The eradication of Helicobacter pylori is a well-established strategy for preventing peptic ulcer disease, gastric cancer, and other gastroduodenal conditions [1]. A major obstacle to successful eradication is clarithromycin resistance, which can be accurately identified using polymerase chain reaction (PCR)-based mutation detection [2]. In regions with a high prevalence of clarithromycin-resistant (CLA-R) strains, current guidelines recommend a 2-week bismuth quadruple therapy (2W-PBMT) as the preferred first-line treatment [3,4]. Specifically, the Maastricht VI/Florence Consensus Report suggests initiating bismuth quadruple therapy when clarithromycin resistance prevalence exceeds 15%. Although this regimen has demonstarted relatively high eradication rates, its prolonged duration, complex dosing regimen, and potential for adverse effects pose challenges for patient adherence. Consequently, a continued need exist to evaluate the clinical effectiveness of shorter-duration treatment regimens or those containing amoxicillin instead of tetracycline for managing confirmed CLA-R H. pylori infections [5,6]. A recent Korean clinical guideline recommends a metronidazole-based triple therapy (PMA) as an alternative regimen for cases with confirmed clarithromycin resistance-associated genetic mutations [4].

Key differences between the Maastricht consensus and the Korean guideline for suspected or confirmed CLA-R infections lie in treatment duration and drug composition. From a patient-centered perspective, the main differences are the treatment duration (2 weeks vs. 1 week) and the inclusion of tetracycline. Previous research has consistently shown that quadruple therapy outperforms triple therapy [7,8]. The addition of bismuth to triple therapy has been shown to improve eradication rates without significantly increasing adverse events or patient discomfort [9]. Based on these considerations, the authors aimed to limit the differences between the regimens, specifically from the patient’s perspective, to treatment duration and the inclusion of tetracycline. To achieve this, they added bismuth to a 1-week PMA. This study was designed to compare the eradication success and medication adherence between the conventional 2W-PBMT and a 1-week bismuth-enhanced PMA (1W-PBMA), focusing on patients infected with H. pylori strains that harbor clarithromycin resistance-related genetic mutations.

An optimal and universally accepted antibiotic regimen for H. pylori eradication has yet to be firmly established [10]. Various regional and international expert groups continue to update treatment guidelines to support clinical decision-making. However, inconsistencies and conflicting recommendations across these guidelines highlight the need for further validation through well-designed studies.

This study aimed to address the inconsistency between treatment recommendations based on in vitro clarithromycin resistance detection and those guided by regional clarithromycin resistance prevalence rates [11]. The regimens evaluated in this study differ in both treatment duration and antibiotic composition. From a patient-centered perspective, shorter treatment courses offer advantages, including improved medication adherence, reduced antibiotic exposure, a lower risk of promoting resistance in other bacterial species, and decreased financial burden.

Among the antibiotics frequently used for H. pylori eradication, tetracycline poses significant challenges, as it must be taken on an empty stomach between meals four times daily to avoid reduced absorption due to food. Additionally, its metallic taste further contributes to poor patient adherence. If tetracycline could be replaced with amoxicillin without compromising efficacy, treatment adherence and patient outcomes might improve. A prospective study conducted in Seoul evaluated the substitution of amoxicillin for tetracycline in first-line bismuth quadruple therapy [5]. In this study, eradication rates for the 2W-PBMT and 2W-PBMA regimens showed no significant differences in ITT analysis (82.8% vs. 87.2%) or PP analysis (96% vs. 96.2%), indicating comparable efficacy between tetracycline and amoxicillin. However, replacing both bismuth and tetracycline with amoxicillin is unlikely to yield equivalent outcomes. Previous studies by the same authors have highlighted the additional benefits of bismuth in enhancing eradication efficacy [9]. A recent randomized controlled trial comparing a 2W-PBMT regimen with a 2W-PMA regimen in patients with clarithromycin resistance-associated genetic mutations reported eradication rates of 80.4% vs. 69.7% (ITT) and 95.1% vs. 76.4% (PP), suggesting potential inferiority of PMA [12]. This implies that combining amoxicillin with bismuth may result in more favorable outcomes. Although a 2-week treatment duration is generally recommended, previous studies comparing 2W-PBMT and 1W-PBMT regimens in CLA-R H. pylori strains found no significant differences in eradication rates (ITT: 84.9% vs. 81.1%; PP: 92.5% vs. 95.6%) [6]. Based on these findings, this study hypothesized that substituting amoxicillin for tetracycline while maintaining a bismuth-containing regimen and shortening treatment duration from 2 weeks to 1 week could achieve comparable eradication efficacy. The study results showed no significant difference in eradication rates between the 2W-PBMT group (94.7% pre-PSM, 94.4% post-PSM) and the 1W-PBMA group (85.7% pre-PSM, 87.0% post-PSM).

When evaluating the eradication success rates as the primary endpoint, the outcomes of both regimens were found to be comparable. However, a major difference was observed between the eradication rates in the ITT and PP analyses within each group. In the 2W-PBMT group, the eradication success rate was 94.7% in the PP analysis, but it dropped to 70.6% in the ITT analysis. A similar pattern was observed in the 1W-PBMA group. The divergence stemmed primarily from whether patients completed the post-treatment UBT and whether their medical records were complete. Therefore, these differences likely reflect not only the inherent limitations of patient follow-up in retrospective studies but also the potential for voluntary dropout due to the inconvenience of the treatment regimen. Nonetheless, among patients who completed the treatment and follow-up, no significant adverse events, discomfort, or poor adherence were reported. These concerns warrant further future prospective studies for clarification.

Culture testing remains the most reliable method for confirming clarithromycin resistance; however, its routine application in clinical practice is limited by several practical constraints [13]. Clarithromycin resistance in H. pylori is primarily linked to point mutations in the peptidyl transferase region of domain V of the 23S ribosomal RNA. These mutations predominantly involve substitutions of adenosine at positions 2143, 2144, or 2142 by guanine, cytosine, or thymidine [14]. In this study, resistance was identified using a commercially available DPO-PCR kit, which detects two key mutations: A2142G and A2143G [15]. However, previous research has shown that the A2142G mutation is associated with eradication rates comparable to those of wild-type strains when treated with clarithromycin-based triple regimens [16,17]. Consequently, the six cases identified with the A2142G mutation were excluded from the analysis.

Adverse events such as nausea, diarrhea, and abdominal discomfort are commonly associated with tetracycline-containing regimens, and in some cases, these symptoms can be severe enough to cause patients to discontinue treatment. These side effects are among the leading causes of treatment discontinuation in patients receiving bismuth-based quadruple therapy. In our study, one patient in the 2W-PBMT group discontinued treatment due to an intolerable adverse event. Although no discontinuations were reported in the 1W-PBMA group, bothersome symptoms such as loose stools and black-colored stools were more frequently reported. These effects may be attributed to the known influence of both amoxicillin and bismuth on bowel habits. Interestingly, despite the shorter treatment duration, the 1W-PBMA group reported a higher frequency of such symptoms. One possible explanation is recall bias, as adverse events were assessed retrospectively through patient interviews. Additionally, amoxicillin may have transiently altered gut microbiota or intestinal motility, contributing to these symptoms.

This study has some limitations. First, its retrospective design inherently raises concerns regarding recall bias and missing data. To minimize potential biases from unmeasured confounders, PSM analysis was employed. However, since this study included only patients who underwent eradication therapy following confirmation of clarithromycin resistance, the overall sample size was limited. Each PSM-matched group included only 25 patients, which may not be sufficient to draw highly reliable or generalizable conclusions. Larger-scale studies are warranted to enable more robust statistical analyses. Another limitation of this study lies in the selection of variables for PSM, which were selected arbitrarily by the authors. Due to the limited sample size, only age, sex, and weight were included as variables to adjust for basic demographic characteristics. Other important variables known to influence eradication outcomes, such as the presence of diabetes or smoking history, could not be included. Additionally, due to the constraints in the statistical package used for the PSM analysis, adjusted standardized mean difference values could not be presented, which may limit the ability to fully evaluate the robustness of our findings. Second, this study was conducted at only two centers, which may limit the generalizability of the findings. A multicenter study encompassing a wider geographic distribution would be more appropriate for comprehensive validation. However, considering that the study was conducted in Seoul and Gyeonggi province, regions with diverse populations representing various demographic backgrounds, the findings may still hold a certain degree of generalizability.

In conclusion, for patients with H. pylori infection harboring the A2143G point mutation, the 1W-PBMA regimen demonstrated comparable eradication efficacy to the 2W-PBMT regimen, with potentially improved medication adherence.