Treating Helicobacter pylori effectively while minimizing misuse of antibiotics

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Experts now recommend that all Helicobacter pylori infections be eradicated unless there are compelling reasons not to. As with other infectious diseases, effective therapy should be based on susceptibility.


  • We recommend clinicians have 2 first-line options to accommodate prior antibiotic use or drug allergy.
  • We recommend 4-drug combinations as first-line treatments, ie, either concomitant therapy or bismuth-containing quadruple therapy, to be taken for 14 days.
  • Concomitant therapy consists of the combination of amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor.
  • Bismuth quadruple therapy consists of the combination of bismuth, tetracycline, metronidazole, and a proton pump inhibitor.
  • After 2 treatments have failed, therapy with different regimens should be based on susceptibility testing.



Helicobacter pylori infection is an infectious disease and should be treated like one, with due consideration of antibiotic resistance and stewardship.1–4

This was the consensus of the 2015 Kyoto H pylori conference,2 and it signaled a fundamental shift in thinking. Up to now, H pylori treatment has not been based on infectious disease principles, leading to suboptimal results and antibiotic resistance. In addition, the conference recommended that H pylori infection be treated whenever it is found unless there are compelling reasons not to.

Here we review current and possible future regimens for eradicating H pylori that we hope will be more effective and will lead to less resistance than in the past.


Not until the late 1980s was H pylori recognized as the cause of peptic ulcer disease, which until then accounted for hundreds of thousands of hospitalizations and more than 100,000 surgical procedures each year.5 Now, peptic ulcer disease is routinely treated by eradicating H pylori. In addition, the World Health Organization has recommended considering H pylori eradication to reduce the risk of gastric cancer,6 which causes 738,000 deaths worldwide per year.7

The problems of how to diagnose and treat H pylori infection were taken on by gastroenterologists, and not by specialists in infectious disease.1 Even now, almost all the major reviews and consensus statements on H pylori come from gastroenterologists and are published in gastroenterology journals.2,8,9

But infectious diseases differ from most gastrointestinal diseases. In gastrointestinal problems such as constipation or inflammatory bowel disease,10 the causes are generally unknown, and there is a large placebo response to therapy. In contrast, in infectious diseases, the cause is generally known, there is no placebo response, and treatment success depends on susceptibility of the organism. Failure of proven regimens is generally due to resistant organisms, poor adherence, or, in the case of H pylori, poorly designed regimens in terms of doses, frequency of administration, or duration of therapy.

The differences extend to clinical trials of treatment.3 In other infectious diseases, treatment is based on susceptibility. The usual comparative approach in infectious diseases is a noninferiority trial in which the new treatment is compared with standard care, ie, a regimen that reliably achieves nearly 100% cure rates. Not so with H pylori. Most trials of H pylori therapy compared regimens in populations with high but unknown prevalences of resistance and therefore are of limited or no help to the clinician in choosing the best regimen for an individual patient.3

Many thousands of H pylori-infected patients participated in clinical trials in which the results would have been predictable if the researchers had assessed susceptibility before giving the drugs.11–13 Worse, many patients were also randomized to receive regimens that the investigators knew provided poor cure rates in the population being studied. This knowledge was generally not shared with the patients. This approach was used to demonstrate that a new regimen was superior to an old one, even though the new one was already known to be less affected by resistance to the key element in the comparator.

Clinicians generally do not test for susceptibility when treating H pylori, one reason being that such testing is often unavailable.3 However, almost every hospital, clinic, and major laboratory in the world provides susceptibility testing for other common local pathogens. H pylori is easy to grow, and laboratories could test for susceptibility if we asked them to.

Current H pylori recommendations may also contribute to the global increase in antimicrobal resistance.

As discussed below, all recent guidelines have recommended 4-drug non-bismuth-containing concomitant therapy as first-line therapy. An infectious disease colleague described it as a “hope therapy” because the prescriber hoped that the infection would be susceptible to either metronidazole or clarithromycin. All who receive this combination receive an antibiotic they do not need. This is an expedient rather than a medically rational choice resulting from failure to deal with H pylori as an infectious disease.


Recommended regimens for Helicobacter pylori

Conceptually, treating infectious disease is straightforward: one should prescribe antimicrobial drugs to which the organism is susceptible3 (Table 1). However, clinical success lies in the details, which include the doses, frequency of doses, duration of therapy, timing of doses in relation to meals, and use of adjuvants such as antisecretory drugs, antacids, and probiotics. A number of regimens reliably yield high cure rates—95% or higher—if the organism is susceptible and the patients are adherent.

The effectiveness of any regimen may vary depending on the population it is used in, due to polymorphisms in drug-metabolizing enzymes such as CYP2C19.

Sequential therapy is obsolete

Sequential therapy for H pylori infection consisted of amoxicillin plus a proton pump inhibitor for 7 days, followed by clarithromycin, tinidazole, or metronidazole plus a proton pump inhibitor for a further 7 days. This regimen should not be used any more because concomitant therapy will always be superior (see below).


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