How widespread and convenient H. pylori susceptibility testing will result in pharmacological opportunities

Abstract

Introduction:

Until recently antimicrobial therapy for Helicobacter pylori infections was almost universally empirical and based on a combination of expert opinion and local effectiveness. However, the average cure rates rarely achieved more than 80%. The new requirement that all therapeutic regimens reliably achieve high cure rates, the introduction of potassium competitive acid blockers and the availability of susceptibility testing many pharmacological opportunities particularly since all current therapies will require optimization. The ability to rapidly and inexpensively obtain H. pylori susceptibility data using stool samples makes obtaining susceptibility data practical and allows using susceptibility-based therapy routinely for both treatment naïve patient and as well as treatment failures.

Areas covered:

We searched the literature from 1990 to current to identify studies reporting the effect of susceptibility testing on H. pylori treatment. This review examines how widespread and convenient H. pylori susceptibility testing will result in pharmacological opportunities. Availability of susceptibility data will promote embracing the principles of antimicrobial stewardship, and reliably achieving high cure rates. The addition of susceptibility testing to post treatment failures helps explain why treatment fails. Many pharmacological opportunities will emanate from a renewal of efforts to develop, propagate, confirm and update best practices based on local and regional susceptibility/resistance patterns.

Expert opinion:

The ability to evaluate treatment decisions and outcomes in susceptible infections and reliably achieve high cure rates should foster precise tailoring of pharmacologic therapy and should achieve the goals of high cure rates while preventing antimicrobial misuse and extending the useful life of current antibiotics.

1. Introduction

Helicobacter pylori (H. pylori) is an infectious cause of gastritis and gastric cancer, the 5th most common cause of cancer deaths [1] Its role in gastric cancer has resulted in the recommendation that H. pylori should be eradicated [2–4]. The eradication of H. pylori requires the presence of a proven effective vaccine, a formal program of detection and antimicrobial therapy, or both. While there are a variety of published treatment guidelines overall treatment success remains poor, compared with other common infectious diseases [5–9]. Until recently, clinicians have been faced with the unavailability of susceptibility testing in the midst of worldwide increasing antimicrobial resistance. Most clinicians have continued to utilize empiric therapies originally developed based on trial and error, and which have not been formally optimized to reliably produce high cure rates. Most treatment guidelines have been based on comparisons of generally poorly performing therapies which has fostered the continued use of specific antibiotics, such as clarithromycin, long after the presence of resistance had rendered it to be no longer effective. Treatment registries have been developed that collect, publish, and comment on what physicians are currently doing without attempting to provide rapid feedback or improve the access to susceptibility testing required to improve outcome locally.

The recent and now universal availability of susceptibility testing in the United States [10,11] and an increasing focus on restricting therapy to susceptibility-based optimized therapies portends a worldwide change in both the approach and the odds of successful therapy of H. pylori infections. Here we examine the correlation between widespread and convenient H. pylori susceptibility testing and pharmacological opportunities concerning H. pylori infection therapy, guideline development and clinical decision-making. We searched PubMed, MEDLINE and Embase database medical literature to identify studies reporting the effect of susceptibility testing on H. pylori treatment. The period from 1990 to date was covered.

2. Current concepts of H. pylori treatment

H. pylori infection is a worldwide concern that involves billions of people. Despite more than a quarter of a century of therapeutic experience and many consensus conferences proposing treatment recommendations and describing treatment regimens for use, independent of susceptibility testing [12]. Treatment success remains poor in comparison with other infectious diseases [5–8]. Most regimens contain an antisecretory drug and one or more antibiotics, including amoxicillin, clarithromycin, metronidazole, a fluoroquinolone, rifabutin, bismuth or tetracycline. Clarithromycin is still widely used and recommended despite that since 2000 it has been clear that increasing resistance had undermined its effectiveness [12,13]. One empiric attempt to overcome clarithromycin resistance was to simply add another antibiotic to produce four-drug therapies most often containing a proton pump inhibitor (PPI), amoxicillin, clarithromycin and metronidazole called sequential, concomitant, hybrid and reverse hybrid therapies [14]. These regimens had in common that they all contained at least one unnecessary antibiotic which has resulted in the annual administration of thousands of kilograms of unnecessary antibiotics/million treatments which likely played a significant role in the increase in antimicrobial resistance worldwide [7,15]. At the same time there has been a move in the opposite direction (i.e., to use only one antibiotic in the combination of an antisecretory drug plus amoxicillin called dual therapy). Interest in dual therapy has greatly increased coincident with the introduction of the potassium competitive acid blockers, (e.g., vonoprazan) as they potentially allow improved control over intragastric pH. Previously, amoxicillin-containing dual therapy had been largely abandoned in western countries as amoxicillin plus a PPI generally had proven ineffective. Currently, most believe that, with optimization, the use of amoxicillin plus a highly effective antisecretory agent will eventially become effective as a dual therapy [16].

By definition all effective antimicrobial therapy is susceptibility-based with susceptibility being proven by local clinical experience, susceptibility testing, or both [7,15]. Current examples regimens that have proven successful as empiric therapies are bismuth quadruple therapy, and in the U.S., rifabutin triple therapy. Bismuth quadruple therapy with high dose metronidazole and a 14-day duration can generally overcome metronidazole resistance which allows it to be used empirically [17]. However, as susceptibility testing becomes more widespread, it is expected that in the presence of susceptibility to metronidazole, bismuth quadruple therapy would be replaced by metronidazole triple therapy. Both strategies of empiric therapy first and susceptibility-based or tailored therapy first strategy have advantages and disadvantages (Table 1) [18]. As we enter an era where susceptibility testing is widely available, it is important to recognize that few therapies, either susceptibility-based or empiric therapies, have yet been optimized [19]. The most widely used comparisons consist of unoptimized tailored vs. locally preferred empiric treatments and will need to be repeated following optimation [9] and the guidelines revised to reflect the results of susceptibility-based therapy rather than what is available now, (i.e., opinion-based guidelines largely based on comparisons of relative differences in outcome from randomized controlled trials (RCTs) or meta-analyses of what were overall primarily poorly performing empiric therapies [19]. The RCTs and relevant pairwise meta-analyses need to take the most important modifiers of treatment outcome, antimicrobial resistance, into consideration.

Table 1.

Pros and cons of Empirical treatment vs Susceptibility-guided treatment (Adapted from reference 20)

Empirical treatment

Pros

• “Test-and-treat” strategy for dyspepsia is recommended for young patients without alarming symptoms by most consensus conferences

• Resistance to amoxicillin, tetracycline and rifabutin is very low, so they can be empirically used

• No resistance to bismuth has been reported, so it can be also empirically used

• Metronidazole resistance has a low impact on the efficacy of treatments when proper duration and dose are taken into account

• Rifabutin and furazolidone are good alternatives for empirical treatment after several eradication failures

• Cumulative H. pylori eradication rate with several successive rescue therapies empirically prescribed reaches almost 100%

Cons

• Empirical treatment may increase resistance of H. pylori to antibiotics and this has led to dramatic increase of resistance worldwide

• Increases unnecessary antibiotic prescription

• Does not provide tailored treatment

• May induce increase of antibiotic resistance to other bacteria

• May induce perturbation of gut microbiota after H. pylori eradication

Susceptibility-guided treatment

Pros

• Provide tailored treatment

• Reduce unnecessary antibiotic prescription

• Limit the emergence of antibiotic resistance worldwide

• Allow performing resistance surveys over time

• Might allow prescribing the optimized clarithromycin-based triple therapy to patients with clarithromycin-susceptible strains in areas with high overall clarithromycin resistance

• Molecular testing on gastric biopsies or stools is a highly accurate diagnostic method.

Cons

• While molecular tests based on gastric biopsies benefit from a long experience, it is not the same with stool samples. However novel commercial molecular kits have recently become available.

• An endoscopy is required to obtain gastric biopsies which is expensive, uncomfortable and possibly has a low rate of acceptance by patients

• Due to low rate of endoscopy findings, this procedure does not contribute to management in young patients (age below 50 years)

• Culture is time-consuming, requires expertise and is not always available on a routine basis

• Expensive (mainly because of endoscopy)

The importance of assessing the outcome of therapy by formally doing a test of cure and using these results as feedback to guide therapy locally should not be underestimated. The actual test used for assessing cure should include susceptibility testing and knowledge regarding whether emergence of resistance was responsible for treatment failure or whether the organisms are still susceptible. This provides data both about emergence of resistance during treatment and whether there are problems with the patients (e.g., adherence) or with the regimen (e.g. too short) and informs about the best choices for retreatment. Ideally, the test of cure should use molecular susceptibility testing of stools provides the data about emergency of resistance and obviates the need for endoscopy [10,11]. We propose an algorithm for the selection of H. pylori regimen based on knowledge of the results of empiric first-line therapies and the results of susceptibility testing in Figure 1 [11].

Figure 1.

Proposed algorithm for the selection of a Helicobacter pylori regimen based on knowledge of the results of empiric first-line therapies and the results of susceptibility testing (from [11] with permission).

3. Antimicrobial stewardship

3.1. Antimicrobial Stewardship

One goal of the principles of antimicrobial stewardship is to prolong the useful life of the antibiotics used by simultaneously improving the treatment outcome, preventing antimicrobial misuse so as to achieve high cure rates combined with a low risk of developing resistance [7,15,16,18–20]. Antimicrobial stewardship also includes regular updating and propagation of best practice guidelines based on susceptibility/resistance surveillance (Table 2) [20].

Table 2.

Definitions of terms to describe outcome of therapy (adapted from ref.21)

TERM	DEFINITION
Successful	Excellent or good results
Excellent results	Reliably achieve 95% or greater cure rates in adherent patients with susceptible infections
Good results	Reliably achieve 90% or greater cure rates in adherent patients with susceptible infections
Optimum duration	Days of therapy required to reliably achieve good to excellent results
Doses and frequency of administration	Those that will reliably achieve good to excellent results

3.2. Adoption of the Principles of Antimicrobial Stewardship for H. pylori therapy.

Adoption of antimicrobial stewardship requires consideration and managing of the numerous vested interests (Table 3, 4) [21]. Antimicrobial stewardship requires that recommendations be proven to reliably produce high cure rates locally which also requires surveillance of treatment outcomes to assure continuing effectiveness. Comparative trials should be restricted to highly effective therapies and generally employ non-inferiority methodology. Any study employing a regimen with a known or suspected low cure rate is by definition unethical and should not be done or published [22,23]. Empiric administration should be restricted to reliably highly effective regimens. Consortia (e.g., the European Registry on H. pylori Management) should be repurposed to provide ongoing surveillance of H. pylori susceptibility to the clinicians involved.

Table 3.

American Society of Infectious Diseases criteria for ethical active-controlled superiority studies of antibacterial agents. (Adapted from reference 22)

1. The control (i.e., the comparator drug) is active against most, or all, of the bacterial strains likely to be encountered in the study;

2. All available drugs that could be used as comparators for the study are inadequately active against the strains likely to be encountered, such that there is no alternative effective therapy possible; or

3. The infection under study is almost universally non-fatal, such that rescue therapy can be instituted rapidly enough to preclude serious sequelae upon recognition that the strain causing the infection is resistant to the comparator drug (e.g., uncomplicated urinary tract infection). The susceptibility of etiologic bacteria is almost never known at the time an infected patient is enrolled in a clinical trial that evaluates initial antimicrobial treatment. Therefore, the comparator drugs chosen for study in antibacterial clinical trials are selected because they are anticipated to be effective against all, or almost all, strains likely to be encountered during conduct of the study.

Table 4.

Guidelines to implement antimicrobial stewardship for treatment of H. pylori infections. (Adapted from reference 22)

• Therapies must be optimized to reliably achieve high cure rates.

• Optimization should include the effects of resistance to the different components. Preferably, optimization should be confirmed in different regions.

• Surveillance programs should be instituted. At a minimum, this should include tests of cure and, preferably, with susceptibility testing available for treatment failures.

• Treatment of H. pylori should be integrated with ongoing or planned prescription and treatment monitoring utilized for other bacterial infections.

• Data from sites where culture and susceptibility testing and/or molecular testing are done locally should be published and kept up to date.

• Susceptibility testing should be reimbursed as for other bacterial pathogens and the results data should be submitted to local and central repositories responsible for monitoring resistance among bacterial pathogens.

• To avoid unethical studies, studies should adhere to the guidelines of the Infectious Diseases Society of America regarding conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens.

4. The effect of widespread and convenient H. pylori susceptibility testing on pharmacological opportunities and clinical practices.

Widespread and convenient H. pylori susceptibility testing will provide new benefits and opportunities particularly in terms of generating testable hypotheses regarding understanding treatment success vs. failure. For example, susceptibility testing directly provides data regarding whether the duration of therapy is appropriate or whether heteroresistance has undermined one or more antibiotics in the regimen. Pretreatment availability of the presence of resistance should call a halt to practices resulting in the current widespread misuse of antibiotics that has accompanied attempts to cure H. pylori infections. In addition, widespread and convenient H. pylori susceptibility testing using stools should largely obviate the need for endoscopy and gastric biopsies.

5. P-CAB in clinical practice: the importance of susceptibility data.

The P-CAB vonoprazan is now available in both the US and Europe. The initial trial in the US and Europe produced unexpectedly low cure rates for both vonoprazan triple and dual therapies even with susceptible infection [24]. It is not yet clear why and the lack of test of cure susceptibility data largely prevents understanding why they achieved low cure rates. For example, treatment failure coupled with post treatment susceptible infections implies that either the patient did not take the medicine, the duration was insufficient, or there is an issue with one or more of the drugs used. Post-treatment resistant infections imply emergence of resistance during treatment (i.e., heteroresistance) indicating that the regimen should be reformulated so as to not contain the antibiotic for which this is a problem. Importantly, the effectiveness of the PPI clarithromycin triple therapy in susceptible infections also failed. Finally, as in Japan, the majority of those who received clarithromycin did not receive any benefit from its presence (i.e., the cure rate with and without clarithromycin were very similar). In Japan currently vonoprazan dual and triple therapy provide non-inferior results further confirming the misuse of clarithromycin. In the US it has been calculated that vonoprazan triple therapy would result in approximately 13 tons of unnecessary clarithromycin/million treatment courses. This makes it even more critical that the vonoprazan dual therapy be optimized to provide high cure rates as it does in Japan as only then can it be used clinically outside of Japan [16].

The US/European vonoprazan data emphasize that the collection of susceptibility testing before and after treatment provides critical data to allow one to potentially discover why a regimen did or did not provide the desired high cure rate. With these data neither clinicians nor pharmaceutical companies need to remain in the dark as these data allow detailed analysis of both treatment successes and failures. These analyses will also promote more rational study design and allow new hypotheses to be tested.

Susceptibility testing has fostered a paradigm shift in the management of H. pylori infections. Paradigm shifts tend to provide opportunities in all aspects related to diagnosis, therapy and follow-up and provide an opening for industry to identify multiple opportunities to identify improvements at each step in the process. The fact that we are better able to consider the role and composition of each therapy and each step in the process implies that the potential for new opportunities is unlimited. History tells us that what first appears as a small step often results in a complete rethinking of the process leading to the emergence of new and unexpected improvements.

6. Expert opinion

The widespread availability of H. pylori susceptibility testing has resulted in the management of H. pylori infections being transferred, at least conceptually, from Gastroenterology to Infectious Disease. The transfer will largely eliminate what has fundamentally been opinion-based recommendations and substitute a traditional susceptibility-based approach utilizing the principles of antibiotic stewardship. This transition will not be smooth nor as easy as guideline development and at least in the near future guidelines and recommendations will likely continue to reside with gastroenterologists for whom the principles of antibiotic stewardship are neither intuitive nor easily incorporated into practice. This will likely result in incremental changes and continuing but diminishing influence of the currently well-established vested interests. The slow rate of progress is illustrated by the fact, mentioned earlier, that by the year 2000 empiric clarithromycin-containing triple therapy was conclusively shown to be ineffective [13,25] and almost a quarter of a century later, the most recent Maastricht Consensus Conference still recommends use of clarithromycin albeit with some minor qualifications [12]. Ultimately, the composition of the bodies responsible for guidelines and recommendations will need to move away from largely consisting of gastroenterologists and include those experienced in developing guidelines for infectious diseases. The widespread availability of susceptibility testing should greatly speed up the process [12]. It is important to note that the FDA recently approved vonoprazan clarithromycin triple therapy despite the fact that at least 94% receiving vonoprazan triple therapy receive no benefit from the clarithromycin (i.e., less than 6% separated the cure rate of those receiving vonoprazan amoxicillin alone and those receiving the clarithromycin-containing triple therapy).

It is also important to note that none of the approved H. pylori therapies were optimized before approval. Even today, no lower boundary for an acceptable cure rate has been considered as part of FDA approval. Prepackaged therapy, especially those containing difficult to obtain ingredients, limit clinician’s ability to adjust duration of therapy. Bismuth quadruple therapy is an excellent example, the commercial product, Pylera, is packaged as a 10-day therapy [26]. The regimen was developed for use in the presence of metronidazole resistance where 14-day therapy is considered best [27]. For those with metronidazole susceptible infections an even shorter duration is recommended or use of metronidazole amoxicillin triple therapy which avoids the use of both the bismuth and tetracycline. The availability of susceptibility testing brings these problems faced daily by clinicians into sharp focus. It will be important for the regulatory agencies to reconsider the status of all currently approved combination therapy especially since none was optimized before approval. Those regimens that are prepackaged may need to be changed to reflect current conditions. We hope that future submissions for regulatory approval will require that the regimes have been optimized before submission as well as for the agencies to establish predefined criteria of what are the minimal acceptable cure rates that must be obtained. Finally, regimens that contain antibiotics that are unneeded and that only contribute to the global increase in antibiotic resistance should neither be used nor approved. Optimization also eliminates arguments or considerations regarding dosages and duration of therapy as is currently present with bismuth quadruple therapy. Comparisons containing PPIs and/or P-CABs will provide the relative antisecretory potency of the drugs utilized, for example, the time the pH is maintained ≥4 after reaching steady state.

PPIs and P-CABs differ greatly in terms of antisecretory activity promoting Strawman comparisons using drugs with which control of intragastric pH is a critical determinant of cure rate (e.g., amoxicillin). Currently, what may superficially appear to be studies comparing PPIs and P-CABs as adjuvants to therapy are generally not valid comparisons of different classes of antisecretory drug but rather comparison between drugs with vastly relative antisecretory effectiveness (e.g., a comparison of pantoprazole 40 mg (9 mg omeprazole equivalent), or lansoprazole 30 mg (27 mg omeprazole equivalent) vs. vonoprazan 20 mg (slightly greater than 70 mg omeprazole equivalent) [28]. A legitimate comparison would require use of antisecretory drugs of equivalent or near equivalent potency (e.g., 40 mg of esomeprazole or rabeprazole b.i.d. vs. vonoprazan 20 mg b.i.d.).

The requirement for optimization should include all the features that affect outcome such as dosing in relation to meals, formulations, etc. [15]. The role the different antisecretory drugs in therapies containing the largely pH-independent drugs such as tetracycline, metronidazole, and bismuth also requires rethinking. The number combinations and permutations required to be able to reliably predict outcome are great and likely contain surprises that only await uncovering. Importantly, susceptibility testing both before therapy and for treatment failures eliminates the problem of whether resistance is present as well as separating preexisting resistance from emergence of resistance during therapy from failure due to other causes (e.g., adherence or an issue with the drugs, dosing or the timing of administration). The use of stool-based susceptibility testing eliminates the need for gastric biopsies which effectively eliminates the major impediment to being able to dissect the reasons or treatment failures and promotes efficient optimization [10].

We also anticipate an end to treatment studies that contain a comparator primarily because journals often seem to require one. The critical comparator is how close the cure rate comes to 100%. We also need reliably effective therapies as well as a better understanding of what parameters are required to achieve that outcome. Comparative studies should be designed to test non-inferiority and generally be limited to proven highly effective regimens.

Figure 2.

Antimicrobial susceptibility testing for Helicobacter pylori (from [11] with permission).

Article highlights.

• Helicobacter pylori (H. pylori) an infectious cause of gastritis and gastric cancer, has become a major target for eradication.

• Until recently, clinicians have been faced with the unavailability of susceptibility testing in the face of worldwide increasing antimicrobial resistance. New ways of providing and using susceptibility data is necessary.

• The current universal availability of susceptibility testing and an increasing focus on restricting therapy to susceptibility-based optimized therapies portends a worldwide change in both the approach and the odds of successful therapy of H. pylori infections.

• The use of stool-based susceptibility testing eliminates the need for gastric biopsies which effectively eliminates the major impediment to being able to dissect the reasons for treatment failures, thus promoting efficient optimization.

• It is expected that the effect of a convenient and widespread H. pylori susceptibility testing will provide pharmacological with many opportunities associated with the need to markedly change clinical practices.