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Effectiveness of Helicobacter Pylori Treatments.17
Effectiveness of Helicobacter Pylori Treatments.17
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*
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
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
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.
In regions where the antibiotic resistance rate of H. pylori is high, eradication treatment with the 3-in-1
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DISCUSSION:
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
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/16/2024
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 threshold. However, it is known that poorer levels of compliance
management since 2013, which was promoted by the European with therapy are associated with significantly lower levels of H.
Helicobacter and Microbiota Study Group (www.helicobacter. pylori eradication (11).
org) (8). All patients included in the study underwent 13C-urea breath
STOMACH
The ethics committee of La Princesa University Hospital test to check the effectiveness of the treatment. The test was
(Madrid, Spain), which acted as the reference institutional review performed at least 4 weeks after finishing the treatment.
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board, approved the protocol of the Hp-EuReg (8). The study Only treatment schemes with more than 10 patients treated
protocol conforms to the ethical guidelines of the 1975 Declara- were considered in the analysis. The treatment schemes used were:
tion of Helsinki as reflected in a previous approval by the insti-
tution’s human research committee. The study was classified by 1. Sequential; with a proton pump inhibitor (PPI) and
the Spanish Drug and Health Product Agency and registered at amoxicillin 1 g, all twice a day (BID) for 5 days followed by
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/16/2024
ClinicalTrials.gov under the code NCT02328131. Written in- PPI standard dose, clarithromycin 500 mg, and tinidazole
formed consent was obtained from all participants. 500 mg, all BID for further 5 days, henceforth reported as
sequential-PPI 1 C 1 A 1 T.
Participants 2. Triple with amoxicillin; with a PPI, clarithromycin 500
Data were recorded in an electronic case report form, collected mg, and amoxicillin 1 g, all BID, henceforth reported as
and managed using the web-based application designed to sup- triple-PPI 1 A 1 C.
port data capture for research studies (REDCap) (9), and hosted 3. Triple with metronidazole or tinidazole; with a PPI,
at the Spanish Association of Gastroenterology (www.aegastro. amoxicillin 1 g, and tinidazole or metronidazole both 500
es), a nonprofit scientific and medical society focused on gas- mg and all BID, henceforth reported as triple-PPI 1 A 1
troenterology research (10). Data were anonymized. Patients M/T.
(older than 18 years) with an H. pylori–positive result for culture 4. Bismuth quadruple with the 3-in-1 single capsule
and antimicrobial susceptibility testing (AST), recruited between (marketed as Pylera); with a PPI and the single capsule 3
January 2013 and December 2021, were included in the analysis. tablets 4 times a day; and the aforementioned capsule
Cases without an antibiogram were excluded. Naive patients were containing bismuth subcitrate potassium (140 mg),
defined as subjects who had never been treated for H. pylori and metronidazole (125 mg), and tetracycline (125 mg),
non-naive those who had previously undergone treatment (one henceforth reported as 3-in-1 single capsule.
or more eradication treatments). 5. Concomitant with metronidazole or tinidazole; with a PPI,
amoxicillin 1 g, clarithromycin 500 mg, and metronidazole
Data management or tinidazole 500 mg, all BID, henceforth reported as
After extracting the data and before the statistical analysis, the concomitant-PPI 1 C 1 A 1 M/T.
database was reviewed for inconsistencies and subsequent data 6. Quadruple with bismuth subcitrate potassium; with a PPI,
cleaning. The data quality review process evaluated whether the amoxicillin 1 g, clarithromycin 500 mg, and bismuth
study selection criteria had been met and whether data were subcitrate potassium 250 mg, all BID, henceforth reported
correctly collected, ensuring the study was conducted according as quadruple-PPI 1 C 1 A 1 B.
to the highest scientific and ethical standards. Data discordances 7. Classic bismuth quadruple; with a PPI, tetracicline 500 mg
were resolved by querying the investigators and through group 4 times a day, metronidazole 500 mg 3 times a day,
emailing. bismuth subcitrate potassium 120 mg 4 times a day,
henceforth reported as quadruple-PPI 1 Tc 1 M 1 B.
Statistical analysis 8. Triple with rifabutin; with a PPI, amoxicillin 1 g BID, and
Variables categorization and definition. Indications for H. pylori rifabutin 150 mg, BID or once a day, henceforth reported
testing were duodenal ulcer, gastric ulcer, uninvestigated or as triple-PPI 1 A 1 R.
functional dyspepsia, among other conditions. Other indications Data analysis. The prevalence of bacterial antibiotic resistance
included a family history of gastric cancer, premalignant gastric was presented as the ratio of the number of the positive cultures
lesions such as atrophic chronic gastritis and intestinal meta- resulting in the different antibiotics among the total number of
plasia, anemia of unknown origin, erosive gastroduodenitis, patients where culture and AST had been performed. To compare
gastric lymphoma, and idiopathic thrombocytopenia. the treatment schemes, subanalyses by the duration of treatment
For H. pylori isolation, gastric biopsy specimens were obtained and adherence to treatment were performed.
from the antrum and/or body of the stomach during endoscopic Continuous variables were shown as arithmetic mean values
examinations. Cultures were performed on selective plates under and SDs and qualitative variables as percentages and corre-
microaerobic conditions. AST was performed with E-test strips in sponding 95% confidence intervals.
most of the centers. Antimicrobial resistance was determined The x2 test was used to compare categorical variables. The
according to the guidelines and criteria of the European Com- statistical significance was established with a P value ˂ 0.05.
mittee of Antibiotic Susceptibility Testing (EUCAST Clinical
Breakpoint Table V.9) (https://www.eucast.org/clinical_
RESULTS
breakpoints).
Dual resistance was defined as resistance to clarithromycin Baseline characteristics
and metronidazole. Triple resistance was defined as resistance to The treatments of 3,970 patients with positive cultures of 27
clarithromycin, metronidazole, and levofloxacin. countries were analyzed. The mean age was 51 years (615 years),
Adequate compliance with treatment was defined by having and 62% (2,462) were women. The countries in which most
taken at least 90% of the prescribed drugs, accepted as an arbitrary H. pylori cultures were obtained were Italy (2,360; 59.4%),
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Helicobacter pylori 649
STOMACH
Nonresistance 1,582 (40%) 1,235 (43%) 347 (31%)
Metronidazole 1,222 (31%) 759 (27%) 463 (41%)
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followed by Spain (454; 11.4%), Norway (368; 9.3%), Greece (248; Among the 627 patients with clarithromycin resistance,
6.2%), and Slovenia (211; 5.3%). eradication rates decreased to 75% for instance with triple-PPI 1
The number of cultures performed in naive and non-naive C 1 A (prescribed in 12 patients). Despite known clarithromycin
patients was 2,852 (79%) and 1,118 (31%), respectively. In naive resistance, the most frequently used regimen was the sequential
patients, 1,235 (43%) were sensitive to all antibiotics vs 347 (31%) regimen—including clarithromycin in 50% (311/627) of cases.
in non-naive patients. The most frequent antibiotic resistance was The treatment scheme with the highest eradication rate was the
to metronidazole (31%) and the least frequent to amoxicillin and 3-in-1 single capsule with 93%. The remaining therapies were
tetracyclines (less than 1%) (Table 1). below 90% effectiveness, except for the quadruple-PPI 1 C 1 A
1 B, reporting 90% eradication rate (Table 3). The concomitant
First-line treatment effectiveness regimen with tinidazole achieved 100% (23/23) eradication vs
Patients sensitive to all antibiotics. The treatments prescribed to 74% (20/27) in those treated with metronidazole.
1,235 patients were analyzed. The most commonly used treat- According to metronidazole resistance. The rate of resistance to
ment scheme was sequential therapy in 556 (45%) patients, classic metronidazole in naive patients was 27% (759/2,852). When
triple therapy in 270 (22%), triple therapy with metronidazole in analyzing the effectiveness of treatments in metronidazole-sensitive
185 (15%), and concomitant therapy with metronidazole or tinida- patients, independent of other resistances, the efficacy remained
zole in 71 cases (6%). An eradication rate of at least 90% was achieved similar to that of patients with no resistance. The highest eradication
in all therapies except in the triple therapy using metronidazole to- rate was with the 3-in-1 single capsule (100%, 81 patients treated)
gether with amoxicillin, where the cure rate was 88% (Table 2). (Table 2). Despite being sensitive to metronidazole, triple therapy
According to clarithromycin resistance. In naive patients, the with metronidazole achieved an eradication rate below 90%.
number of patients with resistance to clarithromycin was 22% Among the 759 patients with metronidazole resistance, all
(627/2,852). treatments had eradication rates below 90%, except quadruple
When analyzing the effectiveness of treatments in patients therapy with bismuth (94%), treatment with the 3-in-1 single
with clarithromycin-sensitive strains, the efficacy of most of the capsule (91%), and triple therapy with levofloxacin (90%), which
regimens was very high. The highest eradication rate (100%) was was used in 49 patients. Most of these patients (39 patients, 80%)
reported with the 3-in-1 single capsule (Table 2). had dual resistance to both clarithromycin and metronidazole
Table 2. Per-protocol effectiveness in naive patients with susceptibility to each of the antibiotics
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
No. patients Eradication No. patients Eradication No. patients Eradication No. patients Eradication
Sequential-PPI 1 C 1 A 1 T 556 526 (95%) 311 271 (87%) 351 314 (89%) 316 293 (93%)
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(Table 3). The concomitant regimen with tinidazole achieved 100% Rescue (from second- to sixth-line) treatment effectiveness
(22/22) eradication vs 73% (16/22) with metronidazole. Among those non-naive, 49% (549/1,118) of patients were re-
According to quinolone resistance. The levofloxacin resistance sistant to clarithromycin. Resistance to metronidazole was 41%
rate in naive patients was 18% (503/2,852). (463/1,118) and 24% (270/1,118) to quinolones.
When we analyzed the effectiveness of the treatments in Overall, no treatment achieved an eradication rate of 90%. The
levofloxacin-sensitive patients, independently of other resis- schemes with the highest eradication rates were the 3-in-1 single
tances, the success rate remained similar to that of patients with capsule with 87% (150/172) and the triple therapy with levo-
no resistance. The highest eradication rate was with the 3-in-1 floxacin with 85% (299/352). The triple therapy with rifabutin
single capsule (98%, 80 patients treated) (Table 2). All treat- achieved an eradication rate of 80% (199/249).
ments achieved eradication rates above 90%, except triple Although they were sensitive to clarithromycin, triple therapy
therapy with metronidazole (87%). In 69 patients treated with with clarithromycin achieved an eradication rate of 76% (see Sup-
triple therapy with levofloxacin, an eradication rate of 88% was plementary Table 2, http://links.lww.com/AJG/D125). The only
reported. treatment that achieved eradication rates of 90% with more than 10
When we analyzed the 503 patients with levofloxacin re- patients treated was the 3-in-1 single capsule (90%). In
sistance, only treatments with quadruple with bismuth (96%), clarithromycin-resistant patients, any of the treatments prescribed to
concomitant with tinidazole (100%), and sequential with more than 10 patients achieved rates equal or greater than 90% (see
amoxicillin and tinidazole (93%) achieved eradication rates Supplementary Table 3, http://links.lww.com/AJG/D125).
higher than 90%. The concomitant regimen with tinidazole In patients sensitive to metronidazole, the only treatment that
achieved 100% (22/22) eradication vs 80% (8/10) with obtained eradications above 90% was the 3-in-1 single capsule.
metronidazole. Triple therapy with metronidazole and levofloxacin achieved
Dual or triple resistance. Among naive patients, 11% had dual eradication rates of 89% and 87%, respectively. In those patients
resistance to both clarithromycin and metronidazole. In those cases with metronidazole-resistant strains, none of the aforementioned
sensitive to both antibiotics, most treatment schemes achieved treatments reached 90% cure rates (see Supplementary Table 3,
eradication rates equal or higher than 90%, being 100% (97 http://links.lww.com/AJG/D125). The best was triple therapy
patients treated) in the case of those prescribed with the 3-in- with levofloxacin.
1 single capsule. Triple therapy with metronidazole achieved In quinolone-sensitive patients, the 2 treatments that reached
87% (197/226) eradication, despite being sensitive to optimal (above 90%) effectiveness were triple therapy with met-
metronidazole. ronidazole (92%) and the 3-in-1 single capsule (91%). In
In patients with dual resistance, triple therapy with levofloxacin levofloxacin-resistant patients, as in the case of metronidazole,
achieved 90% (35/39) eradication (see Supplementary Table 1, none of the treatments achieved 90% cure rates (see Supple-
http://links.lww.com/AJG/D125). The most frequent regimen used mentary Table 3, http://links.lww.com/AJG/D125).
was sequential therapy with amoxicillin and tinidazole, with an Dual or triple resistance. In non-naive patients, 34% (377/1,118)
eradication rate of 85% (157/185), whereas the 3-in-1 single capsule had dual resistance to clarithromycin and amoxicillin. In those cases,
achieved an eradication rate of 86% (24/28). sensitive to both antibiotics, most of the regimens did not achieve
Triple resistance to clarithromycin, metronidazole, and levo- eradication rates equal or higher than 90%, despite susceptibility. The
floxacin in naive patients occurred in 5% of the cases (151/2,852). only treatment scheme that exceeded 90% was the 3-in-1 single
In these cases, the only regimen with more than 15 cases treated capsule with 93% (50/54) effectiveness (see Supplementary Table 4,
was the sequential regimen with amoxicillin and tinidazole, http://links.lww.com/AJG/D125). Eradication was significantly
which achieved an eradication rate of 87% (90/103). The next 2 lower in non-naive patients than in naive patients (see Supplemen-
regimens with more cases treated were the 3-in-1 single capsule, tary Table 4, http://links.lww.com/AJG/D125).
with 88% (15/17), and triple with amoxicillin and rifabutin, which In non-naive patients with dual resistance, all treatment
achieved 100% eradication (10/10). regimens were below 90% in eradication (see Supplementary
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Effectiveness of Helicobacter pylori 651
Table 1, http://links.lww.com/AJG/D125). By number of cases There were fewer studies with triple therapy with levofloxacin
treated, triple therapy with amoxicillin and rifabutin achieved an in first-line treatment. In general, the results were better than with
eradication rate of 84% (112/134), triple therapy with levofloxacin the classical clarithromycin-based triple therapy (18). In our
reached 87% (106/122), and the 3-in-1 single capsule obtained study, we observed that triple therapy combining amoxicillin with
STOMACH
82% (56/68). The effectiveness was reported lower in non-naive levofloxacin in treatment-naive patients that were resistant to
patients than in naive patients (see Supplementary Table 1, http:// clarithromycin achieved an eradication rate of 88%. This scheme
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cure rate (73/80). The others schemes with more than 10 cases patients sensitive to clarithromycin, but dropped by 8% (from
treated were triple therapy with levofloxacin, with 87% (220/254), 95% to 87%) when they were resistant to this antibiotic. In our
triple therapy with amoxicillin and rifabutin, with 70% (39/56), study, sequential treatment tended to be lower than 90% in first-
sequential therapy with clarithromycin and tinidazole, with 81% line treatment and lower than in other studies in first-line treat-
(43/53), triple therapy with amoxicillin and metronidazole, with ment (19). In other countries (not in Italy), treatment with this
89% (33/37), triple therapy with clarithromycin and amoxicillin, scheme had eradication rates higher than 90% (20). In our study,
with 76% (16/21), and concomitant with metronidazole or tini- double resistance to both clarithromycin and metronidazole was
dazole, with 60% (12/20). 11%, which conditioned the effectiveness of this treatment. In
In those non-naive patients with triple resistance, the only studies performed in Italy, double resistance to clarithromycin
regimen with more than 10 cases treated was the triple therapy and metronidazole in naive patients was reported higher than
with amoxicillin and rifabutin, which achieved 86% eradica- 20%, and the effectiveness of the sequential therapy in such
tion rate (99/115), and the 3-in-1 single capsule, with 79% context was only 83% (21,22). On the other hand, in a study
(33/42). comparing the sequential vs the concomitant regimen, the effi-
cacy of the latter was superior (23). The quadruple concomitant
DISCUSSION regimen with metronidazole or tinidazole, recommended by
Clarithromycin and metronidazole are the 2 most commonly many clinical guidelines, usually provides very good results in
used antibiotics in first-line eradication therapy against H. pylori. those strains sensitive to clarithromycin (95%), but the effec-
However, the therapeutical effectiveness will depend on the tiveness decreases in those resistant (86%), and thus, its use in
bacterial resistance to these antibiotics. In recent years, a re- first-line empirical therapy is questionable, especially in those
sistance prevalence of more than 15% has been reported in many regions with high resistance to clarithromycin, similar to those of
geographical areas, which greatly determines the efficacy of the our study. In this same context, regarding the use of metronida-
treatments (6,12). In this study, we observed that triple treatments zole or tinidazole, in our study, we observed that the sequential
with or without clarithromycin, sequential treatments with regimen with tinidazole obtained eradication rates of 92% as
clarithromycin and tinidazole, and hybrid treatments with clar- compared to 80% when metronidazole was used. In a recent re-
ithromycin did not reach 90% eradication rate. On the other view and meta-analysis of randomized controlled trials that
hand, the schemes concomitant-PPI 1 C 1 A 1 T, quadruple- compare standard bismuth quadruple therapy vs concomi-
PPI 1 C 1 A 1 B, and PPI 1 single capsule achieved eradication tant therapy for the first-line treatment do not observe dif-
rates higher than 90% in those treatment-naive patients with ferences between both treatments (24). In contrast to our
resistant strains to clarithromycin. study, Berruti et al (25) performed a study comparing the use
Treatment with the single capsule has shown efficacies above of metronidazole 250 mg 4 times a day or tinidazole 500 BID
90% in first-line empirical treatment (i.e., without guidance of and found no differences between them. Triple therapy with
culture testing) and in those areas where resistance to clari- amoxicillin and metronidazole in naive patients sensitive to
thromycin and metronidazole was above 20%, such is the case of metronidazole did not reach 90% effectiveness in our cohort,
Southern European countries (13,14). Bismuth quadruple treat- as in other published reviews (25,26). Therefore, metroni-
ment with PPI 1 C 1 A 1 B may be also a good option for first- dazole should not be used in the first-line treatment as part of
line empirical treatment as suggested by our study, and likewise triple or sequential regimens. One explanation for this result
confirmed in a recent review (15), in which eradication rates of is the fact that there is no good correlation between the sus-
94% were observed, higher than with concomitant treatment with ceptibility or resistance of metronidazole in vitro and the
metronidazole; however, both were above 90%. efficacy in vivo (27).
A published study of the Hp-EuReg on H. pylori management In non-naive patients, antibiotic resistance increases consid-
in which 21,533 patients treated for 5 years were analyzed showed erably (more than 50%) and the efficacy of treatments decreases
that triple therapy with amoxicillin and clarithromycin during 7 drastically, all being less than 90% in most studies (6). In our
or 14 days was 83% and 87%, respectively, in the per-protocol study, the treatments with the highest eradication rates were the
analysis, independently of the presence or not of bacterial re- 3-in-1 single capsule as well as other combinations that
sistance to clarithromycin (16). When susceptible to clari- approached 90% (such as the triple therapy with levofloxacin). In
thromycin, the effectiveness of triple therapy was 94%, dropping the Hp-EuReg, in which 2,448 patients treated as second line were
to 75% in the case of resistance. Similarly, a review study noted analyzed, triple therapy with levofloxacin, the bismuth-
that triple therapy in first line including clarithromycin or met- levofloxacin quadruple schemes (PPI-bismuth-levofloxacin-
ronidazole should be avoided when resistances are higher than amoxicillin), and the 3-in-1 single capsule were the best treat-
15% for clarithromycin (17). ment options, with eradication rates of 89%, 90%, and 88.5%,
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
652 Bujanda et al
respectively (28). In a later study from the same Hp-EuReg, 5,055 avoided potential mistakes. In addition, all participating re-
patients treated as second line were analyzed, achieving the best searchers had previously used this platform or had received
eradication rates with either levofloxacin-containing bismuth training before data entry. Study investigators were selected by the
quadruple therapy (29) or with the 3-in-1 single capsule (13), study coordinators based on their experience treating H. pylori
STOMACH
which was in line with the recommendations of clinical guidelines infection and their research expertise. Data collection by email or
(5,7). In this sense, to achieve optimal eradication rates in non- paper was not accepted to avoid increasing errors. Finally, to val-
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naive patients, extending the length of treatment to 14 days and idate the data entered by the researchers in the database, study
adding bismuth to triple therapy with metronidazole or levo- monitors systematically checked a random sample of patients from
floxacin should be considered. each researcher and/or participating center.
In our study, we observed that in non-naive patients the in Strengths of this study first included the valuable information
vitro susceptibility of the cultures did not correlate with the ef- from an international multicenter study such as the Hp-EuReg,
YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/16/2024
fectiveness of the treatments in vivo. Thus, e.g., when non-naive which includes a large number of evaluated years (9) and countries.
patients were susceptible to clarithromycin, the effectiveness of Second, the fact that data reflected the daily routine of the clinical
triple therapy was 76%, whereas the same treatment in naive practice among European gastroenterologists and not only tertiary
patients susceptible to clarithromycin obtained 92% effectiveness. hospitals (highly specialized), so in fact allowing for the evaluation
The same results occurred in those cases that were susceptible to of a comprehensive set of data. And the last, the use of the high-
metronidazole, and the triple therapy with amoxicillin and met- quality method to register, store, manage, and monitor the data by
ronidazole was administered (87%), and again also in those cases using the online platform for Collaborative Research of the Spanish
that were susceptible to quinolones, the triple therapy with Association of Gastroenterology-Research Electronic Data Cap-
amoxicillin and levofloxacin was prescribed (88%). ture, allowing the analysis of robust and reliable data.
The efficacy of treatments depends on antibiotic resistance. In In summary, in those regions with high H. pylori antibiotic re-
our study, the resistance in both naive and non-naive patients was sistance rates, quadruple therapies are recommended both in
high to clarithromycin, levofloxacin, and metronidazole. Recently, treatment-naive patients and in those receiving second-line rescue
one of the studies with more cultures performed has been reported regimens. Bismuth quadruple therapy (including the 3-in-1 single
(30). In this study, 31,406 gastroduodenal biopsies from patients capsule) appeared as the best option in all treatment lines, overcoming
older than 15 years were plated on selective media, isolating H. pylori clarithromycin and metronidazole resistances. Other first-line alter-
in 36.7% (30). Susceptibility testing could be performed in 96.6% natives were quadruple therapies with clarithromycin-amoxicillin-
(12,399/12,835) of H. pylori isolates. The study was conducted with tinidazole or clarithromycin-amoxicillin-bismuth. In addition, in
biopsies collected in Basque Country (Spain) between 2000 and second-line therapy, the triple therapy with amoxicillin-levofloxacin
2021. In naive patients, resistance to any antibiotic analyzed was might be also an option. Continuous and systematic monitoring of
found in 49.3%, a little lower to our study (57%). In the past 2 years the antibiotic resistance prevalence is necessary to tailor the treat-
analyzed, the resistance to clarithromycin and levofloxacin has been ments to the best standards of care in each European region.
greater than 15% and 20%, respectively. Resistance to levofloxacin
has increased from 7.6% in 2000 to 21.7% in 2021 (30). ACKNOWLEDGEMENTS
The effectiveness of treatment schemes can vary remarkably We want to thank the Spanish Association of Gastroenterology (AEG)
depending on the area studied because of the variation of resis- for providing the e-CRF service free of charge. The following persons
tances. For example, the efficacy of quadruple with bismuth participated in the European Registry on H. pylori Management
treatment in naive patients in our study was greater than 90% (Hp-EuReg): Giulia Fiorinni, Ilaria Maria Saracino, Manuel Pabon
compared with other geographical areas such as Egypt, Iran, and Carrasco, Alma Keco Huerga, Enrique Alfaro Almajano, Samuel Jesus
Vietnam where it was only 70% (31). Martinez Dominguez, Horacio Alonso Galan, Benito Velayos, Carmen
AST was performed in only 10.5% (2,927/27,776) of naive Dueñas Sadornil, Jose Maria Botargues Bote, Pedro Luis Gonzalez-
patients and 15% of non-naive patients. The number of cultures Cordero, Miguel Areia, Blas Jose Gomez Rodriguez, Rinaldo Pellicano,
has decreased in these past 10 years. It is important to continue Óscar Nuñez, Francesco Franceschi, Sergey Alekseenko, Monica
performing cultures or other techniques (polymerase chain re- Perona, Rustam Abdulkhakov, Manuel Dominguez-Cajal, Pedro
action - fluorescence in situ hybridization) to determine the Almela Notari, Judith Gomez Camarero, Manuel Jimenez Moreno,
tendency of resistance and improve the efficient of treat- Alicia Algaba, Fernando Bermejo, Jose Maria Botargues Bote, Javier
ments (32). Tejedor Tejada, Elida Oblitas Susanibar, Doron Boltin, Sotirios
One of the limitations of our study was the lack of a sufficient Georgopoulos, Colm OMorain, Asghar Qasim, Ian Beales, Natalia
and homogeneous number of cases in which the study on antibiotic Bakulina, Galina Fadeenko, Peter Malfertheiner, Rosa Rosania, Tatiana
susceptibility was performed (70% of the cultures and treatments Ilchishina, Pavel Bogomolov, Igor Bakulin, Oleg Zaytsev, Antonietta
came from Italy and Spain), and therefore, there was not a sufficient Gerarda Gravina, Marco Romano, Alfredo Di Leo, Giuseppe Losurdo,
sample size to study some treatment regimens that are frequently Ludmila Grigorieva, Pedro Delgado Guillena, Marinko Marusic,
prescribed in Europe. Also, the fact of being an observational study Dragan Jurcic, Natalia Nikolaevna Dekhnich, Eduardo Iyo, Luisa
with open inclusion criteria, with the consequent potential higher Carmen de la Peña Negro, Natalia Baryshnikova, Natalia Bakanova,
risk of bias in terms of selection and inclusion of patients, could Halis Simsek, Cem Simsek, Oleksiy Gridnyev, Miguel Fernandez-
have hampered the synthesis of the information. To avoid bias, the Bermejo, Teresa Angueira, Rafael Ruiz- Zorrilla Lopez, Barbara
data selected were defined a priori in the Hp-EuReg protocol to Gomez, Mila Kovacheva-Slavova, Adi Lahat, Javier Alcedo, Ana
specifically answer the objectives of the study. These data were Campillo, Liya Nikolaevna Belousova, Ramon Pajares Villarroya,
collected routinely in consultations at platform for Collaborative Neven Ljubicic, Marko Nikolic, Jesús M González-Santiago, Diego
Research of the Spanish Association of Gastroenterology-Research Burgos Santamaría, Anna Pakhomova, Izabela Sekulic-Spasic, Matteo
Electronic Data Capture in a very simple manner, which ultimately Ghisa, Fabio Farinati, Sabir Irfan Sagdati, Nikola Panic, Frederic
Copyright © 2023 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
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