Addressing the Unmet Needs of Helicobacter pylori Treatment Through Alternative Treatment Options and Antimicrobial Stewardship

GASTRIC CANCER is the third most common cause of cancer death worldwide and is associated with Helicobacter pylori,¹ which is classified as a human carcinogen by the International Agency for Research on Cancer.¹ Chronic infection with H pylori has been demonstrated to cause noncardia gastric carcinoma and low-grade B-cell gastric mucosa-associated lymphoid tissue (MALT) lymphoma.² Over 850,000 deaths were attributed to gastric cancer in 2017. This rate is expected to increase because of increasing life expectancy in developing countries and increased risk in younger generations.¹ Globally, up to 89% of noncardia gastric cancers are attributable to H pylori, which is a total of around 780,000 cases and 6.2% of all cancers worldwide. Of the 2.2 million cancers attributable to infection worldwide in 2008, H pylori was responsible for 36.3%.² Because gastric cancer is a major cause of morbidity and mortality worldwide, the International Agency for Research on Cancer working group recommended that countries explore population-based H pylori screening and treatment programs.¹ Additionally, eradication of H pylori in asymptomatic individuals has been shown to correlate with a reduction in gastric cancer.¹

Circumventing Antibiotic Resistance Through Available Treatment Options

Increasing H pylori antibiotic resistance rates are affecting the efficacy of many traditional treatment options.^3-5 Therefore, alternative treatment options are being explored.

High-dose dual therapy

High-dose dual therapy (HDDT) may be a viable option for first-line therapy. During HDDT, a proton pump inhibitor (PPI) and amoxicillin are given to the patient more than 2 times daily.⁶ A systematic review and meta-analysis aimed to compare the efficacy and safety of HDDT with other regimens and found that HDDT was equivalent to recommended first-line or rescue regimens (84% vs 81% eradication rate; relative risk [RR] = 1.00; 95% CI, 0.96-1.05; P = .870) with fewer adverse effects (17% vs 37%; RR = 0.48; 95% CI, 0.37-0.64; P<.001).⁶ In the 15 reviewed trials (11 conducted in Asia, 3 in Europe, 1 in North America), HDDT was given 3 times daily in 4 trials and 4 times daily in the others. HDDT was compared with control regimens that included triple therapy, bismuth quadruple therapy, nonbismuth quadruple therapy, and a combination of triple therapy and sequential therapy.⁶ An open-label, randomized single-center study conducted in China aimed to determine whether bismuth improved the efficacy of HDDT.7 The cure rates in the nonbismuth group were 96.1% (95% CI, 88.9%-99.2%) compared with 93.3% (95% CI, 85.1%-97.8%) in the bismuth group, but the results were not significant (P = .5).⁷ Interestingly, adding bismuth to HDDT only improved cure rates for smokers; it did not improve cure rates for nonsmokers.⁷ Nevertheless, the study found HDDT to be both an effective and safe candidate for first-line treatment in a population with a high prevalence of antibiotic resistance.⁷

Rifabutin-based therapy

The 2017 American College of Gastroenterology (ACG) Clinical Guideline discusses high-dose rifabutin-based therapy (300 mg) as a salvage therapy,⁴ but does not address the low-dose regimen (150 mg) as a first-line therapy. The omeprazole, rifabutin, amoxicillin combination therapy is designed to combat H pylori antibiotic resistance.8 Rifabutin is ideal for combating H pylori because it has in vitro bactericidal activity against the bacterium, it reaches high intracellular and intragastric concentrations, and resistance is rare and typically only occurs when the drug is administered in high doses for long periods.⁸ In 2019, the FDA approved the first rifabutin-based therapy for the treatment of H pylori infection in adults.⁹ This followed ERADICATE Hp (NCT01980095), a phase 3, double-blind trial that tested the efficacy of RHB-105, a fixed-dose treatment containing a low dose of rifabutin (150 mg/d) plus amoxicillin (3000 mg/d) and omeprazole (120 mg/d), given as 4 capsules every 8 hours for 14 days.⁸ Study participants included 455 treatment-naive adults who had had dyspepsia for at least 2 weeks and confirmed H pylori infection.⁸ At baseline, certain patients were found to carry H pylori strains that were resistant to amoxicillin, clarithromycin, or metronidazole. Others carried isolates that were resistant to both clarithromycin and metronidazole.⁸ In the intention-to-treat data set, the eradication rate was higher with RHB-105 than with the comparator treatment containing amoxicillin (3000 mg/d) and omeprazole (120 mg/d) (83.8% vs 57.7%; P<.001).⁸ The eradication rate in the RHB-105 group remained high regardless of antibiotic resistance or susceptibility of H pylori strains causing the infection.⁸ RHB-105 had favorable tolerability and a similar adherence and adverse event profile to those of the comparator group.⁸ Given these findings, low-dose rifabutin-based therapy can be an effective first-line option, especially in regions where antibiotic resistance has caused traditional H pylori treatment options to fail.

Novel approaches

Most therapies used for H pylori eradication involve combining broad-spectrum antibiotics, bismuth, and acid inhibitors, but increasing resistance rates highlight the importance of developing novel therapeutic approaches. The ACG Clinical Guideline briefly discusses probiotic use as adjuvant therapy for H pylori but acknowledges that any data advocating for probiotic use come from clinical trials of low quality. Although certain probiotics might help reduce adverse effects of frontline eradication therapies and increase adherence with these regimens, such use requires further investigation^.4 Additionally, acid suppression using potassium-competitive acid blockers is currently being investigated.¹⁰

Despite the potential for these novel therapies, rising antibiotic resistance rates underscore the urgency to develop new therapeutic targets and narrow-spectrum antibiotics against H pylori to combat resistance. Numerous H pylori genomes have been sequenced, but clinical translation of factors targeting H pylori major enzymes, such as urease and glutamate racemase, have been disappointing.¹¹ Several studies have investigated a potential vaccine for H pylori but have found limited success. An exception is a large field trial in China that involved a recombinant urease B vaccine given orally with a mucosal adjuvant to teenagers, which resulted in more than 70% efficacy, although further investigation is warranted.¹¹

Applying the Principles of Antibiotic Stewardship to Treating H pylori

Several H pylori consensus treatment guidelines recommend susceptibility-guided therapy. Still, individual antibiotic susceptibility testing is not widely available in North America and antibiotic susceptibility registries akin to those in Europe do not exist on this continent.¹¹ A comprehensive review from Spain considered the advantages and limitations of susceptibility-guided strategies to treat H pylori infection. Assessing the antibiotic susceptibility of the H pylori strain in a patient allows a clinician to determine treatment options for that patient that reduce both resistance development and unnecessary antibiotic prescription. Susceptibility testing also prevents additional costs associated with prescribing antibiotics that lack efficacy and induce adverse events. If susceptibility testing is performed before first-line therapy, the most effective antibiotic regimen can be chosen and administered to the patient.¹² However, obtaining samples for susceptibility testing is difficult and the tests have low sensitivity. Moreover, there is no consensus regarding whether susceptibility testing should be performed before a patient’s first treatment or only after eradication failure.¹² Historically, susceptibility testing has involved obtaining cultures, which is time consuming, is not always available, and only provides useful information for clarithromycin, metronidazole, and quinolones.¹²

Importantly, culture is not the only way to determine antibiotic resistance in H pylori. Different polymerase chain reaction (PCR)-based techniques have been developed as alternative methods to culture.¹² Molecular tests are faster than conventional culture techniques and do not require the long wait times to obtain cultures or present problems with difficult-to-isolate specimens. They can be performed on either stool or gastric biopsy samples. Molecular tests can also be used in small and medium-sized hospitals, which is ideal for developing countries.¹² Although some investigators and clinicians make the specific point that patients should not undergo endoscopy before treatment, there is consensus that both testing for antimicrobial susceptibility and treating H pylori infection in a patient-tailored manner may limit the emergence of antibiotic resistance.¹²

Efficacy and benefits of susceptibility-based therapy

Though susceptibility-based therapy appears to be at least as effective as empirical therapy and can minimize antimicrobial resistance, H pylori treatment regimens are most often prescribed empirically because of the lack of population-based data about antibiotic resistance in H pylori strains, availability of sensitivity testing, institutional approval for molecular testing methods, and sensitivity and specificity in tests.^9,13 Moreover, data comparing the efficacy of susceptibility-guided therapy with that of empirical therapy have major limitations that call into question the comparisons’ reliability.¹² First among these is that trials to date that compare these therapies have not accurately randomized patients, rendering conclusions about therapy effectiveness unreliable.¹² Second, few data exist comparing susceptibility-based therapy with currently recommended bismuth or nonbismuth quadruple therapies; most studies have considered previously recommended triple therapy.¹² A third limitation is that many comparative studies performed susceptibility testing for only 1 antibiotic (clarithromycin); resistance to other antibiotics was not considered.¹² One consequence of these limitations is that advisers must recommend policy based upon low-quality data: The Maastricht V consensus report, for instance, indicates that susceptibility testing is not recommended in populations or regions with well-documented low clarithromycin resistance (<15%), even though little scientific evidence supports this.12><15%), even though little scientific evidence supports this.¹²

Despite these limitations in data, susceptibility-based therapy has proven effective compared with empirical treatment. Multiple studies have shown enhanced efficacy with culture-guided treatments for first-line therapy, although data suggest that susceptibility-guided treatment and the most updated empirical regimens may be equally effective.¹² When susceptibility-guided strategies are used in the second line, however, several studies have shown comparable efficacy between the 2 treatments.¹² In the third line, susceptibility-guided strategies have been proven to have similar efficacy to empirical treatment.¹²

The frequent selection of empirical treatment over equally effective susceptibility-based therapy threatens the efficacy of currently available antibiotics and lowers H pylori eradication rates.¹⁴ High cure rates for H pylori are possible, but current consensus statements and guidelines are based on principles used for other gastrointestinal diseases and rarely consider the different principles and practice of antimicrobial therapy.¹⁴ To minimize antimicrobial resistance and increase eradication rates, susceptibility testing should guide treatment.^9,14

Shifting to antimicrobial stewardship

In 2015, H pylori was officially recognized as an infectious disease. Because of this, investigators are beginning to accept that H pylori should be treated following guidelines and practices governing treatment of other infectious diseases; that is, those of antimicrobial stewardship.¹⁴ These principles prevent antimicrobial misuse, achieve high cure rates, and minimize the risk of developing resistance by optimizing therapy in terms of drugs, dosing, or duration of therapy.¹⁴

Trial-and-error therapeutic approaches to H pylori are a relic of early attempts to treat the disease. Shortly after the discovery of H pylori, investigators showed in vitro that it was susceptible to many antimicrobial agents. Unfortunately, the infection had low cure rates using those antimicrobials. Thus, trial-and-error clinical trials were prompted and used many different antimicrobials.¹⁴ H pylori therapy was initially focused on treatment of peptic ulcer disease where the ulcer was treated with a histamine-2 receptor antagonist and the infection with bismuth triple therapy, which included metronidazole. Shortly after, H pylori developed resistance to metronidazole, so researchers modified the therapy to include a PPI and increase the dosage of metronidazole and the duration of therapy.¹⁴ The development of H pylori therapies with different antibiotics has continued according to the trial-and-error approach with a focus on therapy comparisons, but overall cure rates are poor and declining.¹⁴

Challenges

Adopting antimicrobial stewardship principles requires a major paradigm shift. Because the diagnosis and management of H pylori was the responsibility of gastroenterologists after H pylori was discovered, treatment approaches were probably based on experience with common gastroenterology diseases. Most gastroenterology diseases are characterized as having largely unknown etiologies, and treatments are focused on results rather than on explanations for a poor response. This is the opposite in infectious disease, where the cause of a poor response is discovered. The gastroenterology approach focuses on how well a treatment performs relative to a comparator (often a placebo), whereas the infectious disease approach focuses on the absolute cure rate.¹⁴ Clinical trials involving H pylori have largely been designed according to the rules of gastroenterology, which has resulted in trial arms achieving poor results.¹⁴ Infectious disease treatment approaches focus on attaining predetermined cure rates and have different clinical trial outcome goals. Comparison trials of effective susceptibility-based therapies are rare and if they are performed, generally only involve limited comparisons of proven and highly reliable regimens using noninferiority methods.¹⁴

Another challenge in the shift to the antimicrobial stewardship model is that meta-analysis comparisons of H pylori treatments have had major flaws and are used inappropriately for assessing H pylori therapy. The populations in the trials being compared often have important differences that cannot be compared and trial results are often not generalizable. Generalizability is a key requirement for valid and ethical research according to the guidelines for implementing antimicrobial stewardship for treatment of H pylori infections developed by the Infectious Diseases Society of America.^14,15 Meta-analyses have also been misused when being used to provide guidance for therapy. For instance, the 2017 ACG guideline uses a meta-analysis that compares trials achieving clinically unacceptable cure rates to recommend that bismuth quadruple therapy replace triple therapy, whereas an infectious disease perspective would dictate that neither therapy be recommended in the studied regions.^4,14

Another challenge in the shift to the antimicrobial stewardship model is that meta-analysis comparisons of H pylori treatments have had major flaws and are used inappropriately for assessing H pylori therapy. The populations in the trials being compared often have important differences that cannot be compared and trial results are often not generalizable. Generalizability is a key requirement for valid and ethical research according to the guidelines for implementing antimicrobial stewardship for treatment of H pylori infections developed by the Infectious Diseases Society of America.^14,15 Meta-analyses have also been misused when being used to provide guidance for therapy. For instance, the 2017 ACG guideline uses a meta-analysis that compares trials achieving clinically unacceptable cure rates to recommend that bismuth quadruple therapy replace triple therapy, whereas an infectious disease perspective would dictate that neither therapy be recommended in the studied regions.^4,14

limited. Current consensus statements recommend testing only patients with 2 or more treatment failures, so the demand in the United States is not high and reimbursement is difficult. The United States also lacks both a tradition of susceptibility-based H pylori therapy and the surveillance programs necessary to track resistance patterns and inform therapy.¹⁴ Although hospitals that participate in programs from the Centers for Medicare & Medicaid Services are now required to establish antimicrobial stewardship programs, it appears that H pylori is exempt from the provision.^14,16,17

Requirements

To address H pylori as the infectious disease that it is, treatment guidelines based on the principles of antimicrobial stewardship should be developed and should replace all other recommendations.¹⁴ This will involve adapting clinical trials to focus on achieving high cure rates.¹⁴ It will also involve complying with the Infectious Diseases Society of America’s recommendations regarding the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens.¹⁴ Under new H pylori guidelines, comparative trials must only compare highly effective therapies that use noninferiority methods.¹⁴ The guidelines should clarify that therapies must be optimized to reliably achieve high cure rates where optimization includes the effects of resistance to the different components and is confirmed in different regions. Surveillance programs should be implemented and consist of routine tests of cure.¹⁴ Treatment should be combined with ongoing or planned prescription and treatment monitoring used for bacterial infections. Data from sites where culture and susceptibility testing and/or molecular testing are performed locally should be published and kept up-to-date.¹⁴ For clinicians to be informed about a regimen that should not be prescribed any longer, the new guidelines should recommend that results be reported in a public location that is easy to access.¹⁴ Developing these new guidelines will be a vast undertaking.

Primer for guideline development

To facilitate this transition, Graham and Liou developed a primer for the development of guidelines for H pylori therapy using antimicrobial stewardship that was published in April 2021. The primer establishes antimicrobial stewardship as a set of practices that promote responsible antibiotic use, measure appropriate use of antimicrobial agents, improve selection of optimal drug regimens, and promote the use of antimicrobials for effective and sustainable therapy.¹⁷

The primer’s first principle is to promote responsible use of antimicrobials.¹⁷ This includes complying with the general principles of both antimicrobial stewardship and antimicrobial therapy, the latter of which calls for obtaining an accurate diagnosis, understanding the difference between empiric and definitive therapy, understanding drug characteristics that are specific to antimicrobial agents, accounting for host characteristics that influence antimicrobial activity, and recognizing the adverse effects of antimicrobial agents on the host.¹⁷ Only antimicrobials that are known to be effective against the infection should be used, unless any resistance can be overcome with the concomitant use of another agent.¹⁷

The primer’s second principle is to assess and promote optimal drug regimens, which involves measuring appropriate use of antimicrobial agents. An optimal drug regimen achieves the highest cure rate possible. Although a 100% cure rate is ideal, a rate of 95% or greater might be appropriate for H pylori, which has proved difficult to cure. If choosing among optimized therapies, the H pylori guidelines should consider tolerability, cost, convenience, and other factors.¹⁷

The primer highlights that determining H pylori optimal cure rates for a specific geographic region or population presents several issues. H pylori infections are generally asymptomatic and can reappear within a year following therapy, so the accuracy of determining cure rates depends on the type, number, accuracy, and timing of the tests used. In addition, the rate of false-positive and false-negative tests should be considered. Therefore, the operational optimal cure rate should be adjusted to perhaps 93% or higher rather than 95% or higher, and cure rates of 90% to 94% should be considered conditionally acceptable.¹⁷

In outlining this second principle, the primer highlights how to approach improving cure rates of H pylori therapies; reducing further emergence, selection, and spread of antimicrobial resistance; and prolonging the life span of existing antibiotics. It recommends complying with the World Health Organization’s AWaRe (Access, Watch, and Reserve) classification of antibiotics according to their potential for resistance. This would privilege H pylori therapies using amoxicillin, tetracycline, and metronidazole and emphasize the monitoring of those that use clarithromycin and levofloxacin.¹⁷ The primer also advocates making efforts to expand and utilize susceptibility testing and reporting to reveal regional antimicrobial susceptibility patterns and guide treatment.¹⁷ To the same end of improving H pylori care, the primer notes that future treatment guidelines should clarify that only therapies that reliably achieve high cure rates should be compared in clinical trials and that these trials should generally use a noninferiority design.¹⁷

In the estimation of the primer’s authors, introducing antimicrobial stewardship practices will simplify how H pylori therapies are classified.¹⁷ Moreover, in focusing on the need to reliably achieve high cure rates, the new H pylori guidelines will need to detail drug specifications, doses, formulations, administration frequency, timing of administration relative to meals, duration, and other topics.¹⁷ Additionally, the primer recommends, the guidelines should use factorial design in complicated therapies and should draw upon head-to-head comparisons in metronidazole-resistant populations to determine the optimal duration of bismuth quadruple therapies.¹⁷

The primer’s third principle is to promote the use of antimicrobials in ways that ensure sustainable access to effective therapy for all who need them. Here, the primer emphasizes the need to optimize therapies and minimize antibiotic misuse.¹⁷ Physicians most often misuse therapy in H pylori infection by using an unoptimized treatment regimen.¹⁷ They also prescribe antibiotics that do not cure the infection, such as prescribing 2 antibiotics when only 1 is needed.¹⁷ This third principle advises that new H pylori guidelines direct clinicians to stop using an antibiotic, not when an antibiotic resistance exceeds a certain percentage, as the Maastricht IV consensus report had, but when cure rates fall below 90% or another set percentage.¹⁷

Recommendations during transition

The primer emphasizes that new guidelines should take into consideration the unique problems that H pylori presents and align them with the principles of antimicrobial stewardship. To embrace these antimicrobial stewardship principles, the gastroenterology community will need to discontinue use of current guideline recommendations, optimize antibiotic use, and reduce antimicrobial resistance. The goal is to achieve high cure rates that are reliable for routine clinical practice.¹⁴ While introducing antimicrobial stewardship, Graham recommends the following principles on how to improve empiric therapies. First, only regimens proven to produce high cure rates locally should be included. Next, outcomes obtained using test-of-cure results should be routinely monitored and reported to provide real-time information about whether the goals are being met. Finally, therapies that fail to reliably achieve the desired high cure rates should be stopped or modified.¹⁴ Any antibiotics that do not contribute to a cure rate must be eliminated. Susceptibility testing should be performed; until this is a widely accepted method, the routine test-of-cure data can be used as a surrogate method for susceptibility testing and data should be collected, shared, and integrated into local antimicrobial stewardship programs.^14,17 This will provide real-time information on whether treatments are being successful and permit monitoring and reporting outcomes based on test-of-cure data.¹⁴ All treatment recommendations should comply with the Infectious Diseases Society of America’s 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.¹⁷

To track treatment success, a test-of-cure result should be obtained from all patients regardless of the duration of therapy. Clinically, the definition of a cure is a noninvasive test given to the patient at least 4 weeks after therapy has ended that shows a negative result or a negative stool antigen test at least 6 weeks after therapy.¹⁴ The test-of-cure result should also be used as part of ongoing surveillance where results are reported to a central site and results shared.¹⁴ Because noninvasive tests are only 95% sensitive and specific and used to determine cure, Graham proposes a cutoff of 93% or higher until the testing to define a cure allows a more precise estimate. Population-based clinical results should base the cure rate on modified intention-to-treat results that include only those who have test-of-cure data.¹⁴

While the principles of antimicrobial stewardship are being introduced, the following elements of empiric regimens should be used: (a) experimental identification of antibiotic doses and frequency of administration; (b) unless the regimen has been formally optimized to use a different duration, the duration should be 14 days; and (c) minimum PPI dosage should be 60 mg omeprazole or equivalent (eg, 60 mg omeprazole, 60 mg lansoprazole, 40 mg esomeprazole or rabeprazole).¹⁴ Unneeded antibiotics should not be used and test-of-cure results should be available for ongoing surveillance. Regimens that fail to reach specified end points should be removed from empiric therapies and each approved therapy formally optimized. Therapy optimization should be among the first goals for the implementation of antimicrobial stewardship principles for H pylori treatments.¹⁴

Conclusions

The rise of antimicrobial resistance and declining H pylori eradication rates create a global health challenge that can only be circumvented with new treatment options to address the unmet need. With H pylori being a modifiable risk factor for gastric cancer, a potentially fatal malignancy, development of eradication techniques must continue. Current treatment guidelines were last updated in 2017. Although antibiotic resistance rates have increased and reduced the efficacy of recommended treatments since the guideline update, the H pylori treatment landscape has seen an FDA approval, in addition to other treatments currently being evaluated. Adoption of antimicrobial stewardship principles for H pylori treatments can be useful in reducing antibiotic resistance development and preventing infection spread. Furthermore, coordinated strategies following the Infectious Diseases Society of America’s guidelines can aid in the transition to antibiotic stewardship principles from current gastroenterological treatment plans.

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16. A Rule by the Centers for Medicare & Medicaid Services. Federal Register. 2019. Accessed June 9, 2021. https://federalregister.gov/d/2019-20736

17. Graham DY, Liou JM. Primer for development of guidelines for Helicobacter pylori therapy using antibiotic stewardship. Clin Gastroenterol Hepatol. Published online March 25, 2021. doi:10.1016/j.cgh.2021.03.026

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