The American Gastroenterological Association (AGA) has issued a clinical practice update for managing patients with refractory Helicobacter pylori infection, as published in Gastroenterology.

The Expert Review1 includes 12 Best Practice Advice statements that address treatment regimen selection, patient and systems factors that contribute to treatment efficacy, and other clinical issues involving H pylori, one of the most common chronic bacterial infections worldwide (Table).

H. pylori management has become increasingly challenging due to declining eradication success rates coupled with increasing antibiotic resistance, resulting in more H. pylori infections that are now refractory to first-line therapies,” stated the AGA authors. “Accordingly, this clinical practice update was developed to provide practitioners with practical advice on how to manage patients whose initial H. pylori treatment was unsuccessful.”


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The consequences of failed treatment include clinical complications related to persistent H pylori infection, repeated exposure to antibiotics and high-dose acid suppression, and associated healthcare costs, according to the review authors. “Because the likelihood of successful eradication decreases with each subsequent therapeutic attempt, every effort should be made to address factors that might contribute to eradication failure,” the group commented.

The failure to eradicate H pylori results from the interaction of host-, microbial-, and systems-related factors, including antibiotic resistance and nonadherence to treatment. “Providers should attempt to identify all contributing etiologies before simply prescribing alternative antibiotics,” the authors advised.

Resistance to Antibiotics

Resistance to antibiotics that are commonly used as eradication treatment for patients with H pylori has increased during the past 2 decades. The clinical practice update recommends that providers conduct a thorough review of patients’ medical and pharmacy records and discuss previous medication exposure with both patient and pharmacist. “This should be done prior to the initial eradication attempt, but is especially critical for successfully treating refractory H. pylori infection,” noted the review authors.

Resistance rates are lower for particular antibiotics, including amoxicillin and tetracycline, according to the results of some international studies. H pylori also has demonstrated low primary and secondary resistance to rifabutin.

“Estimating H. pylori resistance rates is particularly challenging in the United States because measuring resistance has been uncommon in clinical practice, ultimately equating to very limited contemporary data to guide treatment considerations,” according to the authors.

Recent evidence has shown H pylori primary resistance rates of 17% for clarithromycin and 44% for metronidazole.2 “Providers who treat H. pylori infection should provide their patients with anticipatory guidance to help ensure maximum adherence,” the authors recommended. “This specifically includes explaining the rationale for therapy, dosing instructions, expected adverse events, and the importance of completing the full therapeutic course.”

Host genetics are also involved in refractory H pylori infection. Polymorphisms that affect intragastric pH — including those of CYP2C19, IL-1B, and MDR1 — are relevant for successful H pylori eradication. However, current data are insufficient to support genetic polymorphism testing for guiding therapeutic selection in refractory or primary eradication therapy, according to the review. Nongenetic, host-related, and lifestyle factors, such as age and smoking, are also associated with eradication treatment failure.

A Treatment Algorithm

The practice update includes an algorithm for regimen considerations in the setting of refractory H pylori and is based on the initial therapy used and the presence or absence of true penicillin allergy. Of these regimens, only proton pump inhibitor (PPI) plus bismuth plus metronidazole plus tetracycline (PBMT) is approved by the US Food and Drug Administration for patients with refractory H pylori infection.

“If bismuth-based quadruple therapy failed as a first-line treatment, shared decision-making between providers and patients should guide selection between (a) levofloxacin- or rifabutin-based triple therapy regimens with high-dose dual PPI and amoxicillin, or (b) an alternative bismuth-containing quadruple therapy, as second-line options,” the update recommends.

Treatment Regimen Selection

Several important factors need to be considered for guiding treatment of refractory H pylori infection, according to the review. Because of the high H pylori resistance rates to clarithromycin and levofloxacin, these antibiotics or others in their class (macrolides and fluoroquinolones, respectively) should not be repeated in subsequent treatment attempts, and an antibiotic history of any of these drug classes for other indications should be considered when selecting subsequent therapy, the update recommends.

“Because primary and secondary resistance to amoxicillin, tetracycline, and rifabutin are very low, these can be used in repeated regimens, even if they have been used previously for H. pylori eradication or other therapy,” the review authors stated.

The practice update also recommends that resistance to nitroimidazoles should not be considered as an absolute preclusion for reuse of this antibiotic class for refractory H pylori therapy, because “in vitro resistance does not reliably correlate with H. pylori eradication failure associated with using this drug,” noted the authors. “Nitroimidazole resistance might be potentially overcome with dose adjustments and addition of bismuth.”

Higher doses of metronidazole, at least 1.5 to 2 g/d, are also associated with significantly improved eradication rates. “Patients should be advised to consume metronidazole in divided doses (TID to QID) with food and to avoid alcohol for the therapeutic duration due to a disulfiram-like reaction,” the review authors advise.

Consistently achieving adequate threshold levels of amoxicillin and intragastric acid suppression are important for successful H pylori eradication.

“Given its value in treating refractory H. pylori infection, in the absence of anaphylaxis, penicillin allergy testing should be considered to delist penicillin allergy and potentially enable the use of amoxicillin,” the review authors stated. “Despite relatively prevalent chart documentation of penicillin allergy, true anaphylaxis to penicillin is rare.”

Inadequate acid suppression may undermine eradication efforts, and adjusting acid suppressive prescriptions may improve eradication outcomes in refractory H pylori infection.

When treatment with multiple eradication efforts has failed, the potential benefits of H pylori eradication should be weighed against the likelihood of adverse effects and inconvenience of repeated high-dose acid suppression and antibiotic exposure, according to the practice update.

Adjunctive Therapies for H pylori

The most effective strategy for managing patients with refractory H pylori is preventing infection by improving the success rate of primary eradication therapy, according to the review authors. Personalizing the initial H pylori eradication therapy by adjusting for individual host genetic, host nongenetic, and microbial factors may help in this effort.

“No truly novel anti-H. pylori therapies are visible on the horizon,” noted the authors.

Some nonantibiotic adjuncts such as statins and probiotics have shown promise, but there is significant trial heterogeneity and concerns regarding the study quality of these agents. “Further rigorous investigation in US populations and specifically in refractory H. pylori infection would be valuable, particularly given the generally favorable side effect and cost profiles of these agents,” stated the review authors.

“When considering the major public health implications associated with persistent H. pylori infection with respect to disease- and treatment-related complications and cost, there is a clear need to prioritize systematic approaches to improve rates of successful H. pylori eradication with the least number of therapeutic attempts,” the AGA review authors commented.

The Expert Review on refractory H pylori was commissioned and approved by the AGA Institute Clinical Practice Updates (CPU) Committee and the AGA Governing Board and underwent internal peer review by the CPU committee and external peer review through the standard procedures of Gastroenterology.

Disclosures: Some of the authors reported affiliations with medical device, diagnostics, and pharmaceutical companies. Please see the original reference for a full list of disclosures.

Best Practice Advice Statements for Refractory Helicobacter pylori Infection

1. The usual cause of refractory H pylori infection (persistent infection after attempting eradication therapy) is antibiotic resistance. Providers should attempt to identify other contributing etiologies, including inadequate adherence to therapy and insufficient gastric acid suppression.
2. Providers should conduct a thorough review of prior antibiotic exposures. If there is a history of any treatment with macrolides or fluoroquinolones, then clarithromycin- or levofloxacin-based regimens, respectively, should be avoided given the high likelihood of resistance. By contrast, resistance to amoxicillin, tetracycline, and rifabutin is rare, and these can be considered for subsequent therapies in refractory H pylori infection.
3. Eradication regimens for H pylori are complex and might not be fully comprehended by patients. Barriers to adherence should be explored and addressed prior to prescribing therapy. Providers should explain the rationale for therapy, dosing instructions, expected adverse events, and the importance of completing the full therapeutic course.
4. If bismuth quadruple therapy failed as a first-line treatment, shared decision-making between providers and patients should guide selection between (a) levofloxacin- or rifabutin-based triple therapy regimens with high-dose dual proton pump inhibitor (PPI) and amoxicillin; or (b) an alternative bismuth-containing quadruple therapy, as second-line options.
5. When using metronidazole-containing regimens, clinicians should consider adequate dosing of metronidazole (1.5-2 g in divided doses) with concomitant bismuth therapy, as this may improve eradication success rates irrespective of observed in vitro metronidazole resistance.
6. In the absence of a history of anaphylaxis, penicillin allergy testing should be considered in a patient labeled as having this allergy to delist penicillin as an allergy and potentially enable its use. Amoxicillin should be used at a daily dosage of at least 2 g administered 3 or 4 times daily to avoid low trough levels.
7. Inadequate acid suppression is associated failure of H pylori eradication attempt. The use of high-dose and more potent PPIs, PPIs not metabolized by CYP2C19, or potassium-competitive acid blockers if available, should be considered in cases of refractory H pylori infection.
8. Longer treatment durations provide higher eradication success rates compared with shorter durations (eg, 14 days vs 7 days). Whenever appropriate, longer treatment durations should be selected for treating refractory H pylori infection.
9. In some cases, there should be shared decision-making regarding ongoing attempts to eradicate H pylori. The potential benefits of H pylori eradication should be weighed carefully against the likelihood of adverse effects and inconvenience of repeated exposure to antibiotics and high-dose acid suppression, particularly in vulnerable populations, such as the elderly.
10. After 2 failed therapies with confirmed patient adherence, H pylori susceptibility testing should be considered to guide the selection of subsequent regimens.
11. Compiling local data on H pylori eradication success rates for each regimen, along with patient demographic and clinical factors (including prior non-H pylori antibiotic exposure) is important. Aggregated data should be made publicly available to guide local selection of H pylori eradication therapy.
12. Proposed adjunctive therapies, including probiotics, are of unproven benefit as treatment for refractory H pylori infection; thus, their use should be considered experimental.

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References

1. Shah SC, Iyer PG, Moss SF. AGA clinical practice update on the management of refractory Helicobacter pylori infection: Expert review. Gastroenterology. Published online January 29, 2021. doi:10.1053/j.gastro.2020.11.059

2. Graham DY, Canaan Y, Maher J, et al. Rifabutin-based triple therapy (RHB-105) for Helicobacter pylori eradication: A double-blind, randomized, controlled trial. Ann Intern Med. 2020;172(12):795-802.