Clinical Microbiology and Infection 25 (2019) 699e704

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Clinical Microbiology and Infection

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Original article

Lactobacillus reuteri DSM 17938 in the prevention of

antibiotic-associated diarrhoea in children: a randomized clinical trial
M. Kołodziej, H. Szajewska*
Department of Paediatrics, The Medical University of Warsaw, Poland

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: To assess the effectiveness of Lactobacillus reuteri DSM 17938 for the prevention of diarrhoea
Received 26 July 2018 and antibiotic-associated diarrhoea (AAD) in children.
Received in revised form Methods: Hospitalized children who received antibiotics were assigned by a computer-generated list to
14 August 2018
receive L. reuteri (at 2
108 CFU) or placebo, twice daily, for the duration of antibiotic treatment. Follow
Accepted 15 August 2018
Available online 25 August 2018
up was for 1 week after antibiotic cessation. The primary outcome measures were diarrhoea and AAD.
Both were defined according to one of three definitions (i) three or more loose or watery stools per day
Editor: L. Leibovici for 48 h; (ii) three or more loose or watery stools per day for 24 h; or (iii) two or more loose or watery
stools per day for 24 h. For AAD, it had to be diarrhoea caused by Clostridium difficile or otherwise
Keywords: unexplained diarrhoea.
Antibiotic Results: A total of 250 children were randomized and 247 were analysed (L. reuteri n ¼ 123, placebo
Lactobacillus reuteri n ¼ 124; median age 4 months). The occurrences of diarrhoea and AAD were similar in both groups,
Randomized clinical trial regardless of the definition used. Using the strictest definition (i.e. definition (i)), the occurrence of
Diarrhea
diarrhoea in the L. reuteri group was 25 (20%) compared with 16 (13%) in the placebo group (absolute risk
Children
reduction e0.07 (e0.17 to 0.02). The occurrence of AAD was 14 (11.4%) in the L. reuteri group compared
with 8 (6.5%) in the placebo group (absolute risk reduction e0.05 (e0.13 to 0.02)). The groups were
similar with respect to all secondary outcome measures, including adverse events.
Conclusions: Lactobacillus reuteri was not effective in the prevention of diarrhoea or AAD in children.
M. Kołodziej, Clin Microbiol Infect 2019;25:699
© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction potential mechanisms is a direct effect of the antibiotics on the

Antibiotic-associated diarrhoea (AAD) refers to unexplained
diarrhoea that occurs in association with antibiotic therapy, after
the exclusion of other possible aetiologies [1]. The frequency of AAD
varies depending on the definitions used; it ranges from 4.3% to
80%, with a median incidence of 22%, and the mean age of patients
with AAD ranges from 18 to 48 months [2]. In children, the main
risk factors for AAD include the age of the child and the type of
antibiotic used [2]. AAD may occur just a few hours after antibiotic
administration or up to 8 weeks after antibiotic administration [3],
and it is associated with increased costs and length of hospital stay
[4]. The mechanism of AAD is not fully understood. One of the
* Corresponding author. H. Szajewska, Department of Paediatrics, The Medical
_
University of Warsaw, Zwirki i Wigury 63A, 02-091 Warsaw, Poland.
E-mail address: hania@ipgate.pl (H. Szajewska).
intestinal mucosa, resulting in alterations in the gut microbiota
composition and the overgrowth of pathogens. Clostridium difficile
is the most common infectious cause of AAD [5]. However, other
pathogens such as Staphylococcus, Candida, Enterobacteriaceae and
Klebsiella, may be involved [6]. The clinical manifestations of AAD
range from mild diarrhoea to colitis or fulminant pseudomem-
branous colitis [7]. Compared with adults, children typically
become symptomatic more rapidly. However, their recovery is
quicker, they suffer fewer complications, and their duration of
disease is shorter compared with adults [2].
Probiotics are defined as ‘live microorganisms that, when
administered in adequate amounts, confer a health benefit on the
host’ [8]. As there is evidence suggesting that AAD results from the
dysbiosis in the commensal gut microbiota caused by antibiotic
therapy, there is a rationale for using probiotics for preventing AAD
[9]. There is currently evidence to recommend the use of Lactoba-
cillus rhamnosus GG and Saccharomyces boulardii for the prevention

https://doi.org/10.1016/j.cmi.2018.08.017
1198-743X/© 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
700 M. Kołodziej, H. Szajewska / Clinical Microbiology and Infection 25 (2019) 699e704
of AAD [10,11]. However, as the effects of probiotics are largely
strain specific, the efficacy and safety of each probiotic strain should
be established separately [12].
Lactobacillus reuteri DSM 17938 is a Gram-positive bacterium
that naturally inhabits the gut of mammals. First described in the
early 1980s, it has been safely used in infants and adults [13]. One
previous randomized controlled trial (RCT) has shown no signifi-
cant difference in the risk of AAD between the placebo group and
the group receiving L. reuteri DSM 17938 at a dose of 108 CFU for the
prevention of AAD (defined as at least three loose or watery stools
per day in a 48-h period that occurred during or up to 21 days after
cessation of antibiotic treatment) in 97 hospitalized children [14].
However, the overall frequency of diarrhoea was surprisingly low
(one case in each study group). As the efficacy of L. reuteri DSM
17938 remains unclear, we conducted a randomized, double-blind,
placebo-controlled trial, with allocation of 1:1, to test whether the
administration of L. reuteri DSM 17938 would reduce the risk of
diarrhoea and AAD.
Methods
Study design
The trial was conducted in two paediatric hospitals in Poland
(The Medical University of Warsaw and the General Hospital in
Łuko w). The Ethics Committee of the Medical University of Warsaw
approved the study. Written informed consent was obtained from
all parents or legal guardians. Consent was also obtained from
participants themselves if they were 16 years of age. The trial was
registered at ClinicalTrials.gov (NCT02871908). The full protocol of
this trial was published before enrolment of the first patient [15].
The guidelines from the CONSORT statement were followed for
reporting this trial [16].
Participants
Children younger than 18 years who received oral or intrave-
nous antibiotic therapy, which was started within 24 h of enrol-
ment, were included in this study. We excluded participants who
had pre-existing acute or chronic diarrhoea, a history of chronic
gastrointestinal disease (e.g. inflammatory bowel disease, cystic
fibrosis, coeliac disease, food allergy) or other severe chronic dis-
ease (e.g. neoplastic diseases), immunodeficiency, use of probiotics
within the 2 weeks before enrolment, use of antibiotics within the
4 weeks before enrolment, prematurity, or exclusive breastfeeding.
Randomization and masking
A computer-generated randomization list prepared by a person
unrelated to the trial was used to allocate participants with a block
of eight. All investigators were blinded to the block size until all the
data were analysed. Children were stratified according to partici-
pating hospital. Sequentially numbered, sealed, opaque envelopes
containing the treatment assignment were prepared from
computer-generated randomization schedules by a person not
involved directly in the trial and were concealed from the enrolling
physicians. When all eligibility criteria were met by the participant,
an envelope containing the treatment assignment was opened by
the enrolling physician. The patient was assigned to the group ac-
cording to the code. The active product and placebo were packaged
in identical bottles. The contents of the bottles looked and tasted
the same. All the investigators, caregivers, outcome assessors, and
the person responsible for the statistical analysis remained blinded
to the intervention until the completion of the study and the
analysis of the data.
Interventions
Participants were randomly assigned to receive the study
productsdL. reuteri DSM 17938 at a daily dose of 2
108 CFU or
placebo, orally, twice daily, in drops (i.e. 2
5 drops), during the
entire period of antibiotic treatment. The placebo drops consisted
of a mixture of pharmaceutical grade medium-chain triglycerides
and sunflower oil together with pharmaceutical grade silicon di-
oxide to give the product the correct rheological properties. Both
the placebo and L. reuteri DSM 17938 formulations were identical.
Outcome measures
The primary outcome measures were the occurrences of diar-
rhoea and AAD, as defined in previous studies carried out in our
setting [17,18]. We used three different definitions of diarrhoea/
AAD:
(i) three or more loose or watery stools per day for a minimum
of 48 h (strictest definition)
(ii) three or more loose or watery stools per day for a minimum
of 24 h
(iii) two or more loose or watery stools per day for a minimum of
24 h.
AAD was diagnosed in cases of diarrhoea, defined clinically as
above, caused by C. difficile or for otherwise unexplained diarrhoea
(i.e. negative laboratory stool tests for infectious agents).
The secondary outcome measures included the frequencies of
infectious diarrhoea (rotavirus, adenovirus, norovirus, Salmonella,
Shigella, Campylobacter, Yersinia and C. difficile), the need for
discontinuation of the antibiotic treatment, the need for hospital-
ization to manage the diarrhoea (in outpatients), the need for
intravenous rehydration in any of the study groups, and adverse
events. All were recorded daily.
Study procedure
Throughout the study period, healthcare providers and/or
caregivers recorded daily the number and consistency of stools in a
standard stool diary. To record stool consistency in children
younger than 1 year, we used the Amsterdam Infant Stool Scale, and
loose or watery stools corresponded to A-consistency [19]. In
children older than 1 year, we used the Bristol Stool Form scale, and
loose or watery stools corresponded to scores of 5 to 7 [20]. In the
case of missing or incomplete data, we used data from the hospital
chart.
In the event of loose or watery stools, we investigated the stool
sample for the presence of viral or bacterial pathogens. For this
analysis, we used a standard rapid, qualitative, chromatographic
immunoassay that simultaneously detects rotaviruses, adenovi-
ruses and noroviruses. Standard microbiological techniques were
used to isolate and identify bacterial pathogens (Salmonella spp.,
Shigella spp., Campylobacter spp., Yersinia spp.). Clostridium difficile
toxins A and B were identified by standard enzyme immunoassay.
Sample size
The primary outcome of the study was the frequency of diar-
rhoea. The frequency of AAD in earlier trials varied, depending on
the definition of AAD used in the study [21e23]. Based on data from
studies previously conducted at The Medical University of Warsaw
[17], we assumed the baseline rate of AAD to be 23% in the placebo
group. To detect an absolute reduction of 15% difference between
groups, with a power of 80% and a significance level of 5% and
 M. Kołodziej, H. Szajewska / Clinical Microbiology and Infection 25 (2019) 699e704
taking into account that 20% of the patients would be lost to follow
up, we calculated that 250 children would be needed.
Statistical analysis
Data were analysed on an intention-to-treat basis, including all
participants in the groups to which they were randomized for
whom outcomes were available. The computer software STATSDIRECT
ver 3.1.20 (version 3.1.20) was used to calculate the relative risk
(RR) and absolute risk reduction (ARR) with a 95% CI. The difference
between study groups was considered significant when the 95% CI
for RR did not include 1.0. All statistical tests were two-tailed and
performed at the 5% level of significance.
Results
Enrolment lasted from December 2016 through March 2018.
Fig. 1 presents the participant flow through the study. Overall, 432
children who required antibiotic treatment were assessed for
eligibility. A total of 250 children were enrolled in the study, among
them 125 were randomized to the placebo group and 125 were
randomized to the L. reuteri DSM 17938 group. One child from the
placebo group and two children from the L. reuteri DSM 17938
group were lost to follow up. Table 1 presents baseline character-
istics of the study group and data on antibiotic therapy by in-
dications and class.
Primary and secondary outcomes
Table 2 presents primary and secondary outcomes. Using the
strictest definition (three or more loose or watery stools per day for
a minimum of 48 h), the occurrence of AAD appeared to be less
common with placebo compared with L. reuteri DSM 17938 (8 of
124 (6.5%) versus 14 of 123 (11.4%), respectively). However, this
difference between groups was not significant (RR 1.76, 95% CI
0.79e3.98, ARR e0.05, 95% CI e0.13 to 0.02). Similarly, the
Fig. 1. CONSORT flow diagram.
701
occurrence of diarrhoea appeared to be less common with placebo
compared with L. reuteri DSM 17938 (16 of 124 (13%) versus 25 of
123 (20%), respectively); however, this difference between groups
was not significant (RR 1.58, 95% CI 0.9e2.79, ARR e0.07, 95% CI
e0.17 to 0.02) The occurrence of diarrhoea and AAD using other
definitions were similar in both groups.
There also was no statistically significant difference between the
L. reuteri DSM 17938 and placebo groups for any of the secondary
outcomes. Both study products were well tolerated. The incidence
of adverse effects (i.e. abdominal pain, spitting) was similar in both
groups.
There were no differences between groups in the frequencies of
diarrhoea and AAD according to the type of antibiotic used or the
number of antibiotic classes used in the same patient (see
Supplementary material, Table S1).
Compliance
Compliance with the study protocol was assessed by direct
interview with the patient and/or caregiver and by measuring the
amount of fluid left in the bottle, assuming that 1 mL equals 20
drops. As stated in the protocol of the study, based on previously
published trials, we assumed that participants receiving <75% of
the recommended doses were treated as non-compliant. All par-
ticipants in our study were compliant, i.e. received >75% of the
recommended doses of preparations.
Discussion
Summary of findings
In this randomized, double-blind, placebo-controlled trial, the
occurrences of diarrhoea and AAD were similar in the L. reuteri DSM
17938 and placebo groups, regardless of the definition used. The
groups were similar with respect to all secondary outcome mea-
sures, including adverse events. The findings from our study
702 M. Kołodziej, H. Szajewska / Clinical Microbiology and Infection 25 (2019) 699e704

Table 1
Baseline characteristics and data on antibiotic therapy by indications and class

Characteristics Placebo Lactobacillus reuteri

Characteristics at entry
n 125 125
Age (months), mean (SD) 25.8 (33.8) 25.7 (35.2)
Age distribution
<6 months, n (%) 43 (34.4%) 49 (39.2%)
6 to 24 months, n (%) 36 (28.8%) 31 (24.8%)
24 to 48 months, n (%) 26 (20.8%) 21 (16.8%)
48 months to 5 years, n (%) 7 (5.6%) 11 (8.8%)
5 years, n (%) 13 (10.4%) 13 (10.4%)
Sex, male/female, n 71/54 72/53
Fever 38 C, n (%) 93 (74.4%) 73 (58.4%)
Body weight (kg), mean (SD) 12.1 (10.3) 12.8 (11.8)
Antibiotic therapy by indications and class
Reasons for antibiotic therapy
Respiratory tract infection, n (%) 73 (58.4%) 68 (54.4%)
Urinary tract infection, n (%) 14 (11.2%) 15 (12.0%)
Otolaryngology infection, n (%) 22 (17.6%) 23 (18.4%)
Fever of unknown source, n (%) 12 (9.6%) 15 (12.0%)
Skin infection, n (%) 0 2 (1.6%)
Other infections, n (%) 4 (3.2%) 2 (1.6%)
Antibiotic classes
Aminopenicillins, n (%) 26 (20.8%) 37 (29.6%)
Cephalosporins second-generation, n (%) 79 (63.2%) 70 (56%)
Cephalosporins third-generation, n (%) 13 (10.4%) 15 (12%)
Macrolides, n (%) 6 (4.8%) 3 (2.4%)
Lincosamides, n (%) 1 (0.8%) 0
Combination antibiotic therapy
One class, n (%) 121 (96.8%) 123 (98.4%)
Two classes, n (%) 4 (3.2%) 2 (1.6%)
Length of antibiotic treatment, days, mean (SD) 9.1 (2.2) 8.9 (2.3)

Table 2
Primary and secondary outcomes

Outcome Placebo Lactobacillus RR (95% CI) ARR (95% CI)

(n ¼ 124) reuteri (n ¼ 123)

Primary outcomes
Diarrhoea
three or more loose or watery stools per day for a minimum of 48 h, n (%) 16 (12.9%) 25 (20.3%) 1.58 (0.9e2.79) e0.07 (e0.17 to 0.02)
three or more loose or watery stools per day for a minimum of 24 h, n (%) 26 (21%) 27 (21.7%) 1.05 (0.65e1.68) e0.01 (e0.11 to 0.09)
two or more loose or watery stools per day for a minimum of 24 h, n (%) 26 (21%) 27 (21.7%) 1.05 (0.65e1.68) e0.01 (e0.11 to 0.09)
Antibiotic-associated diarrhoea (caused by Clostridium difficile or for otherwise unexplained diarrhoea, i.e. negative laboratory stool tests for
infectious agents)
three or more loose or watery stools per day for a minimum of 48 h, n (%) 8 (6.5%) 14 (11.4%) 1.76 (0.79e3.98) e0.05 (e0.13 to 0.02)
three or more loose or watery stools per day for a minimum of 24 h, n (%) 17 (13.7%) 16 (13%) 0.95 (0.51e1.77) 0.01 (e0.08 to 0.09)
two or more loose or watery stools per day for a minimum of 24 h, n (%) 17 (13.7%) 16 (13%) 0.95 (0.51e1.77) 0.01 (e0.08 to 0.09)
Secondary outcomes
Infectious diarrhoea
Rotavirus, n (%) 5 (4%) 10 (8.1%) 2.02 (0.74e5.51) e0.04 (e0.11 to 0.02)
Adenovirus, n (%) 0 2 (1.6%) e0.02 (e0.06 to 0.01)
Norovirus, n (%) 0 0
Salmonella spp., n (%) 4 (3.2%) 1 (0.8%) 0.25 (0.04e1.65) 0.02 (e0.02 to 0.07)
Shigella spp., n (%) 0 0
Campylobacter spp., n (%) 0 0
Yersinia spp., n (%) 0 0
Clostridium difficile, n (%) 1 (0.8%) 0 0.01 (e0.02 to 0.04)
Unknown infectious aetiology, n (%) 17 (13.7%) 16 (13%) 0.95 (0.51e1.77) 0.01 e 0.08 to 0.09)
Need for discontinuation of the antibiotic treatment, n (%) 5 (4%) 3 (2.4%) 0.60 (0.16e2.24) 0.02 (e0.03 to 0.07)
Need for intravenous rehydration, n (%) 83 (66.9%) 76 (62%) 0.92 (0.76e1.11) 0.05 e 0.07 to 0.17)
Need for hospitalization to manage diarrhoea (in outpatients) 0 0
Adverse effects, n (%) 7 (5.6%) 3 (2.4%) 0.43 (0.12e1.5) 0.03 (e0.02 to 0.09)
Abdominal pain 3 (2.4%) 1 (0.8%) 0.34 (0.05e2.31) 0.02 (e0.02 to 0.06)
Spitting up 2 (1.6%) 1 (0.8%) 0.50 (0.07e3.80) 0.01 (e0.03 to 0.05)
Flexing 2 (1.6%) 1 (0.8%) 0.50 (0.07e3.80) 0.01 (e0.03 to 0.05)

complement previous studies that examined the effects of probiotic
administration on the risk of AAD.
There are several possible reasons for the lack of an effect of
L. reuteri DSM 17938 in our study. First, the dose of the studied
probiotic (2
108 CFU). With regard to diarrhoeal diseases, the
effective dosing remains unclear. Two earlier studies carried out by
our group that evaluated the efficacy of using L. reuteri DSM 17938
at different doses (108 and 109 CFU/day, respectively) showed no
effect in preventing nosocomial diarrhoea in children [24,25].
However, other studies have documented the effectiveness of
 M. Kołodziej, H. Szajewska / Clinical Microbiology and Infection 25 (2019) 699e704
L. reuteri DSM 17938 at a dose of 108 CFU/day both in the man-
agement of diarrhoeal diseases and other indications [26e28]. Still,
the optimal dose of L. reuteri DSM 17938 has not been clearly
established. In our study, the timing of administration of L. reuteri
DSM 17938 in relation to the administration of antibiotics was not
predefined. Although it is likely that the study products were
administered between antibiotic doses, simultaneous administra-
tion by parents or care-providers cannot be excluded. As lactoba-
cillus species, including L. reuteri DSM 17938, are sensitive to
antibiotics [29], the lack of effect may be due to the insufficient
colonization rate of L. reuteri, and hence its inability to exert its
probiotic effects.
Strengths and limitations of the study
The overall occurrence of diarrhoea, (not including AAD), ranged
from 13% to 21.7% and it ranged from 6.5% to 21.7% if both diarrhoea
and AAD are considered; thus, it was generally in line with our
initial assumptions, and the study was not underpowered. As there
is no one standard definition of AAD, and the rate depends on the
definition used, we used three different definitions. This approach
allows a more precise comparison with other studies. The majority
of included children (82%) were younger than 4 years of age and
received the most commonly used antibiotics in the paediatric age
group such as second-generation cephalosporins and amino-
penicillins, so the findings are generalizable.
Nevertheless, the trial has several limitations. First, patients
were only followed up for 1 week after their antibiotic treatment.
As diarrhoea may occur up to 2 months after the end of antibiotic
treatment [2], some cases of AAD may have been missed. Second,
only relatively minor overall percentages of the patients in the
placebo (7.2%) and L. reuteri group (12.9%) had infectious diarrhoea
of known aetiology. However, in the case of diarrhoea, the stool
samples were tested for most common enteropathogens only; so,
one cannot exclude the possibility that some of the cases of un-
explained diarrhoea were caused by unidentified infectious agents.
Moreover, this study also did not allow one to reach conclusions
about the efficacy of administering L. reuteri DSM 17938 in the
prevention of C. difficile-associated diarrhoea, a clinically important
condition, because only one patient developed C. difficile. Finally,
the study was also not powered to detect significant differences in
any of the secondary outcomes.
Comparison with other studies
A 2016 systematic review investigated the efficacy of L. reuteri
DSM 17938 in the management of various types of diarrhoeal dis-
eases in children. Overall, eight RCTs, involving 1229 participants,
were identified. In preventive trials carried out in hospitalized
children, based on the findings from two RCTs (n ¼ 290), there was
no significant reduction in the risk of nosocomial diarrhoea, rota-
virus diarrhoea or diarrhoea of any origin with L. reuteri adminis-
tration. Based on one RCT (n ¼ 97), there was no effect of L. reuteri
use on the risk of AAD. However, as stated earlier, the evidence is
limited because the overall frequency of diarrhoea was surprisingly
low [25].
A more recent open RCT involved 1013 children aged 3e14 years
in primary care settings who received amoxicillin ± clavulanic acid
or cephalosporins. In this trial, children who received L. reuteri DSM
17938 at a dose of 2
108 CFU (sachets) compared with any pre-
ventive therapy had a reduced risk of antibiotic-related gastroin-
testinal symptoms. However, the findings are available in abstract
form only [30]. Until a full publication is available, the methodo-
logical details, including the definition of outcome measures,
remain unclear.
703
Conclusions
In this randomized, double-blind, placebo-controlled trial, we
found no evidence that the administration of L. reuteri DSM 17938
at a daily dose of 2
108 CFU was effective in preventing diarrhoea
or AAD, regardless of the definition used, in children <18 years
(median age 4 months) treated with antibiotics administered orally
or intravenously.
Until more data are available, according to current guidelines, if
the use of probiotics for preventing AAD is considered, the use of
Lactobacillus GG or Saccharomyces boulardii is recommended [12].
However, the prudent use of antibiotics, only in situations of clear
clinical benefit, remains the best method of preventing AAD.
Transparency declaration
MK declares no competing interests. HS has participated as a
clinical investigator, and/or advisory board member, and/or
consultant, and/or speaker for Arla, Biogaia, Biocodex, Danone,
Dicofarm, Hipp, Nestle, Nestle Nutrition Institute, Nutricia and
Mead Johnson.
Acknowledgements
We thank Dr Anna Kołodziej from the General Hospital in
w for her help in the recruitment.
Łuko
Authors' contributions
HS initially conceptualized this study. All authors contributed to
the study protocol. MK conducted the study. MK analysed the data
under the supervision of HS. HS and MK wrote the manuscript. Both
authors contributed to (and agreed upon) the final version. Both
authors have full access to all the data in the study. HS is the
guarantor for the data.
Funding
The study products were manufactured and supplied by BioGaia
(Lund, Sweden), free of charge. This trial was fully funded by The
Medical University of Warsaw (Young Investigators research grant
number: 1W44/PM1/17). The funder of the study had no role in
study design, data collection, data analysis, data interpretation or
writing of the report.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.cmi.2018.08.017.
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