WageningenAcademic

P u b l i s h e r s

Beneficial Microbes, September 2012; 3(3): 189-194

Cost/benefit of synbiotics in acute infectious gastroenteritis: spend to save

Y. Vandenplas1, S. De Hert2 and the Probiotical study group
1Universitair

KinderZiekenhuis Brussel, Department of Pediatrics, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090
Brussels, Belgium; 2Department of Anaesthesiology, UZ Gent, De Pintelaan 185, 9000 Ghent, Belgium;
yvan.vandenplas@uzbrussel.be
Received: 8 February 2012 / Accepted: 3 May 2012
2012 Wageningen Academic Publishers

Abstract
The cost/benefit ratio of probiotics in the ambulatory treatment of acute infectious gastro-enteritis with or without a
synbiotic food supplement (containing fructo-oligosaccharides and probiotic strains of Streptoccoccus thermophilus,
Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacterium lactis and Bifidobacterium infantis) has been
studied. 111 children (median age 37 and 43 months for the synbiotic and placebo group, respectively) with acute
infectious gastroenteritis were included in a randomised, prospective placebo-controlled trial performed in primary
health care. All children were treated with an oral rehydration solution and with the synbiotic food supplement
(n=57) or placebo (n=54). Physicians were allowed to prescribe additional medication according to what they
considered as necessary. Cost of add-on medication and total healthcare cost were calculated. Median duration of
diarrhoea was 1 day shorter (95% confidence interval -0.6 to -1.9 days) in the symbiotic than in the placebo group
(P<0.005). Significantly more concomitant medication (antibiotics, antipyretics, antiemetics) was prescribed in the
placebo group (39 prescriptions in 28 patients) compared to the synbiotic group (12 prescriptions in 7 patients)
(P<0.001). The difference was most striking for antiemetics: 28 vs. 5 prescriptions. The cost of add-on medication in
the placebo group was evaluated at 4.04/patient (median 4.97 (interquartile (IQ) 25-75: 0-4.97)) vs. 1.13 /patient
in the synbiotic arm (P<0.001). If the cost of the synbiotic is considered, median cost raised to 7.15/patient (IQ
25-75: 7.15-7.15) (P<0.001). The extra consultations needed to prescribe the concomitant medication resulted in a
higher health care cost in the placebo group ( 14.41 vs. 10.74/patient, P<0.001). Synbiotic food supplementation
resulted in a 24 h earlier normalisation of stool consistency. Although use of the synbiotic supplementation increased
cost, add-on medication and extra consultations were reduced, resulting in a reduction of health care cost of 25%.
Keywords: acute diarrhoea, acute gastroenteritis, benefit, cost, prebiotic, probiotic, synbiotic

1. Introduction
Recommended treatment of acute infectious diarrhoea
consists of oral rehydration solution (ORS) to correct
dehydration. ORS has reduced the incidence of mortality
and morbidity caused by diarrhoea but it does not shorten
its duration, as it does not change the consistency of the
stools and does not normalise gastrointestinal flora (Sazawal
et al., 2006). Probiotics are living microorganisms that
survive in the gastrointestinal tract and, when ingested in
sufficiently large amount, confer a health benefit on the
host. The European Society for Paediatric Gastroenterology,

Hepatology and Nutrition (ESPGHAN) stated that some

strains of probiotics may be an effective adjunct to the
management of acute infectious gastroenterititis (Guarino
et al., 2008). We showed recently that a synbiotic food
supplement (Table 1) reduced the median duration of
diarrhoea in children with acute infectious gastroenteritis
with one day (Vandenplas et al., 2011). The number of
children with normal stool consistency was higher in
the symbiotic group on day 2 and 3 (Vandenplas et al.,
2011). However, it is still debated if the 24 hour reduction
in diarrhoea compensates for the cost of a probiotic or
synbiotic product. Therefore, we compared the need for

ISSN 1876-2833 print, ISSN 1876-2891 online, DOI 10.3920/BM2012.0007189

Y. Vandenplas et al.
Table 1. Composition of the synbiotic food supplement.1
Compound

Probiotic species2

Streptococci
Lactobacilli

Streptococcus thermophilus
Lactobacillus rhamnosus
Lactobacillus acidophilus
Bifidobacterium infantis
Bifidobacterium lactis

Bifidobacteria

Weight

Fructo-oligosaccharides
Ascorbic acid
1

20 mg
1.2 mg

Cost: 7.15/10 capsules.

total: 6.5109 cfu/capsule.

2 In

add-on medication and extra consultations in the treatment

of acute diarrhoea in children and compared the costs in
both treatment arms.

2. Material and methods

This randomised, prospective, double-blind placebo
controlled trial was conducted in children (age between 3
and 186 months) presented in ambulatory care in Belgium
(Table 2) between April and December 2010. Infants
presenting an episode of mild to moderate acute diarrhoea
(3 (semi-)watery stools/day according to Bristol criteria
(Bristol criteria 6) of likely infectious origin since at least
one day and lasting less than or equal to 7 days, were eligible
for inclusion. The number of children having more than 3
days diarrhoea was similar in both groups before inclusion.
Dehydration was evaluated on clinical grounds and
estimated weight loss. Patients had to be mild and
moderately dehydrated (Guarino et al., 2008). Exclusion
criteria concerned both chronic conditions (e.g.
known chronic uncontrolled intestinal disease such as
Table 2. Clinical and demographical composition of the study
group.
Synbiotic group Placebo group
(n=57)
(n=54)
Gender (m/f)
Age (months)1
Weight (kg)1
Diarrhoea duration before
inclusion (days)1
Number of children with diarrhoea
>3 days before inclusion
Dehydration >5%
1

29/28
37 (2-186)
16.4 (5.9-75.0)
1 (1-7)

27/27
43 (1-159)
17.0 (4.9-38)
1 (1-6)

12

11

Data are expressed as median with range.

190

coeliac disease, cystic fibrosis, food allergy, immune

deficiency, inflammatory bowel disease, gastrointestinal
malformations, abnormal gastrointestinal motility) and
more acute conditions (antibiotic treatment during the
preceding 7 days, the presence of macroscopic blood
in the faeces, use of probiotic products except for the
probiotics present in infant formula if the patient developed
the diarrhoea while being fed with this formula). More
details regarding inclusion and exclusion criteria were
published elsewhere (Vandenplas et al., 2011). All patients
were treated according to recommendations with the same
hypo-osmolar oral rehydration solution (ORS) ad libitum
(Soparyx; Melisana, Brussels, Belgium; Na+ 60, Cl- 50,
K+ 20, and citrate 10 mmom/l; osmolarity 140 mmol/l)
(Guarino et al., 2011; Thomas and Greer, 2010). Every
participating physician was active in primary health care
and received 10 blinded treatments. The synbiotic product
(Probiotical) and placebo were supplied by Phacobel
(Tinlot, Belgium) that had no role in the concept, design,
or conduct of the study nor in the analysis or interpretation
of the data. The active product and placebo were packed
in identical boxes, that had the same colour, weight, smell,
and taste. Parents were instructed not to give additional
over-the-counter (OTC) medication without prior contact
with the treating physician. The primary endpoint was the
duration of diarrhoea and the number of children that had
a normalised stool consistency according to the Bristol
criteria (stool score 4) during the study. Normalisation
of stool consistency is the equivalent for the duration of
diarrhoea.
Randomisation for every participating physician was done
by computer. Patients were enrolled according to the
computer-determined allocation to synbiotic and placebo.
Random allocation was made in blocks of ten to obtain
groups of similar size. The sequence was concealed until
treatments were assigned. Participating physicians had
to open a neutral envelope to know to which group the
patient was allocated. The synbiotic group received the
synbiotic product (Probiotical, Phacobel) and the placebo
group received the placebo at 1 capsule/day for 7 days. The
unblinding procedure was performed after the study was
completed and after the statistical analyses were finalised.
It was impossible for the physician and patient to know to
which treatment arm (active product versus placebo) they
had been allocated. On day 4, which is the average duration
of diarrhoea, physicians were asked to assess satisfaction
with treatment outcome. According to the protocol, it
was planned that physicians were allowed to prescribe
additional medication according to what they would
consider good clinical practice, if the response of the patient
to the study treatment (ORS and synbiotic or placebo)
was insufficient. It was hypothesised that prescription of
concomitant medication should not differ between both
groups if efficacy of active product and placebo would be
Beneficial Microbes 3(3)

Cost/benefit of synbiotics in acute infections of gastroenteritis

similar. Physicians were asked to register every concomitant

medication prescribed between the start of the trial and the
recovery of the diarrhoea. Health care cost was calculated
and compared for both groups.
Only an intention to treat analysis was performed.
Statistical significance was accepted at P<0.05. MannWhitney U-test and Chi-square or Fishers exact tests were
performed as appropriate.

3. Results
No physician reported on day 4 that treatment outcome
was unacceptable or poor in a patient. However, overall,
physicians were more satisfied with the synbiotic food
supplement than with placebo (P=0.005) (Table 3).
Compliance of intake of medication in both treatment
arms was excellent. Prescription of concomitant medication
was limited to antipyretics, antiemetic medication and
antibiotics. Antidiarrhoea medication such as adsorbants,
antisecretory drugs and motility inhibitors, was not used.
Additional medication was significantly prescribed to
more patients in the placebo group (28/54 patients, 52%)
compared to the synbiotic group (7/57 patients, 12%)
(P<0.001). Significantly more concomitant medication was
Table 3. Treatment satisfaction as estimated by the parents
and physicians on day 4.1
n (%)

Synbiotic group

Placebo group

Patients2
Poor
Acceptable
Good
Very good
Excellent

55
0 (0%)
0 (0%)
8 (14.5%)
24 (43.6%)
23 (41.8%)

53
0 (0%)
4 (7.5%)
15 (28.3%)
25 (47.2%)
9 (16.9%)

Outcome of treatment was always assessed as at least acceptable by

the physicians.
2 Parents of 3 patients did not provide information on satisfaction. Global
satisfaction was better in the synbiotic group than in the placebo group
(P=0.005).

prescribed in the placebo arm (39 prescriptions) compared

to the synbiotic product group (12 prescriptions) (P<0.001)
(Table 4). The difference was most striking for antiemetics:
28 prescriptions in the placebo group of 54 patients vs. 5
prescriptions in the synbiotic group of 57 patients. It cannot
be excluded that the difference in antiemetic medication
is related to different pathogens, which was not evaluated.
Antibiotics tended to be more frequently prescribed in the
placebo group, 6 (0.11/patient) in the placebo group versus
only 1 (0.02/patient) in the synbiotic group (P=0.0563).
There was no difference in prescription of antipyretics
between both groups.
For cost calculation (2012 prices), the most popular
compound in each class of medication was considered:
antipyretic (Perdolan syrup (paracetamol), cost 7.10/200
ml; Janssen-Cilag, Tilburg, the Netherlands), antiemetic
(Motilium Paediatric Syrup (domperidone), cost 4.97/100
ml; Janssen-Cilag), antibiotic (amoxicillin syrup 250 mg/5
ml, cost 7.27/100 ml). As a result, the cost of concomitant
medication in the placebo group is 4.04/patient vs.
1.13/patient in the synbiotic treatment arm (P<0.001).
However, because the cost of the synbiotic product is
7.15/10 capsules, the total cost in the synbiotic treatment
arm reaches 8.28/patient (P<0.001) (Table 5).
However, not only the cost of extra medication should
be considered, but also the costs of extra consultations.
We hypothesised that each patient to whom concomitant
medication was prescribed would need (at least) one
additional consultation. In Belgium, primary health care
for children is carried out by general practitioners and
paediatricians. The consultation cost of a paediatrician is
approx. 35 and of a general practitioner approx. 20. In
this study we considered that all consultations were done
by general practitioners: 28 extra consultations increase
health care cost with 560 in the placebo group, resulting
in an extra cost of 10.37/patient and a total healthcare
cost of 14.41/patient. In the synbiotic treatment group,
7 extra consultations result in an extra cost of 140 and a
total cost of 10.74/patient (P<0.001). Extra healthcare cost
in daily routine may even be higher than calculated. As the
participating physicians were all very motivated, there were
no visits to the emergency room. In daily routine, it can

Table 4. Prescription incidence of concomitant medication.

Synbiotic group
Placebo group
P-value1
1 NS

Antipyretics
n (% patients)

Antiemetics
n (% patients)

Antibiotics
n (% patients)

Total medication
n (% patients)

6 (10%)
5 (9%)
NS

5 (9%)
28 (52%)
<0.001

1 (2%)
6 (11%)
NS

7 (12%)
28 (52%)
<0.001

= not significant.

Beneficial Microbes 3(3)

191

Y. Vandenplas et al.
Table 5. Health care cost (/patient).
Synbiotic group
Cost of add-on medication (mean)
Cost of all medications
Mean
Median
Interquartile 25-75
Range
Cost extra consultation/patient (mean)
Total healthcare cost (mean)

1.13
8.28
7.15
7.15-7.15
7.15-26.49
2.46
10.74

be hypothesised that part of the children with persisting

symptoms will be presented to emergency units, with higher
costs induced by emergency physicians, paediatricians,
nurses, etc. The cost of the initial consultation was not
considered, as every patient obviously would need this.
Also the cost of the scheduled consultation on day 4 was
not considered, as this was part of the study design.
One patient in the placebo group needed to be hospitalised
(Vandenplas et al., 2011). We did not consider the extra
cost caused by this hospitalisation. Cost of hospitalisation
differs among hospitals, but are over 100/day. This cost of
even only one patient out of a group of 54 patients (placebo
group) on the total health care cost (compared to zero
hospitalisations in the synbiotic group) is substantial, as
total cost of ambulatory care for the 54 patients in the
placebo group was calculated at 860. We did not consider
indirect costs, such as missing work days by the parents,
related to the fact that children suffered diarrhoea one day
more or less at home.

4. Discussion
In Europe, probiotics are advised along with appropriate
rehydration and patient education in the management of
acute diarrhoea in childhood (Guarino et al., 2008). The
number of children with diarrhoea lasting longer than
3 days before inclusion was comparable in both groups.
Data from a study with Saccharomyces boulardii suggest
that the sooner probiotics are started in the course of an
acute gastroenteritis, the better the outcome (Villaruel
et al., 2007). The finding that no physician scored
treatment outcome as poor or unsatisfactory in both
groups, strengthens the hypothesis that outcome of acute
gastroenteritis is excellent in industrialised countries and
supports the idea that probiotics are merely used to fulfil a
parental demand for medication. The fact that in primary
health care hardly ever an adverse event of probiotics has
been reported, seems to justify this choice. However, if
physicians were asked to quantify the degree of satisfaction
as poor, acceptable, good, very good and excellent, outcome
in the synbiotic treatment arm was evaluated significantly
192

Placebo group
4.04
4.04
4.97
0-4.97
0-19.34
10.37
14.41

P-value
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001

better. Until now, satisfaction of physicians was not assessed

in similar studies.
Few attempts have been made to evaluate the cost
of probiotics or synbiotics in the treatment of acute
gastroenteritis. In a study comparing S. boulardii with
yoghurt fluid, yogurt treatment was cheaper than S.
boulardii in ambulatory care, whereas in hospitalised
patients treatment the cost was similar (Eren et al., 2010).
Dinleyici et al. (2011) calculated the cost of S. boulardii
as add-on in children less than 5 years old with acute
rotavirus gastroenteritis (RVGE) in Turkey. The pharmacoeconomic model consisted of a theoretical scheme offering
the possibility to conduct simulations of health processes
associated with costs of first line and emergency care visits,
hospitalisations and medication through estimates obtained
from data available from clinical trials performed in Turkey.
There were 1,317,000 births in Turkey (in 2008), and 482,896
RVGE cases in children under 5 years of age. The authors
hypothetically subdivided all RVGE cases that were seen
by general practitioners, at emergency care units or needed
hospitalisations in two equal groups. Cost was calculated
in the first group with add-on S. boulardii to conventional
treatment (oral rehydration therapy, intravenous fluids, etc.)
and in the second group without S. boulardii. If S. boulardii
would be administered in all RVGE cases in children under
5 years of age during one year, the additional cost caused
by S. boulardii are US $ 1,860,014. However, the total cost
of RVGE would be reduced to US $ 78,568,164 from US $
87,869,690 hypothesising one day less diarrhoea and one day
less hospitalisation as a result of S. boulardii administration
(Dinleyici et al., 2011). These findings can be extrapolated
to all cases of diarrhoea due to viral origin.
In our study, duration of diarrhoea was reduced by one
day in the synbiotic treatment group (Vandenplas et al.,
2011). Although the difference in children more than 5%
dehydrated was not significant, it cannot be excluded that
the higher trend in the placebo group (8/54) compared to
the synbiotic group (5/57) has interfered with the increased
healthcare cost. Prescription of add-on medication was
limited to antipyretics, antibiotics and antiemetics.
Beneficial Microbes 3(3)

There was no difference in the prescription rate for

antipyretics. Although the prescription of antibiotics is
not recommended in the treatment of acute gastroenteritis
(Basu et al., 2007), they were prescribed in 11% in the
placebo group vs. 2% in the synbiotic group. It is likely
that the longer duration of diarrhoea and possibly also the
vomiting in the placebo group contributed to the higher
prescription rate of antibiotics in this group. One relevant
conclusion of this study is that antibiotic prescription by
general practitioners and paediatricians is still elevated. As
a consequence, appropriate educational campaigns should
be considered.
Vomiting is a predominant symptom in children with acute
gastroenteritis, but antiemetics are not recommended in
the treatment. Therefore, parents were instructed not to
give OTC-medication. According to an Italian survey, the
majority of responders reported prescribing of antiemetics
for paediatric gastroenteritis (Albano et al., 2006). Although
there is insufficient evidence to justify the use of antiemetics,
their use is widely present among paediatricians (Albano et
al., 2006). According to data from Canada, France, Germany,
Italy, Spain, UK and USA, between 2% and 23% of children
with an acute gastro-enteritis receive prescriptions for
antiemetic medications (Pfeil et al., 2008). Ondansetron, the
only drug with evidence-based antiemetic efficacy in acute
gastroenteritis, is prescribed in few cases (Pfeil et al., 2008).
However, diarrhoeal episodes increased in several studies
with ondansetron (DeCamp et al., 2008). In other words,
epidemiologic data suggest a broad use of domperidone
to treat emesis in acute gastroenteritis, although there
are no data suggesting efficacy. Our study shows that the
prescription rate of antiemetics was significantly lower in
the synbiotic group, suggesting that vomiting was more
important in the placebo group: 52% of children in the
placebo group were given antiemetics compared to 9% in
the synbiotic group (P<0.001). Few other studies evaluated
vomiting, but data available confirm a strong reduction of
vomiting induced by probiotics (Grandy et al., 2010). When
the primary outcome of the probiotic on the duration of
diarrhoea is negative, there is also no impact on vomiting
(Basu et al., 2007). To our knowledge, our study is the
first that looked at the use of antiemetic medication in a
prospective placebo-controlled study evaluating probiotics
in paediatric acute gastroenteritis. These findings are of
interest, as according to recent data from the USA and
Canada, use of probiotics remains uncommon, while
ondansetron administration has become routine (Freedman
et al., 2011). Indirect evidence for an effect of probiotics on
upper gastro-intestinal motility comes from data of Indrio
et al. (2011) showing that Lactobacillus reuteri accelerates
gastric emptying and reduces regurgitation in infants.
To the best of our knowledge, this study is the first to report
on the health care cost related to the administration of
probiotic products in the treatment of acute gastroenteritis.
Beneficial Microbes 3(3)

Cost/benefit of synbiotics in acute infections of gastroenteritis

It is very likely that we have underestimated the cost related

to contacts with health care professionals, because we
have hypothesised that only one extra consultation was
sufficient in all children needing additional medication.
Moreover, we have hypothesised that each contact would
be a regular visit to a general practitioner, while in reality
many consults would be by appointment, at an emergency
room or with a specialist that are all more expensive. We
have calculated the global cost and not the reimbursed and
not-reimbursed costs, because these differ from country
to country and for each individuals insurance. However,
reimbursed or not, the global cost of treatment is the cost
that should be considered. We could demonstrate that
systematic prescription of the synbiotic product tested
reduced the need for an additional consult with 77% (52%
vs. 12%), the need for additional medication with 71% (72%
vs. 21%), and reduced health care cost with 25% ( 14.41
vs. 10.74/patient).
In conclusion, although the total medication cost (including
cost of probiotics) is two-fold higher in synbiotic-treated
patients, this is more than compensated for by the lower
cost as a consequence of less frequent consultation in this
group compared to placebo-treated patients.

Acknowledgements
Phacobel Belgium provided the test products (synbiotic
and placebo). The Probiotical study group comprised
of D. Abrassart, F. Adriaens, N. Balduck, G. Biart, J.-M.
Carbonnelle, C. Dauge, P. David, U. Ehrentreich, G. Feron,
F. Garbentz, D. Gob, R. Graindorge, B. Hins, A. Hutsebaut,
S. Jacquart, I. Jacquemart, C. Leblanc, A.-L. Lenoir, C.
Lietaer, K. Logghe, A.-S. Loicq, S. Nouri, J. Poncelet, A. Van
Damme, D. Van Damme, L. Van De Vyver, A. Verbist, M.
Verboven, I. Verheyden and S. Ballard, Belgium.

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