Introduction
Helicobacter pylori infection, present in approximately 50% of the global population,1 is a major cause of chronic gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer.2 Over the past three decades, highly effective regimens have been established for the eradication of H. pylori infection. Historically, proton pump inhibitor (PPI)-based clarithromycin triple therapy, consisting of a PPI plus clarithromycin and amoxicillin or metronidazole, was widely used as a first-line regimen.2 However, increasing clarithromycin resistance has substantially reduced its efficacy, and current guidelines no longer recommend empirical PPI-clarithromycin triple therapy when clarithromycin susceptibility is unknown.2,3 Instead, optimized bismuth quadruple therapy (BQT) is recommended as an important empirical first-line option, while rifabutin-based therapy and potassium-competitive acid blocker (PCAB)-amoxicillin dual therapy are additional options in appropriate clinical settings.3 Initially, these regimens achieved eradication rates exceeding 85% in general populations. However, following widespread clinical application, acquired antibiotic resistance has emerged, and the prevalence of clarithromycin and metronidazole resistance in H. pylori has increased substantially. From the 1990s to the 2020s, the prevalence of antibiotic resistance in H. pylori increased substantially.4-9 Specifically, metronidazole resistance is extremely high worldwide, exceeding 50–90% in many regions, and clarithromycin resistance rates surpass 20–30% in many European, Asian, and American populations, having exceeded 40% in some Middle Eastern and East Asian countries by the early 2020s.10 Levofloxacin resistance has exceeded 15–20% in most countries and 40% in parts of Asia and Africa.10 Amoxicillin resistance remains low in most regions (typically <2%), making it a reliable antibiotic for eradication. However, substantially higher resistance has been reported in some African settings.10,11 Most importantly, antibiotic resistance is the major determinant of eradication efficacy.6,12 As early as 1993, Xia et al.13 reported that H. pylori was eradicated by a 1-week triple regimen of colloidal bismuth subcitrate, metronidazole, and tetracycline in 92.3% (60 out of 65) of patients with metronidazole-sensitive strains and in 62.5% (15 out of 24) with metronidazole-resistant strains (P < 0.001), indicating that resistance to metronidazole reduces the efficacy of the triple regimen. This finding has been confirmed by later observations.14 The global rise in metronidazole resistance (42.1%-90.0%) and clarithromycin resistance (22.2%-51.7%) has rendered conventional triple regimens ineffective, resulting in eradication failure.15-17
The European Helicobacter and Microbiota Study Group recommends that first-line H. pylori treatment should achieve eradication rates of ≥90%.2 However, achieving this goal in the era of rising antibiotic resistance is challenging. Besides antibiotic resistance, inadequate acid suppression, inappropriate regimen selection, and poor patient compliance also contribute to eradication failure.18,19 Therefore, the central argument of this review is that management of H. pylori infection should move from undifferentiated empirical regimen selection toward risk-stratified precision treatment. This transition does not mean replacing empirical therapy with susceptibility-guided therapy (SGT) in every patient. Rather, it requires matching the intensity of diagnostic support and regimen selection to the probability and consequences of resistance by integrating local resistance surveillance, previous antibiotic exposure and treatment history, access to susceptibility testing, and the capacity to provide potent and sustained acid suppression.2,3
Current practical antibiotic approaches
Antibiotic resistance in H. pylori is primarily attributed to point mutations in specific genes.2,20-22 For example, clarithromycin resistance arises primarily from point mutations in the 23S rRNA gene (e.g., A2142G, A2143G), which reduce macrolide binding to the ribosome, and fluoroquinolone resistance results from mutations in the quinolone resistance-determining region of gyrA and gyrB. Metronidazole resistance is linked to inactivation or reduced expression of nitroreductases (e.g., rdxA, frxA), impairing conversion of the prodrug into its active form. Amoxicillin resistance is associated with alterations in penicillin-binding proteins and less commonly, changes in outer membrane permeability; although these mechanisms usually confer low-level resistance, they may still reduce eradication rates under suboptimal conditions. In addition, multidrug resistance occurs from efflux pump overexpression or multiple genetic mutations.23,24
Antibiotic resistance in H. pylori mediated by genetic mutations is generally persistent and may compromise subsequent eradication regimens.3,25,26 Once these mutations are present, the bacteria typically remain resistant even after the antibiotic is stopped. Thus, it is not easy to “restore” susceptibility in H. pylori, and current management focuses on selecting effective regimens based on avoiding resistance, not reversing resistance. Empirical therapy (EMT) refers to the selection of an eradication regimen without individual-level susceptibility testing, based on the best available evidence regarding local or regional resistance patterns, previous antibiotic exposure, guideline recommendations, and expected regimen efficacy. EMT does not necessarily require avoidance of every antibiotic with a high resistance prevalence, because some regimens can retain substantial activity despite resistance to an individual component.2,3 For example, optimized BQT remains effective in many settings despite high prevalence of metronidazole resistance, particularly when appropriate dosing and treatment duration are used. Accordingly, the key principle of EMT is not simply to avoid all resistance-prone antibiotics, but to select regimens with a sufficiently high probability of achieving successful eradication in the relevant population.2,3,14,27 SGT provides a rational means of avoiding antibiotics to which an individual H. pylori strain is resistant. However, current evidence does not demonstrate that SGT is universally superior to EMT. Earlier studies and meta-analyses found no consistent overall advantage of SGT,28,29 whereas more recent randomized trials have reported improved eradication rates in selected populations, particularly in settings with high clarithromycin resistance and when molecular susceptibility testing can be performed rapidly, compared with EMT regimens (Table 1).30-33 SGT is recommended by various guidelines.2,3,27,34,35
| First authors | Year | Country | Study
design | Antibiotic susceptibility test | Antibiotics
tested | Eradication regimen | | Eradication rate*(ITT/mITT) |
|---|
| | | | | | SGT | EMT | SGT | EMT |
| Lee30 | 2024 | Republic of Korea | RCT | Culture-based susceptibility guided | CLR, MTZ | CLR-s & MTZ-s: LCA, 10D | LCAM, 10D | 84.2% | 83.3% |
| | | | | | CLR-s & MTZ-r: LCA, 10D | | | |
| | | | | | CLR-r & MTZ-s: LMA, 10D | | | |
| | | | | | CLR-r & MTZ-r: LTBM, 10D | | | |
| Cho31 | 2025 | Republic of Korea | RCT | DPO-PCR | CLR | CLR-s: LCA, 10D | LCAM, 10D | 92.0%* | 85.0%* |
| | | | | | CLR-r: LTBM, 10D | | | |
| Yu32 | 2025 | China | RCT | RT-PCR | CLR | CLR-s: RBAC, 14D | RBAC, 14D | 87.4% | 82.0% |
| | | | | | CLR-r: RBAF, 14D | | | |
| Suo33 | 2025 | China | RCT | PCR coupled CYP2C19 polymorphism test | CLR, LEV | CLR-s: EACB, 7D | EACB, 14D | 87.7% | 80.8% |
| | | | | | LEV-s & CLR-r: EALB, 7D | | | |
| | | | | | CLR-r & LEV-r: EAMB, 14D | | | |
Rifabutin-based triple therapy represents an additional option for both initial and rescue treatment. The 2024 ACG guideline conditionally suggests 14-day rifabutin triple therapy as an empirical first-line alternative in treatment-naïve patients without penicillin allergy.3 In a phase 3 randomized trial, rifabutin-based triple therapy achieved an eradication rate of 83.8% in treatment-naïve patients, with efficacy unaffected by clarithromycin or metronidazole resistance.36 Rifabutin-based therapy may also be considered in patients with previous eradication failures or limited treatment alternatives, as rifabutin resistance remains relatively uncommon compared with resistance to clarithromycin or fluoroquinolones.37 Two multicenter randomized non-inferiority trials involving patients with at least two previous eradication failures showed that PPI- or vonoprazan-based rifabutin triple therapy was non-inferior to BQT, supporting its use as an alternative rescue regimen.37,38 However, rifabutin should not be regarded as a resistance-independent strategy, and its use should be balanced against hematologic toxicity and the potential selection of rifamycin resistance. Non-bismuth concomitant therapy, consisting of a PPI plus clarithromycin, amoxicillin, and metronidazole, remains an option for first-line eradication in selected settings. Its efficacy, however, depends on local clarithromycin and metronidazole resistance and treatment duration. Recent randomized trials support 14-day concomitant therapy, while susceptibility-guided approaches may provide additional benefit in selected high-resistance populations. Therefore, concomitant therapy should be considered according to regional resistance patterns rather than as a universally preferred regimen.2,30,39,40
For SGT, susceptibility testing is required before eradication therapy. At present, culture-based susceptibility testing is the reference standard; however, it is limited by its availability, time-consuming procedures, and technical complexity, restricting its routine use.2 Polymerase chain reaction-based susceptibility testing, mainly for clarithromycin and fluoroquinolone resistance mutations from gastric biopsies or stool samples, enables rapid, non-culture-based guidance of therapy.22,41-43 In addition, whole-genome sequencing has been applied to provide a comprehensive resistance profile.17,44 However, it is expensive and may not be available in resource-limited settings. Moreover, patients need an additional visit to the hospital to start the eradication therapy, which incurs additional costs, including transportation and lost productivity. Therefore, a balance between clinical efficacy and cost also needs to be considered when SGT is implemented.45-47
Many non-antibiotic factors, such as patient compliance, gastric acid suppression, CYP2C19 genotype, bacterial load and distribution, and host immune response, influence the clinical efficacy of antibiotic-containing eradication therapy, and optimization of these factors may improve H. pylori eradication rates, including in antibiotic-resistant strains, as described later. Moreover, several non-antibiotic agents possessing anti-H. pylori properties have been recently reported to be effective against both antibiotic-susceptible and antibiotic-resistant strains, when used alone or in combination with antibiotics, as described later. Therefore, SGT may no longer be the only optimal option for overcoming antibiotic resistance in H. pylori.
Emerging antibiotic and non-antibiotic approaches
The rising prevalence of antibiotic resistance in H. pylori has stimulated interest in searching for approaches that bypass classical antibiotic targets, i.e., emerging antibiotic or non-antibiotic approaches. The underlying mechanisms for these approaches include optimization of the microenvironment to overcome resistance, reduction of the selective pressure for resistance, disruption of bacterial survival, enhancement of localized drug delivery, and vaccination.
Optimizing the microenvironment to overcome resistance
Adequate acid suppression enhances antibiotic stability, promotes bacterial replication, and improves antimicrobial activity, particularly that of amoxicillin, and is therefore an important determinant of eradication efficacy in amoxicillin-containing regimens.2,3,19
PPIs, including omeprazole and esomeprazole, have been widely used to achieve sustained gastric acid suppression in H. pylori eradication therapy. However, interindividual variability in PPI metabolism, influenced by CYP2C19 polymorphisms, contributes to inconsistent acid suppression and consequently treatment failure in some patients treated with PPI-based regimens.19,35,48 Vonoprazan and other PCABs, including tegoprazan and keverprazan, provide rapid and sustained acid suppression and are less dependent on CYP2C19 metabolism.48-55 Randomized trials and large real-world studies, particularly from East Asia, have demonstrated that vonoprazan-based regimens, used as first-line or rescue treatment, achieve higher eradication rates than PPI-based therapy for H. pylori, including in clarithromycin-resistant strains, with improved compliance (Table 2).56-68,70-80
| Regimen | Duration | Eradication rate* | Clinical features | Limitations |
|---|
| Vonoprazan-based dual therapy56-62,64-68,70-72 | 7–14 days | approximately 85–96% | Clinically ready; minimizes resistance selection; favorable safety & tolerability | Limited Western data |
| Vonoprazan-based triple therapy57,63,65,70,71,73-78 | 7–14 days | approximately 80–96% | Robust acid suppression; simplified dosing; high patient compliance | Resistance-dependent; higher adverse event risk |
Vonoprazan-based
quadruple therapy71,78-80 | 14 days | approximately 85–95% | Simplified dosing; broad clinical applicability | Limited Western data; higher adverse event risk |
Building on potent acid suppression, vonoprazan-containing dual therapy (vonoprazan plus high-dose amoxicillin) has emerged as a leading antibiotic-minimizing strategy. Recent studies (2022–2024) report intention-to-treat eradication rates of approximately 85–91% and per-protocol rates exceeding 90%, particularly in treatment-naïve patients and in those harboring clarithromycin-resistant H. pylori.59,60,62 Treatment duration and amoxicillin dose vary across studies, and the optimal vonoprazan-amoxicillin dual regimen remains uncertain. Appropriately extended treatment duration may improve efficacy, while lower-dose amoxicillin regimens have also achieved acceptable eradication rates (Table 2).62,67 Moreover, this approach also minimizes the exposure to resistance-prone antibiotics and aligns with principles of antimicrobial stewardship, as described later. Although vonoprazan-based dual, triple, and quadruple regimens have demonstrated high eradication efficacy in Asian populations,71,81 their efficacy varies across populations and treatment settings. The US/European phase 3 trial confirmed clinically meaningful efficacy, particularly against clarithromycin-resistant H. pylori, although overall eradication rates were lower than those reported in some Asian studies.82-85 High efficacy in Asia does not establish that PCAB-based regimens are uniformly superior to optimized high-dose PPI regimens. In some Asian studies, high-dose esomeprazole-amoxicillin dual therapy achieved broadly comparable efficacy, suggesting that the incremental benefit of PCABs may depend on the comparator regimen and clinical setting.68 Conversely, the European Registry on H. pylori Management reported poor efficacy of high-dose PPI-amoxicillin dual therapy, with eradication rates of approximately 51% by modified intention-to-treat analysis and 52% per protocol, indicating that dual-therapy outcomes cannot be directly extrapolated across regions.69 PCAB availability remains geographically uneven, with limited routine availability in Europe, and higher acquisition costs may further limit widespread use. Therefore, region-specific comparative efficacy and cost-effectiveness studies are needed. In addition, the clinical efficacy of another PCAB, tegoprazan, in H. pylori eradication also needs to be further confirmed.75,86
Reduction of the selective pressure for resistance
Current guidelines emphasize principles of antimicrobial stewardship in H. pylori management, including avoidance of ineffective empiric regimens, consideration of the regional prevalence of antibiotic resistance in H. pylori and an individual’s previous antibiotic exposure, and use of SGT to minimize resistance selection and optimize eradication rates.2,3 Therefore, empirical regimens should be selected according to local resistance patterns and expected regimen-level efficacy, rather than by simply avoiding any antibiotic with a high population-level resistance rate. For example, dual therapy with vonoprazan and high-dose amoxicillin has been shown to be highly effective in eradicating H. pylori infection.62
Disruption of bacterial survival
The density of H. pylori colonizing the gastric mucosa not only affects the eradication efficacy but is also associated with acquired antibiotic resistance.87 Interventions that reduce bacterial burden or improve treatment tolerance may therefore have adjunctive effects in increasing the efficacy and preventing acquired resistance.88 Probiotics and prebiotics have been extensively evaluated for their potential roles in H. pylori eradication.89-91 It has been reported that the selected Lactobacillus reuteri strains inhibited the binding of H. pylori to the putative glycolipid receptors asialo-GM1 and sulfatide in vitro, suggesting a strain-specific mechanism of competitive interference with bacterial adhesion.92 Similarly, Saccharomyces boulardii may reduce H. pylori adhesion to host cells through neuraminidase activity.93 In addition, Lactobacillus acidophilus and Lactobacillus rhamnosus have been reported to reduce the bacterial load of H. pylori, although probiotic treatment alone did not achieve eradication.94 Thus, the proposed mechanisms for adjunctive effects of probiotics include interference with epithelial adhesion, production of bacteriocins or organic acids, and modulation of the gastric and intestinal microbiota.90-94 Probiotics do not directly overcome established antibiotic resistance or replace an optimized eradication regimen. They should therefore be regarded as optional adjuncts for improving treatment tolerance in selected patients rather than as a core resistance-overcoming strategy. More recently, fecal or washed microbiota transplantation has also been explored as an adjunctive approach, potentially boosting eradication rates and reducing antibiotic adverse events, but evidence remains preliminary and insufficient for routine eradication practice.95,96
Formation of H. pylori biofilms, which confer up to 1000-fold increased antibiotic tolerance via reduced penetration and slow-growing cell populations, is one of the causes of eradication failure.97 It has been reported that N-acetylcysteine (NAC) cleaves disulfide bonds in the exopolysaccharide matrix of H. pylori biofilms.98 NAC possesses a mucolytic effect, which reduces gastric mucus viscosity, thereby enhancing drug access, and the capacity to disrupt BabA adhesin-mediated epithelial attachment via thiol-based disulfide reduction at the adhesin binding site.99 In a small randomized trial of resistant/refractory H. pylori infection, pretreatment with NAC 600 mg once daily for 7 days before culture-guided therapy increased eradication rates from 20% to 65%.100
Enhancement of localized drug delivery
Nanomaterial-based therapies have emerged in recent years. First, metallic (e.g., silver or bismuth) and metal-oxide (e.g., zinc oxide)-based nanoparticles exhibit direct bactericidal activity against H. pylori, including antibiotic-resistant strains, through membrane disruption, reactive oxygen species generation, and inhibition of urease activity.101In vitro and animal studies have demonstrated that bismuth-based nanoparticles possess improved mucosal adhesion and potential dose-sparing effects compared with conventional bismuth salts102; however, long-term safety and toxicity remain key barriers to clinical translation. In addition, polymer-based and targeted nano-delivery systems have also been reported.103 Polymeric nanoparticles, such as chitosan-based formulations, possess mucoadhesive properties that prolong gastric residence time and enhance local drug concentrations.104 pH-responsive nanoplatforms that exploit the acidic gastric environment have been developed to achieve localized or targeted antimicrobial activity.105 Preclinical studies suggest that polymeric, lipid-based, and pH-responsive nanocarriers can increase local antimicrobial concentrations, improve penetration of the gastric mucus barrier, and facilitate controlled drug release. These properties may enhance antibacterial activity while potentially reducing systemic exposure; however, whether these pharmacological advantages translate into improved clinical eradication rates and clinically meaningful reductions in toxicity remains to be established in human studies.103,106,107 Well-designed clinical studies are required to confirm this assumption. Recently, nanozyme-based approaches targeting urease activity and photothermal nanoparticles activated by near-infrared light have also been explored.108,109Table 3 summarizes some recently explored emerging nanomaterial-based approaches.102,105,109-116 Despite their antibiotic-resistance-independent activity in experimental models, significant technical and practical challenges currently limit the clinical applicability of these strategies.
| Strategy | Primary mechanism | Development stage | Translational barrier |
|---|
| Nanomaterial-based approaches |
| Bismuth nanoparticles102,110 | Urease inhibition; mucosal adhesion; disruption of H. pylori membranes and biofilms | Preclinical–early translational | Safety profiling |
| Silver / ZnO nanoparticles111,112 | ROS-mediated killing | Preclinical | Cytotoxicity |
| Chitosan nano-delivery113,114 | Mucoadhesive drug targeting | Preclinical | Manufacturing scale-up |
| pH-responsive nanoplatforms109,115 | Targeted gastric release | Preclinical | Clinical validation |
| Nanozymes105,116 | Microenvironment disruption | Preclinical | Delivery feasibility |
Vaccination
Theoretically, vaccination is a promising antibiotic-independent strategy to prevent H. pylori acquisition. Scientists have been investigating vaccines, using various whole-cell, subunit, DNA, and live-vector candidates, against H. pylori infection for over three decades.117-119 However, vaccine development has been disappointing from a clinical-translation perspective.120,121 Despite encouraging animal and human studies,117,118,120,122 the landmark phase 3 trial by Zeng et al.122 in children demonstrated 71% efficacy strictly in preventing new H. pylori infections over one year; it did not demonstrate therapeutic efficacy in clearing established, chronic infections. So far, neither prophylactic nor therapeutic vaccines have been approved for clinical management of H. pylori infection. Major barriers include immune evasion, extensive genetic diversity among strains, uncertain correlates of protection, and the inability to induce durable and effective gastric mucosal immunity.119,121 Nevertheless, due to increasing concerns regarding antibiotic resistance, especially the need for H. pylori prevention and eradication as the primary gastric cancer prevention strategy, vaccine development is continuing.123,124 Following advances in mucosal immunology, novel antigen discovery, next-generation vaccine platforms, and improved adjuvant systems, vaccination should be viewed with cautious optimism; however, it remains a long-term research objective rather than a realistic near-term solution to antibiotic resistance in routine H. pylori management.
Future directions
From a translational gastroenterology perspective, future H. pylori management depends on bridging mechanistic insights with clinical solutions. The immediate priority is not to replace guideline-based therapy with experimental approaches, but to use proven regimens more judiciously. When susceptibility is unknown, an EMT approach should remain a major first-line option in settings where local antibiotic resistance data are known, while SGT is especially valuable after treatment failure or when the use of resistance-prone antibiotics is contemplated.2,3,27 PCAB-based regimens, particularly vonoprazan-amoxicillin dual therapy, are promising antibiotic-minimizing options in Asian populations,61,125 but region-specific validation is required in other populations, especially in Europe.126 Nano-formulated bismuth and targeted antimicrobial delivery systems have shown improved gastric retention, site-specific release, and microbiome-sparing antibacterial activity in preclinical models.103,107,110 Antibiotic-independent responsive biomaterials and nanozyme-based therapies are also promising, whereas vaccines remain a research priority and microbiome-directed interventions are currently better regarded as adjunctive strategies (Fig. 1).107,127,128 However, most of these approaches remain preclinical and require substantial translational and safety validation.103,107 Finally, at the population level, improvements in socioeconomic and household conditions, access to safe water and sanitation, food hygiene, and reduction of household crowding are known to be associated with lower H. pylori prevalence and thus are biologically plausible measures to reduce transmission of the infection.1,10
Limitations
This review has several limitations. First, as a narrative review, the literature search was non-systematic and may therefore be subject to selection bias. Second, the quality and consistency of the available evidence are heterogeneous, particularly for adjunctive interventions such as probiotics and microbiota-based therapies, as well as for SGT. Third, although randomized trials increasingly support PCAB-based regimens, particularly vonoprazan-amoxicillin dual therapy, much of the available evidence remains derived from East Asian populations, and differences in treatment regimens, antimicrobial resistance patterns, host characteristics, and prescribing practices may limit direct extrapolation to other regions. Fourth, evidence for nanomaterial-based therapies, microbiome-modulating approaches, and vaccination remains predominantly preclinical or early translational, and their long-term safety and clinical efficacy have not been established. Finally, no quantitative synthesis or formal meta-analysis was performed; therefore, the eradication rates reported in this review should be interpreted descriptively rather than as pooled estimates.
Conclusions
The impact of antibiotic resistance on H. pylori eradication is best minimized through a risk-stratified hierarchy rather than by choosing between EMT, SGT, and PCAB-based therapy as equivalent alternatives. When individual susceptibility is unavailable, clinicians should use a locally validated, guideline-recommended empirical regimen; in settings with high or unknown clarithromycin resistance, optimized 14-day BQT is the most broadly supported default. SGT should be prioritized after treatment failure or when a clarithromycin- or fluoroquinolone-containing regimen is contemplated, but it is not universally superior to a well-selected empirical regimen. For patients without penicillin allergy, vonoprazan-amoxicillin dual therapy provides a clinically mature antibiotic-minimizing option where amoxicillin resistance is low and regional effectiveness, availability, and affordability support its use. Its importance lies in demonstrating that potent acid suppression can reduce antibiotic burden, not in establishing universal superiority across populations. Across all pathways, adequate acid suppression, optimized dosing and treatment duration, adherence support, and confirmation of eradication remain essential. Nanomaterial-based therapies, vaccines, and other resistance-independent strategies are promising but remain investigational and should not displace validated treatment in current clinical practice. Continued integration of resistance surveillance, optimized acid suppression, affordable SGT, and translational technologies will be essential to sustain eradication rates above the accepted thresholds and to realize the long-term clinical and population-level benefits of H. pylori control.
Declarations
Funding
This study was supported by Jiangsu Province Hospital (the First Affiliated Hospital with Nanjing Medical University) Clinical Capacity Enhancement Project (JSPH-MB-2024-12).
Conflict of interest
XZ has been an Editorial Board Member of the Journal of Translational Gastroenterology since 2023, CAO has been Honorary Editor-in-Chief of the Journal of Translational Gastroenterology since 2026, and HHXX has been Editor-in-Chief of the Journal of Translational Gastroenterology since 2026. The other authors declare no conflicts of interest.
Author contributions
Study design and initial drafting of the manuscript (XZ, ZW, HY); data collection and figure preparation (YW); critical revision of the manuscript for important intellectual content (CAO, HHXX). All authors critically reviewed and approved the final manuscript.