Advances in the Management of Refractory Helicobacter pylori Infection: From Antimicrobial Resistance to Precision Eradication

Abstract

Helicobacter pylori infection represents a global public health issue strongly associated with gastric cancer and peptic ulcer disease. Increasing antibiotic resistance has markedly reduced the efficacy of standard eradication regimens, resulting in a growing prevalence of refractory infection and a critical clinical challenge. Refractory H pylori causes substantial patient discomfort and economic costs while worsening antimicrobial resistance. This review summarizes the mechanisms underlying eradication failure and advances in diagnostic approaches from conventional culture to molecular testing. We critically evaluate evidence for personalized salvage therapies based on drug susceptibility and novel acid-suppressive agents including potassium-competitive acid blockers. We propose an integrated clinical framework for diagnosis, treatment, and management and highlight future directions such as new antimicrobials, vaccines, digital health, and global antibiotic stewardship. We stress that a shift from empirical therapy to test-guided precision medicine is essential. Optimized diagnostics, individualized regimens, and comprehensive management will help achieve successful first-line eradication and control the further spread of antibiotic resistance.

Introduction

Helicobacter pylori is a microaerophilic Gram-negative bacillus that infects nearly half of the global population, with infection rates varying markedly across regions and countries—remaining persistently high in developing areas such as East Asia, Latin America, and Africa.1, 2, 3 Classified as a definite group I carcinogen, H pylori infection is a major etiological factor for chronic active gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer.3, 4, 5 Eradication of H pylori not only effectively promotes ulcer healing but also significantly reduces the risk of gastric cancer development. For this reason, the World Health Organization and numerous international gastroenterology societies recommend active eradication therapy for all individuals with H pylori infection to control the onset and progression of associated diseases.6, 7, 8, 9

However, the escalating global misuse of antibiotics has led to a continuous rise in the resistance rate of H pylori to key antibiotics including clarithromycin, metronidazole, and levofloxacin, resulting in a sharp drop in the eradication rate of standard triple therapy from the initial 80% to 90% to below 70% and to as low as approximately 32% in populations with clarithromycin-resistant strains.^10,11 Refractory or difficult-to-eradicate H pylori infection is defined as the failure to achieve successful bacterial eradication in patients who have received at least 2 courses of standardized treatment with distinct regimens.^8,12 Beyond increasing the risk of carcinogenesis in patients, refractory infection also imposes a substantial economic burden, elevated risk of adverse drug reactions, and significant psychological distress due to repeated treatment attempts.³ Confronted with this formidable challenge, the traditional one-size-fits-all empirical treatment model is no longer sustainable, and a paradigm shift toward a precision medicine approach based on etiological testing and host characteristics has become an inevitable trend.

This review aims to provide a comprehensive and in-depth synthesis and analysis of the advances in the diagnosis and management of refractory H pylori infection, systematically elaborate on the multifactorial mechanisms underlying eradication failure, the evolution of precision diagnostic strategies, and the development of evidence-based individualized salvage regimens and offer a prospective discussion on future research and clinical directions.

Mechanisms Underlying Eradication Failure in Refractory Helicobacter pylori Infection

The development of refractory H pylori infection is a complex process driven by the interplay of multiple factors involving the bacterium itself, the host, and the external environment. A thorough understanding of these failure mechanisms constitutes a fundamental prerequisite for formulating effective precision treatment strategies. In general, the underlying causes can be categorized into 3 major groups: bacterial factors including antibiotic resistance and phenotypic adaptation, host-related genetic and physiological factors, and external factors associated with treatment and patient behavior.

Bacterial Factors

Bacterial intrinsic factors represent the most direct and core cause of treatment failure, with antibiotic resistance being the primary challenge.

The global prevalence and regional heterogeneity of antibiotic resistance are key driving forces

• •Clarithromycin resistance in H pylori is primarily mediated by point mutations in the V region (peptidyltransferase loop) of the 23S rRNA gene, with A2143G and A2142G being the most common mutations most strongly associated with treatment failure; these mutations reduce the binding affinity of clarithromycin for the 50S ribosomal subunit, thereby leading to treatment failure.^13,14 Epidemiological data reveal significant global variability in clarithromycin resistance rates, with reported figures of 30.7% in China,¹⁵ 35.6% in India,¹⁶ 31.5% in the United States,¹⁷ 22.4% in Europe,¹⁸ and 15% in Africa⁹ (Figure 1). These rates consistently exceed the 15% threshold for empirical triple therapy, significantly undermining the efficacy of clarithromycin-containing triple regimens.
• •Metronidazole resistance in H pylori is primarily attributable to defective prodrug activation: as a nitroimidazole-containing prodrug, metronidazole must be reduced to bioactive toxic metabolites by the bacterial nitroreductase system to induce DNA damage. Inactivating mutations or promoter region variants in genes such as rdxA (oxygen-insensitive nicotinamide adenine dinucleotide phosphate nitroreductase) and frxA (nicotinamide adenine dinucleotide phosphate-flavin oxidoreductase) can attenuate or abrogate this reductive process, consequently conferring metronidazole resistance.^6,13 Furthermore, upregulation of efflux pumps (eg, hefA) and mutations in regulatory genes such as fur also contribute to the development of resistant phenotypes, rendering high-accuracy prediction by molecular testing reliant on a single target unattainable.^12,13,19 Metronidazole resistance remains high globally, with prevalence rates of 91% in Africa,⁹ 77.7% in India,¹⁶ 70.1% in China,¹⁵ 62.4% in Europe,¹⁸ and 42.1% in the United States.¹⁷
• •Resistance to fluoroquinolones such as levofloxacin is primarily driven by point mutations in the quinolone resistance-determining region of the DNA gyrase A (gyrA) subunit, including N87K and D91Y.^20,21 Global surveillance shows levofloxacin resistance rates of 37.6% in the United States,¹⁷ 33.0% in China,¹⁵ 32.8% in India,¹⁶ 20.3% in Europe,¹⁸ and 14% in Africa.⁹
• •Amoxicillin resistance rates remain low in the United States, Europe, and China, at 2.6%,¹⁷ 3.5%,¹⁸ and 2.4%,¹⁵ respectively. In contrast, resistance rates are markedly high in India and Africa, reaching as high as 38%.^9,16 Tetracycline resistance is similarly low, with rates of 0.87% in the United States,¹⁷ 2.5% in China,¹⁵ 0.5% in Europe,¹⁸ 11.6% in India,¹⁶ and 13% in Africa.⁹
• •A Chinese study has additionally documented a low furazolidone resistance rate of 1.4%.¹⁵ Notably, furazolidone achieves excellent efficacy for multidrug-resistant (MDR) H pylori in China and several Asian regions, while it is not universally available in Europe, America, and other regions due to regional drug approval policies.²²
• •MDR is becoming increasingly prevalent, defined as resistance to at least 3 distinct classes of antibiotics.²³ One study has shown that the rate of primary MDR ranges from ≤10% to 40% across different countries, and the MDR rate can reach as high as 31.6% in post-treatment patients.²⁴ This renders the selection of empirical treatment exceedingly challenging.

Figure 1.

Comparison of Helicobacter pylori antibiotic resistance rates among different geographic regions. Bar chart illustrating regional resistance rates of H pylori to amoxicillin, clarithromycin, metronidazole, levofloxacin, and tetracycline across the United States, Europe, China, India, and Africa.

Phenotypic adaptation of H pylori also plays a critical role

• •Biofilm formation impairs antibiotic penetration via the extracellular polymeric substance barrier; additionally, mechanisms including reduced metabolism or a dormant state, an increased abundance of persister cells, and efflux pump upregulation confer a roughly 10- to 1000-fold higher tolerance of biofilm-embedded bacteria to commonly used antibiotics compared with planktonic cells, thereby elevating the risk of eradication failure.25, 26, 27
• •The coccoid form represents a dormant state adopted by H pylori under adverse conditions (eg, antibiotic pressure, nutrient deprivation), during which metabolic activity is drastically diminished and the bacterium exhibits high tolerance to antibiotics acting on replicating cells, such as β-lactams (eg, amoxicillin). Once environmental conditions improve, these coccoid forms can revert to the spiral morphology and cause recurrent infection.28, 29, 30
• •Furthermore, variations in virulence factors such as cytotoxin-associated gene A and vacuolating cytotoxin A (VacA) alter the inflammatory microenvironment of the gastric mucosa and bacterial colonization, which may in turn impair the distribution and efficacy of drugs at the infection site.^31,32

Host-Related Factors

Host physiological and genetic characteristics represent another key determinant of treatment success or failure, with pharmacokinetic variability being particularly critical.

A classic example is the CYP2C19 gene polymorphism associated with the metabolism of proton pump inhibitors (PPIs). As the foundational acid-suppressive agents in H pylori eradication regimens, PPIs are prodrugs that require activation in an acidic environment and are predominantly metabolized by the hepatic CYP2C19 enzyme. Polymorphisms in the CYP2C19 gene give rise to extensive metabolizer (EM), intermediate metabolizer, and poor metabolizer phenotypes in the human population.^33,34 Among these, the EM phenotype confers a higher risk of eradication failure when first-generation PPIs (omeprazole, lansoprazole, and pantoprazole)—which are primarily metabolized by CYP2C19—are administered, whereas rabeprazole and esomeprazole are relatively less affected by CYP2C19 activity. EM patients rapidly clear PPIs from the circulation, resulting in lower plasma drug concentrations that fail to maintain the optimal intragastric pH (>6) throughout the day, thereby markedly compromising the stability and bactericidal efficacy of pH-dependent antibiotics such as amoxicillin and clarithromycin.^10,33 A systematic review and meta-analysis has clearly demonstrated that patients carrying the CYP2C19 EM alleles have a significantly elevated risk of eradication failure with PPI-based therapy (odds ratio = 2.52), and this risk is even higher (odds ratio = 4.44) in patients with confirmed treatment adherence and clarithromycin-susceptible strains.³³ The distribution of CYP2C19 polymorphisms varies across ethnic groups: for instance, the proportion of the poor metabolizer phenotype is higher in Asian populations than in Caucasian populations. This finding partly explains the regional variations in PPI dosing and selection recommendations in clinical treatment guidelines.^7,10

Beyond CYP2C19, other genetic polymorphisms that modulate the intragastric microenvironment may also contribute to treatment outcomes. For example, polymorphisms in the interleukin-1β gene are closely associated with gastric acid secretion; individuals with certain variants exhibit suppressed gastric acid production, and a chronic hypoacidic intragastric environment may alter the survival status of H pylori and impair antibiotic activity.^10,33 A meta-analysis revealed that carriers of interleukin-1β low-expression genotypes have a 1.72-fold higher risk of eradication failure compared with those with high-expression genotypes.³³

In addition, the physical and chemical properties of the intragastric microenvironment—including fluctuations in intragastric pH, mucus layer thickness, and the degree of inflammation—exert a marked influence on the distribution, stability, and antimicrobial activity of drugs.^6,10 Optimal acid suppression, defined as maintaining an intragastric pH > 6 for more than 70% of a 24-hour period, is critical for eradication regimens containing pH-dependent antibiotics such as clarithromycin and amoxicillin.^6,10

Treatment- and Behavior-Related Factors

Extrinsic factors during the treatment course are also non-negligible.¹⁰ Poor patient adherence is a common cause of treatment failure, including missed doses, nonadherence to the prescribed dosing schedule, and incomplete treatment courses.^35,36 Complex medication regimens—such as polypharmacy and multiple daily administrations—markedly increase the treatment burden on patients and reduce adherence.^35,37 Suboptimal antibiotic dosing and administration frequency, particularly the use of subtherapeutic doses in empirical therapy, may also provide an opportunity for the development of bacterial resistance.³⁸ For example, the interaction between omeprazole and clopidogrel reduces antiplatelet efficacy and may lead to premature treatment discontinuation, indirectly lowering eradication success. Interactions between PPIs and methotrexate, digoxin, and other agents may alter the efficacy of either drug or increase the risk of adverse reactions, leading to modification or discontinuation of the treatment regimen.^39,40

In summary, refractory H pylori infection is a complex clinical outcome arising from the interplay of multiple factors, including bacterial resistance, host genetic susceptibility, and inadequate treatment management (Figure 2). A comprehensive assessment of these factors is essential when formulating salvage treatment strategies, which is a prerequisite for the fundamental paradigm shift from empiricism to precision individualization.

Figure 2.

Multifactorial contributors to eradication failure in refractory Helicobacter pylori infection. Schematic diagram summarizing bacterial factors, host-related factors, and treatment-/behavior-related factors that drive persistent H pylori infection and treatment failure. IM, intermediate metabolizer; PM, poor metabolizer.

Precision Diagnostic Strategies: the Shift From Empiricism to Testing-Driven Approaches

Precision treatment begins with accurate diagnosis. In recent years, considerable advances have been made in H pylori resistance testing, evolving from traditional phenotypic culture to rapid and sensitive molecular assays, providing strong support for clinical decision-making.

Traditional Culture and Antimicrobial Susceptibility Testing (Culture-Based Antimicrobial Susceptibility Testing)

Conventional gastric mucosal biopsy culture combined with antimicrobial susceptibility testing has long been regarded as the “gold standard” for resistance detection^41,42 (Table 1).This approach involves endoscopic sampling of gastric mucosa, isolation and culture of H pylori on selective media, followed by determination of the minimum inhibitory concentration of various antibiotics using agar dilution, E-test, or disk diffusion.⁴²

• •Advantages: It provides a complete susceptibility profile covering not only commonly used antibiotics but also susceptibility to agents such as tetracycline and furazolidone, offering critical information for the management of MDR strains.^42,43
• •Limitations: First, it has relatively low sensitivity, especially after multiple failed treatments, where bacterial load is reduced or unevenly distributed, leading to a high false-negative rate; some studies report culture success rates below 60%.⁴⁴ Second, it is time-consuming, often requiring 1 week or longer for culture and antimicrobial susceptibility testing, which may delay clinical intervention.45, 46, 47, 48 Finally, the method is technically demanding and costly, requiring specialized equipment, reagents, and well-trained personnel, which restricts its large-scale promotion in primary hospitals and resource-limited regions globally, limiting its widespread use in primary-care hospitals.⁴⁴

Table 1.

Comparison of Available Laboratory Methods for Helicobacter pylori Antimicrobial Resistance Detection

Method	Principle	Sensitivity	Specificity	Turnaround time (h)	Invasiveness	Cost	Main advantages and limitations
Culture-based AST	Bacterial culture in vitro with assessment of antibiotic-induced growth inhibition	Moderate (<60% after failed treatment)	High (gold standard)	168	Invasive (endoscopy)	High	Advantages: phenotypic results, ability to detect novel resistance. Limitations: slow, technically demanding, low sensitivity.
Real-time PCR (qPCR)	Amplification and detection of specific resistance-associated gene mutations	High	High	4–6	Invasive/noninvasive	Moderate	Advantages: rapid, sensitive, quantifiable. Limitations: restricted to predefined known mutations.
Next-generation sequencing (NGS)	High-throughput sequencing and comprehensive genomic analysis of resistance determinants	Very high	Very high	24–72	Invasive/noninvasive	High	Advantages: comprehensive, noninvasive, identifies novel mechanisms. Limitations: high cost, complex data analysis, relatively long turnaround.
CRISPR-based POCT	Recognition of specific nucleic acid sequences using CRISPR systems	Very high	Very high	<1	Noninvasive/invasive	Low (future)	Advantages: ultra-fast, high sensitivity. Limitations: mostly investigational, technically immature.

AST, antimicrobial susceptibility testing; POCT, point-of-care testing; qPCR, quantitative polymerase chain reaction.

Molecular Diagnostic Techniques: Rapid, Precise, and Minimally Invasive

To overcome the limitations of conventional methods, nucleic acid amplification-based molecular assays have emerged. These approaches determine phenotypic resistance by directly detecting resistance-associated gene mutations, demonstrating great potential for clinical application.

Polymerase chain reaction and derivative techniques

Polymerase chain reaction (PCR) and its derived technologies represent the most widely used molecular diagnostic tools at present.

Real-time quantitative PCR (qPCR)

With specific probes or primers, qPCR enables rapid and sensitive detection of known resistance mutations, such as the A2143G mutation in the 23S rRNA gene or the D91Y mutation in the gyrA gene. Assays can be completed within hours and allow quantitative analysis to estimate the proportion of resistant strains (mutation abundance).^49,50 Commercial kits (eg, GenoType HelicoDR) combine multiplex PCR with reverse hybridization, allowing simultaneous detection of multiple common resistance mutations with relatively simple procedures, making them suitable for routine clinical use.^13,51

Allele-specific PCR

Allele-specific primers are designed for targeted mutation sites; amplification occurs only if the mutation is present in the template DNA, yielding extremely high specificity suitable for rapid screening of known mutations.^52,53

Application in Different Sample Types

Molecular detection technologies can be applied to a variety of clinical samples, each with distinct characteristics and applicable scenarios.

• •Gastric mucosa samples: Gastric mucosal biopsy specimens represent the most commonly used invasive samples for molecular detection, with stable and reliable analytical performance.⁵⁴ Methods such as real-time PCR enable direct detection of H pylori and its drug resistance genes in biopsy tissues, delivering high sensitivity and specificity. Notably, H pylori DNA can still be identified by PCR even when histological examinations yield negative results.⁵⁴
• •Fecal samples: Fecal molecular testing has emerged as a major research focus in recent years. Multiple studies have confirmed that qPCR detection of H pylori and its resistance genes using fecal samples achieves diagnostic performance highly consistent with gastric mucosal biopsy.^55,56 One study reported a pooled sensitivity of 0.93 and a pooled specificity of 0.98 for fecal 23S rRNA testing in predicting clarithromycin resistance.⁵⁷ As a noninvasive approach, fecal testing is particularly valuable for patients who cannot tolerate or decline endoscopy, as well as for dynamic monitoring of eradication efficacy post-treatment.
• •Gastric fluid samples: The value of gastric fluid analysis—a readily obtainable sample during endoscopy—has gained increasing attention. A prospective study systematically compared the diagnostic performance of gastric mucosa, gastric fluid, and fecal samples and found that gastric fluid exhibited significantly higher sensitivity and better concordance with the gold standard for detecting H pylori infection (97.6% vs 91.3%) and resistance genes for clarithromycin and levofloxacin compared with fecal samples.⁵⁸ This indicates that collecting a small volume of gastric fluid during routine endoscopy for molecular testing represents an efficient, minimally invasive strategy for resistance assessment.

Next-generation sequencing

Next-generation sequencing (NGS) represents the future direction of resistance detection. By performing high-throughput parallel sequencing of H pylori DNA or RNA, NGS enables:

• •Comprehensive characterization of resistance mechanisms: It can detect not only known point mutations but also gene insertions, deletions, copy number variations, plasmid carriage, and novel resistance genes, providing a panoramic resistance profile for MDR or even pan-drug-resistant strains.^7,59,60
• •Noninvasive testing: Metagenomic sequencing of DNA from fecal or gastric fluid samples allows direct acquisition of resistance information without bacterial culture, making it especially useful for culture-negative cases.^7,59
• •Dynamic monitoring: Quantitative sequencing allows tracking of changes in the proportion of resistant strains during treatment, providing evidence for efficacy evaluation and regimen adjustment.⁶¹

A US study using NGS for resistance detection in formalin-fixed paraffin-embedded gastric biopsy specimens achieved a 95% success rate with results available within 72 hours, demonstrating its high efficiency and great potential in clinical practice.⁶²

Emerging Diagnostic Technologies and Future Perspectives

Emerging technologies such as the CRISPR-Cas system are also being explored for the rapid detection of H pylori. The CRISPR-Cas system can recognize and cleave specific nucleic acid sequences with extremely high specificity and sensitivity. When combined with reporter molecules, it holds great promise for developing point-of-care testing devices that can deliver results within tens of minutes, although most applications are still in the research stage.^63,64

Evidence-Based Individualized Rescue Therapy Strategies

Definition of recommended therapy: Regimens that achieve ≥90% eradication rate in susceptible strains and ≥80% in resistant strains with acceptable safety.^6,65

Following the determination of the H pylori resistance profile and comprehensive consideration of host factors, the next key step is to tailor an optimal rescue therapy regimen for each patient with refractory infection. In recent years, with the emergence of novel pharmaceuticals, particularly potassium-competitive acid blockers (P-CABs), and the exploration of new therapeutic strategies, the eradication success rate of refractory H pylori infection has been significantly improved.

Core Principles for the Selection of Treatment Regimens

Susceptibility-guided therapy

This is the internationally recognized first-choice strategy. For patients with refractory infection, antimicrobial susceptibility information should be obtained as far as possible via culture or molecular approaches to select antibiotics to which the strain is susceptible.^7,46

Avoidance of cross-resistance

A detailed review of the patient’s previous medication history is required to ensure that antibiotics in the chosen regimen (especially clarithromycin and levofloxacin) have not been used repeatedly, thereby preventing further induction and selection of drug-resistant strains.^8,66

Intensive acid inhibition

Potent and long-lasting acid-suppressive agents (such as P-CABs or high-dose PPIs) should be administered for an adequate treatment duration (14 days is generally recommended) to achieve an optimal intragastric pH environment and maximize the bactericidal efficacy of antibiotics.^6,12

Improvement of patient adherence

Simplify the dosing regimen and adequately communicate the importance of treatment to patients to enhance adherence.³⁵

Evidence-Based Regimens Recommended According to Resistance Profiles

Clinically, H pylori treatment is divided into 2 major categories: susceptibility-guided therapy and empirical therapy (Table 2). For empirical salvage therapy, clinicians should presume resistance to clarithromycin, metronidazole, and levofloxacin if the patient has prior exposure to these 3 antibiotics and avoid repeated use. If the patient has no history of using part of the above antibiotics, these agents can be selectively incorporated into salvage regimens based on local epidemiological resistance data, which explains their presence in individual rescue schemes.6, 7, 8

Table 2.

Summary of Evidence-Based Salvage Regimens for Refractory Helicobacter pylori Infection

Regimen	Drug combination (example)	Duration (d)	Main indications	ITT/mITT eradication rate (%)	Main adverse events
Bismuth quadruple therapy (BQT)	PPI + bismuth + tetracycline + metronidazole	14	Clarithromycin resistance, empirical therapy	85.0–94.66,7	Gastrointestinal disturbance, dizziness, headache, nausea/vomiting, black stool
Vonoprazan-based (V-BQT)	Vonoprazan + bismuth + amoxicillin + furazolidone	14	Multidrug resistance, clarithromycin/metronidazole resistance	91.967	Nausea/vomiting, fever, diarrhea
Rifabutin-containing therapy	PPI + amoxicillin + rifabutin	14	Multidrug resistance, penicillin-tolerant	89.068	Fever, rash
High-dose dual therapy (PPI-HDDT)	Esomeprazole 40 mg q8h + amoxicillin 1 g q8h	14	Multidrug resistance, clarithromycin/metronidazole resistance	81.069	Gastrointestinal disturbance, rash (amoxicillin)
VA-HDDT	Vonoprazan + amoxicillin 750 mg q6h	14	Multidrug resistance, clarithromycin/metronidazole resistance	88.070	Gastrointestinal disturbance, rash (amoxicillin)
Vonoprazan-tetracycline (VT)	Vonoprazan + tetracycline	14	Penicillin allergy, salvage therapy	90.671	Gastrointestinal disturbance, dizziness, nausea/vomiting
Levofloxacin-based quadruple	PPI + bismuth + tetracycline/amoxicillin + levofloxacin	10–14	Clarithromycin/metronidazole resistance, levofloxacin-susceptible	84.8–98.072,73	Tendinitis, central nervous system reactions
Furazolidone-based quadruple	PPI + bismuth + amoxicillin + furazolidone	14	Multidrug resistance (common in China)	94.574	Hemolytic anemia (G6PD deficiency), gastrointestinal disturbance, headache

mITT, modified intention-to-treat.

Definition: Refractory H pylori infection is defined as the persistence of H pylori despite at least 2 courses of standard eradication therapies.

Standardization of amoxicillin dosing in high-dose dual therapy: Irrespective of the coadministration of a proton pump inhibitor (PPI) or vonoprazan, the standard amoxicillin regimen is uniformly established at 750 mg every 6 hours or 1.0 g every 8 hours.

The following regimens are summarized mainly based on recently published high-quality clinical studies and systematic reviews.

For clarithromycin resistance

• •Bismuth quadruple therapy (BQT) is recommended by multiple guidelines as the first-line empirical or rescue regimen in regions with high clarithromycin resistance. The standard BQT consists of a PPI plus bismuth, tetracycline (or amoxicillin), and metronidazole, administered for 14 days.^7,8 A Chinese multicenter randomized controlled trial (RCT) demonstrated that BQT-containing furazolidone achieved an eradication rate exceeding 90% in regions with a high prevalence of clarithromycin resistance.⁷⁵ For clarithromycin-susceptible strains, clarithromycin-based triple therapy (PPI + amoxicillin + clarithromycin) remains a first-line regimen in some regions. This strategy is only recommended when the local eradication rate is confirmed to be ≥90%, with a standard treatment course of 14 days.⁶
• •Levofloxacin-containing regimens: For strains still susceptible to levofloxacin, triple therapy comprising PPI + amoxicillin + levofloxacin may be used,⁷ or the preferable quadruple therapy of PPI + bismuth + tetracycline + levofloxacin, both for 14 days.^76,77 However, efficacy declines markedly when the prevalence of levofloxacin resistance exceeds a certain threshold. A meta-analysis reported an eradication rate of approximately 81.1% with levofloxacin-containing triple therapy in susceptible strains, which decreased to around 36.3% in resistant strains.⁷⁸

For metronidazole resistance

• •High-dose metronidazole: If susceptibility testing indicates that the strain remains susceptible to metronidazole, increasing the daily dosage of metronidazole to 1.5 to 2.0 g, administered in 3 to 4 divided doses, may improve the therapeutic efficacy.^12,79
• •Substitution with alternative agents: A more common strategy is to directly replace metronidazole with furazolidone or tetracycline. Regimens containing furazolidone are widely used in China and have achieved favorable outcomes.⁸

Multidrug-resistant strains

• •Rifabutin-containing regimens: Rifabutin, a rifamycin antibiotic, retains excellent activity against MDR H pylori and is commonly used as third-line or rescue therapy. The regimen consists of PPI + amoxicillin + rifabutin for 10 to 14 days.^7,80,81 An RCT demonstrated that rifabutin triple therapy as rescue treatment achieved an intention-to-treat (ITT) eradication rate of 89.0%, with comparable efficacy to BQT but fewer adverse events and better adherence.⁶⁸
• •High-dose dual therapy (HDDT): This regimen comprises a potent PPI (eg, esomeprazole 40 mg q8h) and high-dose amoxicillin (eg, 1.0 g q8h) for 14 days. It overcomes clarithromycin and metronidazole resistance via profound acid inhibition and pH-dependent bactericidal activity.^69,82 An RCT conducted in China, enrolling patients with failed initial therapy for rescue treatment, showed that 14-day HDDT achieved an eradication rate of 81.0% (modified ITT analysis), comparable to standard BQT, but with a significantly lower incidence of adverse events (11.1% vs 26.8%).⁶⁹ High-dose dual therapy (PPI/PCAB plus high-dose amoxicillin) has demonstrated favorable efficacy in several Asian studies, yet high-quality evidence from RCTs is lacking in North American populations. As stated in the guidelines issued by the American College of Gastroenterology, this regimen cannot currently be recommended for empirical treatment.⁷
• •Furazolidone-containing quadruple therapy: For strains resistant to clarithromycin, levofloxacin, and metronidazole, furazolidone-containing BQT represents an important option in regions including China at present.^8,74,83

The Revolutionary Role of Potassium-Competitive Acid Blockers

Vonoprazan, the first approved P-CAB, has brought revolutionary changes to H pylori eradication therapy. Its mechanism of action differs from that of PPIs: it reversibly and competitively inhibits the potassium-binding site of the gastric parietal cell H⁺/K⁺-ATPase, without requiring activation in an acidic environment. Consequently, it acts more rapidly, provides stronger and more sustained acid suppression, and is unaffected by CYP2C19 genetic polymorphisms.^84,85

Multiple RCTs and meta-analyses have confirmed that vonoprazan-containing regimens are superior or noninferior to PPI-containing regimens in terms of H pylori eradication rates, with a more pronounced advantage in populations with clarithromycin resistance.86, 87, 88 An RCT of BQT rescue therapy conducted in China showed that the BQT group using vonoprazan instead of a PPI achieved a significantly higher ITT eradication rate (91.9%) than the PPI group (83.8%).⁶⁷

Vonoprazan can also be incorporated into HDDT. A meta-analysis demonstrated that vonoprazan-based HDDT achieved a higher ITT eradication rate than PPI-based HDDT (88.0% vs 82.7%), with comparable safety and adherence.⁷⁰ For penicillin-allergic patients, amoxicillin in HDDT can be replaced with tetracycline. A recent Chinese study showed that 14-day vonoprazan–tetracycline (VT) dual therapy as rescue treatment yielded an eradication rate similar to that of BQT (modified ITT: 90.6% for VT vs 89.3% for BQT). As first-line therapy in penicillin-allergic individuals, VT also achieved comparable eradication rates to BQT with significantly fewer adverse events.⁷¹

P-CABs (eg, vonoprazan 20 mg twice daily) exert faster, stronger, and longer-lasting acid suppression than the most potent widely used PPIs (esomeprazole 40 mg twice daily, rabeprazole 40 mg twice daily), and the 2 classes of agents are not interchangeable clinically. High-dose PPIs can only be used as an alternative when P-CABs are unavailable due to cost or regional accessibility. For H pylori strains fully susceptible to all antibiotics, PPIs and P-CABs achieve equivalent eradication rates. P-CABs become the preferred option when there is no significant cost difference between the 2 agents or when clinicians choose P-CAB-amoxicillin dual therapy for resistant strains.

Clinical application: Vonoprazan-based BQT, triple therapy, and even dual therapy have been approved in several countries, including Japan and China, and have rapidly become first- and second-line treatments of choice.^89,90 Its high eradication efficacy and favorable safety profile provide a powerful tool for addressing refractory H pylori infection.

Adjuvant Therapy

Probiotics (eg, Saccharomyces boulardii and Lactobacillus reuteri) have been shown to improve eradication rates and patient tolerance to some extent by modulating gut microbiota, enhancing immunity, and reducing antibiotic-associated diarrhea.^6,76,91

Antioxidants (eg, vitamin C, N-acetylcysteine) have also been demonstrated to improve gastric inflammation and microenvironment, which may potentiate the efficacy of antibiotics.^92,93

Clinical Decision Pathways and Future Perspectives

In the face of the complex challenge of refractory H pylori infection, the establishment of a clear and practical clinical decision pathway is critical. Meanwhile, the active adoption of new technologies and concepts is key to improving eradication rates and containing antimicrobial resistance in the future.

Practical Clinical Decision-Making Algorithm

A scientific clinical decision pathway should integrate patient history, accessible testing resources, and local epidemiological data (Figure 3). A proposed 4-step decision-making workflow is as follows:

Figure 3.

Step-wise clinical decision-making algorithm for managing refractory Helicobacter pylori infection. Four-step clinical workflow including patient assessment, diagnostic evaluation, regimen selection, and post-treatment follow-up, together with future research perspectives.

Step 1: Comprehensive assessment and history taking

Thoroughly inquire about and document all previous H pylori treatment regimens, including specific drugs, dosages, administration schedules, treatment duration, and outcomes. Evaluate the patient’s general health status, medication adherence, drug allergy history, and concomitant medications.6, 7, 8, 9

Step 2: Evaluation of diagnostic feasibility

Assess the feasibility and necessity of susceptibility testing (either by culture or molecular methods) based on the patient’s clinical conditions (eg, willingness to undergo endoscopy, economic status, and local medical resources) and the clinician’s experience.^6,7 In high-resistance regions, assume resistance to clarithromycin, metronidazole, and levofloxacin after first-line failure.⁶

Step 3: Selection of individualized treatment regimens

• •If susceptibility results are available: select at least 2 antibiotics to which the strain responsible for previous treatment failure remains susceptible, and combine them into an effective regimen (eg, BQT, HDDT, or a rifabutin-containing regimen).⁷
• •If susceptibility results are unavailable or inconclusive: use empirical therapy based on local antibiotic resistance rates. For instance, in regions with a high prevalence of MDR such as China, quadruple regimens containing furazolidone or rifabutin may be prioritized. Concurrently, intensive acid suppression should be implemented using a P-CAB (eg, vonoprazan) or high-dose PPI, with the treatment course extended to 14 days.7, 8, 9

Step 4: Enhanced patient education and follow-up

Before treatment initiation, communicate thoroughly with patients to emphasize the importance of strict adherence to dosage and timing, and inform them of potential adverse events and corresponding management. At 4 to 6 weeks after treatment completion, a reliable test such as the ¹³C- or ¹⁴C-urea breath test should be used to confirm eradication. In case of repeated treatment failure, referral to a specialized center with adequate capacity or enrollment in a clinical trial is recommended.6, 7, 8

Future Research Directions and Potential Opportunities

To ultimately achieve the goal of “test-and-treat eradication in one attempt” and effectively control H pylori drug resistance worldwide, future research and development should focus on the following directions:

Development of novel antimicrobial agents and nonantibiotic therapies

• •Novel antibiotics: Development of new antimicrobials effective against drug-resistant strains, such as sitafloxacin (a broad-spectrum quinolone active against gyrA mutant strains).^94,95
• •Anti-virulence therapies: Development of neutralizing antibodies or small-molecule drugs that inhibit H pylori adhesion (eg, SabA inhibitors), colonization, or release of VacA. These strategies aim to disarm rather than kill the bacterium, thereby reducing the drug-resistant selection pressure imposed by conventional bactericidal therapy. To date, most evidence remains at the in vitro and animal model stages. SabA/VacA have been repeatedly validated as feasible targets, yet mature humanized neutralizing antibodies or marketed anti-virulence agents for clinical eradication are still lacking.^96,97
• •Phage therapy and antimicrobial peptides: As alternatives to antibiotics, they show great potential against MDR infections but remain in the early developmental stage.^96,98
• •Accelerated development of effective vaccines: Despite decades of effort, an effective prophylactic and/or therapeutic H pylori vaccine is still unavailable. Subunit vaccines, live vector vaccines, and DNA vaccines based on multiple protective antigens (eg, urease, cytotoxin-associated gene A, and VacA) are under active development and clinical trials. Success may depend on inducing robust mucosal immune responses.^99,100

Deep integration of digital health and artificial intelligence

• •Artificial intelligence (AI)-assisted decision-making systems: Development of AI algorithms that integrate individual patient data (eg, genotype, previous treatment history) and real-time updated local resistance databases to provide clinicians with optimal individualized prescription recommendations.¹⁰¹
• •mHealth Apps: Development of smartphone applications offering medication reminders, adverse effect tracking, symptom documentation, and educational materials to patients, thereby significantly improving treatment adherence and management efficiency.¹⁰²

Strengthening global antimicrobial resistance stewardship

• •Establishment of national surveillance networks: Global establishment of standardized H pylori resistance surveillance networks, particularly in low- and middle-income countries, with regular publication and sharing of resistance data to inform empirical therapy.^6,18,103
• •Optimization of antibiotic use strategies: Promotion of antibiotics-sparing agents such as bismuth that carry low resistance-inducing potential, together with strict restriction of unnecessary antibiotic use, to slow the emergence and spread of new resistance.^6,104

Conclusion

Refractory H pylori infection has become a severe global public health challenge, driven by the continuous spread of antibiotic resistance and the failure of traditional therapeutic strategies. Addressing this challenge requires a paradigm shift from a one-size-fits-all empirical approach to a novel healthcare model based on precise diagnosis and centered on individualized therapy. This paradigm emphasizes the use of advanced molecular testing to comprehensively characterize the bacterial resistance profile and host genetic background, thereby enabling the design of highly effective and safe tailored regimens.

In the era of precision medicine, P-CABs represented by vonoprazan provide a powerful new tool for potent acid inhibition, greatly enhancing the eradication efficacy of regimens including BQT, particularly against MDR strains. Meanwhile, innovative strategies such as high-dose dual therapy have opened new avenues for overcoming limitations in drug selection. Nevertheless, technological advances represent only part of the solution. Establishing rational clinical decision pathways, strengthening holistic patient management, and enhancing antimicrobial stewardship through global collaboration are collectively critical to ultimately overcoming refractory H pylori infection.

Looking ahead, the development of novel antimicrobials, effective vaccines, and AI-assisted diagnostic and therapeutic systems will provide additional weapons. Ultimately, however, the profound transformation from empirical to precision medicine, together with sustained promotion of rational antibiotic use worldwide, constitutes the fundamental approach to curbing drug resistance and safeguarding human health.