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Korean J Helicobacter  Up Gastrointest Res > Volume 23(3); 2023 > Article
Choe: Antibiotic Resistance and Helicobacter pylori Eradication Therapy
There are various reasons why Helicobacter pylori eradication treatment fails, but the most important is antibiotic resistance. Over the past 20 years, the antibiotic resistance of clarithromycin (CLR), metronidazole, and levofloxacin has steadily increased. In particular, the eradication rate of the CLR-containing triple therapy has dropped by about 20% [1]. Antibiotic resistance is shared within antibiotic classes, which is, of course, related to the degree of antibiotic use of the background population for all indications, not just H. pylori. In order to achieve a high eradication rate again, it is necessary to recognize H. pylori as an infectious disease and apply the concept of antibiotic management like an infectious disease doctor [2]. Ideally, antibiotics in a population, sometimes in an individual consideration should be given to using a targeted regimen based on knowledge of tolerance. This improves eradication rates, minimizes antibiotic overuse, and aids resistance in organisms other than H. pylori.
Ideally, therapies that have been demonstrated to be effective with an eradication success rate of at least 90% should be used. To achieve high eradication rates, three things must be done. First, the eradication rate of currently used regimens must be accurately measured. Second, it is necessary to identify the regional resistance rate and utilize it. Third, if it is unclear which regimen to choose, antibiotic susceptibility testing should be used.
The European Registry has registered about 60,000 patients, and as a result of tracking antibiotic resistance and providing feedback to doctors, it is said that it has been able to increase the eradication rate from 85 to 93% over the past ten years [3].
There are two main methods for testing antibiotic resistance. The classical method is culture and molecular testing for antibiotic resistance. While the success rate of culture is about 50 to 60%, molecular testing gives about 90% results, and recently, it can be relatively easily performed for six antibiotics through next-generation sequencing. There are studies on antibiotic resistance published in the last five years in Korea (Table 1) [4-7]. In a study conducted in 2019 on 590 people nationwide, the resistance rates of CLR, amoxicillin, and metronidazole were 18, 10, and 30%, respectively [8]. In addition, resistance rate studies conducted in Seoul in 2020 and 2021 showed, 25~30%, 7~20%, and 24~35%, respectively [4-6]. Further studies on regional resistance are needed.
The most important principle in H. pylori eradication is that initial treatment is the most important. This is because the highest chance of success lies in early treatment. In order to optimize initial treatment, the first requirement is to determine the patient's prior antibiotic exposure. CLR and quinolones should be avoided in areas with high Helicobacter resistance. Second, it is better to avoid antibiotics that have been previously used or have a resistance rate of 15% or higher. However, bismuth quadruple therapy (BQT) is known to be resistant to metronidazole but can be overcome by increasing the dose or duration of administration [9]. Ideally, a sensitivity test should determine the treatment method. Since patient compliance is one of the major causes of treatment failure, optimizing dosage and frequency is also important. In addition, intragastric acid suppression should be maintained at a pH of 6 or higher.
So far, most studies on treatment outcomes have been conducted in East Asia and Europe. In the first-line treatment of H. pylori, there was a recent meta-analysis that tailored therapy was more favorable than empirical therapy (odds ratio 1.14; 95% confidence interval 1.08‒2.20) [10,11]. However, the difference in the efficacy was not very large. There was heterogeneity for each treatment regimen and treatment period. In the randomized controlled trial (RCT) comparing tailored therapy and empirical therapy in Korea, all recent studies showed similar eradication success rates, and the difference was not significant (Table 2) [12-14].
As a first-line treatment not only in Korea but also in Europe and the United States, CLR triple therapy has a very low success rate of less than 60% [3,15]. BQT is recommended as first-line treatment, and concomitant therapy was recommended only when there was qualification at the guidelines [16,17]. Proton pump inhibitor (PPI)-based CLR triple therapy is recommended only when the regional CLR resistance is less than 15%, the local eradication success rate is high, the CLR susceptible strain is known, and there is no previous macrolide exposure.
BQT consistently showed an eradication success rate of over 85%, even including metronidazole-resistant areas, but there was no correlation between in vitro metronidazole resistance and actual results. Of course, there is a downside to poor compliance. Concomitant therapy has proven effective in Europe, but has the disadvantage of taking at least one antibiotic unnecessarily. In addition, high-dose PPI dual (PPI+amoxicillin) has low potency, and Rifabutin triple (PPI+amoxicillin+rifabutin) has low tolerance and has some side effects, making both of them not favored as first-line therapy.
A preferred method for the future is a potassium-competitive acid blocker (PCAB)-based therapy. PCAB has a higher acid secretion inhibitory effect than PPI and acts quickly. It also has the advantage of having a long half-life, no relation to CYP2C19 metabolism, and no relation to meal time. The results of the “Lansoprazole triple vs. Vonoprazan triple vs. Vonoprazan dual” study conducted in the US and Europe last year were less impressive than those in Japan. In particular, patients with CLR resistance strains showed more significant results (32% vs 66% vs 70%, P<0.001) [18]. Korean RCT on the efficacy of PCAB-based regimen, showed some predominant efficacy. With tegoprazan and lansoprazole as the base, respectively, standard triple therapy showed intention-to-treat (ITT, 63% vs. 61%, P<0.05) and per-protocol (PP, 69% vs. 67%, P<0.05) [19], and BQT showed ITT (80% vs. 77%, P<0.05) and PP (90% vs. 82%, P<0.05) [20].
The goal of refractory H. pylori infection is to avoid unnecessary antibiotics and to optimize the patient's experience in terms of costs and side effects. As with first-line therapy, the key principle is to avoid antibiotics already used. However, in case of BQT failure, the duration of administration may be increased, or the dose of metronidazole may be increased. Korean literature on salvage therapy is relatively small, with few RCTs. The most important thing is to increase the success rate of primary treatment. If salvage therapy is required, molecular antibiotics sensitivity or a PCAB-based regimen may be an important option [17].
The major cause of eradication failure for H. pylori infection is antibiotic resistance. Antibiotic resistance testing should allow for personalized treatment that improves eradication rates. More studies comparing susceptibilitybased therapy with empirical therapy should be conducted. In addition, PCAB-based therapy may be a good option to eradication therapy in the future.



Data sharing is not applicable to this article as no datasets were generated or analyzed during the study.


There is no potential conflict of interest related to this work.





Table 1.
Studies on Antibiotic Resistance Performed in Korea over the Past 5 Years
Author Publication year Region Subject (n) CLR-R (%) AMX-R (%) MDZ-R (%) LVF-R (%)
Kang et al. [6] 2021 Seoul 257 24.9 7.0 34.6 -
Park et al. [5] 2020 Seoul 174 28.6 20.0 27.1 42.9
Kim et al. [4] 2020 Seoul 247 29.6 10.0 23.9 36.0
Lee et al. [7] 2019 Nationwide 590 17.8 9.5 29.5 37.0

AMX-R, amoxicillin resistance; CLR-R, clarithromycin resistance; LVF-R, levofloxacin resistance; MDZ-R, metronidazole resistance.

Table 2.
Randomized Controlled Trials Performed in Korea over the Past 5 Years to Compare Tailored and Empirical Therapy for Helicobacter pylori
Author Publication year Tailored therapy
Empirical therapy
Regimensa Eradication rate (ITT) Eradication rate (PP) Regimensa Eradication rate (ITT) Eradication rate (PP)
Kim et al. [14] 2022 PAC-14 or PBMT-14 145 (85.5) 129 (94.6) PACM-14 145 (82.8) 132 (88.6)
Cho et al. [13] 2022 PAC-14 or PBMT-14 141 (80.9) 127 (89.0) PBAM-14 141 (85.8) 124 (93.5)
Choi et al. [12] 2021 PAC-14 or PBMT-14 110 (82.7) 101 (90.1) PACM-14 107 (82.2) 95 (91.6)

Values are presented as number (%).

ITT, intention-to-treat; PP, per-protocol; PPI, proton pump inhibitor.

a PAC=PPI+amoxicillin+metronidazole; PACM=PPI+amoxicillin+clarithromycin+metronidazole; PBAM=PPI+busmuth+amoxicillin+metronidazole; PBMT=PPI+bismuth+metronidazole+tetracyclin.

All three studies used a PPI.

All three studies had no significant difference in eradication rates between tailored and empirical therapy.


1. Ho JJC, Navarro M, Sawyer K, Elfanagely Y, Moss SF. Helicobacter pylori antibiotic resistance in the United States between 2011 and 2021: a systematic review and meta-analysis. Am J Gastroenterol 2022;117:1221–1230.
crossref pmid
2. Graham DY, Liou JM. Primer for development of guidelines for Helicobacter pylori therapy using antimicrobial stewardship. Clin Gastroenterol Hepatol 2022;20:973–983; e1.
crossref pmid pmc
3. Nyssen OP, Bordin D, Tepes B, et al.; Hp-EuReg Investigators. European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients. Gut 2021;70:40–54.
crossref pmid
4. Kim YM, Lee KH, Kim JH, et al. Is only clarithromycin susceptibility important for the successful eradication of Helicobacter pylori? Antibiotics (Basel) 2020;9:589.
crossref pmid pmc
5. Park JY, Shin TS, Kim JH, Yoon HJ, Kim BJ, Kim JG. The prevalence of multidrug resistance of Helicobacter pylori and its impact on eradication in Korea from 2017 to 2019: a single-center study. Antibiotics (Basel) 2020;9:646.
crossref pmid pmc
6. Kang S, Kim Y, Ahn JY, et al. Role of antimicrobial susceptibility testing before first-line treatment containing clarithromycin for Helicobacter pylori eradication in the clinical setting. Antibiotics (Basel) 2021;10:214.
crossref pmid pmc
7. Lee JH, Ahn JY, Choi KD, et al.; Korean College of Helicobacter.; Upper Gastrointestinal Research. Nationwide antibiotic resistance mapping of Helicobacter pylori in Korea: a prospective multicenter study. Helicobacter 2019;24:e12592.
crossref pmid pdf
8. Lee JY, Kim N, Nam RH, In Choi S, Lee JW, Lee DH. Primary and secondary antibiotic resistance of Helicobacter pylori in Korea from 2003 to 2018. Helicobacter 2019;24:e12660.
crossref pmid pdf
9. Choe Y, Kim JS, Choi HH, et al. The influence of past metronidazole exposure on the outcome of Helicobacter pylori eradication. Front Microbiol 2022;13:857569.
crossref pmid pmc
10. Nyssen OP, Espada M, Gisbert JP. Empirical vs. susceptibility-guided treatment of Helicobacter pylori infection: a systematic review and meta-analysis. Front Microbiol 2022;13:913436.
crossref pmid pmc
11. Ma Q, Li H, Liao J, Cai Z, Zhang B. Tailored therapy for Helicobacter pylori eradication: a systematic review and meta-analysis. Front Pharmacol 2022;13:908202.
crossref pmid pmc
12. Choi YI, Chung JW, Kim KO, et al. Tailored eradication strategy vs c oncomitant t h erapy for Helicobacter pylori eradication treatment in Korean patients. World J Gastroenterol 2021;27:5247–5258.
crossref pmid pmc
13. Cho JH, Jin SY, Park S. Comparison of tailored Helicobacter pylori eradication versus modified bismuth quadruple therapy in Korea: a randomized controlled trial. Expert Rev Anti Infect Ther 2022;20:923–929.
crossref pmid
14. Kim SJ, Jee SR, Park MI, et al.; Busan and Gyeongnam Society of Helicobacter and Upper Gastrointestinal Research. A randomized controlled trial to compare Helicobacter pylori eradication rates between the empirical concomitant therapy and tailored therapy based on 23S rRNA point mutations. Medicine (Baltimore) 2022;101:e30069.
crossref pmid pmc
15. Argueta EA, Alsamman MA, Moss SF, D'Agata EMC. Impact of antimicrobial resistance rates on eradication of Helicobacter pylori in a US Population. Gastroenterology 2021;160:2181–2183.e1.
crossref pmid pmc
16. Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol 2017;112:212–239.
crossref pmid pdf
17. Malfertheiner P, Megraud F, Rokkas T, et al.; European Helicobacter and Microbiota Study group. Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut 2022;Aug 8 [Epub]. https://doi.org/10.1136/gutjnl-2022-327745.
18. Chey WD, Mégraud F, Laine L, López LJ, Hunt BJ, Howden CW. Vonoprazan triple and dual therapy for Helicobacter pylori infection in the United States and Europe: randomized clinical trial. Gastroenterology 2022;163:608–619.
crossref pmid
19. Choi YJ, Lee YC, Kim JM, et al. Triple therapy-based on tegoprazan, a new potassium-competitive acid blocker, for first-line treatment of Helicobacter pylori infection: a randomized, double-blind, phase III, clinical trial. Gut Liver 2022;16:535–546.
crossref pmid pmc
20. Kim JS, Ko W, Chung JW, Kim TH. Efficacy of tegoprazan-based bismuth quadruple therapy compared with bismuth quadruple therapy for Helicobacter pylori infection: a randomized, double-blind, active-controlled study. Helicobacter 2023;28:e12977.
crossref pmid

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