Treatment of Helicobacter pylori Infection in Korea: An Evidence-Based Analysis of the Upcoming 2025 Guideline

Article information

Korean J Helicobacter Up Gastrointest Res. 2026;26(1):23-36

Publication date (electronic) : 2026 March 5

doi : https://doi.org/10.7704/kjhugr.2025.0085

Chang Seok Bang^,1,2, Seung Joo Kang³, Su Youn Nam^4,5, Sung Eun Kim⁶, Seung Young Kim⁷, Hyunchul Lim⁸, Chung Hyun Tae⁹, Moon Won Lee¹⁰, Seung Han Kim¹¹, Hye-Kyung Jung⁹, Byung-Wook Kim¹²

¹Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea

²Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, Korea

³Department of Internal Medicine, Seoul National University Hospital Gangnam Center, Seoul, Korea

⁴Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea

⁵Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Hospital Chilgok Hospital, Daegu, Korea

⁶Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea

⁷Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea

⁸Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea

⁹Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea

¹⁰Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea

¹¹Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea

¹²Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author Chang Seok Bang, MD, PhD Department of Internal Medicine, Hallym University College of Medicine, 77 Sakju-ro, Chuncheon 24253, Korea E-mail: csbang@hallym.ac.kr

Received 2025 December 1; Revised 2025 December 18; Accepted 2025 December 29.

Abstract

INTRODUCTION

Helicobacter pylori infection remains one of the most prevalent chronic bacterial infections worldwide, affecting approximately 50% of the Korean population [1-3] and contributing to chronic gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma [4]. Successful eradication of H. pylori significantly reduces the risk of these sequelae, making effective therapy a critical component of gastric cancer prevention and peptic ulcer management [5-7]. However, the efficacy of traditional regimens has decreased in recent years, posing a therapeutic challenge for clinicians [8].

Previous Korean guidelines recommended 14-day clarithromycin-containing triple therapy (TT), consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin, as the primary empirical treatment. However, it now achieves an eradication success rate of only about 66.9% by intention-totreat (ITT) analysis, falling below the internationally accepted 80% threshold [9,10]. This decline stems primarily from increasing antibiotic resistance among H. pylori isolates: clarithromycin resistance rates from 17.8% in 2018 to 33.3% in 2021–2023,9,11 levofloxacin resistance has reached 37%–62.2% [12,13], and multidrug-resistant (MDR); resistant to at least two key antibiotics, strains now account for 37.1% of isolates [14]. These trends make traditional treatments ineffective, requiring guideline updates.

In response, the 2025 Korean clinical practice guidelines for H. pylori management will represent a shift in treatment philosophy. The new approach moves away from multiple empirical regimen choices (which traditionally include TT, bismuth quadruple therapy [BQT], sequential therapy [ST], and concomitant therapy [CT]) [15,16] toward a more stratified strategy that emphasizes precision medicine and efficacy. The revised guidelines prioritize antibiotic susceptibility testing (AST) when feasible, adoption of potassium-competitive acid blockers (P-CABs) as potent alternatives to PPIs, appropriate empirical options, introduction of salvage therapy options, and deliberate elimination of regimens with unacceptably low success from the recommended use [15,16]. This review highlights the evidence underpinning these changes and provides an analysis of how the dual strategy of empirical quadruple vs. tailored therapy can be applied in clinical practice to optimize H. pylori eradication in Korea. A summary comparison of the key recommendations of the 2020 and 2025 guidelines is presented in Table 1.

Table 1.

Summary of key changes: 2020 vs. 2025 Korean H. pylori treatment guidelines

DECLINING EFFICACY OF CLARITHROMYCIN-CONTAINING TT

Clarithromycin-containing TT has been the most widely used first-line eradication therapy since the publication of the 1998 Korean H. pylori guidelines [17]. Its advantages include being the most familiar regimen to clinicians, having a simple drug composition, and imposing a relatively low-cost burden. Unfortunately, accumulating evidence shows that the efficacy of this regimen has fallen below acceptable levels in the Korean population [9,18]. The 2020 Korean guidelines have attempted to salvage this regimen by extending the treatment duration from 7 to 14 days, hoping that prolonged antibiotic exposure might compensate for the rising resistance [15,16]. This strategy proved insufficient. In a multicenter registry study from 2021– 2023, the overall first-line eradication rate in routine practice was only about 70.5% in ITT analyses despite most patients receiving 14-day therapy, below acceptable thresholds [9]. When a strain is clarithromycin-resistant, TT success drops dramatically (often <50% success against resistant strains). Given that one-third or more Korean patients harbor clarithromycinresistant H. pylori, it is unsurprising that the overall cure rates with TT are now unacceptably low.

We performed a systematic review using an established search strategy by experts in this field and found nine Korean randomized controlled trials (RCTs) [19-27] relevant to 14 days clarithromycin-containing TT efficacy. Eradication rates were analyzed using three RCTs published after 2018 [25-27], and six studies [19-24] from the previous guidelines (Table 2). Specifically, the eradication rates for the three studies prior to 2009 [19-21] were ITT 79.8% (95% confidence interval [CI], 75.9%–83.2%) and per-protocol (PP) 87.6% (95% CI, 84.1%–90.5%). For the three studies conducted between 2010 and 2019 [22-24], rates were ITT 76.1% (95% CI, 71.8%–79.9%) and PP 84.3% (95% CI, 80.3%– 87.6%). For the three studies after 2018 [25-27], rates dropped to ITT 66.9% (95% CI, 63.1%–70.5%) and PP 76.2% (95% CI, 72.4%–79.7%), showing a significant difference in eradication rates over time (p<0.001).

Table 2.

Evidence table about the eradication rate of 14-day clarithromycin-containing TT in H. pylori infection

Because it fails to meet the criterion that the ITT eradication rate should be at least 80% to be recommended as a primary therapy, it is difficult to consider TT as a first-choice option for empirical first-line treatment without AST [10]. Furthermore, as the use of TT has recently decreased, recent regional data on eradication rates according to antibiotic resistance rates are lacking. International guidelines also do not recommend TT as a first-line treatment in regions such as Korea, where clarithromycin resistance exceeds 15% [28,29]. The implementation of TT mandates AST-guided selection of appropriate regimens [29].

TAILORED THERAPY BASED ON MOLECULAR TESTING: A NEW FIRST-LINE STRATEGY

In response to the limited efficacy of empirical approaches, molecular testing using polymerase chain reaction (PCR) or sequencing has facilitated the adoption of tailored therapy [30]. Tai-lored therapy refers to selecting a treatment regimen based on the patient’s specific H. pylori antibiotic susceptibility profile, rather than using a one-size-fits-all regimen [31]. In practice, this often involves PCR-based testing of gastric biopsy specimens for known resistance mutations, particularly the 23S rRNA mutations conferring clarithromycin resistance [32]. Dual-priming oligonucleotide (DPO)-based multiplex PCR assays have been developed in Korea to rapidly determine clarithromycin susceptibility from biopsy or even stool samples [9,27].

PCR-based testing accurately detects 23S rRNA point mutations (e.g., A2142G and A2143G) associated with clarithromycin resistance, demonstrating a concordance rate of over 95% with phenotypic tests such as the E-test [33-35]. Tailored therapy based on resistance detection has been shown to improve eradication rates. Additionally, this method allows for the partial analysis of levofloxacin resistance by detecting gyrA mutations with a sensitivity of over 90% [36]. Compared to culture tests, PCR offers superior rapidity and high sensitivity. In terms of cost-effectiveness, economic benefits are generally observed when the eradication rate is below 80% or when the clarithromycin resistance rate exceeds 20% [37].

In regions with high clarithromycin resistance, implementing tailored therapy yields results superior to or comparable to those of empirical therapy. However, the universal application of this approach in routine practice requires careful consideration of the regional medical environments and economic factors. The overall eradication success of tailored therapies in previous studies was influenced by the therapeutic potency of the control regimen. We conducted a systematic review of 5 Korean RCTs and 16 prospective or retrospective studies (published up to August 2024). In most studies, clarithromycin-resistant patients received BQT and clarithromycin-susceptible patients received TT. The control group included regimens that were previously recommended as first-line therapies (clarithromycin-based TT, BQT, CT, or metronidazole-based TT). A meta-analysis was performed on four of these RCTs that specifically utilized BQT for clarithromycin-resistant cases and clarithromycin-containing TT for susceptible cases [27,38-40]. The meta-analysis revealed that in the ITT analysis, the eradication rate for tailored therapy was 84.3% (95% CI, 78.5%–90.1%), whereas the rate for empirical therapy was 77.3% (95% CI, 63.0%–91.6%), with a risk ratio (RR) of 1.11 (95% CI, 1.05–1.17). In the PP analysis, the eradication rate for tailored therapy was 91.6% (95% CI, 83.4%–99.7%) compared to 84.8% (95% CI, 71.9%–97.6%) for empirical therapy, with an RR of 1.08 (95% CI, 1.03–1.13). Both the ITT and PP analyses demonstrated that the eradication rate of tailored therapy was significantly higher than that of empirical therapy. The pooled eradication rate across all included 21 studies also showed ITT 80.9% (95% CI, 77.4%–84.4%) and PP 90.0% (95% CI, 88.2%–91.7%) of eradication success in tailored therapy, which is an acceptable level for first-line therapy.

More recent nationwide RCTs conducted in Korea have also confirmed this result and demonstrated that tailored therapy— comprising BQT or clarithromycin-containing TT (based on clarithromycin resistance)—yielded superior therapeutic outcomes compared to a CT control group. These regimens achieved eradication success rates exceeding 80% in the ITT analysis and 90% in the PP analysis [41]. Similarly, another nationwide study reported that such tailored therapy demonstrated superior efficacy compared to a TT control group [27].

As an alternative strategy, a prospective study was conducted in Korea using the Drug Utilization Review system to screen antibiotic medication history and assign treatment (BQT or clarithromycin-containing TT) accordingly [42]. This study demonstrated that strategically designed empirical treatment based on medication history is a feasible alternative to genotypic resistance-guided therapy [43,44].

However, despite these advantages, tailored therapies do not always guarantee complete eradication. Potential reasons for reduced success rates include: 1) mixed infection and heteroresistance: the coexistence of H. pylori strains with different resistance profiles can lead to treatment failure [45-47]. 2) Diagnostic limitations (sensitivity and resistance variants): rare atypical mutations (e.g., A2142C) may be missed. Furthermore, there is a risk of misidentifying resistant strains as susceptible owing to sampling errors caused by variations in bacterial density across different gastric regions. 3) Lack of adherence: poor medication adherence remains a significant cause of treatment failure independent of antibiotic resistance patterns. 4) Resistance to other antibiotics: tailored regimens often focus solely on clarithromycin resistance, potentially overlooking resistance to the other antibiotics included in the regimen.

Overall, in regions with high clarithromycin resistance, tailored strategies have resulted in significant improvements in eradication rates, particularly when clarithromycin-containing TT is used as the control [48]. It is also a cost-effective strategy for H. pylori eradication in Korea, particularly in the context of high clarithromycin resistance rates [48]. Conversely, in studies where reinforced empirical therapies (e.g., BQT) served as the control, or in studies with small sample sizes, the statistical superiority of tailored therapy may not be clearly established.

We recommend performing a DPO-PCR or a similar genotypic test for clarithromycin resistance in all patients before starting therapy, whenever feasible. This approach discourages the previous concept of multiple empirical first-line options [15,16] in favor of precision medicine guided by the molecular detection of genotypic resistance to clarithromycin (23S rRNA A2142G or A2143G). If a clarithromycin-resistant mutation is detected, BQT is recommended as the first-line treatment; if no mutation is found (i.e., a susceptible strain), a clarithromycin-containing TT can be used with careful monitoring.

OPTIMIZING EMPIRICAL FIRST-LINE THERAPY: FROM TT TO QUADRUPLE-AND STEWARDSHIP CONSIDERATIONS

For cases where AST is not performed (or results are awaiting), the guidelines recommend empirical regimens that cover likely resistance. As noted above, clarithromycin resistance now exceeds 30%, indicating that a large proportion of patients harbor clarithromycin-resistant strains. When clarithromycin is ineffective, the efficacy of TT decreases (amoxicillin rarely encounters resistance, but resistance to clarithromycin is sufficient to cause failure). In cases where tailored therapy is not used, the 2025 guidelines recommend empirical regimens that can achieve the highest possible eradication rates in the face of prevalent resistance. Given the shortcomings of TT, this necessitates a shift toward four-drug regimens (quadruple therapies) for empirical treatment in most patients. Two main strategies have been highlighted: CT and BQT, including newer “modified” combinations (modified quadruple therapies [mQTs] [e.g., PACB: PPI+amoxicillin+clarithromycin+bismuth, or PAMB: PPI+amoxicillin+metronidazole+bismuth]) adapted for Korean practice. These regimens have high intrinsic cure rates despite prevalent resistance. Notably, 10-day CT has gained popularity in Korea; its usage as a first-line therapy increased sharply after 2019,49 and the 2025 guidelines list CT as an effective empiric option alongside BQT. The role of ST has been deemphasized. This is attributed to poor medication adherence, difficulties in selecting salvage regimens due to multiple antibiotic exposure upon treatment failure, and lower eradication rates compared to CT and BQT [49]. Similarly, metronidazole-based TT (PAM: PPI+amoxicillin+metronidazole), which was recommended by the 2020 Korean guidelines as an alternative for clarithromycin-resistant strains, is no longer endorsed as a first-line empirical option. This decision reflects the high domestic metronidazole resistance rate (29.5%) [11] and concerns that prior metronidazole exposure may compromise the efficacy of BQT, a standard second-line salvage regimen. Instead, bismuth-augmented regimens (e.g., PAMB), which can overcome metronidazole resistance through intensified dosing, are preferred. Overall, the main message was that the 14-day clarithromycin-containing TT should only be used in low-risk or confirmed susceptible cases, whereas quadruple therapies should be used upfront in most Korean patients to ensure higher success, given the resistance landscape [50].

Continuing clarithromycin use when over one-third of strains are resistant is against antibiotic stewardship and has been a major driver of rising resistance. Paradoxically, previous Korean guidelines (and some practitioners) still recommended clarithromycin-based TT despite high resistance levels, due to inertia and limited alternatives [50]. The 2025 revision breaks from this position: it emphasizes that we are at a “critical juncture where it may be necessary to discontinue empirical clarithromycin-containing TT in Korea.” In other words, unless there is evidence that a patient is susceptible (via AST), a clarithromycin-based regimen should not be chosen empirically.

CT refers to a non-bismuth quadruple regimen consisting of a PPI (or P-CAB), amoxicillin, clarithromycin, and nitroimidazole (typically metronidazole or tinidazole) administered simultaneously for 10–14 days. This regimen essentially adds nitroimidazole to TT, thereby attacking H. pylori with three antibiotics simultaneously. CT has demonstrated high eradication rates (>90% in many studies), even in populations with significant clarithromycin or metronidazole resistance because the likelihood of a strain being resistant to all components is low. Indeed, CT’s efficacy in Korea has far surpassed that of TT alone. Our meta-analysis of 58 studies showed no significant difference in CT success rates between studies published before 2018 and those after 2018 [51-53]. Notably, 10-day CT achieved over 80% ITT and over 90% PP eradication (Table 3), with no higher incidence of adverse events than other regimens. CT was also marginally more effective than ST, likely owing to its superior performance against single-drug resistance. Specifically, CT outperformed ST in clarithromycin-resistant strains [51,52] and in strains resistant to metronidazole but susceptible to clarithromycin [51,53]. Nonetheless, the guideline authors urge caution in using CT because of stewardship concerns; deploying three antibiotics upfront could broaden antimicrobial resistance and increase the risk of adverse events. We acknowledge that while CT is highly effective, it should be reserved for cases of truly high resistance risk (e.g., when tailored therapy is unavailable) and used for as long as necessary.

Table 3.

Evidence table about the eradication rate of CT in H. pylori infection (meta-analysis)

To ensure a balance between efficacy and antibiotic stewardship, the updated guidelines place particular emphasis on bismuth-containing quadruple regimens as the empirical regimens of choice. Bismuth-based regimens typically include a bismuth salt plus two antibiotics and an acid suppressor, meaning that they use only two antibiotics rather than three. BQT uses PPI, bismuth, tetracycline, and metronidazole. However, tetracycline is not always easily available or well tolerated by patients. Evidence supports that the addition of bismuth substantially improves eradication rates. A recent systematic review and meta-analysis examined randomized trials comparing bismuth-containing regimens to comparable regimens without bismuth as a first-line therapy [54]. The meta-analysis included 13 studies (over 2500 patients), and found that overall, bismuth supplementation led to significantly higher cure rates. The odds of successful eradication were 1.63 times higher with bismuth (95% CI 1.33–2.00) in ITT analysis. When considering only patients who were fully compliant with the therapy (PP analysis), the benefit was even greater (OR highest 2.05, 95% CI 1.58–2.68). There were no significant differences in adverse event rates or compliance between the bismuth and non-bismuth regimens. The benefits of bismuth are particularly pronounced in populations with high clarithromycin resistance. In trials conducted in high-resistance areas, the addition of bismuth increased the odds of eradication by approximately 1.66-fold (ITT) to 2.22-fold (PP) compared to non-bismuth regimens. These findings validate the recommendations of the guidelines to augment empirical therapy with bismuth in Korea.

The modified regimens proposed in Korea add bismuth to the standard TT backbone, creating hybrid regimens that are effective quadruple therapies with familiar components. The two mQT regimens highlighted in the guidelines are PACB (PPI or P-CAB+amoxicillin+clarithromycin+bismuth) and PAMB (PPI or P-CAB+amoxicillin+metronidazole+bismuth).

In PACB, bismuth is added to a PAC (PPI-amoxicillin-clarithromycin) clarithromycin-containing TT. This may be suitable in regions or patients where clarithromycin resistance is not exceedingly high as long as bismuth is present to boost efficacy. In PAMB, clarithromycin is omitted (replaced by metronidazole) and bismuth is added, which resembles a metronidazole TT with bismuth and is useful if clarithromycin resistance is known or strongly suspected. Both regimens leverage bismuth’s ability to enhance antibiotic effectiveness. Bismuth compounds have multimodal antibacterial actions against H. pylori and help overcome resistance by synergizing with antibiotics and perhaps mildly suppressing H. pylori on their own [55].

PAMB (14-day in particular) achieved high eradication rates (87%–93% ITT, highest 95% PP) in diverse populations [56-59] and was statistically non-inferior or superior to the standard first-line regimens (including CT and BQT). PACB also yielded high cure rates (77.8%–93% ITT, highest 95% PP), although its efficacy decreases in clarithromycin-resistant cases [58,60]. PAMB is effective despite high clarithromycin and/or metronidazole resistance, essentially bypassing clarithromycin resistance and overcoming metronidazole resistance with aggressive dosing [58]. PACB improves outcomes over clarithromycincontaining TT empirically and can partly overcome low-level clarithromycin resistance [58], but is still significantly compromised by high-level clarithromycin resistance. Neither regimen is affected by fluoroquinolone or tetracycline resistance because these drugs are not used, and bismuth has no resistance [61,62].

P-CAB: OPTIMIZING ACID SUPPRESSION

Another advancement in empirical therapy is the introduction of P-CABs as the preferred acid-suppressive agents. Achieving a high intragastric pH is crucial for H. pylori treatment efficacy, as it enhances antibiotic stability and activity (especially for acid-labile drugs such as clarithromycin) and promotes the replicative state of H. pylori (making bacteria more susceptible to antibiotics) [55,63]. Since P-CABs provide faster and more stable acid suppression than PPIs, they may enhance antibiotic efficacy, potentially allowing for reduced anti-biotic dosages or shorter treatment durations. Given reports that P-CAB-based eradication is more effective against clarithromycin-resistant strains, effective regimens that reduce the number, dose, or duration of antibiotics based on resistance profiles in tailored therapy can be anticipated [64,65]. However, the primary barriers to using P-CABs for H. pylori eradication are the limited number of studies on various P-CAB agents and the restricted scope of insurance coverage in Korea. P-CABs may have a higher initial cost than PPIs and the financial burden on patients varies depending on insurance coverage. However, if high eradication rates are confirmed, as seen with vonoprazan, there is the potential to reduce long-term medical resource consumption by decreasing the need for retreatment. Moreover, P-CAB efficacy is not influenced by the CYP2C19 genotype, and higher eradication rates can be expected even against resistant strains [66].

We systematically searched for RCTs that compared the eradication rates of P-CAB-and PPI-containing regimens. A meta-analysis was conducted on 19 studies [65,67-84] that compared the same antibiotic combinations (Table 4). These included 14 studies [65,67-70,72-74,76-79,83,84] on vonoprazan, four on tegoprazan, and one on keverprazan. Most studies were designed to test the non-inferiority of P-CABs to PPIs, while four vonoprazan studies tested for superiority. P-CAB-based eradication therapies were more effective than PPI-based therapies (86.3% vs. 78.8%; RR 1.08, 95% CI 1.04–1.12). Specifically, vonoprazan demonstrated superior eradication outcomes compared with PPIs (88.4% vs. 79.0%; RR 1.10, 95% CI 1.05–1.15). When analyzing only four studies testing for superiority, the efficacy was even more pronounced (86.1% vs. 72.0%; RR 1.19, 95% CI 1.09–1.30). In contrast, the meta-analysis of tegoprazan (all non-inferiority trials) showed that it was not significantly more effective than PPIs for eradication (79.3% vs. 76.8%; RR 1.03, 95% CI 0.98–1.09). In a meta-analysis of 16 studies that reported adverse events with P-CAB- or PPI-containing regimens, the incidence of adverse events was 32.8% for P-CABs and 31.8% for PPIs. No significant difference was observed between the groups (RR 1.01, 95% CI 0.93–1.11).

Table 4.

Evidence table about the comparative efficacy between P-CAB-based- vs. PPI-based regimens in H. pylori eradication

In summary, while P-CAB regimens showed superior overall eradication efficacy compared to PPI-based regimens, tegoprazan (which is available in Korea) did not demonstrate superiority, indicating that its eradication rate was comparable to that of PPIs. Based on these findings, the guideline will conclude that P-CAB-based therapy can be used as an alternative to traditional PPI-based regimens for first-line H. pylori eradication. Korean guidelines encourage the use of P-CABs in both tailored and empirical regimens, whenever available, to maximize the probability of success. This is especially relevant in rescue regimens or patients who rapidly metabolize PPIs. By combining P-CAB-enhanced acid suppression with either fourdrug combinations or bismuth-supplemented therapy, empirical treatment can achieve efficacy on par with tailored approaches, while mitigating resistance development by avoiding ineffective clarithromycin use.

SALVAGE THERAPY AFTER TREATMENT FAILURE

With more effective first-line treatment, the overall proportion of patients requiring salvage therapy should decrease. Nonetheless, the guidelines have updated and clarified the recommended second- and third-line options for cases in which the initial treatment (whether tailored or empirical) fails. The overarching principle is to avoid repeating any antibiotic to which the strain has already been exposed and to use the most effective available regimen for salvage, taking into account cumulative resistance (Fig. 1).

Fig. 1.

Flowchart summarizing the H. pylori treatment algorithm, from first-line AST-guided or empirical therapy to second- and third-line salvage options. AST, antibiotic susceptibility test; PCR, polymerase chain reaction; TT, triple therapy; BQT, bismuth quadruple therapy; mQTs, modified quadruple therapy; CT, concomitant therapy.

Third-line rescue therapy

If both the first- and second-line treatments fail, the H. pylori strain is likely to be MDR. At this stage, expert consultation and susceptibility testing are strongly advised. The 2025 guidelines outline several options for third-line therapy, emphasizing regimens involving antibiotics that have not been previously used. It is considered inappropriate to reuse clarithromycincontaining regimens after failure of second-line BQT (following failure of first-line clarithromycin-containing TT or CT) or after failure of first-line BQT. Failure of these regimens implies that clarithromycin resistance is either confirmed via molecular diagnosis or strongly suspected due to prior exposure. Generally, reusing clarithromycin, levofloxacin, or rifabutin is not recommended if resistance is present or suspected; however, amoxicillin and metronidazole can be reused [91]. Studies indicate that empirical therapy based on a carefully reviewed history of failed antibiotics can achieve efficacy comparable to susceptibility-guided therapy in second- or third-line settings [92]. Based on these principles, the preferred rescue regimens include rifabutin TT, modified BQT (incorporating previously unused antibiotics), or, in restricted cases, levofloxacin-based therapy.

Rifabutin is an antibiotic primarily used for tuberculosis, but possesses activity against H. pylori with no cross-resistance to other antibiotic classes. A typical regimen consists of PPI, amoxicillin, and rifabutin (150 mg twice daily or 300 mg once daily) for 10–14 days. Clinical evidence supports its use as rescue therapy. A Chinese study comparing 14-day rifabutin TT versus 14-day BQT as third-line treatment found no significant difference in ITT eradication rates (89.0% vs. 89.6%) [93]. However, the rifabutin group demonstrated significantly fewer moderate- to-severe adverse events (14.3% vs. 28.6%) and higher adherence (96.2% vs. 85.4%) compared to the BQT group. Although this study targeted patients naïve to BQT, a Korean RCT specifically investigated patients who failed BQT.14 Although efficacy depends on resistance, the rifabutin resistance rate in Korea is estimated to be extremely low, recently reported to be 0.8% [14]. Thus, rifabutin TT remains a viable salvage option, achieving success rates in the 60%–80% range for refractory cases [14]. However, caution is required due to cost, rare but serious myelotoxicity (necessitating monitoring), and the potential for inducing resistance in Mycobacterium tuberculosis [94].

Another third-line strategy involves designing a regimen that includes two antibiotics to which the patient has not been previously exposed, combined with bismuth and a strong acid suppressant. This is referred to as the mQT. For example, if a patient fails to respond to regimens containing clarithromycin, metronidazole, and tetracycline, the third-line mQT might utilize levofloxacin or amoxicillin. While no RCTs have specifically addressed the efficacy after BQT failure, studies in thirdline settings have demonstrated non-inferiority to traditional BQT. A Chinese study comparing a regimen of PPI, bismuth, amoxicillin, and levofloxacin against traditional BQT showed similar ITT eradication rates (83.0% vs. 88.1%) but significantly fewer adverse events (5% vs. 22.4%) [95]. Another RCT replacing tetracycline with amoxicillin found no significant difference in eradication rates (ITT: 88.5% vs. 87.2%) but noted significantly higher adverse events in the traditional BQT group [96]. These findings suggest that mQTs offer a flexible and effective alternative, although further research is needed to confirm its effectiveness, specifically in patients who have already failed traditional BQT.

Levofloxacin TT (PPI+amoxicillin+levofloxacin) has been used as a salvage regimen in Korea, but its utility is increasingly limited by resistance rates exceeding 30% [9]. Recent registry findings indicate that levofloxacin-based therapy achieves suboptimal success rates (around 70%–80%) as a third-line treatment in Korea [9]. A Korean study analyzing efficacy by treatment duration in patients who failed both first-line clarithromycincontaining TT and second-line BQT reported ITT eradication rates of 58.3% (7-day), 62.5% (10-day), and 73.7% (14-day) [97]. Even when restricting analysis to 10–14-day regimens, the rate was only 67.4%, which is lower than other rescue options. Therefore, levofloxacin TT should be attempted only on a limited basis, considering prior antibiotic history and regional resistance patterns or if susceptibility is confirmed. While some international reports suggest that levofloxacin quadruple or sequential therapies offer superior efficacy compared to levofloxacin TT in rescue settings [88], domestic data regarding these regimens are lacking in Korea. The resistance rate of H. pylori to levofloxacin in Korea has steadily increased over the past 20 years, reaching 36.0%–42.9% in recent studies conducted between 2019 and 2020.98 Consequently, eradication success cannot be guaranteed even in second- or third-line settings because of high resistance rates. Furthermore, following the failure of standard therapy, selection pressure for levofloxacin resistance occurs, and cross-resistance between clarithromycin and fluoroquinolones—leading to increased secondary resistance— has been confirmed [99]. Regarding other therapeutic options, sitafloxacin, which is widely used even as a first-line agent in Japan, is currently unavailable in Korea. Moxifloxacin TT lacks sufficient study numbers to allow for generalization [100,101]. Similarly, high-dose dual therapy, utilized in other countries, currently lacks sufficient evidence for recommendation owing to the absence of domestic studies [102].

In cases where two or more eradication therapies fail, referral to a specialized center capable of performing susceptibility-based tailored therapies is strongly recommended. If second-line rifabutin- or levofloxacin-based therapies or mQTs fail after first-line BQT, expert judgment is required. Even in refractory cases, susceptibility-guided therapy can achieve relatively high eradication rates of over 80%–90% in ITT analysis [43,92]. Through this stepped approach (Table 5), first-line tailored or empirical quadruple, second-line BQT, and third-line individualized rescue, the goal is to achieve eradication while minimizing unstructured retrials that drive further resistance.

Table 5.

Summary comparison of empirical versus tailored treatment strategies for H. pylori eradication

CONCLUSION

The 2025 revisions of the Korean H. pylori treatment guidelines have replaced clarithromycin-containing TT with a strategy that prioritizes efficacy and precision. To address high antibiotic resistance, the guidelines establish a robust “dual-pillar” framework: pragmatic empirical treatment using high-efficacy quadruple regimens (CT or bismuth-based) and precision medicine utilizing PCR-guided tailored therapy. Both pathways, reinforced by extended treatment durations (10–14 days), aim to maximize first-line cure rates. In particular, the guidelines highlight mQTs (e.g., PACB or PAMB) as the preferred empirical first-line option in Korea’s high-resistance setting. This approach balances high efficacy with prudent antibiotic use, and aligns with the principles of antibiotic stewardship.

A significant update is the formal incorporation of P-CABs. P-CABs are recognized as valuable tools that offer potent acid suppression comparable or superior to that of PPIs, and serve as integral components to counteract resistance. For rescue therapy, the guidelines provide a clear stepwise algorithm. BQT is reaffirmed as the standard second-line regimen, whereas fluoroquinolone- or rifabutin-based therapies are reserved for third-line salvage, ideally guided by antimicrobial susceptibility testing.

These guidelines address the resistance patterns in Korea. The framework targets eradication rates of >9%, thereby minimizing the development of secondary resistance. The successful implementation of these recommendations is expected to reduce treatment failures and significantly lower the burden of H. pylori-related diseases, including gastric cancer, across the population. Future efforts should focus on ongoing resistance surveillance and real-world research to sustain these clinical gains.

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