Introduction

Resistance to many of the antibiotics used to treat Helicobacter pylori (HP) infection is on the rise. Indeed, the WHO has included H. pylori on their priority list of antibiotic-resistant bacteria to guide research and development into novel antimicrobials. To this end, computer aided drug design was deployed against the purine nucleoside phosphorylase enzyme (PNP), a key survival enzyme of HP. Protein-ligand docking of 550k+ compounds was carried out against the enzyme and the lead candidate antimicrobials testing against clinical isolates of the bacterium.

Aims & Methods

Our study aims were (i) To perform in silico protein-ligand docking to identify compounds with potential inhibitory activity against HP via potential PNP enzyme inhibition, (ii) and to test the in vitro antimicrobial and cytotoxicity activity of the compounds on clinical isolates of HP and the gastric epithelial cell line AGS.
Methods: The binding site of the PNP enzyme was analysed using computational tools and a library of compounds was virtually screened via protein ligand docking, carried out on the Irish Centre for High End Computing's supercomputer "Kay", to identify several lead-hits to carry forward to in vitro screening. Lead-hits were tested for antimicrobial efficacy against reference strains (J99 and ATCC60190) and clinical isolates of HP using a broth microdilution approach. Clarithromycin was used as a positive control. Selectivity was established using a viability assay with a stomach epithelial cell line AGS.

Results

7 lead-hits were selected from protein-ligand docking and tested in vitro. All compounds showed antimicrobial activity against the reference strains and both clarithromycin-sensitive and clarithromycin-resistant clinical isolates of HP (MIC₅₀ 4.34– 73 µg/mL). 2 compounds showed significant selectivity against human cells, having no activity on the viability of human gastric cells.

Conclusion

Protein-ligand docking provided a cost-efficient method to identify, selective antimicrobial agents for H. pylori resulting in the identification of several lead targets that may be further developed to increase selectivity and potency.

Introduction

The Maastricht VI/Florence Consensus recommends eradication of all Helicobacter pylori (Hp) infections. However, retreatment strategies after therapeutic failure remain inconsistent.

Aims & Methods

To evaluate the reasons and associated factors for non-retreatment after a failure of Hp eradication treatment.
Systematic, prospective, multicenter, non-interventional registry of clinical practice by European gastroenterologists on the management of Hp infection (Hp-EuReg). Patients who failed eradication treatment between 2013-2024 and were registered in AEG-REDCap were analysed and categorised into two groups: retreatment (control group) and non-retreatment. Reasons for no retreatment were also classified according to either the medical or the patient perspective. Multivariate logistic regression was conducted to identify factors associated with no retreatment from both the patient and medical perspectives, each compared with the control group.

Results

Overall, 6,904 patients were evaluated; 950 (14%) were not retreated: 41% due to a medical decision, 50% due to a patient decision, and 9% due to other reasons. The most frequent reasons for no retreatment were: previous poor tolerance, unclear indication, multiple prior eradication attempts, and previous non-compliance. From the medical perspective, factors significantly associated with no retreatment were: age ≥ 71 years (OR 1.49; 95% CI 1.04-2.13), previous non-compliance (OR 4.27; 95% CI 2.64-6.93), number of previous attempts (OR 2.07-9.25; 95% CI from 1.57-2.73 to 6.15-13.93) and previous treatment discontinuation due to adverse events (OR 2.06; 95% CI 1.19-3.56). From the patient perspective, the factors significantly associated with no retreatment included: being male (OR 1.34; 95% CI 1.10-1.63), having undergone two to four previous eradication attempts (OR 1.69-3.60; 95% CI from 1.16-2.44 to 1.75-7.41) and previous non-compliance (OR 10.04; 95% CI 7.37-13.68).

Conclusion

A significant proportion (14%) of European patients are not retreated after Hp eradication failure. Key barriers include advanced age, a history of poor treatment adherence, and multiple prior eradication failures. The decision to avoid re-treatment was frequently driven by patient-related factors, although medical reasons also played a relevant role, highlighting the importance of shared decision-making and enhanced patient education.

References

1. Gisbert JP, Alcedo J, Amador J, Bujanda L, Calvet X, Castro-Fernández M, et al. V Spanish Consensus Conference on Helicobacter pylori infection treatment. Gastroenterol Hepatol Engl Ed. mayo de 2022;45(5):392-417.
2. Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. septiembre de 2022;71(9):1724-62.
3. Banks M, Graham D, Jansen M, Gotoda T, Coda S, Di Pietro M, et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut. septiembre de 2019;68(9):1545-75.

Disclosure

Olga P. Nyssen has served as a speaker or has received research funding from Allergan, Mayoly Spindler, Richen, Biocodex and Juvisé.
Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from Mayoly, Allergan/Abbvie, Diasorin, Richen, Juvisé, Biocodex.
The remaining authors declare no conflicts of interest.

Introduction

Antibiotic resistance in H. pylori (Hp) is becoming a more significant challenge in the management of Hp infection. Resistance surveillance is recommended to guide clinicians in the most appropriate therapy in a given population. Molecular methods offer a more rapid alternative for the detection of Hp resistance to antibiotics than traditional culture-based methods.

Aims & Methods

To evaluate the diagnostic accuracy of molecular-based clarithromycin susceptibility testing in Hp compared to culture and E-test in the Irish healthcare setting.
Following ethical approval and informed consent, adults were recruited prospectively from 2 centres (Tallaght University Hospital and Letterkenny University Hospital, Ireland), regardless of previous Hp treatment history. During routine gastroscopy, subjects had two supplementary biopsies (1 antrum and 1 corpus) taken for Hp culturing and DNA extraction. After successful Hp growth, clarithromycin susceptibility testing was performed by the Etest (Biomerieux) method and resistance was determined according to EUCAST 2023 guidelines. DNA was then extracted from biopsies and underwent PCR using the RIDA®GENE Helicobacter pylori assay (R-Biopharm AG, Germany) for detection of Hp and clarithromycin resistance-associated point mutations (A2146C, A2146G and A2147G).

Results

In all, samples from 191 culture-positive patients (mean age 48.4 ± 15.3 years; 45.0% (N=86) female) were analysed. The rates of clarithromycin resistance detected by culture-based and molecular methods were 49.2% (N=94/191) and 38.7% (N=74/191), respectively (P=0.05; Fisher’s exact test). Results were in agreement between both methods in 84.3% (N=161/191) of cases. The sensitivity and specificity of the Ridagene assay compared to culture for the detection of clarithromycin resistance were 74.2% (95% CI: 64.4-82.6%) and 94.7% (95% CI: 88.0-98.3%), respectively. The positive predictive value was 93.5% (95% CI: 85.5-97.9%) and the negative predictive value was 78.1% (95% CI: 69.4-85.3%).

Conclusion

While the Ridagene assay was easy to use and more rapid than Hp culture, the low sensitivity compared to culture in our cohort may limit its use to cases where culture-based methods are unsuccessful. Further studies are required to characterise the full spectrum of clarithromycin resistance mechanisms present in our population.

Introduction

Antibiotic resistance is one of the main reasons for H. pylori treatment failure. International guidelines recommend that the choice of antibiotics used to treat H. pylori in a given population should be based on the pattern of antibiotic resistance in that region. However, H. pylori antibiotic resistance testing is not routinely carried out in the majority of Irish Hospitals. Recent evidence from the European Helicobacter and Microbiota Study Group has indicated that resistance to certain commonly used antibiotics to eradicate H. pylori varies between European countries, and in certain areas resistance has reached a sufficient level to avoid prescribing these antibiotics as empirical therapy (1). In addition, previous antibiotic use positively correlates with resistance for two major classes of antibiotics commonly used to treat H. pylori infection (1). Because antibiotic resistance is a constantly evolving process, the European Helicobacter and Microbiota Study Group and the Maastricht VI/Florence consensus report (2) have highlighted the importance for local resistance surveys to be carried out on a regular basis in order to guide clinicians in their choice of therapy for successful eradication of H. pylori.

Aims & Methods

In this multisite study we aimed to assess the rate of primary and secondary antibiotic resistance for H. pylori in Ireland, with a view to guiding national treatment strategies. The study comprised of four sites with samples analyzed from two large urban teaching hospitals and two rural teaching hospitals. Patients attending for gastroscopy were invited to participate in the study. Following informed consent, 1 antrum and 1 corpus gastric biopsy were collected from each patient and transported to the laboratory in selective medium. Antibiotic susceptibility testing was carried out by E-test (bioMerieux) and resistance classified according to the EUCAST clinical breakpoints MIC values.

Results

In total, 126 isolates were successfully cultured and antimicrobial susceptibility assessed. 103 of these were isolates of treatment naïve patients (50±16 years old, 59% male) and 23 were of previously treated patients (48±12 years old, 61% female). As can be seen in table 1, primary antibiotic resistance rates have reached alarmingly high levels for both clarithromycin and metronidazole, and reach nearly double the rate of resistance with the previously treated group.

Conclusion

Antibiotic resistance rates have reached significant levels for all major classes of antibiotics for the treatment of H. pylori. Of note, first-line clarithromycin triple therapy can no longer be recommended in Ireland.

References

(1) Megraud F et al. Helicobacter pylori resistance to antibiotics in Europe in 2018 and its relationship to antibiotic consumption in the community. Gut. 2021
(2) Malfertheiner P, et al Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report Gut 2022;71:1724-1762.
(3) Smith, S. et al. The Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of H. pylori infection in adult patients in Ireland. Eur. J. Gastroenterol. Hepatol. 29, 552–559 (2017).

Introduction

After an initial attempt to eradicate Helicobacter pylori (Hp), around 20% of patients remain infected. As treatment failures accumulate, the effectiveness of subsequent Hp therapies tends to decrease. Therefore, current clinical guidelines discourage repeated use of the same treatment regimen following an initial failure.

Aims & Methods

To evaluate the use and effectiveness of the triple therapy with amoxicillin-clarithromycin and of the bismuth quadruple therapy (either classical and as single-capsule format) when empirically prescribed as retreatment, despite previous eradication failure with the same regimen.
All patients registered at e-CRF AEG-REDCap as part of the European Registry on Hp management (Hp-EuReg) from 2013-2024, who had received triple therapy with amoxicillin-clarithromycin or bismuth quadruple therapy (either classical or as single-capsule) in at least 2 different treatment lines (not necessarily consecutive), were analysed separately.

Results

Triple therapy with amoxicillin-clarithromycin: Out of 518 patients treated with triple therapy from 2^nd to 6^th rescue treatment line, 230 cases received the same therapy at least in 2 different treatment lines: 199 re-treatments in 2^nd line having previously failed in 1^st line with this therapy; 19 re-treatments in 3^rd line (of which 9 had previously received the same therapy only in the 1^st line and 10 had received the same therapy in both 1^st and 2^nd line); 4 in 4^th line; 5 in 5^th line; and further 3 in 6^th line. The overall effectiveness of triple therapy with amoxicillin-clarithromycin when empirically prescribed repeatedly in 2^nd line was 74%. When the effectiveness was subanalysed by treatment length, there were increasing efficacy rates according to it: 50% with 7 days, 72% with 10 days, and 82% with 14 days. The cases retreated in 3^rd line had an overall effectiveness of 56%.
Bismuth quadruple classical therapy: Out of 672 patients treated with bismuth quadruple classical therapy from 2^nd to 6^th rescue treatment line, 13 cases received the same therapy at least in 2 different treatment lines: 6 re-treatments in 2^nd line, having previously failed in 1^st line; 2 re-treatments in 3^rd line, both had previously received the same therapy in 2^nd line; 2 in 4^th line; 1 in 5^th line; and further 2 in 6^th line. The effectiveness of bismuth quadruple classical therapy when empirically prescribed repeatedly in the 2^nd line was 69%, although the number of patients in this cohort was limited.
Bismuth quadruple therapy as single-capsule: Out of 2,579 patients treated with the single-capsule from 2^nd to 6^th rescue treatment line, 101 cases received the same therapy at least in 2 different treatment lines: 67 re-treatments in 2^nd line having previously failed in 1^st line with the single-capsule; 16 re-treatments in 3^rd line, of which 12 had previously received this same therapy in 2^nd line; 11 in 4^th line; 4 in 5^th line; and further 3 in 6^th line. The effectiveness of bismuth quadruple therapy as single-capsule when empirically prescribed repeatedly in 2^nd line was over 90%, and achieved almost 80% in all cases retreated in the 3^rd line.

Conclusion

Repeated use of triple therapy with amoxicillin-clarithromycin in patients with prior eradication failures with the same regimen demonstrated notable success rates, particularly in 2^nd line re-treatments lasting 14 days (>80%). On the other hand, bismuth quadruple therapy as single-capsule, when prescribed as re-treatment in 2^nd line after previous failure with the same therapy, achieved optimal effectiveness (>90%).

References

1. Malfertheiner P, Megraud F, Rokkas T, Gisbert JP, Liou JM, Schulz C, et al. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut. 2022;71(9):1724–62.
2. Nyssen OP, Vaira D, Pérez Aísa Á, Rodrigo L, Castro-Fernandez M, Jonaitis L, 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.

Disclosure

Olga P. Nyssen has served as a speaker or has received research funding from Allergan, Mayoly Spindler, Richen, Biocodex and Juvisé.
Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from Mayoly, Allergan/Abbvie, Diasorin, Richen, Juvisé, Biocodex.
The remaining authors declare no conflicts of interest.

Introduction

After a first eradication attempt, a relevant proportion of patients fail to cure Helicobacter pylori infection.

Aims & Methods

To evaluate the effectiveness of second-line empirical treatment.
A systematic, prospective, registry of the clinical practice of European gastroenterologists (38 countries) on H. pylori management was established (Hp-EuReg, Hp-WorldReg’s partner). All infected adult patients were systematically registered at AEG-REDCap e-CRF until January 2025. Modified intention-to-treat (mITT) and per-protocol (PP) analyses were performed.

Results

Overall, 8,901 patients received a second-line empirical therapy. Mean age was 51 years, 67% were women, and 4.7% had penicillin allergy. Most frequent treatment indications were dyspepsia (74%) and gastroduodenal ulcer (13%). Overall effectiveness was 82% (both by mITT and PP). Overall, 96.5% of patients were compliant. Adverse events were reported in 19% of the cases, most of them mild. The overall effectiveness of most frequent empirical second-line treatments is shown in Table 1, showing that uniquely bismuth quadruple therapies, either with metronidazole-tetracycline or clarithromycin-amoxicillin, when prescribed for 14 days and with high-dose PPIs provided over 90% success rates. After failure of first-line clarithromycin-containing therapy, the most effective second-line treatments were triple therapy with amoxicillin and either rifabutin or levofloxacin providing 85% and 80% effectiveness, respectively. Additionally, bismuth quadruple therapy with regimens containing tetracycline-metronidazole in single-capsule and classical formulation, with clarithromycin-amoxicillin and with levofloxacin-amoxicillin achieved 87%, 84%, 88% and 85% cure rates, respectively. Within the same subgroup but in patients receiving optimised therapy —defined as a 14-day course with standard or high-dose PPIs at >40mg omeprazole equivalent twice daily —, certain regimens yielded even higher cure rates. Among these, triple therapy with amoxicillin-levofloxacin obtained 87% success rate, while non-bismuth concomitant therapy with amoxicillin-clarithromycin-metronidazole reached 86%. Bismuth quadruple therapy with either tetracycline-metronidazole (administered either as a single capsule or in the classical prescription) reported 89% success; but with amoxicillin-metronidazole or clarithromycin-amoxicillin highest effectiveness was reported, that is, 91% and 92%, respectively. After failure of bismuth quadruple therapy either in the classical format or when prescribed as the single-capsule, bismuth quadruple therapy with clarithromycin-amoxicillin achieved 95.5% and 95% cure rates, respectively; whereas, the single capsule obtained 93% and 89%, respectively.

Conclusion

In Europe, empirical second-line treatment overall effectiveness is generally suboptimal (<90%); however, successful results were obtained with bismuth quadruple therapies, either with tetracycline-metronidazole or clarithromycin-amoxicillin, when prescribed for 14 days and with high-dose PPIs. Optimization of regimen selection, treatment duration, and PPI dosing is necessary after first-line therapy failure.

Disclosure

Javier P. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from: Mayoly, Allergan/Abbvie, Diasorin, Richen, Juvisé and Biocodex.
Olga P. Nyssen received research funding from: Mayoly, Allergan/Abbvie, Richen, Juvisé and Biocodex.