020, RR: 0.64,
95% CI: 0.39–1.04, random effect model). No significant
heterogeneity was found (v2
= 9.56, P = 0.39, I2
= 6%).
However, subgroup analysis based on age, showed that
the administration of S. boulardii reduced the risk of
C. difficile-associated diarrhoea in children (two RCTs,
n = 579, RR: 0.25, 95% CI: 0.08–0.73), but not in adults
(nine RCTs, n = 1441, RR: 0.80, 95% CI: 0.47–1.34;
Figure 2).
Based on the findings from six RCTs, there was no
need for discontinuation of antibiotic treat-
ment.13, 22, 25, 27, 28, 32
Based on data from two RCTs,
there was no need for hospital treatment because of diar-
rhoea in the out-patients or intravenous rehydration in
any of the study groups.13, 22
Adverse events. Data regarding therapy-related adverse
effects were available from 16 of the included
Study or Subgroup
2.1.1 S. boulardii for preventing C. difficile-associated diarrhea in adults
Bravo 500 mg
Can 500 mg
Duman 1000 mg
Surawicz 1000 mg
Cindoruk 1000 mg
McFarland 1000 mg
Pozzoni 500 mg
Kyriakos 50 mg
Lewis 226 mg
Subtotal (95% CI)
Total events
2.1.2 S. boulardii for preventing C. difficile-associated diarrhea in children
Shan 500 mg
Kotowska 500 mg
Subtotal (95% CI)
Total events
Total (95% CI)
Total events
Test for subgroup differences: Chi2 = 3.67, df = 1 (P = 0.06), I2 = 72.7%
Events
0
0
0
3
6
3
3
3
5
23
1
3
4
27
Total
41
73
196
116
21
97
141
34
33
752
167
119
286
1038
Events
0
2
1
5
8
4
2
2
3
27
8
10
18
45
Total
45
78
180
64
20
96
134
36
36
689
166
127
293
982
Weight
2.6%
2.3%
11.4%
27.0%
10.4%
7.3%
7.7%
12.2%
80.8%
5.4%
13.7%
19.2%
100.0%
M-H, Random, 95% CI
Not estimable
0.21 [0.01, 4.37]
0.31 [0.01, 7.47]
0.33 [0.08, 1.34]
0.71 [0.30, 1.69]
0.74 [0.17, 3.23]
1.43 [0.24, 8.40]
1.59 [0.28, 8.93]
1.82 [0.47, 7.02]
0.80 [0.47, 1.34]
0.12 [0.02, 0.98]
0.32 [0.09, 1.14]
0.25 [0.08, 0.73]
0.64 [0.39, 1.04]
SB Control Risk Ratio
Risk of bias legend
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
? ? + + + +
? ? + + + +
? ? – + ? +
? ? + + – ?
+ ? + + ? +
? ? ? ? ? +
+ + + + + +
? ? – + ? +
? ? ? ? + –
+ + – ? ? +
+ + + + + +
Risk of Bias
A B C D E F
Risk Ratio
M-H, Random, 95% CI
0.01 0.1 1 10 100
Favours S. boulardii Favours control
Figure 2 | Effect of Saccharomyces boulardii for preventing Clostridium difficile-associated diarrhoea.

trials.13–17, 20, 22, 24–31, 33
In these trials, S. boulardii was
well tolerated. Adverse events rate was similar in experi-
mental and control groups.
Publication bias. The funnel plot for publication bias is
presented in Figure S5. There was no evidence of publi-
cation bias among trials on S. boulardii and AAD.
DISCUSSION
Summary of evidence
This systematic review and meta-analysis has confirmed
our previous findings that S. boulardii administration,
concomitantly with antibiotics, compared with placebo
or no intervention, reduces the risk of AAD in adults
and children treated with antibiotics for any reason. The
NNT to avoid one case of AAD was 10. There is also
evidence that S. boulardii may reduce the risk of C. diffi-
cile-associated diarrhoea; however, this finding was sig-
nificant only in a subgroup of children and the wide
confidence interval calls for caution. For all outcomes,
the GRADE quality of evidence assessment revealed
moderate to low quality of evidence. One characteristic
that makes our meta-analysis distinct from other reviews
is that it focuses exclusively on only one well-defined
probiotic, S. boulardii; thus, the findings can be directly
applied to clinical practice.
The mechanism by which S. boulardii exerts its action
in preventing AAD and C. difficile-associated diarrhoea
remains unclear. However, a number of mechanisms have
been suggested, as discussed in detail elsewhere.34, 35
One
of the mechanisms, which has been demonstrated in ani-
mals, involves the production of a 54 kDa serine protease
that inactivates a receptor for toxin A of C. difficile and
directly degrades C. difficile toxins A and B.36
Another
mechanism involves secretion of increased levels of secre-
tory immunoglobulin A (IgA) and IgA antitoxin A.37
Moreover, both in vitro and in vivo studies have shown
that S. boulardii exerts its anti-inflammatory activity, in
part, by modulating host MAP kinase signalling pathways.
In particular, S. boulardii-conditioned media inhibited IL-
8 production induced by either IL-1b or toxin A in a dose-
dependent fashion.38
Additional mechanisms include
competition for attachment sites and blocking C. difficile
adherence to cells in vitro.39, 40
Strengths and limitations
An important strength of this systematic review and
meta-analysis is the use of rigorous methodology devel-
oped by the Cochrane Collaboration. We employed sev-
eral methods to reduce bias (i.e. comprehensive literature
search, pre-specified criteria for methodological assess-
ment and analysis, no restrictions by language or year of
publication, attempts to identify unpublished trials).
However, one major limitation is that the methodological
quality of the included trials varied. Only two trials were
at low risk of bias. Finally, an important limitation is the
difference in how AAD and/or diarrhoea were defined in
the included trials. We noted a small sample size and
lack of sample size calculations in many trials; however,
the total sample size in the meta-analysis was sufficient
to draw trustworthy conclusions.
Agreement and disagreement with other studies or
reviews
Our findings add to an accumulated body of evidence
from previously published meta-analyses, which docu-
mented that treatment with probiotics compared with
placebo or no treatment reduces the risk of AAD in chil-
dren and adults.41–44
The effect size was comparable with
one shown by us in the current meta-analysis. In large
part, these meta-analyses pooled data on various probi-
otics. However, in the meta-analysis by Hempel et al.,
subgroup analysis based on the probiotic genus was per-
formed. This subgroup analysis of 16 RCTs showed that
a yeast-based intervention [Saccharomyces boulardii
(cerevisiae) or Hansen CBS 5926] reduced the risk of
AAD by 52% (RR: 0.48, 95% CI: 0.35–0.65). Similar to
our meta-analysis, trials in which antibiotics were used
as part of H. pylori eradication therapy, typically consist-
ing of proton pump inhibitors and two antibiotics, were
included. However, there is evidence that the use of pro-
ton pump inhibitors, which are part of H. pylori eradica-
tion regimens, increases the risk of gastrointestinal (and
respiratory) tract infections.45, 46
Thus, our approach
was to report the evidence on the effect of S. boulardii
as supplementation to H. pylori eradication therapy sepa-
rately. Collectively, these data support the use of
S. boulardii for the prevention of diarrhoea associated
with antibiotic treatment, regardless of the reason for
which the antibiotics were used.
Implications for practice
With regard to specific recommendations, one important
question remains whether the use of S. boulardii should
be considered in all subjects receiving antibiotics or only
in select populations. The findings of our meta-analysis
apply to patients similar to those enrolled in the trials.
Both children and adults were well represented, except
for those of extreme ages (<6 months and >65 years).

The decision of whether to treat or not to treat a very
young or an older individual will require clinical judge-
ment. In clinical trials, S. boulardii was safe and well tol-
erated, also in those of extreme ages. However, special
concern is needed in specific populations such as
immune-compromised subjects or in patients with other
life-threatening illnesses managed in intensive care units.
In those populations, S. boulardii can cause fungaemia.47
Risk factors for developing AAD include the type of
antimicrobials used. The results of this meta-analysis
show that S. boulardii significantly reduces the risk of
diarrhoea in patients treated with antibiotics in general.
However, they do not allow conclusions about the effi-
cacy of S. boulardii in preventing diarrhoea attributable
to any single antibiotic class. Again, the decision to treat
or not to treat an individual treated with a specific
antibiotic with S. boulardii will require clinical judge-
ment.
The optimal dose of probiotics, including S. boulardii,
has not been established. However, at least one recent
study showed that probiotic efficacy improves in a dose-
dependent manner.48
In the current systematic review
and meta-analysis, various doses of S. boulardii were
used with no clear dose-dependent effect. Until more
data on the optimal dose of S. boulardii become avail-
able, a daily dose of not less than 250 mg but not more
than 500 mg in children and not more than 1000 mg in
adults could be used to match the doses used in RCTs.
To match clinical trials showing a clear benefit,
S. boulardii administration should be started early in the
course of antibiotic treatment before alteration of the gut
flora and overgrowth of pathogens occurs. Based on the
published trials, it seems appropriate to continue the
administration of S. boulardii for the duration of antibi-
otic treatment. Whether longer administration is neces-
sary is not clear, as S. boulardii was administered after
cessation of antibiotic therapy in only two RCTs with no
clear benefit. On the other hand, as diarrhoea may occur
up to several months following cessation of such treat-
ment, some cases of AAD may have been missed.
CONCLUSIONS
As numerous different probiotic products are available, it
is important to know the efficacy of a specific product,
not of probiotics in general. The current meta-analysis
helps to resolve such uncertainty. In cases in which an
antibiotic is recommended, moderate quality evidence
showed that the use of S. boulardii reduced the risk of
AAD. The findings apply to both children and adults.
Even if included trials reported no adverse effects related
to S. boulardii, its consumption is not without risk in
specific patient groups such as immunocompromised
subjects or in patients with other life-threatening ill-
nesses managed in the intensive care unit.47
Although
available data are encouraging, it seems that the prudent
use of antibiotics remains the best method of preventing
AAD.
AUTHORSHIP
Guarantor of the article: HS.
Author contributions: HS initially conceptualised this
study. Both authors were responsible for data collection,
data analysis, data interpretation and preparation of the
report. HS assumed the main responsibility for the writ-
ing of this manuscript. Both authors contributed to (and
agreed upon) the final version.
ACKNOWLEDGEMENTS
Declaration of personal interests: HS has served as a
speaker for Biocodex, the manufacturer of S. boulardii.
MK declares no conflict of interest.
Declaration of funding interests: This study was funded
in full by the Medical University of Warsaw.
SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Identification process for eligible trials.
Figure S2. Methodological quality summary.
Figure S3. Effect of S. boulardii for preventing antibi-
otic-associated diarrhoea in children.
Figure S4. Effect of S. boulardii for preventing antibi-
otic-associated diarrhoea in adults.
Figure S5. Funnel plot for publication bias.
Table S1. Characteristics of the included studies.
Table S2. Characteristics of the excluded studies.
Table S3. GRADE evidence profile summarising the
effect of Saccharomyces boulardii supplementation vs.
placebo or no intervention on antibiotic-associated diar-
rhoea.
Table S4. GRADE evidence profile summarising the
effect of Saccharomyces boulardii supplementation vs.
placebo or no intervention on Clostridium difficile-associ-
ated diarrhoea.

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