DOI: 10.1111/hel.

12371

ORIGINAL ARTICLE

New bismuth-­containing quadruple therapy in patients

infected with Helicobacter pylori: A first Italian experience in
clinical practice

Antonio Tursi1 | Francesco Di Mario2 | Marilisa Franceschi3 | Rudi De Bastiani4 | 

Walter Elisei5 | Gianluca Baldassarre3 | Antonio Ferronato3 | Simone Grillo2 | Stefano
Landi2 | Maria Zamparella4 | Manuela De Polo4 | Laura Boscariolo4 | Marcello Picchio6

1
Gastroenterology Service, ASL BAT, Andria
(BT), Italy
2
Department of Clinical & Experimental
Medicine, Gastroenterology Unit, University
of Parma, Parma, Italy
3 Aims: To test the efficacy and safety of the new bismuth-­containing quadruple ther-
Digestive Endoscopy Unit, ULSS4 Alto
Vicentino, Santorso, Schio (VI), Italy
4
Italian Association for Gastroenterology in
Primary Care (GICA-CP), Feltre (BL), Italy
5
Division of Gastroenterology, ASL RM6,
Albano Laziale (Roma), Italy
6
Division of Surgery, “P. Colombo”
Hospital, ASL RM6, Velletri (Rome), Italy
Correspondence
Antonio Tursi, MD, Servizio di
Gastroenterologia Territoriale, ASL BAT,
Andria (BT), Italy.
Email: antotursi@tiscali.it
Abstract
Background: Rising antibiotic resistance requires the evaluation of new and effective
therapies.
apy in patients infected with Helicobacter pylori.
Material and Methods: Consecutive H. pylori-­positive dyspeptic patients were en-
rolled, either naïve or with previous failure treatment. Patients were treated with
Pylera® (three-­in-­one capsules containing bismuth subcitrate potassium 140 mg, met-
ronidazole 125 mg, and tetracycline 125 mg) three capsules q.i.d. plus omeprazole
20 mg or esomeprazole 40 mg b.i.d. for 10 days. Eradication was confirmed using an
urea breath test (at least 30 days after the end of treatment). Efficacy was assessed by
UBT and safety by means of treatment-­emergent adverse events.
Results: One hundred and thirty-­one patients were included in the study: 42% of pa-
tients were naïve, and 58%, with previous failure treatment. H. pylori eradication was
achieved in 124 patients (94.7%, 95% confidence intervals (CIs) 89.3-­97.8) in ITT pop-
ulation. In the PP population, the percentage was 97.6% (95%, CIs 93.3-­99.2). No dif-
ference in eradication rate was found either between naïve and previously treated
patients (92.7% vs 96.0%, P=.383), or smoking and nonsmoking ones, or in patients
taking omeprazole or esomeprazole.
Treatment-­emergent adverse events occurred in 35 patients (26.7%, 95% CIs 19.9-­
34.9). They were mild in all cases except in four, who discontinued the study due to
diarrhea (three patients) and diffuse urticarial rush (one patient).
Conclusions: Pylera® achieved a remarkable eradication rate in clinical practice, irre-
spective if it was used as first treatment or as a rescue therapy. Treatment-­emergent
adverse events were uncommon generally mild.

KEYWORDS
antibiotics, bismuth-containing therapy, Helicobacter pylori, treatment

Helicobacter. 2017;22:e12371. wileyonlinelibrary.com/journal/hel © 2017 John Wiley & Sons Ltd  |  1 of 4
https://doi.org/10.1111/hel.12371
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125 mg, and tetracycline 125 mg) three capsules q.i.d. The proton-­

1 |  INTRODUCTION
pump inhibitor (PPI) was taken for further 3 weeks in case of active
peptic ulcer or severe gastritis, detected at endoscopy.
Helicobacter pylori (H. pylori) plays an important role in chronic ac-
Patients were strongly encouraged to comply fully. Each patient
tive gastritis, peptic ulcer, low-­grade mucosa-­associated lymphoid
was asked to return for an office visit after completion of treatment
tissue lymphoma, and gastric cancer development.1 Amoxicillin-­
to confirm H. pylori eradication, to assess the compliance with therapy
clarithromycin or amoxicillin-­metronidazole-­based triple therapies
by counting of remaining pills. Optimal compliance was considered as
have been used for long time in clinical practice.2 However, the effi-
taking at least 80% of the prescribed drugs.
cacy of the clarithromycin-­containing triple therapies is decreasing
One month after conclusion of anti-­H. pylori treatment, H. pylori
worldwide,3 mostly due to an increased prevalence of clarithromycin
presence was checked by ¹³C-­urea breath test (Expirobacter®; Sofar
resistance.4,5
S.p.A, Trezzano Rosa (MI), Italy), performed in accordance with the
Sequential treatment has been successfully used for some
European Standard Protocol.17 The patients were instructed to avoid
years, even if it is quite complex,6,7 but it seems now ineffective.8
any acid suppressive treatment 2 weeks before follow-­up.18
Concomitant treatment (PPI plus clarithromycin plus metronidazole
Treatment-­emergent adverse events (TEAEs) were assessed and
plus amoxicillin) has shown more interesting results, reaching higher
graded as mild (causing no limitation of usual activities), moderate
eradication rates.9,10
(causing some limitation of usual activities), and severe (causing inabil-
However, bismuth-­containing quadruple treatments seem to be
ity to carry out usual activities).
a more reliable option. Maastricht V and other recent Guidelines on
H. pylori management claimed that in areas of high clarithromycin re-
sistance, bismuth-­containing quadruple treatments are recommended 2.1 | Statistical analysis
for first-­line empirical treatment, with concomitant treatment or a
The efficacy endpoint was the H. pylori eradication rate, defined as
nonbismuth quadruple treatment as an alternative.11,12 However,
one negative ¹³C-­urea breath test performed 1 month after treatment.
these quadruple treatments were affected by low compliance for many
Mean with 95% confidence intervals (CIs) was calculated for continu-
years, due to the high number of pills to take.1 A recent three-­in-­one
ous data and frequency counts and percentages for categorical data.
formulation, with a single pill containing bismuth, metronidazole, and
Exact 95% CIs about the eradication and TEAE rates were calculated.
tetracycline, is now becoming available. Two recent randomized, open-­
We performed both intention-­to-­treat (ITT) and per-­protocol (PP)
label, noninferiority, phase III trials, one conducted in USA13 and one
analysis. ITT analysis included all enrolled subjects who took at least
in Europe,14 found this formulation significantly better than standard
one dose of study medication; PP analysis included all subjects who
triple therapy in eradicating H. pylori. The same effectiveness has been
completed the study without any events that could potentially bias
recently found with respect to rescue therapy in patients failing erad-
the study outcome.
ication.15,16 Although this new formulation has become available in
The collection and analysis of data were performed using
several national markets for use in clinical practice, any data about its
MedCalc® Release 14.8.1 (MedCalc Software, Mariakerke, Belgium).
effectiveness and safety in clinical practice are not available yet.
Fisher’s exact test was used for categorical data. The level of signifi-
The aim of this study was to assess the cure rate achieved by this
cance was P=.05.
10-­day regimen of three-­in-­one pill containing bismuth, tetracycline,
and metronidazole pill in clinical practice.

2 |  MATERIAL AND METHODS
A prospective study was conducted analyzing 131 consecutive dys-
peptic patients with H. pylori infection between March 2016 and
September 2016. Either naïve or with previous failure treatment pa-
tients were enrolled. Criteria of exclusion from the study were preg-
nancy, allergy to tetracycline or to nitroimidazoles, and concomitant
serious illnesses (such as renal or hepatic insufficiency). Upper gastro-
intestinal endoscopy was performed in all patients: During endoscopic
examination, six biopsy samples were obtained from the fundus, cor-
pus, and antrum. Additional biopsies were obtained for histologic ex-
amination at endoscopist’s convenience.
After assessment of H. pylori infection, all patients were treated
during 10 days with a combination formulation containing omeprazole
20 mg or esomeprazole 40 mg b.i.d. plus Pylera® (three-­in-­one cap-
sules containing bismuth subcitrate potassium 140 mg, metronidazole
3 | RESULTS
The ITT population included 131 patients. The characteristics of the
study group are reported in Table 1. No case of uncompliant patient
occurred. PP analysis included 127 patients, because four (3.0%) pa-
tients interrupted the study due to TEAEs.
The H. pylori eradication was achieved in 124 patients (94.7%,
95% CIs 89.3-­97.8) in the ITT population. In the PP population, the
percentage was 97.6% (95% CIs 93.3-­99.2). The proportion of pa-
tients who achieved H. pylori eradication was similar in naïve patients
(51 of 55 [92.7%, 95% CIs 85.9-­99.6]) and in patients who received a
previous eradication therapy (73 of 76 [96.0%, 95% CIs 89.0-­98.6]);
P=.383. H. pylori eradication was also similar in nonsmoking patients
(86 of 92 [93.5%, 95% CIs 86.5-­97.0]) and in smoking patients (38
of 39 [97.4%, 95% CIs 86.8-­99.5]); P=.619, as well as in patients
taking omeprazole (69 of 72 [95.8%, 95% CIs 91.2%-­100.4%]) or
esomeprazole (55 of 59 [93.2%, 95% CIs 86.8%-­99.6%]); P=.789.
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T A B L E   1   Demographic and clinical characteristics of the study T A B L E   2   Treatment-­emergent adverse events

group
Number 35
Number 131 CNS disorders
Mean (95% CI for the mean) age, yr 50.9 (48.9-­52.9) Dizziness 7 (20.0)
Gender, male 59 (45.0) Dysgeusia 1 (2.8)
Body mass index (kg/m2) 27.1 (24.2-­29.4) Gastrointestinal disorders
Smoking 39 (29.8) Nausea 9 (25.7)
Previous eradication therapy 76 (58.0) Diarrhea 6 (17.1)
Type of previous eradication therapy 27 (62.8) Abdominal pain 3 (8.6)
7-­day triple therapy with 53 (69.7) Vomiting 1 (2.8)
PPI-­amoxicillin-­clarithromycin
Glossitis 1 (2.8)
10-­day triple therapy with 1 (1.3)
Flatulence 1 (2.8)
PPI-­amoxicillin-­clarithromycin
General disorders
Sequential” therapy 5 (6.6)
Darkening of the tongue 3 (8.6)
Second-­line “Sequential” therapy (with 1 (1.3)
levofloxacin and tetracycline) Asthenia 3 (8.6)
Multiple therapies 16 (21.1) Values are expressed as number (percentage) of patients.
13
C-­urea breath test
Helicobacter pylori positive 128 (97.7)
impressive in clinical practice. In fact, we found that around 95% of
Helicobacter pylori negative 3 (2.3) H. pylori-­positive people was successfully treated with this regimen.
Endoscopic finding Our results have several strengths. First, these are the first data
Gastritis 127 (96.9) coming from clinical practice, confirming that the use of this new qua-
Duodenitis 21 (16.0) druple therapy is very effective. Moreover, we found that this therapeu-
Gastric ulcer 6 (4.5) tic regimen is always effective, both as first treatment and as a salvage
Duodenal ulcer 16 (12.2) therapy. In fact, in both cases, eradication rate was always >92%. We
Histologya 4 (9.3) also found that this quadruple therapy had eradication rates similar to

Helicobacter pylori positive 104 (95.4)

Helicobacter pylori negative 5 (4.6)
Values are expressed as number (percentage) of patients, unless otherwise
specified. CI, confidence interval.
a
Percentages are based on number of patients with available data.
Treatment-­emergent adverse events occurred in 35 patients
(26.7%, 95%, CIs 19.9-­34.9) and are showed in Table 2. Gastrointestinal
symptoms were the most common TEAEs. All TEAES were graded as
mild except the four cases, which led to protocol discontinuation. In
particular, three patients complained of diarrhea and one patient suf-
fered from a diffuse urticarial rush.
4 | DISCUSSION
Colonization with H. pylori causes a wide range of upper gastrointestinal
disorders in humans. Unfortunately, eradication therapy is not always
successful. This is probably due to the increasing incidence of clarithro-
mycin resistance. For example, a twofold increase in primary clarithromy-
cin resistance occurred in the last 15 years in Italy, increasing from 10.2%
5
in the period 1989-­1990 to 21.3% in the period 2004-­2005. Eradication
rate, when using standard triple therapy, has subsequently declined, and
this regimen is almost ineffective in the majority of people now.3,4
Our results show that the new 10-­day treatment with three-­in-­
one bismuth-­based quadruple therapy yields H. pylori eradication rates
the one obtained in the controlled studies. The first noninferiority trial
using this therapeutic regimen found an eradication rate of 93% in PP
and 80% in ITT analysis,14 similar to our results. Moreover, Delchier
et al.15 recently found that this regimen, used as rescue therapy,
reached an eradication rate of 93% in the ITT population and 95% in
the PP population. As we reached similar results in clinical practice, we
can affirm that this therapeutic regimen may be successfully used not
only as rescue therapy, but also as first-­line therapy in clinical practice,
too. Maybe the efficacy was so high because few or no patients were
previously treated with metronidazole. In fact, triple therapy contain-
ing clarithromycin but not metronidazole has been the most prescribed
one in Italy during the last years, and only the occurrence of increasing
detection of clarithromycin-­resistant H. pylori strains led to the devel-
opment of new treatments, especially the sequential one. This too high
confidence of Italian physician with 7-­day clarithromycin-­containing tri-
ple therapy also explains why the vast majority of our population with
prior failure of eradication therapy has been treated with this regimen.
Switching to nonbismuth concomitant treatment might be an option,
even considering the results of the recent trial from Taiwan.10 Thus,
considering the high clarithromycin resistance in Italy, we decided to
use Pylera® to avoid any risk of treatment failure.
The second point to consider is that it seems always effective. In
fact, we found that neither gender, or smoke, or naïve-­anti-­H. Pylori
status or prior failure to an anti-­H. pylori regimen, or type of PPI used
seem to influence the efficacy of this therapeutic regimen. Even com-
pliance does not seem to be influenced by the high number of pills,
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which have to be taken during the day, as all enrolled people were
fully compliant. This is very important to consider in clinical practice,
because we know that low compliance may affect other recent ther-
apeutic regimens.7 Obviously, the impressive eradication rate both
in naïve and in patients with prior failure to an anti-­H. pylori regimen
opens the question whether this regimen has to be advised as pri-
mary or salvage therapy. All current guidelines advise to prescribe
bismuth-­based quadruple therapy as first-­line treatment in areas with
high resistance to clarithromycin.2,11,12 In this way, this three-­in-­one
bismuth-­based regimen should be advised as first-­line treatment at
least in Southern Europe, in which clarithromycin resistance has dra-
matically increased.5,19,20 Of course, a 10-­day anti-­H. pylori course with
Pylera® has significant cost, as its price in Italy is €64.09. However, this
is counterbalanced by the high efficacy of the therapy and the use of a
single type of pill, increasing patients’ compliance with the treatment.
The third strength of this study is the safety of this regimen. We
found that TEAEs occurred in 26.7% of treated people and that in only
a minority of cases, they caused discontinuation of treatment. This TEAE
rate was similar to the one recorded when using triple or sequential ther-
apy,10,20 but significantly lower than the one reported in the first experi-
ences with this quadruple therapy.13-15 In fact, mild TEAEs were recorded
in 58% of patients in the American trial and in 47% of subjects in the
European trial. Similarly, Delchier et al. reported mild TEAEs in 67% of pa-
tients. However, more cases of nausea, dizziness, and diarrhea occurred
in our population, and diarrhea led to discontinuation of treatment in
three cases. The reason why this significant difference occurs is unknown.
The present study is limited by the small population enrolled when
compared to recent large studies. However, we have to consider that
Pylera® has become available in Italy only at the beginning of 2016
and this study is the first experience with this formulation. Another
limit is that no antibiotic testing was performed in our population be-
fore starting treatment. However, antibiotic testing is difficult to per-
form in clinical practice, and the very high eradication rate reached in
our population overcomes this limit.
In conclusion, the new three-­in-­one bismuth-­containing quadruple
therapy seems to be very effective and safe in real life. Further studies
enrolling larger population are warranted to confirm these results.
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How to cite this article: Tursi A, Di Mario F, Franceschi M,
et al. New bismuth-­containing quadruple therapy in
patients infected with Helicobacter pylori: A first Italian
experience in clinical practice. Helicobacter. 2017;22:e12371.
https://doi.org/10.1111/hel.12371