Gastroenterology & Hepatology

March 2024 - Volume 20, Issue 3

Best Practices for Helicobacter pylori Management

David Y. Graham, MD
Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas

Corresponding author: 
Dr David Y. Graham
Michael E. DeBakey Veterans Affairs Medical Center
2002 Holcombe Blvd
Rm 3C-109
Houston, TX 77030
Tel: (713) 795-0232

Abstract: For decades, antimicrobial therapy for Helicobacter pylori infection has been given empirically, and the results of therapy (success or failure) have either not been confirmed or when confirmed have not been used to modify prescribing behavior. These practices coupled with increasing antibiotic resistance have resulted in low cure rates overall. Susceptibility testing for H pylori has increasingly become available, especially in the United States. Availability of susceptibility-based therapy has encouraged adoption of the principles of antimicrobial stewardship for H pylori infection (eg, limiting antibiotic choice to antibiotics for which the infection is susceptible given at optimal doses, formulations, frequency of administration, and duration). Antimicrobial regimens can now be classified as empiric therapies, susceptibility-based therapies, potentially effective therapies requiring optimization, and therapies containing unneeded antibiotics that should not be used. This article describes current best practices and recommendations for integrating culture-based and molecular-based susceptibility testing into H pylori therapy. 

Helicobacter pylori was discovered during investigations of the cause of gastric inflammation.1,2 The focus rapidly expanded from inflammation to the gastritis-associated diseases, peptic ulcer, and gastric cancer.3 Cure of the infection was subsequently proven to heal or prevent gastritis, peptic ulcers and gastric cancer. Diagnostic tests were developed allowing rapid diagnosis. However therapy remains problematic and largely empiric rather than susceptibility-based as with other infectious diseases (Figure 1).4 The widespread use of empiric therapies despite increasing antimicrobial resistance has resulted in declining cure rates.5-8 Antimicrobial susceptibility testing (AST) has finally become commercially available especially in the United States,9 and susceptibility-based therapy is now being integrated into current diagnostic and treatment algorithms.4 This article focuses on implementing best practices into the routine management of H pylori infection. 

Antimicrobial Stewardship

Antimicrobial stewardship focuses on the optimal use of antibiotics to obtain a cure.10,11 Successful therapy requires use of antibiotics or antibiotic combinations to which the infection is susceptible given at optimal doses, formulations, frequency of administration, and duration to reliably achieve high cure rates. Ideally, therapy should be tailored specifically for individual patients based on antimicrobial susceptibility data obtained by culture, molecular testing, or by knowledge and local experience to identify reliably and highly effective empiric therapies.11,12 Worldwide, the most common locally proven highly effective therapy is bismuth quadruple therapy, although dual therapy with a potassium-competitive acid5 blocker (P-CAB) plus amoxicillin may provide a second reliable, highly effective, and likely preferred option after undergoing local optimization.13 Continued use of any therapy is dependent on continuing effectiveness. Thus, treatment outcomes should always be assessed with a test of cure (eg, urea breath test) to confirm treatment success; treatment failures should be investigated as to the cause of failure. 

History of Helicobacter pylori Infection Management

The initial period of learning to treat H pylori infection involved experimentation with a wide variety of antibiotics.14 In 1990, the first effective therapy consisting of bismuth, metronidazole, and tetracycline (bismuth triple therapy) was identified.15 Later, metronidazole resistance resulted in a decline in efficacy that often could be restored by the addition of a proton pump inhibitor (PPI), producing what is now known as bismuth quadruple therapy.16 However, the lack of universal availability of bismuth and associated common side effects of this therapy limited its overall usefulness. When clarithromycin was introduced, its potential role for treatment of H pylori was promptly evaluated by a number of investigators.17-23 Although monotherapy was ineffective, a 3-drug therapy that contained an antisecretory drug such as a PPI, clarithromycin, and either amoxicillin24 or metronidazole appeared especially promising.25 

The development and approval of clarithromycin triple therapy by the US Food and Drug Administration (FDA) was the result of a joint effort of 2 pharmaceutical companies, one that licensed clarithromycin and one that introduced the first PPI, omeprazole, for treatment of acid-peptic disease.26 Importantly, and a harbinger of current issues, resistance to clarithromycin was noted to emerge during therapy and was a common cause of treatment failure.26 This problem was attributed to the high level of H pylori in the stomach, which increases the frequency of spontaneous development of resistance (the inoculum effect), resulting in the presence of a mixed population of susceptible and resistant organisms at the start with the resistant organisms remaining undetected because of the low percentage (ie, heteroresistance).27 Although the addition of low-dose amoxicillin to reduce or eliminate the small populations of resistant strains initially proved an effective strategy, clarithromycin resistance developing during H pylori therapy has continued to plague its prescribers. Large double-blind studies of omeprazole plus clarithromycin and amoxicillin or omeprazole plus amoxicillin and metronidazole in Europe (the MACH studies) confirmed that both regimens were able to produce excellent results.28-31 Importantly, in the presence of susceptible infections, both PPIs and histamine receptor antagonists produced similar results with clarithromycin triple therapy.32,33 The therapies were then heavily marketed, and consensus meetings around the world were sponsored (eg, Maastricht I).34

As predicted based on the development trials, clarithromycin resistance rapidly became a clinical issue and by 2001, meta-analyses confirmed that clarithromycin triple therapies had become generally ineffective in Europe.35,36 In 2007, the increasing failure of clarithromycin-based therapy resulted in the Maastricht recommendation to prescribe clarithromycin only if the local resistance was less than 15% to 20%.37 The lack of susceptibility testing limited the application of that rule. In retrospect, a target such as eliminating its use if cure rates fell below 85% would have been more useful. 

One empiric solution to treatment failure related to clarithromycin resistance was to add a third antibiotic to produce a 4-drug combination consisting of a PPI, clarithromycin, metronidazole, and amoxicillin called concomitant therapy.38 However, this approach violates the principles of antimicrobial stewardship, as it required that all patients receive at least 1 unnecessary antibiotic and overuse of antibiotics promotes the global spread of antimicrobial resistance.39,40 For example, concomitant therapy results in administration (misuse) of more than 60 tons of unnecessary antibiotics per million treatments. Despite this problem, concomitant is still recommended by the Maastricht guidelines,5 and the European registry on H pylori management (Hp-EuReg) reports that concomitant therapy is one of the most commonly used regimens among registry participants.41,42 Both concomitant therapy and clarithromycin triple therapy containing the P-CAB, vonoprazan, which is most commonly used in Japan, contain unneeded clarithromycin (in Japan at least 80% of the clarithromycin in vonoprazan triple therapy is unneeded).43 Recently, vonoprazan plus clarithromycin triple therapy was tested in US and European studies44 and was approved by the FDA for use despite poor cure rates and the fact that the majority of patients treated received unneeded clarithromycin.43,45 Vonoprazan triple therapy had now joined concomitant therapy on the list of H pylori regimens that should not be used. Nonetheless, the excellent experience in China and Japan with vonoprazan-amoxicillin dual therapy suggests that if vonoprazan-amoxicillin dual therapy can be optimized to produce high cure rates consistently without requiring clarithromycin, it might have a major role as long as amoxicillin resistance remains low.46 

It is now clear that clarithromycin, metronidazole, and levofloxacin triple therapies should be abandoned in regions still lacking AST unless they are proven, and continually reconfirmed, to remain reliably highly effective. Although vonoprazan has increasingly become available worldwide, the original success in Japan with vonoprazan-amoxicillin dual therapy has not been confirmed in either Thailand47 or the United States and Europe,45 consistent with the notion that one should only rely on local or regional results. As noted above, worldwide, where bismuth is available, bismuth quadruple therapy appears to provide good to excellent cure rates. Resistance to tetracycline also remains rare; however, side effects of bismuth quadruple therapy are common, requiring patient education. It is important to note that the term quadruple therapy used in studies may refer to a combination other than traditional bismuth quadruple therapy. For example, in China, a variety of effective quadruple therapies are used in which amoxicillin or furazolidone is employed to replace a locally unavailable drug such as tetracycline.48

Current Helicobacter pylori Therapies

The availability of AST makes it possible for H pylori infection to be managed using the same principles as other infectious diseases.12 Therapies can be considered as 4 broad categories (Table 1).12 Therapies in the first category are highly effective locally (ie, resistance is low, and effectiveness is high) and they can be used empirically (ie, without susceptibility testing). The second category includes therapies that should only be used as susceptibility-based therapies. All regimens containing clarithromycin and fluoroquinolones (eg, levofloxacin) fall into the susceptibility-based therapy category. The third category consists of potentially effective regimens that have yet to be optimized. The fourth category of therapies contains at least 1 antibiotic that provides no antimicrobial benefit and should not be used.  

Traditional Culture-Based Susceptibility Testing 

Until recently, AST required culture of the bacterium and performance of its antibiogram. This approach can provide susceptibility results for all commonly used antibiotics in a standardized way (Table 2).9 The primary limitation to this method is that gastric biopsy (or gastric tissue) is required. Although gastric sampling can be performed using a string, brush, or forceps introduced through the mouth, such methods are not widely used. Currently, sample collection is most often obtained during endoscopy where preferably at least 1 antral and 1 corpus biopsy are taken for culture. A second and practical limitation of endoscopically acquired gastric biopsies is that the clinicians and medical staff who handle the specimens must strictly adhere to the conditions required in order to maintain the viability of the organisms during transport of biopsies.9 Biopsies should be placed in specific transport media to avoid desiccation and kept at 4°C or frozen to –70°C or less in transport media to maintain viability and avoid the outgrowth of other bacteria from the gastric microbiota. In the laboratory, proper handling of the samples requires experienced technicians. The final issue is that results often do not become available until several weeks after endoscopy. Realistically, this is a minor issue as the infection has typically been present for decades, and there is no emergency to treat. Although H pylori are also present in stools, the bacteria are within the complex fecal microbiota and no longer viable. However, their DNA is present making molecular testing possible.

Molecular Susceptibility Testing

Recently, molecular techniques have become available for H pylori susceptibility testing.

Polymerase Chain Reaction Assay

Polymerase chain reaction (PCR) assays, such as real-time PCR, are based on detection of H pylori DNA and the mutations associated with resistance. Clarithromycin resistance mutations occur in 23S ribosomal RNA genes. The real-time PCR method includes fluorescence resonance energy transfer followed by a melting curve analysis or an equivalent. Currently, this approach is practically limited to clarithromycin susceptibility. However, the method is reliable as there are only a few mutations involved in resistance and the correlation with the phenotypic result (antibiogram) is very good.49 In the past, many laboratories did not possess a thermocycler to facilitate PCR. Following the COVID-19 pandemic, such an apparatus can be found in almost every laboratory. PCR-based methods have several advantages because DNA is relatively stable and transport conditions are not as strict as for culture. Biopsies used for a rapid urease test can also serve for this purpose, even biopsies that have been stored at room temperature for several weeks.50 The results of PCR are rapidly available as the assay can be performed in at most a few hours. Overall, the cost of performing each PCR assay is low, and several kits are commercially available in Europe and Asia. In the United States, there is often a disconnect between cost and price, and it is best to check with the specific vendor for details. Although PCR testing for clarithromycin resistance should theoretically be available in every hospital laboratory in the United States, no test kits have yet achieved FDA approval, and the test available commercially is only for stools (see Table 2).9 Currently, PCR testing of stools for clarithromycin resistance is only offered by Mayo Clinic Laboratories.

Importantly, real-time PCR testing can also be performed on stools where fragments of the bacteria (antigens, DNA) are present in low amounts. However, the success of the test requires a DNA extraction method documented to be highly effective with stools, and as noted above, a real-time PCR assay specifically designed for H pylori in stools is not yet commercially available for general laboratories to purchase. Because of the difficulties of extraction and the low concentration of H pylori DNA in stools, the sensitivity of stool real-time PCR is less than that of gastric biopsies. Finally, real-time PCR can also be performed on formalin-fixed gastric biopsies despite the possible DNA fragmentation following the fixation.51

Levofloxacin resistance is currently detected using multiplex PCR with strip hybridization currently available in kit form in Europe (GenoType HelicoDR, Hain Lifescience, Germany).52 The kit detects H pylori and the mutations associated with both clarithromycin and levofloxacin resistance. This method is required for fluoroquinolones because several mutations not inducing resistance can also be present. Its performance also takes longer than real-time PCR and requires a trained individual to interpret the strip. An alternative to test for levofloxacin resistance would be an amplification and sequencing of the gyrase A gene.

Next-Generation Sequencing

Next-generation sequencing (NGS) for H pylori detection and antibiotic resistance has become commercially available in the United States9 as well as internationally. NGS has the advantage of providing resistance information for the 6 antibiotics commonly prescribed for H pylori infection. This method can also be used on fresh or formalin-fixed gastric biopsy tissues as well as stools. The genes currently tested for their involvement in H pylori resistance are shown in Table 3. Results are available in several days. Susceptibility testing using stools provides truly noninvasive testing. NGS has potential as a reflexive stool test, with samples initially evaluated with stool antigen or H pylori–specific PCR and negative samples being charged only a minimal fee. Positive samples would automatically be sent for AST (Figures 2 and 3). 

Reflexive Molecular Stool Susceptibility Testing 

If the full complement of tests becomes universally available in the future, reflexive stool testing will likely become the standard for patients who do not require endoscopy (see Figure 2).4 Currently, real-time PCR for clarithromycin and NGS for all 6 currently used antibiotics are available as stool tests.9 In this method, the stool sample is first tested for the presence of H pylori using a stool antigen or PCR test, both of which have been confirmed to have good reliability. Stools that test negative are reported as such, and patients are charged only for the diagnostic test. Stools with H pylori–positive results reflexly receive molecular testing.4 Pretreatment AST allows the H pylori antibiotic regimen to obtain the highest possible rate of success. 

Selection of Antimicrobial Susceptibility Testing

The choice of AST depends on whether an endoscopy is necessary, as culture currently requires endoscopy. The majority of H pylori–infected individuals are asymptomatic. Nonetheless, they may be at increased risk for gastric cancer based on ethnicity, family history, physical findings, and age greater than 50 years, or they may have significant symptoms such that endoscopy is frequently indicated.5,7,12 Patients at higher risk typically undergo endoscopy for risk stratification, which involves gastric mucosal biopsies for histology. Biopsies for culture and/or molecular testing can be obtained at the same time and if culture fails, the formalin-fixed paraffin blocks can still be used for molecular H pylori AST. It is generally agreed that a confirmed diagnosis of an H pylori infection should be followed by H pylori eradication.5,7,8 When endoscopy is not necessary, noninvasive testing using stool is preferred for AST.

Practical Aspects of Antimicrobial Susceptibility Testing 

Antimicrobial therapies can be divided into those for which AST is optional and those for which it is required (ie, empiric vs susceptibility-based therapies as shown in Table 1).12 Empiric therapies are defined as regimens that reliably produce high cure rates locally without prior AST. Currently, the only available therapy that can be empirically used worldwide is bismuth quadruple therapy. As noted earlier, in some areas of China and in Japan, a high-dose, high-potency PPI (eg, 40 mg of esomeprazole) or vonoprazan plus amoxicillin dual therapy has also proven effective.53,54 In the United States, rifabutin triple therapy is also used empirically given that rifabutin resistance is seldom present. As noted earlier, although the original attempt with vonoprazan triple therapy in United States and Europe produced relatively low cure after optimization (ie, higher doses of vonoprazan), vonoprazan plus amoxicillin dual therapy will likely become the preferred empiric therapy. 

The Critical Role of Optimization

The goal of optimization is to be able to reliably achieve the highest cure rates (eg, 95% or higher) practically achievable locally.55 Optimization must include all important parameters, including dosage, duration, and frequency of administration. Few, if any, H pylori therapies have been formally optimized. No FDA-approved H pylori regimen has been optimized, and in the United States, some H pylori regimens are only available as expensive (approximately $1000/course) proprietary-packaged medication, making optimization difficult and expensive. For example, with the traditional bismuth quadruple therapy (bismuth, tetracycline, metronidazole, and a PPI), duration is an important variable with a longer duration (ie, 14 days) preferred in the presence of metronidazole resistance.56 As noted previously, the name bismuth quadruple therapy is given to a wide variety of different formulations. In some regions of the world, 3-in-1 packages of bismuth quadruple therapy are available in which reduction of the pill burden is achieved by having the capsules also containing a second small capsule with metronidazole. Four to 7 days of bismuth quadruple therapy is sufficient in the presence of metronidazole-susceptible strains.57 The branded bismuth quadruple therapy is marketed for 10 days, whereas traditionally the therapy was administered for 14 days.58 In regions where metronidazole resistance is common, or cure rates with branded bismuth quadruple therapy are less than 95% in adherent patients, optimization of the duration could be considered to identify if a longer treatment is advantageous.58

Worldwide there has been a decline in the effectiveness of triple therapies containing a PPI plus amoxicillin and clarithromycin, metronidazole, or levofloxacin (the legacy triple therapies), resulting in them being relegated to the category of susceptibility-based therapies.59-61 With both clarithromycin and levofloxacin resistance, the affected antibiotic drops out leaving only 1 effective drug (ie, amoxicillin), and with triple therapies, producing a PPI or P-CAB plus amoxicillin dual therapy. For a population, the cure rate thus becomes the sum of the 2 remaining therapies (ie, for susceptible infections, a triple therapy, and for resistant infections, a dual therapy).62 This effect can be visualized using an H pylori nomogram (Figure 4).62 Because resistance tends to be high for clarithromycin and levofloxacin, these therapies should currently only be administered as susceptibility-based triple therapies. The cure rates with metronidazole in the presence of resistance are reduced but remain high, and the mechanism for this is not completely understood. 

Need for Routine Testing of Cure

The goals of H pylori therapy are to eradicate the infection, cure H pylori–related peptic ulcer disease, heal gastritis, and halt the progression of gastric mucosal damage to reduce, although likely not eliminate, gastric cancer risk. Cure also eliminates the carrier status of the patient, thus potentially reducing further spread of the infection.

Treatment of H pylori infection should universally be followed by a test to determine whether the therapy was successful. Noninvasive testing is available using the urea breath test or stool antigen test. Either of these tests can be coupled with AST in stools for noninvasive investigation of the possible causes of treatment failure. The susceptibility status both before and after treatment failure is the critical variable required for interpretation of the results. An example is the presence of clarithromycin resistance after therapy for a clarithromycin-susceptible infection. The emergence of resistance during therapy is a typical manifestation of the presence of heteroresistance.63 In contrast, an infection that is clarithromycin susceptible both before and after therapy would imply that either the drugs were not taken properly or there was a pharmacologic problem with the regimen administered (eg, with the dose, duration, or adherence to the protocol).4


The science and technology are finally in place to transform the H pylori treatment paradigm to a new standard based on AST that aligns with antimicrobial stewardship and abides by the treatment approach for other infectious diseases. However, actualizing this transformation will require deliberate interventions to improve provider awareness regarding best practices for H pylori management and lay the foundation for susceptibility-guided treatment.58 Indeed, even if H pylori demonstrates unequivocal susceptibility to the prescribed antibiotics, these antibiotics will only be effective if the patient: consumes them; consumes them at the correct frequencies, dosages, and duration; and consumes them while concomitantly achieving appropriate gastric acid suppression (target intragastric pH of at least 6 for amoxicillin-containing regimens). Patient adherence and appropriate antimicrobial treatment (dosage, administration, duration, and intragastric acid suppression) are adjunctive tenets that are critical to successfully executing susceptibility-guided H pylori treatment. Finally, interventions are immediately needed to improve the frequency of H pylori posttreatment test of cure, which is recommended in all persons at least 4 weeks following H pylori treatment owing to rising eradication failure rates. However, the data consistently demonstrate that a nonserologic test of cure is most often not performed. Recent nationwide cohort studies in the United States have reported that as many as 76% of treated individuals have no recorded test.64 Having consistent test-of- cure data available might also facilitate the development of robust H pylori registries to monitor local eradication success rates and practice patterns, which can provide valuable information to facilitate dynamic data-driven modifications to the H pylori therapeutic approach. 


Dr Graham is an unpaid consultant for RedHill Biopharma and Phathom Pharmaceuticals regarding novel H pylori therapies and has received research support for the culture of H pylori. He has been a consultant for Janssen Research & Development regarding potential gastrointestinal effects of drugs under development and has collaborated on research projects with American Molecular Laboratories regarding molecular diagnostics for H pylori. He is supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs, Public Health
Service Grant DK56338, which funds the Texas Medical Center Digestive Diseases Center and by the Cancer Prevention and Research Institute of Texas (RP220127).


1. Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983;1(8336):1273-1275. 

2. Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfill Koch’s postulates for pyloric Campylobacter. Med J Aust. 1985;142(8):436-439. 

3. Marshall B. Helicobacter connections. ChemMedChem. 2006;1(8):783-802. 

4. Graham DY. Implications of the paradigm shift in management of Helicobacter pylori infections. Therap Adv Gastroenterol. 2023;16:17562848231160858. 

5. 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;71(9):gutjnl-2022-327745. 

6. Liu WZ, Xie Y, Lu H, et al. Fifth Chinese National Consensus Report on the management of Helicobacter pylori infection. Helicobacter. 2018;23(2):e12475. 

7. El-Serag HB, Kao JY, Kanwal F, et al. Houston Consensus Conference on testing for Helicobacter pylori infection in the United States. Clin Gastroenterol Hepatol. 2018;16(7):992-1002. 

8. Sugano K, Tack J, Kuipers EJ, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut. 2015;64(9):1353-1367.

9. Graham DY, Moss SF. Antimicrobial susceptibility testing for Helicobacter pylori is now widely available: when, how, why. Am J Gastroenterol. 2022;117(4):524-528. 

10. Dyar OJ, Huttner B, Schouten J, Pulcini C. What is antimicrobial stewardship? Clin Microbiol Infect. 2017;23(11):793-798.

11. Graham DY, Liou JM. Primer for development of guidelines for Helicobacter pylori therapy using antimicrobial stewardship. Clin Gastroenterol Hepatol. 2022;20(5):973-983.e1. 

12. Lee YC, Dore MP, Graham DY. Diagnosis and treatment of Helicobacter pylori infection. Annu Rev Med. 2022;73(1):183-195. 

13. Zhou BG, Mei YZ, Zhang M, Jiang X, Li YY, Ding YB. High-dose dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis with trial sequential analysis. Therap Adv Gastroenterol. 2023;16:17562848221147756. 

14. Borsch GM, Graham DY. Helicobacter pylori. In: Collen MJ, Benjamin SB, eds. Pharmacology of Peptic Ulcer Disease. Springer-Verlag; 1991:107-148. Handbook of Experimental Pharmacology; vol 99. 

15. George LL, Borody TJ, Andrews P, et al. Cure of duodenal ulcer after eradication of Helicobacter pylori. Med J Aust. 1990;153(3):145-149. 

16. Borody TJ, Brandl S, Andrews P, Ferch N, Jankiewicz E, Hyland L. Use of high efficacy, lower dose triple therapy to reduce side effects of eradicating Helicobacter pylori. Am J Gastroenterol. 1994;89(1):33-38.

17. Logan RP, Gummett PA, Misiewicz JJ, Karim QN, Walker MM, Baron JH. Two-week eradication regimen for metronidazole-resistant Helicobacter pylori. Aliment Pharmacol Ther. 1993;7(2):149-153. 

18. Axon AT. The role of omeprazole and antibiotic combinations in the eradication of Helicobacter pylori—an update. Scand J Gastroenterol Suppl. 1994;205(205):31-37. 

19. Hardy DJ, Hanson CW, Hensey DM, Beyer JM, Fernandes PB. Susceptibility of Campylobacter pylori to macrolides and fluoroquinolones. J Antimicrob Chemother. 1988;22(5):631-636. 

20. Logan RP, Gummett PA, Hegarty BT, Walker MM, Baron JH, Misiewicz JJ. Clarithromycin and omeprazole for Helicobacter pylori. [letter]. Lancet. 1992;340(8813):239-239. 

21. Peters DH, Clissold SP. Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential. Drugs. 1992;44(1):117-164. 

22. Fukuda Y, Yamamoto I, Tonokatsu Y, Shimoyama T. [The role of eradication of Helicobacter pylori in healing and recurrence of gastric ulcer]. Jpn J Clin Med. 1993;1993(51):3278-3284. 

23. Graham DY, Opekun AR, Klein PD. Clarithromycin for the eradication of Helicobacter pylori. J Clin Gastroenterol. 1993;16(4):292-294. 

24. Lamouliatte H, Cayla R, Megraud F, et al. Amoxicillin-clarithromycin-omeprazole: the best therapy for Helicobacter pylori infection. Acta Gastroenterol Belg. 1993;56:A139.

25. Bazzoli F. Efficacy and tolerability of a short term, low dose triple therapy for eradication of Helicobacter pylori. Gastroenterology. 1993;104:A40.

26. Hopkins RJ. Current FDA-approved treatments for Helicobacter pylori and the FDA approval process. Gastroenterology. 1997;113(6)(suppl):S126-S130. 

27. Graham DY. Antibiotic resistance in Helicobacter pylori: implications for therapy. Gastroenterology. 1998;115(5):1272-1277. 

28. Lind T, Veldhuyzen van Zanten S, Unge P, et al. Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I study. Helicobacter. 1996;1(3):138-144. 

29. Lind T, Megraud F, Unge P, et al. The MACH2 study: role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies. Gastroenterology. 1999;116(2):248-253. 

30. Malfertheiner P, Bayerdorffer E, Diete U, et al. The GU-MACH study: the effect of 1-week omeprazole triple therapy on Helicobacter pylori infection in patients with gastric ulcer. Aliment Pharmacol Ther. 1999;13(6):703-712. 

31. Zanten SJ, Bradette M, Farley A, et al. The DU-MACH study: eradication of Helicobacter pylori and ulcer healing in patients with acute duodenal ulcer using omeprazole based triple therapy. Aliment Pharmacol Ther. 1999;13(3):289-295. 

32. Breuer T, Kim JG, El-Zimaity HM, et al. Clarithromycin, amoxycillin and H2-receptor antagonist therapy for Helicobacter pylori peptic ulcer disease in Korea. Aliment Pharmacol Ther. 1997;11(5):939-942. 

33. Graham DY, Hammoud F, El-Zimaity HM, Kim JG, Osato MS, el-Serag HB. Meta-analysis: proton pump inhibitor or H2-receptor antagonist for Helicobacter pylori eradication. Aliment Pharmacol Ther. 2003;17(10):1229-1236. 

34. Malfertheiner P, Megraud F, O’Morain C, et al. Current European concepts in the management of Helicobacter pylori infection–the Maastricht Consensus Report. The European Helicobacter Pylori Study Group (EHPSG). Eur J Gastroenterol Hepatol. 1997;9(1):1-2. 

35. Laheij RJ, Rossum LG, Jansen JB, Straatman H, Verbeek AL. Evaluation of treatment regimens to cure Helicobacter pylori infection- a meta-analysis. Aliment Pharmacol Ther. 1999;13(7):857-864. 

36. Moayyedi P, Feltbower R, Crocombe W, et al. The effectiveness of omeprazole, clarithromycin and tinidazole in eradicating Helicobacter pylori in a community screen and treat programme. Leeds Help Study Group. Aliment Pharmacol Ther. 2000;14(6):719-728. 

37. Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56(6):772-781. 

38. Treiber G, Ammon S, Schneider E, Klotz U. Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter. 1998 1998;3(1):54-58. 

39. Dang BN, Graham DY. Helicobacter pylori infection and antibiotic resistance: a WHO high priority? Nat Rev Gastroenterol Hepatol. 2017;7:383-384.

40. Dang BN, Graham DY. It is time to rethink H. pylori therapy. J Gastrointestin Liver Dis. 6/2017 2017;26(2):115-117. 

41. 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(1):40-54. 

42. Nyssen OP, Pratesi P, Spínola MA, et al; On Behalf of the Hp-EuReg Investigators. Analysis of clinical phenotypes through machine learning of first-line H. pylori treatment in Europe during the period 2013-2022: data from the European Registry on H. pylori management (Hp-EuReg). Antibiotics (Basel). 2023;12(9):1427. 

43. Graham DY, Lu H, Shiotani A. Vonoprazan-containing Helicobacter pylori triple therapies contribution to global antimicrobial resistance. J Gastroenterol Hepatol. 2021;36(5):1159-1163. 

44. 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(3):608-619. 

45. Graham DY. Why the vonoprazan Helicobacter pylori therapies in the US-European trial produced unacceptable cure rates. Dig Dis Sci. 2023;68(5):1691-1697. 

46. Du RC, Hu YX, Ouyang Y, et al. Vonoprazan and amoxicillin dual therapy as the first-line treatment of Helicobacter pylori infection: a systematic review and meta-analysis. Helicobacter. 2024;29(1):e13039.

47. Ratana-Amornpin S, Sanglutong L, Eiamsitrakoon T, Siramolpiwat S, Graham DY, Mahachai V. Pilot studies of vonoprazan-containing Helicobacter pylori eradication therapy suggest Thailand may be more similar to the US than Japan. Helicobacter. 2023;28(6):e13019. 

48. Zhou L, Lu H, Song Z, et al; on behalf of Helicobacter pylori Study Group of Chinese Society of Gastroenterology. 2022 Chinese national clinical practice guideline on Helicobacter pylori eradication treatment. Chin Med J (Engl). 2022;135(24):2899-2910. 

49. Bénéjat L, Ducournau A, Lehours P, Mégraud F. Real-time PCR for Helicobacter pylori diagnosis. The best tools available. Helicobacter. 2018;23(5):e12512. 

50. Li Y, Rimbara E, Thirumurthi S, et al. Detection of clarithromycin resistance in Helicobacter pylori following noncryogenic storage of rapid urease tests for 30 days. J Dig Dis. 2012;13(1):54-59. 

51. Greer CE, Peterson SL, Kiviat NB, Manos MM. PCR amplification from paraffin-embedded tissues. Effects of fixative and fixation time. Am J Clin Pathol. 1991;95(2):117-124. 

52. Cambau E, Allerheiligen V, Coulon C, et al. Evaluation of a new test, genotype HelicoDR, for molecular detection of antibiotic resistance in Helicobacter pylori. J Clin Microbiol. 2009;47(11):3600-3607. 

53. Du RC, Hu YX, Ouyang Y, et al. Vonoprazan and amoxicillin dual therapy as the first-line treatment of Helicobacter pylori infection: a systematic review and meta-analysis. Helicobacter. 2024;29(1):e13039. 

54. Han YY, Long H, Lin Y, et al. Optimized dual therapy for treatment-naive patients of Helicobacter pylori infection: a large-scale prospective, multicenter, open-label, randomized controlled study. Helicobacter. 2022;27(5):e12922. 

55. Gisbert JP, McNicholl AG. Optimization strategies aimed to increase the efficacy of H. pylori eradication therapies. Helicobacter. 2017;22(4):e12392. 

56. Graham DY, Dore MP, Lu H. Understanding treatment guidelines with bismuth and non-bismuth quadruple Helicobacter pylori eradication therapies. Expert Rev Anti Infect Ther. 2018;16(9):679-687. 

57. de Boer SY, Meeberg PC, Siem H, de Boer WA. Comparison of four-day and seven-day pantoprazole-based quadruple therapy as a routine treatment for Helicobacter pylori infection. Neth J Med. 2003;61(6):218-222. 

58. Shah SC, Iyer PG, Moss SF. AGA clinical practice update on the management of refractory Helicobacter pylori infection: expert review. Gastroenterology. 2021;160(5):1831-1841. 

59. Graham DY, Hernaez R, Rokkas T. Cross-roads for meta-analysis and network meta-analysis of H. pylori therapy. Gut. 2022;71(3):643-650. 

60. Rokkas T, Gisbert JP, Malfertheiner P, et al. Comparative effectiveness of multiple different first-line treatment regimens for Helicobacter pylori Infection: a network meta-analysis. Gastroenterology. 2021;161(2):495-507.e4. 

61. Yeo YH, Shiu SI, Ho HJ, et al; Taiwan Gastrointestinal Disease and Helicobacter Consortium. First-line Helicobacter pylori eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis. Gut. 2018;67(1):20-27. 

62. Graham DY. Hp-normogram (normo-graham) for assessing the outcome of H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype. Helicobacter. 2015;21(2):85-90. 

63. Mascellino MT, Porowska B, De Angelis M, Oliva A. Antibiotic susceptibility, heteroresistance, and updated treatment strategies in Helicobacter pylori infection. Drug Des Devel Ther. 2017;11:2209-2220. 

64. Shah S, Cappell K, Sedgley R, et al. Diagnosis and treatment patterns among patients with newly diagnosed Helicobacter pylori infection in the United States 2016–2019. Scientific Reports. 2023;13(1):1375.

65. Endo launches first generic version of Pylera® (bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride) capsules [press release]. Endo International plc; March 10, 2023.

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