Saccharomyces boulardii CNCM I-745 plus sequential therapy for Helicobacter pylori infections: a randomized, open-label trial

Abstract

Aim
To determine the effect of Saccharomyces boulardii CNCM I-745 (S. boulardii) plus sequential therapy on Helicobacter pylori (H. pylori) eradication rate.

Methods
This open-label prospective study randomized (1:1) patients with confirmed H. pylori infection to standard sequential therapy of twice-daily (bid) omeprazole 20 mg plus amoxicillin 1 g for 5 days, followed by bid omeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg for the next 5 days (control group), or sequential therapy plus bid S. boulardii 250 mg (experimental group). Adverse events (AEs) were recorded throughout the study, and the H. pylori eradication rate was determined 4 weeks after treatment.

Results
The study was conducted from May 2013 to May 2016 and included 199 patients (51.3% male; mean age 44.6 ± 13.6 years). The H. pylori eradication rate was higher in the experimental group than the control group (86.0% vs. 74.7%; P = 0.02). Compared with the control group, patients in the experimental group experienced a significantly lower overall incidence of AEs (17.0% vs. 55.7%; p < 0.001) and the incidence of antibiotic-associated diarrhea (2.0% vs. 46.4%; P = 0.02). The experimental group showed improved treatment compliance over the 10-day study period compared with the control group (95.0% vs. 91.2%, P < 0.001).

Conclusion
Addition of S. boulardii to sequential therapy improved H. pylori eradication rate and reduced the incidence of treatment-associated AEs in Moroccan patients with H. pylori infection.

Full text

CLINICAL TRIAL
Saccharomyces boulardii CNCM I-745 plus sequential therapy
for Helicobacter pylori infections: a randomized, open-label trial
Hassan Seddik
1
&Hanae Boutallaka
1
&Ilham Elkoti
1
&Fouad Nejjari
1
&Reda Berraida
1
&Sanaa Berrag
1
&
Khaoula Loubaris
1
&Sara Sentissi
1
&Ahmed Benkirane
1
Received: 14 August 2018 / Accepted: 2 January 2019
#Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Aim To determine the effect of Saccharomyces boulardii CNCM I-745 (S. boulardii)plussequentialtherapyonHelicobacter
pylori (H. pylori) eradication rate.
Methods This open-label prospective study randomized (1:1) patients with confirmed H. pylori infection to standard sequential
therapyoftwice-daily(bid)omeprazole20mgplusamoxicillin1gfor5days,followedbybidomeprazole20mg,clarithromycin
500 mg and metronidazole 500 mg for the next 5 days (control group), or sequential therapy plus bid S. boulardii 250 mg
(experimental group). Adverse events (AEs) were recorded throughout the study, and the H. pylori eradication rate was deter-
mined 4 weeks after treatment.
Results The study was conducted from May 2013 to May 2016 and included 199 patients (51.3% male; mean age 44.6 ±
13.6 years). The H. pylori eradication rate was higher in the experimental group than the control group (86.0% vs. 74.7%;
P= 0.02). Compared with the control group, patients in the experimental group experienced a significantly lower overall
incidence of AEs (17.0% vs. 55.7%; p<0.001) and the incidence of antibiotic-associated diarrhea (2.0% vs. 46.4%; P=0.02).
The experimental group showed improved treatment compliance over the 10-day study period compared with the control group
(95.0% vs. 91.2%, P<0.001).
Conclusion Addition of S. boulardii to sequential therapy improved H. pylori eradication rate and reduced the incidence of
treatment-associated AEs in Moroccan patients with H. pylori infection.
Keywords Antibiotic-induced diarrhea .Helicobacter pylori .H. pylori eradication rate .Saccharomyces boulardii .Sequential
treatment .Treatment compliance
Introduction
Helicobacter pylori is a pathogenic gram-negative bacteria
affecting more than half of the world’s population [1].
H. pylori infection plays a role in the etiology of various dis-
eases including dyspepsia, gastric ulcer disease, lymphoma
and gastric cancer [2–4]. The prevalence of H. pylori infection
remains high in developing countries, with around 75% of the
Moroccan population infected with the pathogen [5]. The
main risk factor for H. pylori infection is low socioeconomic
status [6].
H. pylori infection is generally treated with a combina-
tion of antibiotics plus proton pump inhibitors (PPIs) [7].
However, increased use of antibiotics has led to antibiotic
resistance, making the treatment of H. pylori challenging
[8]. The World Health Organization considersH. pylori re-
sistance a high priority for research and development of
Core tip Treatment of Helicobacter pylori infections is challenging due
to antibiotic resistance, and it is often difficult to achieve the
recommended H. pylori eradication rate of >90%. Currently
recommended regimens may achieve an eradication rate of >90%, but
are associated with an increased incidence of adverse events (AEs). The
results of the present study showed that the combination of standard
sequential therapy plus Saccharomyces boulardii CNCM I-745 improved
the H. pylori eradication rate and significantly reduced the incidence of
AEs in Moroccan patients, suggesting that this approach may be benefi-
cial in clinical practice.
*Hanae Boutallaka
hanaeboutallaka@gmail.com
1
Department of Gastroenterology and Digestive Endoscopy,
Mohamed V Military Teaching Hospital of Rabat, Mohamed V
University, FAR Avenue, Hay Riad, 10045 Rabat, Morocco
European Journal of Clinical Pharmacology
https://doi.org/10.1007/s00228-019-02625-0

new antibiotics [9]. Currently, the Maastricht V consensus
recommends bismuth-based quadruple therapy or non-
bismuth concomitant therapy (PPI, amoxicillin,
clarithromycin and nitroimidazole) for 10 to 14 days for
the treatment of H. pylori infection in order to achieve an
eradication rate of >90% [10]. However, while these ther-
apies are associated with better eradication, the incidence
of adverse events (AEs) is higher than with sequential
treatment [11,12].
Probiotic supplementation with antibiotic therapy appears
to be beneficial in improving the eradication rates of H. pylori
infection [13]. Saccharomyces boulardii CNCM I-745
(S. boulardii) is a probiotic yeast reported to be effective in
reducing the incidence of antibiotic-associated diarrhea in
adult and pediatric populations [14,15]. Several meta-
analyses havereported that addition of S. boulardii to standard
therapy in the treatment of H. pylori infection reduces the
incidence of antibiotic-associated AEs and may help in im-
proving the eradication rate [16,17]. Currently, sequential
therapy recommended by Maastricht IV is commonly pre-
scribed in Morocco, with higher eradication rates compared
with triple therapy [18].
The present study aimed at determining the effect of a
combination of S. boulardii plus sequential therapy on the
eradication rate of H. pylori infection and the AEs associated
with antibiotics in a Moroccan population.
Materials and methods
Patients
This open-label prospective study was conducted at the
Gastroenterology II Department, Mohamed V Military
Hospital in Rabat, Morocco. Adult patients with H. pylori
infection confirmed by endoscopic gastric biopsy were in-
cluded in the study. Five gastric biopsy samples were col-
lected for each patient at the time of admission (two fundic,
two antral and one angular) according to the recommenda-
tions of the updated Sydney system for histological study
[19] during esogastroduodenal fibroscopy, and the samples
were histologically studied for the presence of H. pylori
using hematoxylin and eosin staining at the anatomical
pathology laboratory in Mohamed V Military Hospital,
Rabat. Patients who received proton pump inhibitors, H2
antagonists, antibiotics, non-steroidal anti-inflammatory
drugs or bismuth salts 4 weeks prior to the study were
excluded. Pregnant and breastfeeding women and patients
with a history of gastric surgery, allergy to prescribed an-
tibiotics, severe psychiatric conditions or liver and kidney
failure were also excluded. All patients included in the
study provided written informed consent before the study
commenced. The protocol followed the guidelines set forth
in the Declaration of Helsinki and was approved by the
ethics committees of the Mohamed V Military Hospital in
Rabat, Morocco.
Randomization and treatment
Patients were randomized (1:1) using a computer-generated
table into two groups: the control group received a 10-day
sequential treatment consisting of twice-daily omeprazole
20 mg plus amoxicillin 1 g for the first 5 days followed by
twice-daily omeprazole 20 mg, clarithromycin 500 mg and
metronidazole 500 mg for the remaining 5 days, while the
experimental group received the same 10-day sequential treat-
ment combined with twice-daily S. boulardii 250 mg
(ULTRA-LEVURE
®
, Biocodex, Morocco).
Patients were advised to take omeprazole 30 min before
morning and evening meals, while the antibiotics and
probiotics were to be administered after meals.
Endpoints
The H. pylori eradication rate was determined 4 weeks
after the 10-day treatment period using the 13C urea breath
test [20]. Briefly, patients were given 100 mg of 13C urea
with food. Breath samples were collected before and
30 min after administration of 13C urea and were analyzed
for 13CO
2
using infrared spectrophotometry. Analysis was
blinded and was performed at the same laboratory for all
samples.
All AEs reported during the study period were monitored
using a structured questionnaire. The questionnaire consisted
of dichotomous questions about the occurrence of AEs such as
diarrhea, nausea and/or vomiting, gastralgia, metallic taste,
symptoms related to an allergic reaction, cutaneous and/or
mucosal mycosis, headache, dizziness, asthenia or any other
undesirable effect.
Treatment compliance, defined as consumption of >90% of
the prescribed medicines, was determined at the end of the
study period.
The effect of S. boulardii on H. pylori eradication rate and
the incidence of AEs was also studied using binary logistic
regression models, which included the following parameters:
eradication rate, overall incidence of AEs, therapeutic compli-
ance, incidence of antibiotic-induced diarrhea and incidence
of dysgeusia and gastralgia.
Statistical analysis
The sample sizefor the study was estimated at 105 patientsper
group based on a study by Cindoruk and colleagues [21], in
order to detect a difference of 8% in the eradication rate be-
tween the 10-day sequential therapy (estimated eradication
rate of 83%) and the combination of 10-day sequential therapy
Eur J Clin Pharmacol

with S. boulardii (estimated eradication rate of 91%), with a
strength of 0.80 and a bilateral significance level of0.05. With
a presumed withdrawal rate of 20%, at least 126 patients were
required in each group.
The safety population included all randomized patients
who received at least one treatment dose during the study,
while the intention-to-treat population (ITT) included all
randomized patients who received at least one treatment
dose and who were re-examined during the first visit.
The per-protocol analysis included all patients who com-
pleted the study. For any patients with missing data due to
incomplete treatment, therapeutic failure was recorded as
the outcome.
Statistical analysis was performed using SPSS version 20.0
software for Windows [22]. For all statistical analyses, a p
value of <5% was considered statistically significant.
Qualitative variables were compared using the chi-squared
test and Fisher’s exact test, while Student’sttest and the
Mann-Whitney Utest were used for quantitative variables.
The effect of S. boulardii plus sequential therapy on the erad-
ication rate and the incidence of antibiotic-induced AEs was
determined using binary logistic regression.
Results
Patients
A total of 199 H. pylori-positive patients (51.3% male;
mean age 44.6 ± 13.6 years) were enrolled in the study
from May 2013 to May 2016 (Table 1). Of these, 22.1%
were smokers. At baseline, 42.2% of patients had gastric
pain, 20.1% had dyspeptic symptoms, 9.5% had heartburn
and 28.1% had other symptoms including nausea and/or
vomiting, upper gastrointestinal hemorrhage or anemic
syndrome. On histological analysis, gastric metaplasia
was found in 5.5% of patients and gastric atrophy in
12.5%. There were no statistically significant differences
in the baseline characteristics of patients included in the
two study groups (Table 1).
Overall, 12 patients (6.03%) discontinued the study: seven
patients (4 from the experimental group and 3 from the control
group) did not return the breath test used for the diagnosis of
H. pylori, and five patients (2.5%) reported poor treatment
compliance due to incapacitating AEs (Fig. 1). The per-
protocol analysis included 92 and 95 patients in the experi-
mental and control groups, respectively (Fig. 1).
Helicobacter pylori eradication rate
In the ITT population, H. pylori eradication was achieved
in 86 of 100 patients in the experimental group (86.0%)
and 74 of 99 patients in the control group (74.7%), the
difference between the two groups being 11.3% (p=
0.02). In the per-protocol analysis group, H. pylori eradi-
cation was achieved in 87.5% of patients (n= 79) in the
experimental group and 78.9% of patients (n= 75) in the
control group, the difference between the two groups being
9.3% (p= 0.04).
Safety
The overall incidence of AEs in the experimental and control
groups was 17.0% and 55.7%, respectively, representing a
decrease of 38.7% in the experimental group (p< 0.001;
Table 2). The incidence of antibiotic-induced diarrhea in the
experimental group was 2.0%, compared with 46.4% in the
control group (p= 0.02). There was no significant difference
between the experimental and control groups in terms of
gastralgia, dysgeusia, dizziness, or nausea and vomiting
(Table 2).
Regression analysis
Results of the multivariate analysis showed that the combina-
tion of S. boulardii and sequential treatment improved the
H. pylori eradication rate, with a relative risk ratio (RR) of
2.4 (p= 0.02; 95% confidence interval [CI] 0.01, −3.09), and
reduced the overall incidence of AEs by 60% (RR = 0.4; p=
0.01; 95%CI 0.01, −0.55) and the incidence of antibiotic-
induced diarrhea by 93% (RR = 0.07; p= 0.01; 95%CI
0.002, −0.3; Table 3). Treatment compliance increased by
3.8% in the experimental group compared with the control
group (95.0% vs. 91.2%, p<0.001).
Discussion
To our knowledge, this is the first study to determine
the effect of a combination of S. boulardii and sequen-
tial therapy on the eradication of H. pylori infection and
the incidence of antibiotic-induced AEs in Moroccan
patients. The results of the study show that the addition
of S. boulardii to sequential therapy increased the erad-
ication of H. pylori infection by 11.3% and reduced the
overall incidence of AEs by 38.7% compared with se-
quential therapy alone. The combination of sequential
therapy and S. boulardii also significantly reduced the
incidence of antibiotic-associated diarrhea compared
with sequential therapy alone.
The effect of S. boulardii in combination with standard
14-day triple therapy on the eradication rate of H. pylori
infection and on the incidence of AEs has been reported in
previous studies [21–24]. The results of the present study
show that combining S. boulardii with sequential therapy
improved the eradication rate and reduced the incidence of
Eur J Clin Pharmacol

treatment-associated AEs. However, the mechanism by
which S. boulardii reduces H. pylori infections is not clear-
ly understood. Sakarya and colleagues reported that
S. boulardii eradicates H. pylori by releasing a neuramin-
idase which reduces surface α(2-3)-linked sialic acid in
epithelial cells, in turn preventing H. pylori adhesion in
the duodenum [24].
Other studies have reported that probiotics cause a re-
duction in the synthesis of pro-inflammatory cytokines in
the gastric mucosa, in turn decreasing gastric inflammation
[25–27]. It has also been reported that probiotics enhance
the release of antimicrobial products such as lactic acid,
short chain fatty acids and hydrogen peroxide, which re-
duces gastric bacterial colonization [28].
Since the eradication rates of H. pylori infection have
decreased with standard therapies due to antibiotic resis-
tance, there is an urgent need for new first-line therapies
for the treatment of H. pylori in order to achieve an erad-
ication rate of >90% [10]. Presently, the Maastricht V con-
sensus recommends bismuth-based quadruple therapy or
non-bismuth concomitant therapy for 10 to 14 days for
first-line treatment of H. pylori in countries with high an-
tibiotics resistance [10]. Although bismuth-based quadru-
ple therapy is reported to have an eradication rate of >90%
[29,30], the eradication rate with concomitant therapy
Table 1 Baseline characteristics
of patients included in the study
(n=199)
Total
(n= 199)
Experimental group
(n= 100)
Control group
(n= 99)
P
Age, years: mean ± SD 44.6 ± 13.6 43 ± 13.2 46.3 ± 13.8 0.06
Sex ratio (male/female) 1.05 1.01 1.15 0.10
Smokers 44 (22.1) 19 (19.0) 25 (25.3) 0.2
Functional signs 0.3
Burning stomach pain 19 (9.5) 10 (10.0) 9 (9.1)
Gastric pain 84 (42.2) 43 (43.0) 41 (41.4)
Dyspepsia 40 (20.1) 15 (15.0) 25 (25.3)
Other 56 (28.1) 32 (32.0) 24 (24.2)
Histology
Gastric metaplasia 11 (5.5) 3 (3.0) 8 (8.1) 0.1
Gastric atrophy 25 (12.5) 6 (6.0) 19 (19.2) 0.5
H. pylori antral density 0.3
+ 66 (33.2) 29 (29.0) 37 (37.4)
++ 90 (45.2) 50 (50.0) 40 (40.4)
+++ 43 (21.6) 21 (21.0) 22 (22.2)
H. pylori fundic density 0.19
+ 85 (42.7) 48 (48.0) 37 (37.4)
++ 58 (29.1) 29 (29.0) 29 (29.3)
+++ 9 (4.5) 2 (2.0) 7 (7.1)
All values are expressed as n(%) unless otherwise stated. +, sparse; ++, moderate; +++, marked
H. pylori, Helicobacter pylori;SD, standard deviation
Helicobactor pylori infected
paents (n = 199)
Randomizaon
Experimental group
(n = 100)
Control group
(n = 99)
Per protocol (n = 92) Per protocol (n = 95)
Dropout (n = 4):
lost contact (n = 3)
Poor compliance (n = 1)
Dropout (n = 8):
lost contact (n = 4)
Poor compliance (n = 4)
Fig. 1 Patient flow
Table 2 Adverse events reported during the study (n=199)
Experimental group,
n(%)
Control group,
n(%)
P
Total 17 (17.0) 54 (55.7) <0.001
Diarrhea 2 (2.0) 45 (46.4) 0.02
Gastralgia 2 (2.0) 4 (4.1) 0.1
Dysgeusia 10 (10.0) 1 (1.0) 0.3
Dizziness 2 (2.0) 1 (1.0) 0.4
Nausea/vomiting 2 (2.0) 2 (2.1) 0.8
Eur J Clin Pharmacol

varies according to geographical zone and is not statistical-
ly different to the eradication rates obtained with sequential
treatment [31,32]. The eradication rate of 86% with se-
quential treatment plus S. boulardii reported in the present
study indicates that this combination has potential in the
treatment of H. pylori infections, although studies in larger
patient populations are needed.
Antibiotic-based treatment regimens for H. pylori infection
are associated with gastrointestinal AEs [33]. The reported
rates of AEs vary from 48% to 67% with bismuth-based qua-
druple therapy [34,35] and 47% to 58% with non-bismuth
concomitant therapy [35]. The results of this study show that
the combination of S. boulardii and sequential therapy result-
ed in a significant reduction in the overall incidence of AEs,
indicating that this treatment approach can benefit patients and
could be considered as a therapeutic option in patients with
H. pylori infection.
In the present study, treatment compliance increased by
3.8% with S. boulardii plus sequential therapy compared
with sequential therapy alone, which is similar to that re-
ported in previous studies, particularly in children [36].
Although this increase was not significant, these results
show that combining S. boulardii with sequential therapy
improves treatment compliance, which may be attributed
to a decrease in the incidence of treatment-associated AEs
with this combination.
This study had several limitations. First, antibiotic sensitiv-
ity testing and H. pylori culture to determine the profile of
H. pylori were not performed. Second, diagnosis of
H. pylori infection was based on histology alone. Third, the
questionnaire used for recording the AEs only included ques-
tions regarding their incidence, without specifying their sever-
ity. Last, since it was an open-label study, the possibility of
selection bias cannot be ruled out.
In conclusion, the results of the present study show that
combining a once-daily dose of S. boulardii CNCM I-745
with sequential therapy improved the eradication rate of
H. pylori infection and reduced the overall incidence of
antibiotic-induced diarrhea and other AEs in H. pylori-
infected Moroccan patients. Additional studies with this
combination in a larger patient population are warranted.
Acknowledgements The authors thank Nishad Parkar, PhD, of Springer
Healthcare Communications for technical and English editing of theman-
uscript prior to submission. This medical writing assistance was funded
by Biocodex.
Author contributions Hassan Seddik was responsible for study concept
and planning and supervised the statistical analysis and redaction of the
manuscript. Hanae Boutallaka was involved in performing the statistical
analysis and writing the manuscript, with input from all authors. Fouad
Nejjari, Reda Berraida, Khaoula Loubaris, Ilham Elkoti, Sanaa Berrag
and Sara Sentissi were involved in patient enrollment and data collection
and were involved in the preparation of the manuscript. Ahmed
Benkirane was involved in conducting and supervising the study.
Support was provided by Biocodex, France.
Compliance with ethical standards
Informed consent statement All patients included in the study provided
written informed consent before the study commenced.
Conflict of interest The authors have no conflicts of interest to declare.
CONSORT 2010 statement The authors have read the CONSORT 2010
Statement, and the manuscript was prepared and revised according to the
CONSORT 2010 Statement.
Publisher’snoteSpringer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
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