Primer for Development of Guidelines for Helicobacter pylori Therapy Using Antimicrobial Stewardship
Authors: David Y. Graham, Jyh-Ming Liou
Journal: Clinical Gastroenterology and Hepatology (2021)

We provide a primer to assist in the difficult transition of Helicobacter pylori therapy guidelines to those that adhere to the principles of antimicrobial stewardship. This transition will entail abandonment of many of the principles that heretofore formed the basis of treatment guidelines and recommendations. The goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate which largely restricts comparative trials to those which reliably produce high cure rates (eg, ∼95%). Therapies that fail to achieve at least a 90% cure rate should be abandoned as unacceptable. Because only optimized therapies should be prescribed, guidance on the principles and practices of optimization will we required. Therapies that contain antibiotics which do not contribute to outcome should be eliminated. Surveillance, one of the fundamental elements of antimicrobial stewardship, must be done to provide ongoing assurance that the recommended therapies remain effective. It is yet not widely recognized when utilizing otherwise highly successful therapies, the routine test of cure data is an indirect, surrogate method for susceptibility testing. To systematically guide therapy, test of cure data should be collected, shared and integrated into local antimicrobial stewardship programs to provide guidance regarding best practices to both prescribers and public health individuals. Treatment recommendations should be compatible with those of the American Society of Infectious Disease white paper on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens which include criteria for ethical active-controlled superiority studies of antibacterial agents. We provide a primer to assist in the difficult transition of Helicobacter pylori therapy guidelines to those that adhere to the principles of antimicrobial stewardship. This transition will entail abandonment of many of the principles that heretofore formed the basis of treatment guidelines and recommendations. The goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate which largely restricts comparative trials to those which reliably produce high cure rates (eg, ∼95%). Therapies that fail to achieve at least a 90% cure rate should be abandoned as unacceptable. Because only optimized therapies should be prescribed, guidance on the principles and practices of optimization will we required. Therapies that contain antibiotics which do not contribute to outcome should be eliminated. Surveillance, one of the fundamental elements of antimicrobial stewardship, must be done to provide ongoing assurance that the recommended therapies remain effective. It is yet not widely recognized when utilizing otherwise highly successful therapies, the routine test of cure data is an indirect, surrogate method for susceptibility testing. To systematically guide therapy, test of cure data should be collected, shared and integrated into local antimicrobial stewardship programs to provide guidance regarding best practices to both prescribers and public health individuals. Treatment recommendations should be compatible with those of the American Society of Infectious Disease white paper on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens which include criteria for ethical active-controlled superiority studies of antibacterial agents. What You Need to KnowBackgroundUntil recently, Helicobacter pylori therapy has been developed based on trial and error with a focus on comparative analyses of clinical trials with the better therapy recommended irrespective of the actual cure rates. Recognition that H. pylori gastritis was an infectious disease and that it was not exempt from the traditions and practices used for other antimicrobial therapies resulted in the ongoing transition to utilize the principles of antimicrobial stewardship.FindingsThe goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate, which largely restricts choices to those that reliable produce high cure rates (eg, ∼95%). Assessment of antimicrobial susceptibility is also available as the results of testing for cure. We provide a primer to assist in what will likely prove to be a difficult transition to guidelines based on the principles of antimicrobial stewardship.Implications for patient careCurrently, overall H. pylori cure rates are unsatisfactorily low compared with other infectious diseases. Development and implementation of guidelines based on the general principles of antimicrobial therapy, the principles of antimicrobial stewardship, and the recommendations of the Infectious Diseases Society of America should improve treatment outcome of H. pylori infections and reduce unintentional misuse of antibiotics thus reducing the imprint of H. pylori therapy on global antimicrobial resistance. Until recently, Helicobacter pylori therapy has been developed based on trial and error with a focus on comparative analyses of clinical trials with the better therapy recommended irrespective of the actual cure rates. Recognition that H. pylori gastritis was an infectious disease and that it was not exempt from the traditions and practices used for other antimicrobial therapies resulted in the ongoing transition to utilize the principles of antimicrobial stewardship. The goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate, which largely restricts choices to those that reliable produce high cure rates (eg, ∼95%). Assessment of antimicrobial susceptibility is also available as the results of testing for cure. We provide a primer to assist in what will likely prove to be a difficult transition to guidelines based on the principles of antimicrobial stewardship. Currently, overall H. pylori cure rates are unsatisfactorily low compared with other infectious diseases. Development and implementation of guidelines based on the general principles of antimicrobial therapy, the principles of antimicrobial stewardship, and the recommendations of the Infectious Diseases Society of America should improve treatment outcome of H. pylori infections and reduce unintentional misuse of antibiotics thus reducing the imprint of H. pylori therapy on global antimicrobial resistance. Any attempt to modernize the guidelines regarding management of Helicobacter pylori infections and bring them into line with guidelines for treatment other infectious diseases must adhere to the principles of antimicrobial stewardship1Dyar O.J. Huttner B. Schouten J. et al.What is antimicrobial stewardship?.Clin Microbiol Infect. 2017; 23: 793-798Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar and take into consideration guidelines promulgated by the infectious disease community such as the American Society of infectious diseases.2Infectious Diseases Society of AmericaWhite paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens.Clin Infect Dis. 2012; 55: 1031-1046Crossref PubMed Scopus (93) Google Scholar The objectives of antimicrobial stewardship program are to optimize the use of antibiotics, improve patient outcomes, reduce antimicrobial resistance, prolong the lifespan of existing antibiotics, reduce healthcare-associated infection, and save healthcare costs.3World Health OrganizationAntimicrobial stewardship programmes in health-care facilities in low- and middle-income countries: a WHO practical toolkit. Geneva, Switzerland: World Health Organization.https://creativecommons.org/licenses/by-nc-sa/3.0/igoDate: 2019Date accessed: July 15, 2020Google Scholar In the past, the development of H pylori therapy was based largely on trial and error. The primary approach to development of management guidelines for H pylori therapy has been based on comparisons of differences between therapies (ie, a "better than" approach) with little regard for the absolute cure rates obtained.4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar In contrast, the principles of antimicrobial stewardship judge therapies primarily on their ability to reliably achieve prespecified cure rates. Antimicrobial stewardship is often a new concept to gastroenterologists, who are most familiar with treatment of diseases in which curative therapies are not available, treatment response is moderate, and placebo responses to therapy are common. In contrast, H pylori infections can be cured and there is no placebo response that obviates the need for a placebo control group. Fundamentally, antimicrobial stewardship can be considered as a coherent set of actions that (1) promote using antibiotics responsibly, (2) are designed to improve and measure appropriate use of antimicrobial agents and promote selection of optimal drug regimes, and (3) promote using antimicrobials in ways that ensure sustainable access to effective therapy for all that need them.2Infectious Diseases Society of AmericaWhite paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens.Clin Infect Dis. 2012; 55: 1031-1046Crossref PubMed Scopus (93) Google Scholar,4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar Here, we attempt of provide a primer to assist in what will likely prove to be a difficult transition to guidelines based on the principles of antimicrobial stewardship. Use of antibiotics responsibly requires that antibiotics be used in accordance with the general principles of both antimicrobial therapy (Table 1)5Leekha S. Terrell C.L. Edson R.S. General principles of antimicrobial therapy.Mayo Clin Proc. 2011; 86: 156-167Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar,6El-Serag H.B. Kao J.Y. Kanwal F. et al.Houston Consensus Conference on testing for Helicobacter pylori infection in the United States.Clin Gastroenterol Hepatol. 2018; 16: 992-1002Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar and antimicrobial stewardship.1Dyar O.J. Huttner B. Schouten J. et al.What is antimicrobial stewardship?.Clin Microbiol Infect. 2017; 23: 793-798Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar,7Charani E. Holmes A. Antibiotic stewardship–twenty years in the making.Antibiotics. (Basel). 2019; 8: 7Crossref PubMed Scopus (49) Google Scholar Optimal drug regimens should be used. Optimization encompasses all relevant parameters of therapy, including the choice and details of administration of antibiotics (ie, drugs, doses, dosing, formulations, route of administration, formulation, administration in relation to meals, duration of therapy). Only antimicrobials to which the infection is susceptible should be used. Exceptions to this statement include drugs for which resistance can be overcome such as by the concomitant use of clavulanic acid to inhibit Beta-lactamase. H pylori infections are unusual in that it has been possible to overcome metronidazole resistance, the details of which will be discussed subsequently.Table 1Principles of Antimicrobial Therapy for Helicobacter pylori infectionGeneral principles of antimicrobial therapyaAdapted with permission from El-Serag et al.6Obtain an accurate diagnosisUnderstand the difference between empiric and definitive therapyUnderstand drug characteristics that are peculiar to antimicrobial agents (eg, pharmacodynamics and efficacy at the site of infection)Account for host characteristics that influence antimicrobial activityRecognize the adverse effects of antimicrobial agents on the hostClinical definitions of outcomebAdapted with permission from Graham.4TermsDefinitionOptimized (optimal) therapyReliably achieves ≥95% cure rates in adherent patients with susceptible infectionConditionally acceptable therapyReliably achieves 90%–94% cure rates in adherent patients with susceptible infectionOptimal duration of therapyDays of therapy required to reliably achieve an optimal resultDoses and frequency of drug administrationThose that will reliably achieve an optimal resultRecommendation for use of empiric therapybAdapted with permission from Graham.4Empiric therapy should be restricted to therapies locally proven to be highly effective.Treatment effectiveness should always be confirmed by a test of cure.Test of cure data and any other direct and indirect antimicrobial susceptibility data should be collected and shared with other clinicians and integrated into local and the regional antimicrobial stewardship programs.Only treatment outcomes should form the basis of the recommendations regarding which therapies to use and which to avoid locally.a Adapted with permission from El-Serag et al.6El-Serag H.B. Kao J.Y. Kanwal F. et al.Houston Consensus Conference on testing for Helicobacter pylori infection in the United States.Clin Gastroenterol Hepatol. 2018; 16: 992-1002Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholarb Adapted with permission from Graham.4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar Open table in a new tab The definition of an optimized therapy is one that reliably achieves the highest cure rate possible, preferably 100%. Factors such as tolerability, cost, convenience, etc., become important considerations when choosing among different optimized therapies. Cure of H pylori infections has often proved difficult and, operationally, an optimized therapy may be defined as one that will reliably achieve cure rates ≥95% (Table 1).4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar Unacceptable therapies are those that fail to reliably achieve cure rates of at least 90%. It is generally easy to determine that an infectious disease, such as pneumonia or meningitis, has been cured. In contrast, H pylori infections are generally silent, and recrudescence may occur during the year following an apparently successful therapy. The accuracy of determining cure is dependent on the type, number, accuracy, and timing of the tests used. For practical purposes, determination of cure must also be assessed within a reasonable time after the end of therapy. Based on the results of the original treatment trials submitted to the US Food and Drug Administration (FDA), 4 weeks or more after the end of therapy was chosen as the standard. For practical purposes, usually only one noninvasive test, either the urea breath test or the stool antigen test, is utilized with the knowledge that neither is 100% sensitive nor specific. For example, in countries where atrophic gastritis is common, the proportion of false positive urea breath test tests will increase, especially if citric acid is not used. Inadvertent or unrecognized use of antibiotics or other drugs (eg, proton pump inhibitors [PPIs]) may also cause false negative tests. The fact that false positive and false negative tests occur (ie, the ability to identify when 95% cure rates have been obtained) means that it may be useful to consider adjusting the operational optimal cure rate, such as using ≥93%, rather than using ≥95%. We have chosen to use the ≥95% definition and to define cure rates of 90% to 94% as conditionally acceptable and cure rates below 90% as being unacceptable (Table 1).4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar Initial attempts to cure H pylori infections discovered that although the infection could be suppressed, it was difficult or impossible to cure with a single antibiotic.8Borsch G.M. Graham D.Y. Helicobacter pylori.in: Collen M.J. Benjamin S.B. Pharmacology of peptic ulcer disease (handbook of experimental pharmacology, 99). Springer-Verlag, Berlin, Germany1991: 107-148Crossref Google Scholar Cure of H pylori infections is impeded by many, often physical, factors that impair antimicrobial action and increase the likelihood of at least a small population of resistant organisms being present.9Graham D.Y. Antibiotic resistance in Helicobacter pylori: implications for therapy.Gastroenterology. 1998; 115: 1272-1277Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar For example, the organisms reside within the highly acid stomach, which is physically outside of the body and thus poorly accessible to blood-borne antibiotics and the immune system. H pylori is also typically present in vast numbers, resulting in an inoculum effect.9Graham D.Y. Antibiotic resistance in Helicobacter pylori: implications for therapy.Gastroenterology. 1998; 115: 1272-1277Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar It is thought that the inoculum effect is largely responsible for the failure of dual therapy with PPIs clarithromycin, metronidazole, or levofloxacin, as their effectiveness is undermined by emergence of resistance during therapy.10Hopkins R.J. Current FDA-approved treatments for Helicobacter pylori and the FDA approval process.Gastroenterology. 1997; 113: S126-S130Abstract Full Text PDF PubMed Scopus (54) Google Scholar It was subsequently discovered that the addition of PPIs to raise the pH and reduce washout, and amoxicillin to prevent emergence of resistant during therapy, would allow the development of triple therapies consisting of a PPI combined with amoxicillin and clarithromycin, metronidazole, or levofloxacin (see the following). A proportion of H pylori attach to the surface of gastric cells, leading to a biofilm phenomenon, and some are present intracellular by requiring the use of antibiotics capable of penetrating into cells.9Graham D.Y. Antibiotic resistance in Helicobacter pylori: implications for therapy.Gastroenterology. 1998; 115: 1272-1277Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar Finally, H pylori can become dormant in part because they can replicate only when the pH is approximately 6. Such a high pH is infrequently present in the stomach and is difficult to obtain with standard PPIs. Overall, this results in a persister effect,11Graham D.Y. Shiotani A. New concepts of resistance in the treatment of Helicobacter pylori infections.Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 321-331Crossref PubMed Scopus (289) Google Scholar,12Michiels J.E. Van den Bergh B. Verstraeten N. et al.Molecular mechanisms and clinical implications of bacterial persistence.Drug Resist Updat. 2016; 29: 76-89Crossref PubMed Scopus (116) Google Scholar which is often managed by increasing the duration of therapy. The optimal duration of therapy remains unclear and is complicated by the fact that full antisecretory activity of PPIs requires 3–4 days. This makes the actual duration of effective therapy shorter than the days it is administered. Overcoming these problems is largely responsible for the almost universal recommendation for standardization of the duration of therapy at 14 days. However, pharmaceutical companies often have chosen to shorten the recommended duration of therapy to obtain a marketing advantage at the expense of reduced effectiveness. Initially, this was possible because FDA approval was based on the healing of ulcers, rather than based on the cure rates achieved by the therapy.4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar,10Hopkins R.J. Current FDA-approved treatments for Helicobacter pylori and the FDA approval process.Gastroenterology. 1997; 113: S126-S130Abstract Full Text PDF PubMed Scopus (54) Google Scholar H pylori gastritis is an infectious disease and cure of an infectious disease is predicated on the choice of effective antibiotics. The difficulty in obtaining gastric samples for culture and acceptance of "ownership" of H pylori therapy by gastroenterology, rather than by infectious diseases, eventually resulted in a divergence of methods to judge the effectiveness of therapy. Traditionally, for infectious diseases, the cure rate is the primary determinate of effectiveness. Instead, gastroenterology focused on the results of comparisons of what were relatively ineffective, empirically administered therapies. For example, sequential therapy was judged as superior to clarithromycin triple therapy based on trials in which the cure rates with clarithromycin-containing triple therapy were low. They were accepted at face value, despite the knowledge that with clarithromycin susceptible infections, 14-day triple therapy would reliably achieve 95% cure rates. Meta-analyses were conducted and the study- or population-specific results were accepted and generalized (ie, sequential therapy was superior to triple therapy)13Zullo A. de Francesco V. Hassan C. et al.The sequential therapy regimen for Helicobacter pylori eradication: a pooled-data analysis.Gut. 2007; 56: 1353-1357Crossref PubMed Scopus (247) Google Scholar without the caveat that the superiority over triple therapy was only obtained in populations in which the prevalence of clarithromycin resistance was increased and that combined clarithromycin and metronidazole resistance was absent. Subsequent attempts to use sequential therapy in other populations failed, and it was eventually considered obsolete.14Gisbert J.P. Calvet X. O'connor A. et al.Sequential therapy for Helicobacter pylori eradication: A critical review.J Clin Gastroenterol. 2010; 44: 313-325Crossref PubMed Scopus (2) Google Scholar This is an example of how the gastroenterology approach (comparisons of relative effectiveness) failed when compared with the infectious disease approach (ability to reliably achieve high cure rates). The potential of emergence or selection of antimicrobial resistance differs according to the classes of antibiotics. The World Health Organization (WHO) has developed the AWaRe (Access, Watch, and Reserve) classification to the recommend on the use of antibiotics according to their potential of emergence of antimicrobial resistance (Table 2).3World Health OrganizationAntimicrobial stewardship programmes in health-care facilities in low- and middle-income countries: a WHO practical toolkit. Geneva, Switzerland: World Health Organization.https://creativecommons.org/licenses/by-nc-sa/3.0/igoDate: 2019Date accessed: July 15, 2020Google Scholar,15World Health Organization WHO AWaRe Classification of Antibiotics for evaluation and monitoring of use. Volume WHO/EMP/IAU/2019.11. World Health Organization, Geneva, Switzerland2019Google ScholarTable 2WHO AWaRe Committee on Selection and Use of Essential MedicinesGroupCharacteristics of antibiotics or antibiotic classesAntibiotics used for Helicobacter pylori eradicationAccess1. Activity against a wide range of commonly encountered susceptible pathogens2. Showing lower resistance potential3. Should be widely available and affordable4. Essential first-choice or second-choice empirical treatment optionsamoxicillin, tetracycline, metronidazole, doxycycline,Watch1. Higher risk of selection of bacterial resistance2. The highest-priority agents among the critically important antimicrobials for human medicine3. Should be prioritized as key targets of stewardship programs and monitoringclarithromycin, ciprofloxacin, levofloxacin, rifabutinReserve1. Should be reserved for treatment of confirmed or suspected infections due to multi drug-resistant organisms2. Treated as "last-resort" options3. Should be tailored to highly specific patients and settings to preserve their effectivenessminocyclineNOTE. Adapted with permission from the 2019 WHO AWaRe Classification of Antibiotics for evaluation and monitoring of use.15World Health Organization WHO AWaRe Classification of Antibiotics for evaluation and monitoring of use. Volume WHO/EMP/IAU/2019.11. World Health Organization, Geneva, Switzerland2019Google ScholarWHO, World Health Organization. Open table in a new tab NOTE. Adapted with permission from the 2019 WHO AWaRe Classification of Antibiotics for evaluation and monitoring of use.15World Health Organization WHO AWaRe Classification of Antibiotics for evaluation and monitoring of use. Volume WHO/EMP/IAU/2019.11. World Health Organization, Geneva, Switzerland2019Google Scholar WHO, World Health Organization. Antibiotics in the access group have lower resistance potential than do those in the other 2 groups. They should be widely available and affordable. Amoxicillin, tetracycline, and metronidazole are classified as the access group. In contrast, clarithromycin and levofloxacin have higher resistance potential and are classified as the watch group. They should be prioritized as key targets of stewardship program and monitoring. These recommendations should be taken into account in clinical treatment guidelines for H pylori infection. For example, bismuth quadruple therapy containing tetracycline and metronidazole should be considered as first-line therapy in mass eradication programs for gastric cancer prevention. Traditionally, most infectious disease therapy is given empirically and is highly successful. Most H pylori therapy is also given empirically but typically is not highly successful.16Graham D.Y. El-Serag H.B. European Registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners.Gut. 2021; 70: 1-2Crossref PubMed Scopus (13) Google Scholar,17Nyssen O.P. Bordin D. Tepes B. et al.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: 40-54Crossref PubMed Scopus (107) Google Scholar The difference is that with traditional infectious diseases, only proven locally effective, optimized susceptibility-based therapies are used empirically. This is based on the general rule, when the local antimicrobial susceptibility pattern is stable, effective, optimized susceptibility-based therapies can be used empirically until resistance arises. Continuing use of the therapy is predicated on the monitoring of local and regional antimicrobial susceptibility and treatment outcomes. Any changes that are observed are then communicated to clinicians along with recommendations regarding modification of therapy. Surveillance is one of the fundamental elements of antimicrobial stewardship that provides ongoing assurance that the recommended empiric therapies remain effective. For simple infectious diseases, cultures may not be obtained unless there is poor response to therapy. In contrast, with serious acute infections, or chronic infections with the potential for bad outcomes (eg tuberculosis), immediate treatment may be indicated. However, cultures are also obtained so that the therapy can be rapidly revised, if needed. H pylori gastritis is a chronic infection, typically acquired in childhood, that has been present for years (often decades) before it is diagnosed. As such, there are few, if any indications requiring emergency initiation of treatment; therapy can be safely delayed until the best treatment has been identified. There are many H pylori therapies that will reliably achieve high cure rates with susceptible infections.18Matsumoto H. Shiotani A. Graham D.Y. Current and Future Treatment of Helicobacter pylori Infections.Adv Exp Med Biol. 2019; 1149: 211-225Crossref PubMed Scopus (44) Google Scholar,19Liou J.-M. Chen P.-Y. Kuo Y.-T. et al.Toward population specific and personalized treatment of Helicobacter pylori infection.J Biomed Sci. 2018; 25: 70Crossref PubMed Scopus (24) Google Scholar However, currently most H pylori infections receive empiric therapy, and the clinician does not know or even have access to treatment guidance based on local or regional antimicrobial susceptibility patterns. To date, H pylori has remained excluded from local and regional antimicrobial surveillance programs, and few hospitals or clinics offer susceptibility testing. Although the paucity of susceptibility testing and data has been recognized as a serious national problem and has prompted calls for action, nothing has been done.6El-Serag H.B. Kao J.Y. Kanwal F. et al.Houston Consensus Conference on testing for Helicobacter pylori infection in the United States.Clin Gastroenterol Hepatol. 2018; 16: 992-1002Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Although the Centers for Medicare and Medicaid Services finalized a new regulation requiring all hospitals participating in its programs to establish antimicrobial stewardship programs by March 30, 2020, which included a requirement for susceptibility testing, there has been no action, suggesting that H pylori infections have been exempted.20Medicare Medicaid Programs Regulatory Provisions to Promote Program Efficiency, Transparency, and Burden Reduction; Fire Safety Requirements for Certain Dialysis Facilities; Hospital and Critical Access Hospital (CAH) Changes to Promote Innovation, Flexibility, and Improvement in Patient Care.Fed Regist. 2019; 84: 51732-51834Google Scholar,21Graham D.Y. El-Serag H.B. CMS's new rule for antibiotic stewardship: The case of H. pylori. GI and Hepatology News.https://www.mdedge.com/gihepnews/article/217819/practice-management/cmss-new-rule-antibiotic-stewardship-case-h-pylori?sso=trueDate: February 25, 2020Date accessed: July 15, 2020Google Scholar The continued use of this approach has been justified by the fact that susceptibility testing for H pylori is largely unavailable. Notably, none of the gastroenterology, infectious disease, or H pylori study groups has stepped up and attempted to solve the problem. Currently, a few major reference laboratories have begun to offer H pylori culture and susceptibility testing, plus molecular-based H pylori testing is now commercially available for commonly used antibiotics using fresh or formalin-fixed gastric biopsies or stools.22Graham D.Y. Molecular-based Helicobacter pylori susceptibility testing is almost ready for prime time.Gastroenterology. 2021; 160: 1936-1937Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,23Argueta E.A. Alsamman M.A. Moss S.F. Agata E.M.C. Impact of antimicrobial resistance rates on eradication of Helicobacter pylori in a United States population.Gastroenterology. 2021; 160: 2181-2183.e1Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar In retrospect, and as discussed in detail subsequently, clinicians have long had the data needed to provide guidance regarding which therapies to use and which to avoid. These data are available as the test of cure data obtained to confirm H pylori eradication; they provide an indirect assessment of local antibiotic resistance, as defined by the World Health Organization as an antimicrobial resistance surveillance program.4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar Traditionally, treatment of an H pylori infection consists of diagnosis and treatment, followed 4 or more weeks later by a test of evaluate whether the infection was cured (the test of cure). This has become increasingly important as cure rates have fallen. The importance of these data has been greatly underestimated, and there are many examples of test of cure data routinely collected and even linked to individual treatments without understanding how it could best be utilized.17Nyssen O.P. Bordin D. Tepes B. et al.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: 40-54Crossref PubMed Scopus (107) Google Scholar,24Ginnebaugh B.D. Baker J. Watts L. et al.S1348 Triple Therapy for Primary Treatment of Helicobacter pylori: a 19-year U.S. single center experience.Am J Gastroenterol. 2020; 115: S680-S681Crossref Google Scholar Fundamentally, if the regimen is one that reliably provides high cure rates with susceptible infections, the test of cure data provides an indirect assessment of susceptibility and resistance and can be used systematically to guide therapy.17Nyssen O.P. Bordin D. Tepes B. et al.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: 40-54Crossref PubMed Scopus (107) Google Scholar,24Ginnebaugh B.D. Baker J. Watts L. et al.S1348 Triple Therapy for Primary Treatment of Helicobacter pylori: a 19-year U.S. single center experience.Am J Gastroenterol. 2020; 115: S680-S681Crossref Google Scholar It is important to collect and share these data with other physicians, but especially with those with charged with collecting and disseminating local resistance and susceptibility data for infectious diseases. The data, along with monitoring of prescription practices, should be integrated into local antimicrobial stewardship programs designed to provide guidance regarding best practices to both prescribers and public health individuals. One can imagine that, if the European registry on H pylori management had designed their program to collect and disseminate their test of cure results to the participants and the local public health individuals, the overall outcome in terms of the proportion of H pylori infectious cured would likely have markedly improved.16Graham D.Y. El-Serag H.B. European Registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners.Gut. 2021; 70: 1-2Crossref PubMed Scopus (13) Google Scholar,17Nyssen O.P. Bordin D. Tepes B. et al.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: 40-54Crossref PubMed Scopus (107) Google Scholar Table 14Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar provides recommendations on how to use test of cure data to promote rational empiric therapy of H pylori infections. The recent era that employed trial and error as the main method for discovery of H pylori therapies relied primarily on comparison of therapies, especially by meta-analyses, to judge outcome and provide treatment guidance. Assessing therapies by attempting to determine which was superior independent of actual cure rates has been superseded by employing the principles of antimicrobial stewardship that judge therapies in terms of outcome or cure with the goal of 100%. Because antimicrobial stewardship requires that clinicians prescribe only those therapies that reliably achieve high cure rates, differences between regimens or factors such as duration that fail to achieve high cure rates are no longer of interest.4Graham D.Y. Transitioning of Helicobacter pylori therapy from trial and error to antimicrobial stewardship.Antibiotics (Basel). 2020; 9: 671Crossref PubMed Scopus (38) Google Scholar Only therapies that reliably achieve high cure rates (eg, 94% vs 96%) should be compared, and most often the comparison will use a noninferiority design.25Riedner G. Rusizoka M. Todd J. et al.Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis.N Engl J Med. 2005; 353: 1236-1244Crossref PubMed Scopus (227) Google Scholar Because the differences in cure rate of acceptable therapies are small, future comparative studies will likely focus primarily on factors such as tolerability, cost, convenience, duration, etc.