Differences and trends in worldwide clinical guidelines for Helicobacter pylori infection

Introduction

Background

In 1994, the International Agency for Research on Cancer of the World Health Organization categorized Helicobacter pylori as a Group I carcinogen for gastric cancer (1,2). Gastric cancer associated with long-term H. pylori infection arises from multifactorial interactions, including atrophy, intestinal metaplasia, H. pylori virulence factors (cagA, vacA, and oipA), genetic factors, family history, and environmental factors (salt, smoking, and meat) (3-5). Clinical trials and meta-analysis have shown that persistent H. pylori infection and its eradication are associated with an increase or decrease in gastric cancer risk, not only in patients with atrophic gastritis, but also in patients who have undergone endoscopic or surgical treatment for gastric cancer (3,6-9). A meta-analysis of randomized control trial (RCT) revealed that eradication significantly reduced gastric cancer risk compared with infected controls, with a relative risk (RR) of 0.52 [95% confidence interval (CI): 0.38–0.71, 3 RCTs] in patients after gastric cancer resection (metachronous gastric cancer) and 0.64 (0.48–0.84, 8 RCTs) in patients with atrophic gastritis (naive for gastric cancer) (10). Therefore, H. pylori eradication is the first-line strategy for gastric cancer prevention (11-37).

H. pylori infection can cause various abdominal symptoms, such as pain, discomfort, reflux-related symptoms, diarrhea, and constipation. Due to the diversity of these symptoms, it is crucial to differentiate H. pylori infection from functional disorders, chronic indigestion, gastrointestinal cancer, and inflammatory bowel disease. Therefore, even when considering other abdominal diseases, it is important to properly diagnose the infection while also considering the possibility of H. pylori infection. Furthermore, abdominal symptoms may persist due to unsuccessful eradication therapy, which can affect the evaluation of comorbid conditions. A comprehensive evaluation of chronic gastrointestinal disease must consider infectious mimickers and ensure the highest likelihood of success in eradication strategies by optimal clinical guidelines and consensus reports.

Although many regions have developed clinical guidelines and consensus reports for H. pylori management, recommended treatment regimens should be tailored to individual and local characteristics (such as drug susceptibility, available medications, and insurance coverage), and are regularly updated over time (Figure 1) (11-37). Recommended regimens vary significantly across countries and regions, depending on the publication date and the approach taken to develop the recommendations. These discrepancies can create confusion in clinical practice. Therefore, comparing and evaluating previously published clinical guidelines and consensus reports is important, highlighting their discrepancies.

Figure 1 Clinical guideline and consensus reports in the world.

Rationale and knowledge gap

Several associations, such as the European Helicobacter and Microbiota Study Group, the American College of Gastroenterology (ACG), the Japanese Society for Helicobacter Research, and the Korean College of Helicobacter Upper Gastrointestinal Research, have developed clinical guidelines and consensus reports for H. pylori infection (Figure 1) (11-37). However, available medications {such as potassium-competitive acid blocker (P-CAB), bismuth preparations, tetracycline (TC), and quinolones [sitafloxacin (STFX)]} differ across countries and regions, as do the infection rates of antibiotic-resistant strains [such as clarithromycin (CAM), metronidazole (MNZ), and levofloxacin (LVFX)], and recommended doses and treatment durations. Consequently, recommended regimens vary widely across guidelines. Therefore, clarifying environmental differences across regions and indicating the differences in guidelines and consensus reports for each region is essential for resolving confusion in daily clinical practice.

Objective

This review aimed to clarify the differences between H. pylori and environmental factors across regions by elucidating the variations in regional clinical guidelines and consensus reports.

Eradication therapy in clinical guidelines and consensus reports

Factors influencing successful eradication

As shown in Table 1, several factors influence the success or failure of H. pylori eradication therapy. Major factors include antibiotic susceptibility (such as CAM, amoxicillin (AMPC), MNZ, and LVFX) (39-41,56-58); insufficient acid inhibition during therapy, influenced by drug-metabolizing enzyme gene genotype (such as cytochrome P450 2C19 (CYP2C19) and CYP3A4/5), drug transporter gene genotype [such as multidrug resistance protein-1 (ABCB1)], proinflammatory cytokine gene genotype [including interleukin (IL)-1B and IL-1RN], inadequate drug dosing [such as oid for proton pump inhibitor (PPI)], inappropriate treatment schedule, and type of acid-inhibitory drug (43,47,58); and poor medication adherence (54,55). Minor factors include environmental influences (such as smoking) (52,53), drug allergy (49-51), and presence of H. pylori strains of lower virulence (such as cagA-negative strains, vacA s2 genotype, and dupA-negative strains) (47,48) (Table 1). To achieve high eradication rates, treatment regimens should be optimized by considering the factors listed in Table 1. Improving adherence through counseling, selecting antimicrobial agents effective against H. pylori, and optimizing drug selection and dosing to maintain adequate 24-h acid suppression are considered essential for achieving high eradication rates.

Eradication therapy and acid inhibition

Potent acid inhibition throughout the 24 h of eradication therapy has been recognized as an important factor for successful eradication. Notably, among patients receiving PPI-AMPC-CAM therapy, those with successful eradication had a significantly higher median intragastric pH (6.4; range, 5.0–7.6) and a shorter median pH <4 holding time ratio (HTR) (0.5%; range, 0.0–31.6%) compared with patients in whom eradication failed (pH 5.2; range, 2.2–6.2; pH <4 HTR; 26.7%, range, 6.0–72.2%) (43). Among patients receiving bismuth-based quadruple therapy (BQT), significant differences in pH (median; 6.1, 95% CI: 4.4–7.0 vs. 5.7, 95% CI: 4.9–6.0, P=0.038) and in median pH <4 HTR [96% (95% CI: 92.0–96.0%) vs. 87.5% (67.0–100.0%), P=0.019] are observed between successful and failed eradication (59). Therefore, during eradication therapy, pH >4 should be maintained for 24 h, ideally >6.0. pH control using depends on the type of acid-inhibitory drugs (PPI and P-CAB), specific PPI used (such as esomeprazole, rabeprazole, lansoprazole, and pantoprazole), dosage (amount per administration and daily frequency), combination therapy [concomitant dosing with histamine 2 receptor antagonist (H2RA)], and genetic polymorphisms affecting drug-metabolizing enzyme (CYP2C19 and CYP3A4/5) and drug transporter (ABCB1) genes (Table 1) (60-67).

Most guidelines and consensus reports recommend twice-daily administration of standard- or double-dose PPIs during eradication therapy (Tables 2-7) (11-17,19-37,71).

Grade system is classified four categories: High quality evidence stems from well conducted studies with consistent results, often RCTs or meta-analyses, indicating high confidence in effect estimates, Moderate quality evidence suggests further research may affect the confidence or estimates of the effect, Low quality evidence implies a high likelihood that future studies may alter conclusions, very low quality evidence indicates substantial uncertainty, often relying on expert opinion or flawed studies.

However, PPI bids often fail to achieve pH values that meet the above criteria in all patients, especially in CYP2C19 ultra-rapid metabolizers with *17 and rapid metabolizers (CYP2C19 *1/*1) (64). In rapid metabolizers, the median 24-h pH after rabeprazole 20 mg bid was 5.0 (4.0–6.6), and the median pH <4 HTR was 30.5% (4.1–56.0%) (64). When PPIs are administered during eradication, increasing dosing frequency rather than single-dose escalation is more effective. Tailored therapy adjusting the dose according to CYP2C19 genotypes and additional treatment with PPI and H2RA are useful (62,76). In contrast, vonoprazan (VPZ) 20 mg bid inhibits acid secretion across 24 h (pH ≥4 HTR: nearly 100%), regardless of CYP2C19 genotype (67), and plays a rapid onset of action and an antisecretory profile which is not dependent on activation of parietal cells, selection of P-CAB including VPZ in eradication will be considered to be useful.

VPZ-containing first-line regimens generally showed significantly higher eradication rates than PPI-containing regimens (77,78). Several recent guidelines published within 5 years mention the position of P-CABs as acid-inhibitory drugs during eradication and efficacy (14,16,23,25). However, because evidence of the benefits of P-CAB had not yet been accumulated at the time of publication, some guideline consensus reports were unable to include a mention of it and recommendations. The Japanese Society for Helicobacter Research, in the 2024 updated version, states that for first-line therapy, VPZ is strongly recommended over PPI, regardless of CAM susceptibility (Recommendation: Strong, Evidence level: A). The ACG guideline [2025] (14) notes that dual therapy with a P-CAB and AMPC may be considered a first-line option, and in treatment-naive patients with unknown CAM susceptibility, P-CAB-containing triple therapy is suggested over PPI-containing therapy. The US and European RCTs showed that VPZ-containing triple therapy is non-inferior to lansoprazole-containing triple therapy in patients with CAM-sensitive strains as the primary analysis and that VPZ-containing therapy is superior to lansoprazole-containing therapy among patients with CAM-resistant strains and among the entire study population as superiority analyses (79). Although VPZ-containing regimens have been largely limited to East Asia (80,81), differences in effectiveness compared with Western countries have also been demonstrated (79,82). Thus, although more data from Western cohorts are needed, recent a network meta-analysis including 68 RCTs with 22,975 patients shows that VPZ-containing therapy achieved cure rates of >90% and this regimen has the best result compared with other regimens (83) and pharmacological and bacterial evidence show that potent acid inhibition has efficacy for H. pylori eradication (43,59). Meta-analysis shows that a significant difference between VPZ triple therapy and PPI triple therapy (RR: 1.17, 95% CI: 1.11–1.22, P=0.0001) in 4 RCT at the first-line treatment and (RR: 1.13, 95% CI: 1.09–1.17, P=0.0001) in 5 observational study (78). Therefore, we believe that for future eradication therapy, P-CABs are expected to replace PPIs as the first-line acid secretion suppressants in most of clinical guideline and consensus reports.

Currently, evidence supporting VPZ as the leading P-CABs is accumulating, but the efficacy of other P-CABs, such as tegoprazan and keverprazan, also needs to be examined in the future (84-87).

First-line H. pylori eradication therapy

Clinical guideline and consensus reports

When the Committee for Clinical Guidelines and Consensus Reports establishes the recommended regimens for first-line therapy, several points mentioned in Table 1 should be considered to have a high eradication rate, low incidence of adverse events, and high cost-effectiveness (11-37). Whether tailored treatment based on susceptibility is recommended, whether the region/country and population have higher rates of CAM-resistant (>15% or lower) and MNZ-resistant strains, whether bismuth preparations and tetracycline can be used in the region or country, and whether P-CAB can be used in the region/country make significantly different recommended regimens. The threshold for the optimal regimen for patients infected with strains sensitive to antimicrobial agents should be an eradication rate >95% per protocol (PP) analysis and >90% success in intention-to-treat (ITT) analysis (33,88).

This review focused on the latest clinical guidelines or consensus reports published in the target region or country for adults. A PubMed search was conducted using the keywords “H. pylori”, “Helicobacter”, “eradication”, “treatment”, “guideline”, and “consensus report”. Because each guideline and consensus report employ different published year and different methods for determining recommendation grades and levels of evidence, careful attention is required to understand their content (Table 2). Updated joint ESPGHAN/NASPGHAN guidelines have also been published for children; however, since management strategies, drug types, and dosages differ between children and adults, this review does not address them for children (89).

A susceptibility-guided strategy and tailored treatment

Culture testing for H. pylori infection is generally excellent regarding specificity (diagnostic accuracy: sensitivity of 68–98% and specificity of 100%) (90) and allows for strain preservation, typing of strain (such as virulence and genetic susceptibility to antimicrobial agents), and antimicrobial cultural susceptibility testing. As mentioned above, infection with antimicrobial agent-resistant H. pylori is one of the major factors determining eradication (Table 1). Recently, the number of resistant strains has increased with the increasing use of antimicrobial agents, including CAM, fluoroquinolones, and MNZ (91), necessitating the careful consideration of countermeasures to achieve successful eradication. Several RCTs have confirmed lower eradication rates in resistant strains to antimicrobial agents compared with sensitive strains (38,92-94). A meta-analysis demonstrated that susceptibility-guided therapy significantly reduced treatment failure compared with standard triple therapy [ITT analysis: relative risk (RR), 0.84; 95% CI: 0.77–0.90; eradication rates: 85.4% vs. 71.5%] (92). Based on this evidence, several clinical guideline and consensus reports (11,16,22-26,33,71) recommend a susceptibility-guided first-line therapy (Tables 3,4). Currently, tailored systems that mainly consider CAM susceptibility have been established; however, it is necessary to develop systems that incorporate susceptibility to other antimicrobial agents in the future.

Macrolides (such as CAM), fluoroquinolones (LVFX and STFX), and nitroimidazole (MNZ) readily induce secondary and cross-drug resistance and are thus likely to induce drug resistance in patients with a previous history of drug use, ultimately increasing the risk of eradication failure (25). Therefore, the Chinese guideline recommends antimicrobial agent history-guided tailored therapy as a first-line approach (25). It is important to carefully confirm the patient’s past medical history, especially infectious disease and treatment history prior to eradication therapy, and to inquire about their medical history.

The Bangkok Consensus Report states that if the local pattern of resistance is unknown because first-line regimens vary regionally depending on the pattern of antimicrobial resistance in each country, the rule is to use what works best locally (33). The Maastricht VI/Florence Consensus Report (16) states that, if molecular and cultural susceptibility testing is unavailable, treatment should be implemented according to local resistance rates derived from prior studies. These guidelines recommend BQT in areas reported as high (>15%) in previous research or with unknown CAM resistance (16). An RCT performed in the US and Europe reported a CAM resistance rate at 22.2% (91) and a meta-analysis of US isolates from 2011–2021 showed a pooled rate of 31.5% (95), indicating that, in Western countries, the rate of CAM-resistant bacteria is >15%, and BQT may be recommended. BQT performs well and is tolerated, achieving consistent eradication rates of over 90% by overcoming resistance to CAM and MNZ, despite high levels of resistance in the US and Europe (96,97). Therefore, in regions with high CAM-resistant strains, BQT may be useful when its use is feasible. In areas with low CAM resistance (<15%), the Bangkok consensus report recommended the selection of CAM-containing triple therapy for 14 days (33). In patients infected with CAM-sensitive strains, eradication rates for CAM-containing triple therapy were 97.5%, and no significant difference was observed between VPZ 20 mg bid and lansoprazole 30 mg bid as acid inhibitors (97.6% and 97.3%, respectively) (98). In addition, a Japanese RCT showed that in CAM-sensitive strains, the eradication rates for triple therapy with VPZ-CAM-AMPC and PPI-CAM-AMPC were 87.3% (95% CI: 75.5–94.7%) and 88.9% (95% CI: 77.4–95.8%), respectively (99). Therefore, for patients confirmed to be infected with CAM-sensitive strains or those living in areas where the CAM resistance rate is low (<15%), CAM-containing triple therapy is considered acceptable.

Many clinical guidelines and consensus reports provide “strong recommendations” for this susceptibility-guided strategy; however, the level of evidence varies from low to high. This difference may arise depending on the timing of publication and the targeted antimicrobial agent (CAM alone or other antimicrobial agents) (Table 3). Furthermore, eradication therapy based on susceptibility testing includes regimens recommended for first-line eradication, second-line eradication, and third-line eradication (Tables 3-6). While cost-effectiveness warrants discussion, considering H. pylori as an infectious disease, treatment based on susceptibility testing is considered appropriate to select the right antibiotic and prevent the emergence of new resistant strains.

BQT and non-BQT therapies as the first-line eradication therapy without individual susceptibility testing

As the first-line treatment, BQT is strongly recommended because of its high evidence level (Tables 3,4) (11,14-21,25-27,71). BQT typically comprises a bismuth salt (bismuth subcitrate or subsalicylate), a nitroimidazole (MNZ or tinidazole), tetracycline, or a PPI (or P-CAB). RCTs comparing BQT with PPI-CAM triple therapy have generally shown the superiority or non-inferiority of BQT (100). Advantages of BQT over PPI-CAM triple therapy include its effectiveness against CAM-resistant strains and the lack of susceptibility testing before treatment (14). The disadvantages include the number of pills, a relatively high rate of adverse events with abdominal symptoms, and tetracycline-related contraindications in specific patients (photosensitive patients and women of childbearing potential). Nevertheless, the efficacy of BQT as first-line therapy is sufficient, and in a meta-analysis of seven RCTs and three cohort studies, the eradication rates were 89.2% (1,103/1,236) for VPZ-based BQT and 84.0% (1,021/1,215) for PPI-based BQT (101). This study demonstrated that VPZ-based BQT yields a higher eradication rate and highlights the importance of potent acid inhibition during BQT regimens (101). However, evidence on the importance of acid inhibition when selecting BQT and the usefulness of P-CABs is limited, highlighting the need for further data. To maximize BQT regimen adherence, patients should be educated on the importance of treating H. pylori to prevent gastric cancer and the adverse events that could occur with treatment.

When bismuth preparations are unavailable or contraindicated, non-BQT is recommended, such as sequential, concomitant, and hybrid therapies, as the first-line treatment (Tables 3,4). Although non-BQT regimens risk including ineffective antimicrobial agents, which would be unnecessary if the susceptibility profile is known, concomitant therapy should be the preferred choice given its proven significant effectiveness and less complexity compared with sequential and hybrid therapies (15,16). Concomitant therapy for 14 days is the only therapy other than BQT that consistently achieves an eradication rate of >90% in Hp-EuReg (97). The eradication rates for 10- and 14-day concomitant therapy are 85% and 86% for ITT analysis and 91% and 94% for PP analysis, which is higher than those of standard PPI-AMPC-CAM triple therapy (RR; 1.17, 95% CI: 1.05–1.30 in ITT analysis; RR; 1.15, 95% CI: 1.06–1.25 in PP analysis) (24). A meta-analysis of 24 studies conducted before March 2021 also showed concomitant therapy to be superior to sequential therapy in eradicating H. pylori from PP (RR, 0.96; P<0.001) and modified ITT analysis (RR, 0.94; P=0.005) (102). Given the superiority of concomitant therapy in eradication success over sequential therapy, identical exposure to several antibiotics, similar side-effect profiles, and reduced complexity compared to sequential or hybrid therapies, concomitant therapy should be the preferred non-BQT.

As shown in the table, at the first-line therapy, BQT generally achieves higher eradication rates than non-BQT regimens and is often recommended in guidelines. However, bismuth cannot be used in some regions (i.e., Japan), requiring alternative approaches in such areas. To universalize the importance of BQT over the world, it is considered crucial to clarify the significance of acid inhibition during BQT (e.g., P-CAB use or not) and to standardize and unify the frequency and dosage of antimicrobial administration.

In consideration with many clinical guideline and consensus reports, we summarized first-line treatment selection algorithms by resistance patterns and susceptibility testing in Figure 2.

Figure 2 First-line treatment selection algorithms by resistance patterns and susceptibility testing. *, when bismuth is not available in area, the priority of this regimen is increased. AMPC, amoxicillin; BQT, bismuth quadruple therapy; CAM, clarithromycin; LVFX, levofloxacin; MNZ, metronidazole; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; qid, four-times daily dosing; R, resistant; RFB, rifabutin; tid, three times daily.

Triple therapies as the first-line eradication therapy without individual susceptibility testing

Particularly in regions with low CAM resistance, PPI-CAM-AMPC therapy remains the most common first-line treatment (16,34-36). In fact, the eradication rate for triple PPI-CAM-AMPC therapy in patients infected with a CAM-sensitive strain was 97.5% and acceptable (98). In the Brazilian consensus report (35), where the rate of primary CAM resistance ranges from 2.5–16.9%, triple PPI-CAM-AMPC therapy for 14 days is recommended as the first-line treatment (103,104). The Korean guidelines also recommend standard 14-day triple PPI-CAM-AMPC therapy (CAM resistance rate in Korea: 17.8–31.0%) (24,105). However, the overall pooled eradication rates in a meta-analysis using Korean RCTs were 71.6% (95% CI: 69.9–73.3%) in ITT analysis and 79.6% (76.6–82.2%) in PP analysis, and the eradication rate in 2012–2016 was on the decline compared with 2007–2011 (24). Therefore, when PPI-CAM-AMPC therapy is selected, susceptibility testing is considered essential. Furthermore, regions with high rates of CAM-resistant strain should urgently consider removing PPI-CAM-AMPC therapy from their guidelines.

In the Japanese guidelines, triple therapy is recommended because the selection of quadruple therapy has not been established owing to long-standing clinical practice, and bismuth preparations are not available in Japan (23,106). Of triple therapy, the use of VPZ established by high evidence is fundamental, with VPZ-AMPC-CAM or PPI-AMPC-MNZ being recommended when sensitivity testing is not performed (77,107,108). In Japan, the characteristic susceptibility profile is low MNZ- and high CAM-resistance rates (approximately 5% and >30%), and the PPI-AMPC-MNZ regimen [ITT analysis: 92.5% (95% CI: 89.4–95.0%)] had a higher eradication rate than PPI-AMPC-CAM [70.8% (95% CI: 65.6–75.6%)] in a meta-analysis of Japanese trials (109-111). However, because MNZ is not an acid-sensitive antimicrobial agent, and at present, evidence demonstrating the efficacy of VPZ-AMPC-MNZ therapy compared to PPI-AMPC-MNZ has not been established. Clinical guideline recommending the use of MNZ in first-line triple therapy is rare, but since the choice of antimicrobial agent should be modified based on regional susceptibility patterns, this recommendation is considered acceptable.

Dual therapies as the first-line eradication therapy

As an alternative to switching antimicrobial agents with susceptibility and ignoring concerns about infection by CAM-resistant strains, attention is focused on a dual therapy that optimizes the antimicrobial activity of AMPC by regulating the gastric environment. The ACG guidelines, for treatment-naïve patients with H. pylori infection, dual therapy with P-CAB and AMPC is suggested as a first-line treatment option (14). PCABs inhibit gastric acid secretion by binding to gastric H⁺/K⁺-ATPase, and their antisecretory effect is more rapid, robust, and prolonged than that of standard doses of PPIs (112-114). A twice-daily dose of VPZ 20 mg, the standard dosage for H. pylori eradication therapy, maintained acid inhibition throughout the 24 h. The intragastric pH >4 and >5 holding time ratios were 100% and 99%, respectively (67). AMPC is acid-sensitive, and its antibacterial activity is closely correlated with acid inhibition (115-117). In China, an RCT comparing the efficacy of the VPZ (20 mg, bid)-AMPC (750 mg qid or 1,000 mg bid) dual regimen and the BQT regimen showed that the regimen with the higher dose of AMPC (750 mg qid) was non-inferior to the BQT regimen (118). A meta-analysis of 15 studies involving 4,568 patients reported a pooled eradication rate for VPZ-AMPC dual therapy of85.0% (95% CI: 81.1–88.9%) in ITT analysis and 90.0% (95% CI: 86.5–93.6%) in PP analysis (119). The efficacy of VPZ-AMPC dual therapy was superior to that of PPIs-based triple therapy (82.0% vs. 71.4%, P<0.01) (119). Although the VPZ-AMPC dual regimen has concerns regarding the high number of doses required, the advantages of the VPZ-AMPC dual regimen are simplicity, absence of concerns regarding CAM resistance, and lack of the necessity or role of susceptibility testing before eradication therapy.

As AMPC is both acid-sensitive and a time-dependent antimicrobial agent, it is important to increase the number of daily AMPC doses to maintain blood concentrations above the effective level for an extended period (120). As it has no post-antibiotic effect (34), the antibacterial activity of AMPC depends on the percentage of time above the minimum inhibitory concentration (35). When given twice daily, the eradication rates fall below 60% (120). Therefore, during VPZ-AMPC dual therapy, it is important to maintain acid inhibition for 24 h and increase the number of AMPC administrations by three or more to create an environment where antibacterial effects can be exerted (120).

Duration of treatment

A meta-analysis comparing 7- and 14-day PPI-AMPC-CAM triple regimens showed that although the 14-day regimen significantly increased the rate of adverse events (16.0% vs. 19.6%, P=0.01), it significantly improved the eradication rate (74.9% vs. 83.5%, P<0.001) (121). In the European registry on H. pylori management (Hp-EuReg) using 29,634 first-line eradication treatments, the 7-, 10-, and 14-day PPI + AMPC + CAM regimen achieved 82%, 83%, and 87% in ITT analysis, respectively (96). Based on this evidence, a 14-day regimen appears to be optimal for most regimens (Tables 3,4).

In contrast, in an RCT in Japan comparing 7- and 14-day PPI or VPZ-AMPC-CAM regimens, no significant difference was observed between the two groups (122,123). Therefore, because the 14-day regimen carries a higher risk of adverse events, the 7-day regimen is recommended in Japan (Tables 3,4). This environment and the evidence in Japan are considered unusual.

Second-line eradication therapy

Because CAM, LVFX, and MNZ readily induce secondary and cross-drug resistance at high rates, it is important not to select the same antimicrobial agents during second-line eradication therapy that were used during first-line therapy (Table 5). Therefore, to achieve reliable results, it is important to confirm the presence or absence of resistance to antimicrobial agents planned for use, as was done during the first-line treatment. In fact, clinical guidelines and consensus reports state that empiric second-line therapy should be guided by local resistance patterns assessed by susceptibility testing and eradication rates to receive successful treatment (11,16,18,20,25,28,33,34,36,71). However, susceptibility testing with culture tests requires invasive endoscopy, and molecular tests using stool samples face challenges in confirming the susceptibility to many antimicrobial agents and carry cost-effectiveness concerns. Furthermore, unlike the first-line therapy, evidence supporting susceptibility-guided tailored therapy after H. pylori eradication failure is limited (124,125). In a meta-analysis, when all rescue-therapies are included (13 studies, most as second-line therapy), similar results are observed with both empirical and tailored, both when all studies are included (RR: 1.09; 95% CI: 0.97–1.22) and when only RCTs were included (RR: 1.15; 5% CI: 0.97–1.36) (126). The exact cause is unclear; however, considering that high efficacy is not achieved even with the use of susceptible antimicrobial agents, factors other than susceptibility, such as acid inhibition and adherence to drug intake, may play a significant role in second-line eradication therapy.

Second-line therapy with expected high efficacy requires a different regimen from the first-line therapy. After BQT failure or when bismuth preparations are unavailable, a fluoroquinolone-containing quadruple (or triple) therapy (14,16), the PPI (VPZ)-AMPC dual therapy (16), or rifabutin (RFB)-containing triple therapy (14) may be recommended. In areas with high fluoroquinolone resistance, bismuth combination with other antibiotics or RFB may be an option. PPI-AMPC dual therapy may also be considered. In a meta-analysis of 4 RCTs evaluating this approach in patients with at least one prior failure, eradication rate and adverse events rates were 81.3% [guideline-recommended rescue therapies: 81.5%, RR 1.00 (95% CI: 0.93–1.08)] and 17.9% [19.7%, RR 0.88 (95% CI: 0.62–1.25)] (127). However, the ACG guidelines state that in patients receiving second-line therapy in the US, evidence for high-dose PPI or P-CAB dual therapy is insufficient (14). In addition, this guideline recommends RFB triple therapy for patients with failed BQT (14). When the efficacy of 14-day RFB triple therapy and 14-day BQT was compared in patients who failed at least two times, RFB triple therapy achieved eradication rates of 89.0% (95% CI: 83.6–92.8%) in ITT analysis and 94.0% (95% CI: 89.3–96.7%) in PP analysis, and BQT achieved 89.6% (95% CI: 84.3–93.2%) and 95.3% (95% CI: 90.7–97.7%) (128). The rates of adverse and moderate-to-severe adverse events with RFB triple therapy were 26.4% and 14.3%, respectively, which were significantly lower than those with BQT (54.4% and 28.6%, respectively; both P=0.001) (128). In a systematic review using European studies as a second-line therapy, RFB triple therapy achieved pooled eradication rates of 72.2% (95% CI: 68–77%) in the ITT analysis and 77% (95% CI: 72–80%) in the PP analysis (129). Considering the above, after BQT failure, confirming the presence or absence of fluoroquinolone resistance is advisable to guide selection among fluoroquinolone-based therapy, dual therapy, or RFB triple therapy.

After failure of PPI-AMPC-CAM therapy, recommended second-line options include BQT (14,16,35), fluoroquinolone-containing quadruple (or triple) therapy (16,35), PPI or VPZ-AMPC-MNZ therapy (23), or PPI (VPZ)-AMPC dual therapy (16). As the failure of CAM-containing therapy can cause CAM resistance at a high rate, physicians should avoid CAM-containing therapies. In the Hp-EuReg study, after first-line CAM-containing regimen failure, a sufficient eradication rate of at least 89% was achieved with QBT with or without LVFX (89% and 89%, respectively), but not with LVFX-based triple therapy (81%) (130). Therefore, a fluoroquinolone-containing regimen may be considered for second-line therapy after PPI-AMPC-CAM failure. However, because of rising fluoroquinolone resistance and associated adverse events, they should be avoided in areas with a high resistance rate (131). Therefore, BQT may be a pivotal second-line treatment option, particularly in regions with a high prevalence of fluoroquinolone resistance. A systematic review of European studies evaluating the efficacy of salvage regimens in patients with failed triple therapy revealed that BQT achieved eradication rates of 75.6% (95% CI: 66.1–85.1%) in ITT analysis and 75.7% (95% CI: 65.4–86%) in PP analysis as a second-line therapy (129). In RCTs, using patients with failed eradication was 78.8% in the 10–14-day BQT, which was significantly higher than the 67.8% rate in the 7-day BQT (132).

As mentioned above, Japan has a low MNZ resistance, demonstrating the effectiveness of MNZ in comparison with other countries (133). A meta-analysis of 13 RCTs involving 2,039 patients (PPI-MNZ-AMPC, BQT with or without LVFX, and sequential therapy) reveals that regimens containing MNZ have significantly lower rates of eradication failure than those regimens without MNZ (OR: 0.55; 95% CI: 0.39–0.78) (134) and large Japanese multicenter studies in metropolitan areas have consistently shown eradication rates of over 80% in ITT analysis and over 90% in PP analysis with the PPI or VPZ-AMPC-MNZ regimen (135,136). The Japanese guidelines recommend a PPI or VPZ-AMPC-MNZ regimen as a second-line treatment after failure of PPI or VPZ-AMPC-CAM therapy (16).

Second-line eradication therapy requires using susceptible antimicrobial agents, maintaining potent acid inhibition, and ensuring adherence, similar to first-line eradication therapy. Regimens should differ from those used in first-line eradication treatment, and it is necessary to choose regimens that consider regional characteristics and clinical guidelines.

Third-line eradication therapy

Although third-line regimen recommendations are summarized in Table 6; however, because of the limited evidence levels supported by RCT and meta-analyses, few recommendations are supported by high-level evidence. However, the principles guiding third-line therapy are the same as for first- and second-line therapies. Fundamentally, it is important to use susceptible antimicrobial agents after first- and second-line therapy and maintain an environment where the antimicrobial effect can be achieved. Given the types of antimicrobial agents used during treatment, caution is required because of the narrow range of available drug options.

The ACG guideline (14) and Maastricht VI/Florence Consensus Report (16) recommend 14-day optimized BQT as the preferred option for patients who have not been previously treated with it, and for whom the H. pylori resistance profile is unknown. When bismuth is unavailable, a high-dose PPI (VPZ)-AMPC dual- or RFB-containing regimen can be considered (16).

After failure of first-line treatment with CAM-containing triple- or non-BQTs and second-line therapy with BQT, a fluoroquinolone-containing regimen is recommended (13-16,23,31,34,35). As mentioned above, LVFX is becoming less preferred because its increased use has led to a higher rate of resistant strains. The Japanese guidelines do not recommend selecting LVFX because of its high rate of bacterial resistance. Although not available in many regions, the efficacy of STFX as a third-line eradication therapy has been demonstrated in Japan, and PPI or VPZ-AMPC-STFX is recommended (137-139). STFX previously showed very low resistance rates, achieving high eradication rates not only during third-line therapy but also during first- and second-line eradication (140). However, in a recent Japanese survey, bimodality in the MIC distribution for STFX was seen with peaks at ≤0.03 and 0.25 µg/mL, and MIC 50, 80, and 90 are 0.06, 0.25, and 0.25 µg/mL, respectively (133). The resistance rate of H. pylori Japanese clinical isolates to STFX was 27.6% (259/938). The resistance rate to STX increased with age, although a significant difference was only observed between the 30–49 years age group (18.4%) and the ≥70 years age group (33.7%) (133). Considering these points, the use of STFX for treatment in Japan has limitations, and it is necessary to investigate the presence of resistant strains before using STFX.

In the third-line treatment, caution is required because of the narrow range of available drug options by results of susceptibility testing. It is essential to use drugs that have not been used in at least first-line or second-line eradication therapy, excluding AMPC. The three key strategies are selecting antimicrobial agents with low rates of resistant rate in each region, confirming susceptibility through susceptibility testing, and using P-CABs.

Eradication therapy for patients with allergy

In general, 1% of the population has a true type 1 IgE-mediated allergy to penicillin. Therefore, for patients scheduled for H. pylori eradication therapy who are suspected of having penicillin allergy, referral to an allergist should be suggested to confirm a true allergy (14). Although negative allergy testing enables the use of penicillin, such that these patients are not excluded from the recommended regimen, allergy testing cannot completely screen all patients for allergy (141). Although some clinical guidelines and consensus reports do not mention eradication therapy for patients with penicillin allergy, many guidelines recommend BQT regimens as the first-line treatment for patients with true penicillin allergy (11,14,16,17,20,21,25,26,28-30,33,34). Although the PPI-CAM-MNZ regimen can be used when bismuth is unavailable in areas with low CAM and/or MNZ resistance (16), a previous recommendation for using a PPI-CAM-MNZ regimen as the first-line therapy achieved disappointing results in most Asian countries, where the rates of primary resistance to CAM and MNZ are high (142). If antibiotic susceptibility testing is available, a tailored therapy may be a good alternative. For the second-line treatment in patients with penicillin allergy, BQT may represent an empirical rescue option after failure of the PPI-CAM-MNZ regimen (16,143). In addition, as a second-line therapy, a fluoroquinolone-containing regimen may represent an empirical second-line rescue option.

Although guidelines and consensus reports have established a recommended eradication regimen for patients with penicillin allergy, there are still patients who experience allergic reactions to other selected eradication drugs, even though these reactions are uncommon. Given the frequency of this allergy, establishing evidence for the efficacy of eradication regimens in patients with allergies to other drugs will be difficult. However, to prevent adverse events, it is essential to obtain the history of allergies through patient interviews.

Probiotics during eradication therapy

The guidelines regarding probiotics are summarized in Table 8.

Probiotics may prevent adverse events during eradication therapy for conditions such as diarrhea and may influence eradication rates. Although probiotics may have potential to prevent incidence of adverse events, most guideline and consensus reports recommend against routinely adding probiotics for the purpose of reducing adverse events due to loss of evidence (14-18,20-22,25,26,28,33,35,71). It is undeniable that ACG guideline and Toronto consensus report also state there is insufficient evidence regarding whether eradication rates are improved (14,15). ASEAN guideline mentions that the use of probiotics plus standard therapy may be associated with a modest increase in eradication rate (33).

Conclusions

Multiple factors influence the success of H. pylori eradication therapy, including antibiotic susceptibility, insufficient acid inhibition during eradication therapy, poor medication adherence, the environment, and the presence of an H. pylori strain with low virulence (Table 1). An eradication rate of ≥90% is considered appropriate and optimal. To establish a regimen with a high eradication rate, it is necessary to adjust regimens by considering these factors. Clinical guidelines and consensus reports on H. pylori infection have been published in many countries and regions. The recommended regimens vary widely due to differences in publication timing and local conditions. In practice, clinicians should understand their regional guidelines, considering local characteristics. When selecting available drugs, it is necessary to choose antimicrobial agents with an awareness of susceptibility, and patient education to maintain adherence is considered necessary.

Acknowledgments

We thank Editage for the English language editing of the manuscript.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-159/prf

Funding: This work was supported by the Grant-in-Aid for Scientific Research in Japan (Nos. 21K07949 and 25K11208).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-159/coif). M.S. serves as an unpaid editorial board member of Translational Gastroenterology and Hepatology from August 2025 to June 2027. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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