646 ARTICLE

Effectiveness of Helicobacter pylori Treatments

STOMACH
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c

According to Antibiotic Resistance

Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1

Luis Bujanda, MD, PhD1, Olga P. Nyssen, PhD2, June Ramos, MD1, Dmitry S. Bordin, MD3, Bojan Tepes, MD4, Angeles Perez-Aisa, PhD5,
Matteo Pavoni, MD6, Manuel Castro-Fernandez, PhD7, Frode Lerang, MD8, M arcis Leja, MD9, Luis Rodrigo, PhD10,
Theodore Rokkas, PhD , Juozas Kupcinskas, MD , Laimas Jonaitis, MD , Oleg Shvets, MD13, Antonio Gasbarrini, PhD14,
11 12 12

Halis Simsek, MD15, Perminder S. Phull, MD16, György Miklós Buzás, MD17, Jose C. Machado, MD18, Doron Boltin, MD19,
Lyudmila Boyanova, MD20, Ante Tonkić, MD21, Wojciech Marlicz, MD22, Marino Venerito, MD23, Ludmila Vologzanina, MD24,
Galina D. Fadieienko, MD25, Giulia Fiorini, MD6, Elena Resina, MD2, Raquel Muñoz, MD2, Anna Cano-Català, PhD26, Ignasi Puig, PhD27,
Natalia García-Morales, MD28, Luis Hernández, MD29, Leticia Moreira, PhD30, Francis Megraud, PhD31, Colm O. Morain, PhD32,
Milagrosa Montes, Pharm PhD33, Javier P. Gisbert, PhD2 and on behalf of the Hp-EuReg investigators*
DTZh9NFapZexoio6AI= on 04/22/2024

INTRODUCTION: Antibiotic resistance is one of the main factors that determine the efficacy of treatments to eradicate
Helicobacter pylori infection. Our aim was to evaluate the effectiveness of first-line and rescue
treatments against H. pylori in Europe according to antibiotics resistance.

METHODS: Prospective, multicenter, international registry on the management of H. pylori (European Registry on
H. pylori Management). All infected and culture-diagnosed adult patients registered in the Spanish
Association of Gastroenterology-Research Electronic Data Capture from 2013 to 2021 were included.
RESULTS: A total of 2,852 naive patients with culture results were analyzed. Resistance to clarithromycin,
metronidazole, and quinolones was 22%, 27%, and 18%, respectively. The most effective treatment,
regardless of resistance, were the 3-in-1 single capsule with bismuth, metronidazole, and tetracycline
(91%) and the quadruple with bismuth, offering optimal cure rates even in the presence of bacterial
resistance to clarithromycin or metronidazole. The concomitant regimen with tinidazole achieved an
eradication rate of 99% (90/91) vs 84% (90/107) with metronidazole. Triple schedules, sequential, or

H. pylori treatments according to antibiotic resistance

Positive cultures
Resistances Eradication ≥ 90%
3,970
Three-in-one single capsule
Metronidazole 27% Quad.-PPI+C+A+B
27 included countries Clarithromycin 22%
Naïve Alternative:
(2013-2021) Quinolones 18%
2,852 cultures Conc.-PPI+C+A+T
Dual (C+M) 11%
PPI+L+A+B

Metronidazole 41%
None
Clarithromycin 49% Alternative:
Non-naïve Three-in-one single capsule
1,118 cultures Quinolones 24%
Dual (C+M) 34% Conc.-PPI+C+A+T
PPI+L+A+B

GLOBAL RESULTS: In general, concomitant non-bismuth quadruple therapy, better tinidazole than metronidazol

A, amoxicillin; B, bismuth salts; C, clarithromycin; Conc., concomitant; L,

Bujanda et al. Am J Gastroenterol. 2024. doi:10.14309/ajg.0000000000002600
levofloxacin; M, metronidazole; PPI, proton pump inhibitor; Quad.,
All icons above are from https://www.mapchart.net/. quadruple; T, tinidazole; Tc, tetracycline; Three-in-one single capsule
(marketed as Pylera)

The American Journal of GASTROENTEROLOGY VOLUME 119 | APRIL 2024 www.amjgastro.com

Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
 Effectiveness of Helicobacter pylori 647

concomitant regimen with metronidazole did not achieve optimal results. A total of 1,118 non-naive
patients were analyzed. Resistance to clarithromycin, metronidazole, and quinolones was 49%, 41%,
and 24%, respectively. The 3-in-1 single capsule (87%) and the triple therapy with levofloxacin (85%)

STOMACH
were the only ones that provided encouraging results.
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c

DISCUSSION: In regions where the antibiotic resistance rate of H. pylori is high, eradication treatment with the 3-in-1
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1

single capsule, the quadruple with bismuth, and concomitant with tinidazole are the best options in
naive patients. In non-naive patients, the 3-in-1 single capsule and the triple therapy with levofloxacin
provided encouraging results.
KEYWORDS: Helicobacter pylori; treatment; resistance; non-naive

SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/AJG/D125.

Am J Gastroenterol 2024;119:646–654. https://doi.org/10.14309/ajg.0000000000002600

INTRODUCTION one with a high clarithromycin resistance when clarithromycin re-

DTZh9NFapZexoio6AI= on 04/22/2024

Helicobacter pylori infection is the most prevalent infection in the sistance is equal or higher than 15%–20% (7). Furthermore, antibiotic
world (1). This infection is the main cause of different diseases resistances are markedly increased in patients who have received at
such as functional dyspepsia, gastritis, gastroduodenal ulcers, and least 1 previous treatment, with dual and triple resistances (6).
gastric cancer (2). Based on resistance and the established treatment effectiveness
H. pylori is a bacterium characterized by the development of re- threshold of 90%, most international organizations and guidelines
sistance to multiple antibiotics. The World Health Organization advise abandoning triple therapies that include 2 antibiotics (clari-
(WHO) establishes antibiotic resistance as a global health problem (3) thromycin plus either amoxicillin or metronidazole) and introducing
and determines H. pylori as one of the bacteria that can potentially quadruple regimens (either bismuth or non–bismuth-based) (5).
cause problems during the eradication treatment because of the There are few studies evaluating the efficacy of H. pylori
growing resistance (4). Antibiotic resistance is one of the main factors treatment in routine clinical practice with known antibiotic
that determine the efficacy of the different treatment regimens and sensitivity to H. pylori (i.e, susceptibility-based). Therefore, our
somehow hamper the objective of all therapeutical schemes, which is objective was to evaluate the effectiveness of first-line and rescue
ultimately to achieve an eradication rate equal or higher than 90% (5). treatments against H. pylori in Europe according to the resistance
Other relevant factors are the adherence and the duration of treatment. pattern of the different antibiotics.
In Europe, resistance to clarithromycin, levofloxacin, and metro-
nidazole in naive patients is generally high, which is above 15% (6). METHODS
According to Maastricht VI/Florence Consensus, the first-line eradi- European Registry on H. pylori Management
cation therapy should be based on the prevalence of local The European Registry on H. pylori Management (Hp-EuReg) is
clarithromycin-resistant H. pylori strains (7). A country was defined as an international multicenter prospective noninterventional
1
Department of Gastroenterology, Biodonostia Health Research Institute, San Sebastián; CIBERehd, Centro de Investigación Biomédica en Red de Enfermedades
Hepáticas y Digestivas (CIBERehd), Madrid; Department of Medicine, Universidad Del País Vasco (UPV/EHU), San Sebastián, Spain; 2Gastroenterology
Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Centro de
Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; 3Department of Pancreatic, Biliary and Upper Digestive
Tract Disorders, A. S. Loginov Moscow Clinical Scientific Center, Moscow; Department of Propaedeutic of Internal Diseases and Gastroenterology, A.I. Yevdokimov
Moscow State University of Medicine and Dentistry, Moscow; Department of Outpatient Therapy and Family Medicine, Tver State Medical University, Tver, Russia;
4
Department of Gastroenterology, DC Rogaska, Slatina, Slovenia; 5Digestive Unit, Agencia Sanitaria Costa Del Sol, Marbella, Spain; 6Department of Medical and
Surgical Sciences, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy; 7Aparato Digestivo, Hospital Universitario de Valme, Sevilla, Spain;
8
Department of Gastroenterology, Østfold Hospital Trust, Gr alum, Norway; 9Gastro, Digestive Diseases Centre, Riga; Institute of Clinical and Preventive Medicine,
University of Latvia, Riga, Latvia; 10Gastroenterology, University of Oviedo, Oviedo, Spain; 11Gastroenterology Clinic, Henry Dunant Hospital, Athens, Greece;
12
Institute for Digestive Research and Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania; 13Department of
Gastroenterology, Internal Medicine, National Medical University, Kyiv, Ukraine; 14Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario
Agostino Gemelli IRCCS, Roma, Italy; 15Department of Gastroenterology, Hacettepe University, Ankara; Department of Gastroenterology, HC International Clinic,
Ankara, Turkey; 16Department of Digestive Disorders, Aberdeen Royal Infirmary, Aberdeen, UK; 17Gastroenterology, Ferencváros Health Center, Budapest,
Hungary; 183S–Instituto de Investigação e Inovação Em Saúde da Universidade Do Porto, Porto; Ipatimup–Instituto de Patologia e Imunologia Molecular da
Universidade Do Porto, Porto; Pathology, FMUP–Faculdade de Medicina Do Porto, Porto, Portugal; 19Division of Gastroenterology, Rabin Medical Center,
PetahTikva; Sackler School of Medicine, Tel Aviv University, TelAviv, Israel; 20Department of Medical Microbiology, Medical University of Sofia, Sofia, Bulgaria;
21
Department of Gastroenterology, University Hospital of Split, Split, Croatia; 22Department of Gastroenterology, Pomeranian Medical University in Szczecin,
Szczecin; The Centre for Digestive Diseases, Endoklinika, Szczecin, Poland; 23Department of Gastroenterology, Hepatology and Infectious Diseases, University
Hospital of Magdeburg, Magdeburg, Germany; 24Gastrocenter, Perm, Russia; 25L.T. Malaya Therapy National Institute of the National Academy of Medical
Sciences of Ukraine, Kharkiv, Ukraine; 26GOES Research Group, Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Spain; 27Althaia Xarxa Assistencial
Universitària de Manresa and Universitat de Vic-Universitat Central de Catalunya (UVicUCC), Manresa, Spain; 28Complexo Hospitalario Universitario de Vigo
(CHUVI) and Galicia Sur Health Research Institute (IIS Galicia Sur); SERGAS-UVIGO, Spain; 29Unidad de Gastroenterología, Hospital Santos Reyes, Aranda de
Duero, Spain; 30Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS (Institut
D’Investigacions Biomèdiques August Pi I Sunyer), University of Barcelona, Barcelona, Spain; 31INSERM U1312, Université de Bordeaux, Bordeaux, France;
32
Trinity College Dublin, Dublin, Ireland; 33Department of Microbiology, Donostia University Hospital-Biodonostia Health Research Institute, San Sebastian, Spain.
Correspondence: Luis Bujanda, MD, PhD. E-mail: medik@telefonica.net.
*The investigators in the European Registry on H. pylori Management (Hp-EuReg) study are listed in the Acknowledgements.
Received June 26, 2023; accepted October 2, 2023; published online November 17, 2023

© 2023 by The American College of Gastroenterology The American Journal of GASTROENTEROLOGY

Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
 648 Bujanda et al
registry with a collection of information on H. pylori infection
management since 2013, which was promoted by the European
Helicobacter and Microbiota Study Group (www.helicobacter.
org) (8).
STOMACH
The ethics committee of La Princesa University Hospital
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c
(Madrid, Spain), which acted as the reference institutional review
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1
board, approved the protocol of the Hp-EuReg (8). The study
protocol conforms to the ethical guidelines of the 1975 Declara-
tion of Helsinki as reflected in a previous approval by the insti-
tution’s human research committee. The study was classified by
the Spanish Drug and Health Product Agency and registered at
ClinicalTrials.gov under the code NCT02328131. Written in-
formed consent was obtained from all participants.
Participants
Data were recorded in an electronic case report form, collected
and managed using the web-based application designed to sup-
DTZh9NFapZexoio6AI= on 04/22/2024
port data capture for research studies (REDCap) (9), and hosted
at the Spanish Association of Gastroenterology (www.aegastro.
es), a nonprofit scientific and medical society focused on gas-
troenterology research (10). Data were anonymized. Patients
(older than 18 years) with an H. pylori–positive result for culture
and antimicrobial susceptibility testing (AST), recruited between
January 2013 and December 2021, were included in the analysis.
Cases without an antibiogram were excluded. Naive patients were
defined as subjects who had never been treated for H. pylori and
non-naive those who had previously undergone treatment (one
or more eradication treatments).
Data management
After extracting the data and before the statistical analysis, the
database was reviewed for inconsistencies and subsequent data
cleaning. The data quality review process evaluated whether the
study selection criteria had been met and whether data were
correctly collected, ensuring the study was conducted according
to the highest scientific and ethical standards. Data discordances
were resolved by querying the investigators and through group
emailing.
Statistical analysis
Variables categorization and definition. Indications for H. pylori
testing were duodenal ulcer, gastric ulcer, uninvestigated or
functional dyspepsia, among other conditions. Other indications
included a family history of gastric cancer, premalignant gastric
lesions such as atrophic chronic gastritis and intestinal meta-
plasia, anemia of unknown origin, erosive gastroduodenitis,
gastric lymphoma, and idiopathic thrombocytopenia.
For H. pylori isolation, gastric biopsy specimens were obtained
from the antrum and/or body of the stomach during endoscopic
examinations. Cultures were performed on selective plates under
microaerobic conditions. AST was performed with E-test strips in
most of the centers. Antimicrobial resistance was determined
according to the guidelines and criteria of the European Com-
mittee of Antibiotic Susceptibility Testing (EUCAST Clinical
Breakpoint Table V.9) (https://www.eucast.org/clinical_
breakpoints).
Dual resistance was defined as resistance to clarithromycin
and metronidazole. Triple resistance was defined as resistance to
clarithromycin, metronidazole, and levofloxacin.
Adequate compliance with treatment was defined by having
taken at least 90% of the prescribed drugs, accepted as an arbitrary
The American Journal of GASTROENTEROLOGY
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
threshold. However, it is known that poorer levels of compliance
with therapy are associated with significantly lower levels of H.
pylori eradication (11).
All patients included in the study underwent 13C-urea breath
test to check the effectiveness of the treatment. The test was
performed at least 4 weeks after finishing the treatment.
Only treatment schemes with more than 10 patients treated
were considered in the analysis. The treatment schemes used were:
1. Sequential; with a proton pump inhibitor (PPI) and
amoxicillin 1 g, all twice a day (BID) for 5 days followed by
PPI standard dose, clarithromycin 500 mg, and tinidazole
500 mg, all BID for further 5 days, henceforth reported as
sequential-PPI 1 C 1 A 1 T.
2. Triple with amoxicillin; with a PPI, clarithromycin 500
mg, and amoxicillin 1 g, all BID, henceforth reported as
triple-PPI 1 A 1 C.
3. Triple with metronidazole or tinidazole; with a PPI,
amoxicillin 1 g, and tinidazole or metronidazole both 500
mg and all BID, henceforth reported as triple-PPI 1 A 1
M/T.
4. Bismuth quadruple with the 3-in-1 single capsule
(marketed as Pylera); with a PPI and the single capsule 3
tablets 4 times a day; and the aforementioned capsule
containing bismuth subcitrate potassium (140 mg),
metronidazole (125 mg), and tetracycline (125 mg),
henceforth reported as 3-in-1 single capsule.
5. Concomitant with metronidazole or tinidazole; with a PPI,
amoxicillin 1 g, clarithromycin 500 mg, and metronidazole
or tinidazole 500 mg, all BID, henceforth reported as
concomitant-PPI 1 C 1 A 1 M/T.
6. Quadruple with bismuth subcitrate potassium; with a PPI,
amoxicillin 1 g, clarithromycin 500 mg, and bismuth
subcitrate potassium 250 mg, all BID, henceforth reported
as quadruple-PPI 1 C 1 A 1 B.
7. Classic bismuth quadruple; with a PPI, tetracicline 500 mg
4 times a day, metronidazole 500 mg 3 times a day,
bismuth subcitrate potassium 120 mg 4 times a day,
henceforth reported as quadruple-PPI 1 Tc 1 M 1 B.
8. Triple with rifabutin; with a PPI, amoxicillin 1 g BID, and
rifabutin 150 mg, BID or once a day, henceforth reported
as triple-PPI 1 A 1 R.
Data analysis. The prevalence of bacterial antibiotic resistance
was presented as the ratio of the number of the positive cultures
resulting in the different antibiotics among the total number of
patients where culture and AST had been performed. To compare
the treatment schemes, subanalyses by the duration of treatment
and adherence to treatment were performed.
Continuous variables were shown as arithmetic mean values
and SDs and qualitative variables as percentages and corre-
sponding 95% confidence intervals.
The x2 test was used to compare categorical variables. The
statistical significance was established with a P value ˂ 0.05.
RESULTS
Baseline characteristics
The treatments of 3,970 patients with positive cultures of 27
countries were analyzed. The mean age was 51 years (615 years),
and 62% (2,462) were women. The countries in which most
H. pylori cultures were obtained were Italy (2,360; 59.4%),
VOLUME 119 | APRIL 2024 www.amjgastro.com
 Effectiveness of Helicobacter pylori 649

Table 1. Results of cultures performed in naive and non-naive patients

No. (%) Naive (N 5 2,852) Non-naive (N 5 1,118)

STOMACH
Nonresistance 1,582 (40%) 1,235 (43%) 347 (31%)
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c

Metronidazole 1,222 (31%) 759 (27%) 463 (41%)

Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1

Clarithromycin 1,176 (30%) 627 (22%) 549 (49%)

Quinolones 773 (20%) 503 (18%) 270 (24%)
Amoxicillin 16 (0.4%) 10 (0.3%) 6 (0.5%)
Tetracycline 5 (0.1%) 4 (0.1%) 1 (0.08%)
Dual (C 1 M) 701 (18%) 324 (11%) 377 (34%)
Triple (C 1 M 1 Q) 344 (9%) 151 (5%) 193 (17%)

C, clarithromycin; Q, quinolones; M, metronidazole.

DTZh9NFapZexoio6AI= on 04/22/2024

followed by Spain (454; 11.4%), Norway (368; 9.3%), Greece (248;
6.2%), and Slovenia (211; 5.3%).
The number of cultures performed in naive and non-naive
patients was 2,852 (79%) and 1,118 (31%), respectively. In naive
patients, 1,235 (43%) were sensitive to all antibiotics vs 347 (31%)
in non-naive patients. The most frequent antibiotic resistance was
to metronidazole (31%) and the least frequent to amoxicillin and
tetracyclines (less than 1%) (Table 1).
First-line treatment effectiveness
Patients sensitive to all antibiotics. The treatments prescribed to
1,235 patients were analyzed. The most commonly used treat-
ment scheme was sequential therapy in 556 (45%) patients, classic
triple therapy in 270 (22%), triple therapy with metronidazole in
185 (15%), and concomitant therapy with metronidazole or tinida-
zole in 71 cases (6%). An eradication rate of at least 90% was achieved
in all therapies except in the triple therapy using metronidazole to-
gether with amoxicillin, where the cure rate was 88% (Table 2).
According to clarithromycin resistance. In naive patients, the
number of patients with resistance to clarithromycin was 22%
(627/2,852).
When analyzing the effectiveness of treatments in patients
with clarithromycin-sensitive strains, the efficacy of most of the
regimens was very high. The highest eradication rate (100%) was
reported with the 3-in-1 single capsule (Table 2).
Among the 627 patients with clarithromycin resistance,
eradication rates decreased to 75% for instance with triple-PPI 1
C 1 A (prescribed in 12 patients). Despite known clarithromycin
resistance, the most frequently used regimen was the sequential
regimen—including clarithromycin in 50% (311/627) of cases.
The treatment scheme with the highest eradication rate was the
3-in-1 single capsule with 93%. The remaining therapies were
below 90% effectiveness, except for the quadruple-PPI 1 C 1 A
1 B, reporting 90% eradication rate (Table 3). The concomitant
regimen with tinidazole achieved 100% (23/23) eradication vs
74% (20/27) in those treated with metronidazole.
According to metronidazole resistance. The rate of resistance to
metronidazole in naive patients was 27% (759/2,852). When
analyzing the effectiveness of treatments in metronidazole-sensitive
patients, independent of other resistances, the efficacy remained
similar to that of patients with no resistance. The highest eradication
rate was with the 3-in-1 single capsule (100%, 81 patients treated)
(Table 2). Despite being sensitive to metronidazole, triple therapy
with metronidazole achieved an eradication rate below 90%.
Among the 759 patients with metronidazole resistance, all
treatments had eradication rates below 90%, except quadruple
therapy with bismuth (94%), treatment with the 3-in-1 single
capsule (91%), and triple therapy with levofloxacin (90%), which
was used in 49 patients. Most of these patients (39 patients, 80%)
had dual resistance to both clarithromycin and metronidazole

Table 2. Per-protocol effectiveness in naive patients with susceptibility to each of the antibiotics

All sensitive (no resistance) Clarithromycin-sensitive Metronidazole-sensitive Levofloxacin-sensitive

Most common 1st-line treatments No. patients Eradication No. patients Eradication No. patients Eradication No. patients Eradication
Sequential-PPI 1 C 1 A 1 T 556 526 (95%) 825 783 (95%) 785 740 (94%) 820 761 (93%)
Triple-PPI 1 A 1 C 270 255 (94%) 460 424 (92%) 306 287 (94%) 425 394 (93%)
Triple-PPI 1 A 1 M 185 163 (88%) 197 174 (88%) 220 192 (87%) 220 191 (87%)
Triple-PPI 1 A 1 L 1 1 (100%) 12 11 (92%) 22 19 (86%) 69 61 (88%)
Concomitant-PPI 1 C 1 A 1 M/T 71 68 (96%) 104 99 (95%) 109 103 (94%) 122 112 (92%)
PPI 1 single capsulea 42 42 (100%) 67 67 (100%) 81 81 (100%) 80 78 (98%)
Quadruple-PPI 1 C 1 A 1 B 17 16 (94%) 41 37 (90%) 30 34 (88%) 80 78 (98%)
A, amoxicillin; B, bismuth salts; C, clarithromycin; L, levofloxacin; M, metronidazole; PPI, proton pump inhibitor; T, tinidazole; Tc, tetracycline.
a
Three-in-one single capsule containing bismuth, tetracycline, and metronidazole.

© 2023 by The American College of Gastroenterology The American Journal of GASTROENTEROLOGY

Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
 650 Bujanda et al

Table 3. Per-protocol effectiveness in naive patients with resistance to clarithromycin, amoxicillin, and levofloxacin

Patients sensitive to all Clarithromycin resistance Metronidazole resistance Levofloxacin resistance

STOMACH

No. patients Eradication No. patients Eradication No. patients Eradication No. patients Eradication
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c

Sequential-PPI 1 C 1 A 1 T 556 526 (95%) 311 271 (87%) 351 314 (89%) 316 293 (93%)
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1

Triple-PPI 1 A 1 C 270 255 (94%) 12 9 (75%) 166 146 (88%) 47 39 (83%)

Triple-PPI 1 A 1 M 185 163 (88%) 30 24 (80%) NA NA NA NA
Triple-PPI 1 A 1 L 1 1 (100%) 59 52 (88%) 49 44 (90%) 2 2 (100%)
Concomitant-PPI 1 C 1 A 1 M/T 71 68 (96%) 50 43 (86%) 45 39 (87%) 32 30 (94%)
PPI 1 single capsule a
42 42 (100%) 58 54 (93%) 44 38 (91%) 13 9 (69%)
Quadruple-PPI 1 C 1 A 1 B 17 16 (94%) 10 9 (90%) 17 16 (94%) 45 43 (96%)
A, amoxicillin; B, bismuth salts; C, clarithromycin; L, levofloxacin; M, metronidazole; PPI, proton pump inhibitor; T, tinidazole; Tc, tetracycline; NA, not available.
a
Three-in-one single capsule containing bismuth, tetracycline, and metronidazole.
DTZh9NFapZexoio6AI= on 04/22/2024

(Table 3). The concomitant regimen with tinidazole achieved 100%
(22/22) eradication vs 73% (16/22) with metronidazole.
According to quinolone resistance. The levofloxacin resistance
rate in naive patients was 18% (503/2,852).
When we analyzed the effectiveness of the treatments in
levofloxacin-sensitive patients, independently of other resis-
tances, the success rate remained similar to that of patients with
no resistance. The highest eradication rate was with the 3-in-1
single capsule (98%, 80 patients treated) (Table 2). All treat-
ments achieved eradication rates above 90%, except triple
therapy with metronidazole (87%). In 69 patients treated with
triple therapy with levofloxacin, an eradication rate of 88% was
reported.
When we analyzed the 503 patients with levofloxacin re-
sistance, only treatments with quadruple with bismuth (96%),
concomitant with tinidazole (100%), and sequential with
amoxicillin and tinidazole (93%) achieved eradication rates
higher than 90%. The concomitant regimen with tinidazole
achieved 100% (22/22) eradication vs 80% (8/10) with
metronidazole.
Dual or triple resistance. Among naive patients, 11% had dual
resistance to both clarithromycin and metronidazole. In those cases
sensitive to both antibiotics, most treatment schemes achieved
eradication rates equal or higher than 90%, being 100% (97
patients treated) in the case of those prescribed with the 3-in-
1 single capsule. Triple therapy with metronidazole achieved
87% (197/226) eradication, despite being sensitive to
metronidazole.
In patients with dual resistance, triple therapy with levofloxacin
achieved 90% (35/39) eradication (see Supplementary Table 1,
http://links.lww.com/AJG/D125). The most frequent regimen used
was sequential therapy with amoxicillin and tinidazole, with an
eradication rate of 85% (157/185), whereas the 3-in-1 single capsule
achieved an eradication rate of 86% (24/28).
Triple resistance to clarithromycin, metronidazole, and levo-
floxacin in naive patients occurred in 5% of the cases (151/2,852).
In these cases, the only regimen with more than 15 cases treated
was the sequential regimen with amoxicillin and tinidazole,
which achieved an eradication rate of 87% (90/103). The next 2
regimens with more cases treated were the 3-in-1 single capsule,
with 88% (15/17), and triple with amoxicillin and rifabutin, which
achieved 100% eradication (10/10).
Rescue (from second- to sixth-line) treatment effectiveness
Among those non-naive, 49% (549/1,118) of patients were re-
sistant to clarithromycin. Resistance to metronidazole was 41%
(463/1,118) and 24% (270/1,118) to quinolones.
Overall, no treatment achieved an eradication rate of 90%. The
schemes with the highest eradication rates were the 3-in-1 single
capsule with 87% (150/172) and the triple therapy with levo-
floxacin with 85% (299/352). The triple therapy with rifabutin
achieved an eradication rate of 80% (199/249).
Although they were sensitive to clarithromycin, triple therapy
with clarithromycin achieved an eradication rate of 76% (see Sup-
plementary Table 2, http://links.lww.com/AJG/D125). The only
treatment that achieved eradication rates of 90% with more than 10
patients treated was the 3-in-1 single capsule (90%). In
clarithromycin-resistant patients, any of the treatments prescribed to
more than 10 patients achieved rates equal or greater than 90% (see
Supplementary Table 3, http://links.lww.com/AJG/D125).
In patients sensitive to metronidazole, the only treatment that
obtained eradications above 90% was the 3-in-1 single capsule.
Triple therapy with metronidazole and levofloxacin achieved
eradication rates of 89% and 87%, respectively. In those patients
with metronidazole-resistant strains, none of the aforementioned
treatments reached 90% cure rates (see Supplementary Table 3,
http://links.lww.com/AJG/D125). The best was triple therapy
with levofloxacin.
In quinolone-sensitive patients, the 2 treatments that reached
optimal (above 90%) effectiveness were triple therapy with met-
ronidazole (92%) and the 3-in-1 single capsule (91%). In
levofloxacin-resistant patients, as in the case of metronidazole,
none of the treatments achieved 90% cure rates (see Supple-
mentary Table 3, http://links.lww.com/AJG/D125).
Dual or triple resistance. In non-naive patients, 34% (377/1,118)
had dual resistance to clarithromycin and amoxicillin. In those cases,
sensitive to both antibiotics, most of the regimens did not achieve
eradication rates equal or higher than 90%, despite susceptibility. The
only treatment scheme that exceeded 90% was the 3-in-1 single
capsule with 93% (50/54) effectiveness (see Supplementary Table 4,
http://links.lww.com/AJG/D125). Eradication was significantly
lower in non-naive patients than in naive patients (see Supplemen-
tary Table 4, http://links.lww.com/AJG/D125).
In non-naive patients with dual resistance, all treatment
regimens were below 90% in eradication (see Supplementary

The American Journal of GASTROENTEROLOGY VOLUME 119 | APRIL 2024 www.amjgastro.com

Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.

Table 1, http://links.lww.com/AJG/D125). By number of cases
treated, triple therapy with amoxicillin and rifabutin achieved an
eradication rate of 84% (112/134), triple therapy with levofloxacin
reached 87% (106/122), and the 3-in-1 single capsule obtained
82% (56/68). The effectiveness was reported lower in non-naive
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c
patients than in naive patients (see Supplementary Table 1, http://
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1
links.lww.com/AJG/D125).
Triple resistance to clarithromycin, metronidazole, and levo-
floxacin in non-naive patients occurred in 17% (193/1,118) of
cases. In patients sensitive to the 3 antibiotics, the only scheme
that reached 90% or more was the 3-in-1 single capsule, with 91%
cure rate (73/80). The others schemes with more than 10 cases
treated were triple therapy with levofloxacin, with 87% (220/254),
triple therapy with amoxicillin and rifabutin, with 70% (39/56),
sequential therapy with clarithromycin and tinidazole, with 81%
(43/53), triple therapy with amoxicillin and metronidazole, with
89% (33/37), triple therapy with clarithromycin and amoxicillin,
DTZh9NFapZexoio6AI= on 04/22/2024
with 76% (16/21), and concomitant with metronidazole or tini-
dazole, with 60% (12/20).
In those non-naive patients with triple resistance, the only
regimen with more than 10 cases treated was the triple therapy
with amoxicillin and rifabutin, which achieved 86% eradica-
tion rate (99/115), and the 3-in-1 single capsule, with 79%
(33/42).
DISCUSSION
Clarithromycin and metronidazole are the 2 most commonly
used antibiotics in first-line eradication therapy against H. pylori.
However, the therapeutical effectiveness will depend on the
bacterial resistance to these antibiotics. In recent years, a re-
sistance prevalence of more than 15% has been reported in many
geographical areas, which greatly determines the efficacy of the
treatments (6,12). In this study, we observed that triple treatments
with or without clarithromycin, sequential treatments with
clarithromycin and tinidazole, and hybrid treatments with clar-
ithromycin did not reach 90% eradication rate. On the other
hand, the schemes concomitant-PPI 1 C 1 A 1 T, quadruple-
PPI 1 C 1 A 1 B, and PPI 1 single capsule achieved eradication
rates higher than 90% in those treatment-naive patients with
resistant strains to clarithromycin.
Treatment with the single capsule has shown efficacies above
90% in first-line empirical treatment (i.e., without guidance of
culture testing) and in those areas where resistance to clari-
thromycin and metronidazole was above 20%, such is the case of
Southern European countries (13,14). Bismuth quadruple treat-
ment with PPI 1 C 1 A 1 B may be also a good option for first-
line empirical treatment as suggested by our study, and likewise
confirmed in a recent review (15), in which eradication rates of
94% were observed, higher than with concomitant treatment with
metronidazole; however, both were above 90%.
A published study of the Hp-EuReg on H. pylori management
in which 21,533 patients treated for 5 years were analyzed showed
that triple therapy with amoxicillin and clarithromycin during 7
or 14 days was 83% and 87%, respectively, in the per-protocol
analysis, independently of the presence or not of bacterial re-
sistance to clarithromycin (16). When susceptible to clari-
thromycin, the effectiveness of triple therapy was 94%, dropping
to 75% in the case of resistance. Similarly, a review study noted
that triple therapy in first line including clarithromycin or met-
ronidazole should be avoided when resistances are higher than
15% for clarithromycin (17).
© 2023 by The American College of Gastroenterology
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Helicobacter pylori 651
There were fewer studies with triple therapy with levofloxacin
in first-line treatment. In general, the results were better than with
the classical clarithromycin-based triple therapy (18). In our
study, we observed that triple therapy combining amoxicillin with
STOMACH
levofloxacin in treatment-naive patients that were resistant to
clarithromycin achieved an eradication rate of 88%. This scheme
could represent a good option in first-line empirical treatment in
those areas with high clarithromycin resistance.
Other regimens that were used in some countries such as in
Italy, as the sequential treatment scheme with amoxicillin, clari-
thromycin, and tinidazole, reported very good results in naive
patients sensitive to clarithromycin, but dropped by 8% (from
95% to 87%) when they were resistant to this antibiotic. In our
study, sequential treatment tended to be lower than 90% in first-
line treatment and lower than in other studies in first-line treat-
ment (19). In other countries (not in Italy), treatment with this
scheme had eradication rates higher than 90% (20). In our study,
double resistance to both clarithromycin and metronidazole was
11%, which conditioned the effectiveness of this treatment. In
studies performed in Italy, double resistance to clarithromycin
and metronidazole in naive patients was reported higher than
20%, and the effectiveness of the sequential therapy in such
context was only 83% (21,22). On the other hand, in a study
comparing the sequential vs the concomitant regimen, the effi-
cacy of the latter was superior (23). The quadruple concomitant
regimen with metronidazole or tinidazole, recommended by
many clinical guidelines, usually provides very good results in
those strains sensitive to clarithromycin (95%), but the effec-
tiveness decreases in those resistant (86%), and thus, its use in
first-line empirical therapy is questionable, especially in those
regions with high resistance to clarithromycin, similar to those of
our study. In this same context, regarding the use of metronida-
zole or tinidazole, in our study, we observed that the sequential
regimen with tinidazole obtained eradication rates of 92% as
compared to 80% when metronidazole was used. In a recent re-
view and meta-analysis of randomized controlled trials that
compare standard bismuth quadruple therapy vs concomi-
tant therapy for the first-line treatment do not observe dif-
ferences between both treatments (24). In contrast to our
study, Berruti et al (25) performed a study comparing the use
of metronidazole 250 mg 4 times a day or tinidazole 500 BID
and found no differences between them. Triple therapy with
amoxicillin and metronidazole in naive patients sensitive to
metronidazole did not reach 90% effectiveness in our cohort,
as in other published reviews (25,26). Therefore, metroni-
dazole should not be used in the first-line treatment as part of
triple or sequential regimens. One explanation for this result
is the fact that there is no good correlation between the sus-
ceptibility or resistance of metronidazole in vitro and the
efficacy in vivo (27).
In non-naive patients, antibiotic resistance increases consid-
erably (more than 50%) and the efficacy of treatments decreases
drastically, all being less than 90% in most studies (6). In our
study, the treatments with the highest eradication rates were the
3-in-1 single capsule as well as other combinations that
approached 90% (such as the triple therapy with levofloxacin). In
the Hp-EuReg, in which 2,448 patients treated as second line were
analyzed, triple therapy with levofloxacin, the bismuth-
levofloxacin quadruple schemes (PPI-bismuth-levofloxacin-
amoxicillin), and the 3-in-1 single capsule were the best treat-
ment options, with eradication rates of 89%, 90%, and 88.5%,
The American Journal of GASTROENTEROLOGY
 652 Bujanda et al
respectively (28). In a later study from the same Hp-EuReg, 5,055
patients treated as second line were analyzed, achieving the best
eradication rates with either levofloxacin-containing bismuth
quadruple therapy (29) or with the 3-in-1 single capsule (13),
STOMACH
which was in line with the recommendations of clinical guidelines
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c
(5,7). In this sense, to achieve optimal eradication rates in non-
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1
naive patients, extending the length of treatment to 14 days and
adding bismuth to triple therapy with metronidazole or levo-
floxacin should be considered.
In our study, we observed that in non-naive patients the in
vitro susceptibility of the cultures did not correlate with the ef-
fectiveness of the treatments in vivo. Thus, e.g., when non-naive
patients were susceptible to clarithromycin, the effectiveness of
triple therapy was 76%, whereas the same treatment in naive
patients susceptible to clarithromycin obtained 92% effectiveness.
The same results occurred in those cases that were susceptible to
metronidazole, and the triple therapy with amoxicillin and met-
DTZh9NFapZexoio6AI= on 04/22/2024
ronidazole was administered (87%), and again also in those cases
that were susceptible to quinolones, the triple therapy with
amoxicillin and levofloxacin was prescribed (88%).
The efficacy of treatments depends on antibiotic resistance. In
our study, the resistance in both naive and non-naive patients was
high to clarithromycin, levofloxacin, and metronidazole. Recently,
one of the studies with more cultures performed has been reported
(30). In this study, 31,406 gastroduodenal biopsies from patients
older than 15 years were plated on selective media, isolating H. pylori
in 36.7% (30). Susceptibility testing could be performed in 96.6%
(12,399/12,835) of H. pylori isolates. The study was conducted with
biopsies collected in Basque Country (Spain) between 2000 and
2021. In naive patients, resistance to any antibiotic analyzed was
found in 49.3%, a little lower to our study (57%). In the past 2 years
analyzed, the resistance to clarithromycin and levofloxacin has been
greater than 15% and 20%, respectively. Resistance to levofloxacin
has increased from 7.6% in 2000 to 21.7% in 2021 (30).
The effectiveness of treatment schemes can vary remarkably
depending on the area studied because of the variation of resis-
tances. For example, the efficacy of quadruple with bismuth
treatment in naive patients in our study was greater than 90%
compared with other geographical areas such as Egypt, Iran, and
Vietnam where it was only 70% (31).
AST was performed in only 10.5% (2,927/27,776) of naive
patients and 15% of non-naive patients. The number of cultures
has decreased in these past 10 years. It is important to continue
performing cultures or other techniques (polymerase chain re-
action - fluorescence in situ hybridization) to determine the
tendency of resistance and improve the efficient of treat-
ments (32).
One of the limitations of our study was the lack of a sufficient
and homogeneous number of cases in which the study on antibiotic
susceptibility was performed (70% of the cultures and treatments
came from Italy and Spain), and therefore, there was not a sufficient
sample size to study some treatment regimens that are frequently
prescribed in Europe. Also, the fact of being an observational study
with open inclusion criteria, with the consequent potential higher
risk of bias in terms of selection and inclusion of patients, could
have hampered the synthesis of the information. To avoid bias, the
data selected were defined a priori in the Hp-EuReg protocol to
specifically answer the objectives of the study. These data were
collected routinely in consultations at platform for Collaborative
Research of the Spanish Association of Gastroenterology-Research
Electronic Data Capture in a very simple manner, which ultimately
The American Journal of GASTROENTEROLOGY
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
avoided potential mistakes. In addition, all participating re-
searchers had previously used this platform or had received
training before data entry. Study investigators were selected by the
study coordinators based on their experience treating H. pylori
infection and their research expertise. Data collection by email or
paper was not accepted to avoid increasing errors. Finally, to val-
idate the data entered by the researchers in the database, study
monitors systematically checked a random sample of patients from
each researcher and/or participating center.
Strengths of this study first included the valuable information
from an international multicenter study such as the Hp-EuReg,
which includes a large number of evaluated years (9) and countries.
Second, the fact that data reflected the daily routine of the clinical
practice among European gastroenterologists and not only tertiary
hospitals (highly specialized), so in fact allowing for the evaluation
of a comprehensive set of data. And the last, the use of the high-
quality method to register, store, manage, and monitor the data by
using the online platform for Collaborative Research of the Spanish
Association of Gastroenterology-Research Electronic Data Cap-
ture, allowing the analysis of robust and reliable data.
In summary, in those regions with high H. pylori antibiotic re-
sistance rates, quadruple therapies are recommended both in
treatment-naive patients and in those receiving second-line rescue
regimens. Bismuth quadruple therapy (including the 3-in-1 single
capsule) appeared as the best option in all treatment lines, overcoming
clarithromycin and metronidazole resistances. Other first-line alter-
natives were quadruple therapies with clarithromycin-amoxicillin-
tinidazole or clarithromycin-amoxicillin-bismuth. In addition, in
second-line therapy, the triple therapy with amoxicillin-levofloxacin
might be also an option. Continuous and systematic monitoring of
the antibiotic resistance prevalence is necessary to tailor the treat-
ments to the best standards of care in each European region.
ACKNOWLEDGEMENTS
We want to thank the Spanish Association of Gastroenterology (AEG)
for providing the e-CRF service free of charge. The following persons
participated in the European Registry on H. pylori Management
(Hp-EuReg): Giulia Fiorinni, Ilaria Maria Saracino, Manuel Pabon
Carrasco, Alma Keco Huerga, Enrique Alfaro Almajano, Samuel Jesus
Martinez Dominguez, Horacio Alonso Galan, Benito Velayos, Carmen
Dueñas Sadornil, Jose Maria Botargues Bote, Pedro Luis Gonzalez-
Cordero, Miguel Areia, Blas Jose Gomez Rodriguez, Rinaldo Pellicano,
Óscar Nuñez, Francesco Franceschi, Sergey Alekseenko, Monica
Perona, Rustam Abdulkhakov, Manuel Dominguez-Cajal, Pedro
Almela Notari, Judith Gomez Camarero, Manuel Jimenez Moreno,
Alicia Algaba, Fernando Bermejo, Jose Maria Botargues Bote, Javier
Tejedor Tejada, Elida Oblitas Susanibar, Doron Boltin, Sotirios
Georgopoulos, Colm OMorain, Asghar Qasim, Ian Beales, Natalia
Bakulina, Galina Fadeenko, Peter Malfertheiner, Rosa Rosania, Tatiana
Ilchishina, Pavel Bogomolov, Igor Bakulin, Oleg Zaytsev, Antonietta
Gerarda Gravina, Marco Romano, Alfredo Di Leo, Giuseppe Losurdo,
Ludmila Grigorieva, Pedro Delgado Guillena, Marinko Marusic,
Dragan Jurcic, Natalia Nikolaevna Dekhnich, Eduardo Iyo, Luisa
Carmen de la Peña Negro, Natalia Baryshnikova, Natalia Bakanova,
Halis Simsek, Cem Simsek, Oleksiy Gridnyev, Miguel Fernandez-
Bermejo, Teresa Angueira, Rafael Ruiz- Zorrilla Lopez, Barbara
Gomez, Mila Kovacheva-Slavova, Adi Lahat, Javier Alcedo, Ana
Campillo, Liya Nikolaevna Belousova, Ramon Pajares Villarroya,
Neven Ljubicic, Marko Nikolic, Jesús M González-Santiago, Diego
Burgos Santamaría, Anna Pakhomova, Izabela Sekulic-Spasic, Matteo
Ghisa, Fabio Farinati, Sabir Irfan Sagdati, Nikola Panic, Frederic
VOLUME 119 | APRIL 2024 www.amjgastro.com

Heluwaert, Edurne Amorena, Leticia Moreira, Gloria Fernandez
Esparrach, Ekaterina Yuryevna Plotnikova, Michal Kukla, Victor
Kamburov, Luis Javier Lamuela Calvo, Ivan Rankovic, Antonio
Cuadrado Lavín, Yolanda Arguedas Lazaro, Victor Gonzalez Carrera
Agnieszka Dobrowolska, Piotr Eder, Alla Kononova.
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1
CONFLICTS OF INTEREST
Guarantor of the article: Luis Bujanda, MD, PhD.
Specific author contributions: L.B. and O.P.N.: planned and
coordinated the study, extracted, analyzed, synthetized, and
interpreted the data, wrote the first draft, and approved the submitted
manuscript. O.P.N.: Scientific Director and member of the project’s
Scientific Committee, planned and coordinated the study, designed,
and programmed the electronic case report form, analyzed the data,
and approved the submitted manuscript. L.B., J.R., D.S.B., B.T., A.P.-
A., M.P., M.C.-F., F.L., M.L., L.R., T.R., J.K., L.J., O.S., A.G., H.S.,
P.S.P., G.M.B., J.C.M., D.B., L.B., A.T., W.M., M.V., L.V., G.D.F., G.F.,
DTZh9NFapZexoio6AI= on 04/22/2024
E.R., R.M., M.M. and J.P.G.: acted as recruiters, collected or helped
interpreting data, critically reviewed the manuscript drafts, and ap-
proved the submitted manuscript. L.M., A.C.-C., F.M. and C.O’M.:
members of the project’s Scientific Committee, critically reviewed the
manuscript drafts, and approved the submitted manuscript. J.P.G.:
directed the project and the project’s Scientific Committee, obtained
funding, designed the protocol and planned the study, analyzed and
interpreted the data, collected patients, critically reviewed the
manuscript drafts, and approved the final submitted manuscript.
Financial support: This project was promoted and funded by the
European Helicobacter and Microbiota Study Group (EHMSG) and
received support from the Spanish Association of Gastroenterology
(AEG) and the Centro de Investigación Biomédica en Red de
Enfermedades Hepáticas y Digestivas (CIBERehd). The Hp-EuReg
was cofunded by the European Union programme HORIZON (grant
agreement number 101095359) and supported by the UK Research
and Innovation (grant agreement number 10058099). Views and
opinions expressed are however those of the author(s) only and do
not necessarily reflect those of the European Union or the Health
and Digitial Executive Agency (HaDEA). Neither the European
Union nor the granting authority can be held responsible for
them. The Hp-EuReg was cofunded by the European Union
programme EU4Health (grant agreement number 101101252).
This study was funded by Diasorin; however, clinical data were
not accessible and the company was not involved in any stage of
the Hp-EuReg study (design, data collection, statistical analysis,
or manuscript writing). We want to thank Diasorin for their
support.
Potential competing interests: J.P.G. has served as a speaker, a
consultant, and advisory member for or has received research
funding from Mayoly, Allergan, Diasorin, Gebro Pharma, and
Richen. O.P.N. has received research funding from Mayoly and
Allergan. The remaining authors declare no conflicts of interest.
Informed consent statement: This information is included in
the text. “Written informed consent was obtained from all
participants.”
Institutional review board statement: The Hp-EuReg protocol
was approved by the Ethics Committee of La Princesa University
Hospital (Madrid, Spain), which acted as a reference Institutional
Review Board (December 20, 2012), and was conducted according
to the guidelines of the Declaration of Helsinki, was classified
by the Spanish Drug and Health Product Agency, and was
prospectively registered at ClinicalTrials.gov under the code
NCT02328131.
© 2023 by The American College of Gastroenterology
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Helicobacter pylori 653
Study Highlights
WHAT IS KNOWN
STOMACH
3 Antibiotic resistance is the main factor that determines the
efficacy of treatments to eradicate Helicobacter pylori
infection.
3 In Europe and many other countries around the world the
resistance to clarithromycin, levofloxacin, and metronidazole
in naïve patients is above 15%.
WHAT IS NEW HERE
3 In regions where the antibiotic resistance rate of H. pylori is
high, eradication treatment with the 3-in-1 single capsule, the
quadruple with bismuth and concomitant with tinidazole are
the best option in naïve patients.
3 The 3-in-1 single capsule and triple therapy with levofloxacin
are the best options for non-naïve patients.
REFERENCES
1. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori
infection: Systematic review and meta- analysis. Gastroenterology 2017;
153(2):420–9.
2. Lanas A, Chan FKL. Peptic ulcer disease. Lancet 2017;390(10094):
613–24.
3. WHO. Antibiotics Resistance Report (https://www.who.int/es/news-
room/fact-sheets/detail/resistencia-a-los-antibi%C3%B3ticos) (2022).
4. WHO. WHO Publishes List of Bacteria for Which New Antibiotics Are
Urgently Needed (https://www.who.int/es/news/item/27-02-2017-who-
publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-
needed) (2017).
5. Gisbert JP, Alcedo J, Amador J, et al. V Spanish Consensus Conference on
Helicobacter pylori infection treatment. Gastroenterol Hepatol 2022;
45(5):392–417.
6. Bujanda L, Nyssen OP, Vaira D, et al. Antibiotic resistance prevalence
and trends in patients infected with Helicobacter pylori in the period
2013-2020: Results of the European Registry on H. pylori Management
(Hp-EuReg). Antibiotics (Basel) 2021;10(9):1058.
7. Malfertheiner P, Megraud F, Rokkas T, et al. Management of Helicobacter
pylori infection: The Maastricht VI/Florence consensus report. Gut 2022;
71(9):1724–62.
8. McNicholl AG, O’Morain CA, Megraud F, et al. Protocol of the European
registry on the management of Helicobacter pylori infection (Hp-EuReg).
Helicobacter 2019;24(5):e12630.
9. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture
(REDCap)—a metadata-driven methodology and workflow process for
providing translational research informatics support. J Biomed Inform
2009;42(2):377–81.
10. McNicholl AG, Gisbert JP. Research to the N-Power: The strengths of
networked clinical collaboration in Spain. Am J Gastroenterol 2017;
112(12):1761–4.
11. Nyssen OP, Vaira D, Tepes B, et al. Room for improvement in the
treatment of Helicobacter pylori infection: Lessons from the European
registry on H. pylori management (Hp-EuReg). J Clin Gastroenterol 2022;
56(2):98–108.
12. Megraud F, Bruyndonckx R, Coenen S, et al. Helicobacter pylori
resistance to antibiotics in Europe in 2018 and its relationship
to antibiotic consumption in the community. Gut 2021;70(10):
1815–22.
13. Nyssen OP, Perez-Aisa A, Castro-Fernandez M, et al. European Registry
on Helicobacter pylori management: Single-capsule bismuth quadruple
therapy is effective in real-world clinical practice. United Eur
Gastroenterol J 2021;9(1):38–46.
14. Gravina AG, Priadko K, Granata L, et al. Single capsule bismuth
quadruple therapy for eradication of H. pylori infection: A real-life study.
Front Pharmacol 2021;12:667584.
The American Journal of GASTROENTEROLOGY
 654 Bujanda et al
15. Guo B, Cao NW, Zhou HY, et al. Efficacy and safety of bismuth-
containing quadruple treatment and concomitant treatment for first-line
Helicobacter pylori eradication: A systematic review and meta-analysis.
Microb Pathog 2021;152:104661.
16. Nyssen OP, Bordin D, Tepes B, et al. European registry on Helicobacter
STOMACH
pylori management (Hp-EuReg): Patterns and trends in first-line
empirical eradication prescription and outcomes of 5 years and 21 533
r3KSIrMtBEJrxI0CteBP4sTgKKYhDLYFqp73TDvka5gT7X2UYF/Od1dhFo6+zFF3D9zhHrZYzmrbbopLXnfYF2FKizh4c9JZ0l7c
Downloaded from http://journals.lww.com/ajg by +fw3MKUWPqCo58o39X5nuf0BM6icU076AeKANJ2P0zM7FKan7pNh1
patients. Gut 2021;70(1):40–54.
17. Murata M, Sugimoto M, Mizuno H, et al. Clarithromycin versus
metronidazolee in first-line Helicobacter Pylori triple eradication therapy based
on resistance to antimicrobial agents: Meta-analysis. J Clin Med 2020;9:543.
18. Ye CL, Liao GP, He S, et al. Levofloxacin and proton pump inhibitor-
based triple therapy versus standard triple first-line therapy for
Helicobacter pylori eradication. Pharmacoepidemiol Drug Saf 2014;
23(5):443–55.
19. Lee BE, Kim JS, Kim BW, et al. Consistency of Helicobacter pylori
eradication rates of first-line concomitant and sequential therapies in
Korea: A nationwide multicenter retrospective study for the last 10 years.
Helicobacter 2021;26(2):e12780.
20. Fiorini G, Zullo A, Saracino IM, et al. Pylera and sequential therapy
for first-line Helicobacter pylori eradication: A culture-based study
DTZh9NFapZexoio6AI= on 04/22/2024
in real clinical practice. Eur J Gastroenterol Hepatol 2018;30(6):621–5.
21. Gatta L, Scarpignato C, Fiorini G, et al. Impact of primary antibiotic
resistance on the effectiveness of sequential therapy for Helicobacter
pylori infection: Lessons from a 5-year study on a large number of strains.
Aliment Pharmacol Ther 2018;47:1261–9.
22. Nyssen OP, McNicholl AG, Megraud F, et al. Sequential versus standard
triple first-line therapy for Helicobacter pylori eradication. Cochrane
Database Syst Rev 2016;2016:CD009034.
23. Wang K, Lou D, Dai W, et al. Comparison of sequential therapy with
concomitant therapy in first-line treatment of Helicobacter pylori: An
updated meta-analysis. J Med Microbiol 2022;71(1).
The American Journal of GASTROENTEROLOGY
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
24. Zagari RM, Dajti E, Cominardi A, et al. Standard bismuth
quadruple therapy versus concomitant therapy for the first-line
treatment of Helicobacter pylori infection: A systematic review and
meta-analysis of randomized controlled trials. J Clin Med 2023;12(9):
3258.
25. Berrutti M, Pellicano R, Astegiano M, et al. Helicobacter pylori
eradication: Metronidazolee or tinidazolee? Data from Turin. Minerva
Gastroenterol Dietol 2008;54(4):355–8.
26. Puig I, Baylina M, Sánchez-Delgado J, et al. Systematic review and meta-
analysis: Triple therapy combining a proton-pump inhibitor, amoxicillin
and metronidazole for Helicobacter pylori first-line treatment.
J Antimicrob Chemother 2016;71(10):2740–53.
27. Mégraud F. Antibiotic resistance is the key element in treatment
of Helicobacter pylori infection. Gastroenterology 2018;155(5):
1300–2.
28. Caldas M, Pérez-Aisa Á, Castro-Fernández M, et al. European Registry on
Helicobacter pylori Management: Effectiveness of first and second-line
treatment in Spain. Antibiotics (Basel) 2020;10(1):13.
29. Nyssen OP, Vaira D, Pérez Aísa Á, et al. Empirical second-line therapy in
5000 patients of the European registry on Helicobacter pylori management
(Hp-EuReg). Clin Gastroenterol Hepatol 2022;20(10):2243–57.
30. Gómez-Ruiz de Arbulo M, Tamayo E, Bujanda L, et al. Surveillance of
Helicobacter pylori resistance over 22 years (2000-2021) in northern
Spain. J Glob Antimicrob Resist 2023;34:127–33.
31. Alavinejad P, Nayebi M, Parsi A, et al. Levofloxacin 1 tetracycline
quadruple regimen for eradication of Helicobacter pylori: A multicenter
multinational randomized controlled trial. Middle East J Dig Dis 2023;
15(1):12–8.
32. García-Morales N, Pérez-Aísa Á, Fiorini G, et al. Helicobacter pylori
diagnostic tests used in Europe: Results of over 34,000 Patients from the
European Registry on Helicobacter pylori management. J Clin Med 2023;
12(13):4363.
VOLUME 119 | APRIL 2024 www.amjgastro.com