Primer for Development of Guidelines for Helicobacter pylori Therapy Using Antimicrobial Stewardship

Abstract

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. of disease of Google Scholar Cure of H pylori infections is by often that antimicrobial and the of at least a of being D.Y. Antibiotic resistance in Helicobacter for Full Text Full Text PDF PubMed Scopus Google Scholar For example, the within the highly acid which is of the and thus to antibiotics and the H pylori is also in in an D.Y. 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