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The American Gastroenterological Association (AGA) has updated its guidance for management of patients refractory to initial eradication therapy for Helicobacter pylori. Treating this infection is a growing challenge owing to declining eradication rates coupled with rising antibiotic resistance and the resulting increase in infections refractory to first-line therapies.

In the clinical practice update (CPU), published online in the AGA panel stressed the major public health problem of persistent infection, including the direct health costs as well as the treatment-related complications and increased risks of ulcers as well as .

"There is a clear need to prioritize systematic approaches to improve rates of successful H. pylori eradication with the least number of therapeutic attempts," wrote Shailja C. Shah, MD, of Vanderbilt University Medical Center in Nashville, and colleagues.

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, and some cases require shared decision-making on continuing attempts at eradication, the authors said. "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."

The main recommendations to clinicians are the following:

• Apart from antibiotic resistance, try to identify other possible contributing factors to the initial treatment failure, such as inadequate adherence to therapy and insufficient suppression of gastric acid

• Address barriers preventing adherence to complex eradication regimens before prescribing therapy; explain the rationale for therapy, dosing instructions, expected adverse events, and the need to complete the full course

• Consider high-dose and more potent proton pump inhibitors (PPIs) that are not metabolized by the CYP2C19 liver enzyme or consider using the newer potassium-competitive acid blockers

• Thoroughly investigate prior antibiotic exposure; if there is a history of treatment with macrolides or fluoroquinolones, avoid clarithromycin- or levofloxacin-based regimens given the high likelihood of resistance. Since resistance to amoxicillin, tetracycline, and rifabutin is rare, consider these for subsequent therapies

• When appropriate, select longer treatment durations to decrease the chance of failure

• If first-line bismuth quadruple therapy has failed, discuss second-line options with patients, including either levofloxacin- or rifabutin-based triple therapy with a high-dose dual PPI and amoxicillin or an alternative bismuth-containing quadruple therapy

• When using metronidazole-containing regimens, consider adequate dosing of metronidazole (1.5 to 2 g daily in divided doses) with concomitant bismuth therapy, since this may improve eradication success rates irrespective of metronidazole resistance observed in vitro

• For patients with no history of anaphylaxis, consider testing for penicillin allergy even if they are labeled as being allergic to penicillin, in order to potentially enable its use; amoxicillin should be used at a daily dose of at least 2 g divided over three or four times a day to avoid low trough levels

• After two failed therapies despite confirmed patient adherence, consider susceptibility testing to guide the selection of subsequent regimens

• Proposed adjunctive therapies, including probiotics, are of unproven benefit and should be viewed as experimental only

Shah told MedPage Today that some of the recommendations might surprise gastroenterologists in terms of existing practice.

One involves the testing for penicillin allergy: "H. pylori resistance to amoxicillin is uncommon, generally involving fewer than 5% of strains and is therefore of great value in treating refractory infection," she said. "Unfortunately, penicillin allergy is one of the most common allergies documented in patients' charts, even though true anaphylaxis to penicillin is rare. It is for this reason that we suggested providers consider penicillin allergy testing so that amoxicillin use could be enabled."

In addition, she said, the CPU's highlighting of the importance of adequate, sustained intragastric acid suppression to successful eradication might not be fully appreciated by providers. "There are many factors, including both host and microbial, that impact gastric acid suppression, which we wanted to highlight in this clinical practice update," Shah said.

Providers might also be surprised by the lack of U.S.-based evidence to guide therapeutic decision-making in treating refractory H. pylori, she continued. "By way of this CPU, we also tried to highlight strategies to advance our knowledge and ideally refine and expand the armamentarium of therapeutic options."

And while promising positive results have emerged for non-antibiotic adjuncts such as and , the panelists said limited data are available to guide optimal timing, formulation, dosage, and duration, as well as appropriate patient selection. The CPU calls for further rigorous investigation in U.S. populations, specifically in refractory infection given the generally favorable side effect and cost profiles of these two classes of agent.

Hashem B. El-Serag, MD, MPH, of Baylor College of Medicine and Michael E. DeBakey VA Medical Center in Houston, who was not involved with the CPU, said the recommendations will be useful for clinicians since the information focuses on H. pylori as an infectious disease, on antibiotic stewardship and resistance, and on the steps that should be taken after the first antibiotic failure.

He singled out the importance given to investigating patients' previous exposure to various antibiotics: "This is not a procedure that's often done in practice," he told MedPage Today.

He said that in his view, however, antibiotic susceptibility testing would be better undertaken after one failed round of therapy rather than the two suggested by the CPU. "We need to have surveillance registries showing local patterns of penetration and resistance. The facilities for susceptibility testing are available, but the uptake has been very slow, partly because of the acceptance of a trial-and-error approach," El-Serag explained.

In the CPU's background information, the authors noted that H. pylori is one of the most common chronic bacterial pathogens, infecting approximately half of the and is a World Health Organization–designated carcinogen and the strongest known risk factor for non-cardia gastric adenocarcinoma, the most prevalent form of stomach cancer. And even though only 1%-3% of infected individuals will develop a malignancy, H. pylori accounts for 15% of the total cancer burden globally, is responsible for as much as and the costs associated with treatment failure are estimated to be more than in the U.S.

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