Helicobacter pylori Treatment Guidelines

Background

Helicobacter pylori is a chronic bacterial infection with significant global impact. Although the mechanism of transmission is unclear, it usually is acquired during childhood. The prevalence is estimated to be 35% in the United States, with higher rates among Alaskan indigenous inhabitants, people of lower socioeconomic status, and immigrant populations. ^{[1, 2]}

Testing

Complications of H pylori include peptic ulcer disease (PUD), gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. Patients with gastric MALT lymphoma have a high regression rate with H pylori eradication. Additionally, eradication of H pylori in patients with early gastric cancer (EGC) is associated with a decreased incidence of metachronous gastric cancer. Given this, patients with active or prior history of PUD (without prior cure of H pylori infection), low-grade gastric MALT lymphoma, or a history of endoscopic resection of EGC should be tested for H pylori and treated if positive. ^[1]  

Additional indications to consider for H pylori testing include history of dyspepsia and chronic non-steroidal anti-inflammatory (NSAID) use. ^[1] Noninvasive H pylori testing can be considered in patients younger than 60 years with uninvestigated dyspepsia without alarm features and treated if positive. When a patient with dyspepsia undergoes endoscopic evaluation, gastric biopsies should be obtained to assess for H pylori.  Patients who require low-dose aspirin or need to initiate chronic NSAIDs should be tested for H pylori and treated if positive to reduce the risk for PUD and ulcer-related bleeding. ^[1]  The benefit of preventing bleeding from PUD is less clear in patients who are already on chronic NSAIDs. ^[1]

Unexplained iron deficiency anemia (IDA) with prior appropriate evaluation as well as idiopathic thrombocytopenic purpura (ITP) are other indications to consider for testing for H pylori. For patients with IDA, H pylori infection interferes with gastric iron absorption, and patients who achieve eradication had better response to oral iron supplementation. ^[1]  Patients with ITP had a greater response to eradication of H pylori when they had less severe thrombocytopenia and in areas of higher H pylori prevalence. ^[1]

There is insufficient evidence to support testing and treatment of H pylori in asymptomatic people with a family history of gastric cancer and patients with lymphocytic gastritis, hyperplastic gastric polyps, and hyperemesis gravidarum.

Overall, there has been declining success in treating ​H pylori owing to multiple factors, including antibiotic resistance, complex drug regimens, and issues with adherence. Whenever H pylori is diagnosed and treated, testing is essential to confirm eradication at least 4 weeks after the completion of antibiotic therapy and after proton-pump inhibitor (PPI) therapy has been withheld for 1–2 weeks, using either a urea breath test, fecal antigen test, or endoscopic evaluation with biopsies. ^[1]  

When considering treatment options for patients, they should be asked about prior antibiotic exposures (including macrolides and fluoroquinolones) along with prior reactions and allergies. Bismuth quadruple therapy, including a PPI, bismuth, tetracycline, and a nitroimidazole, for 10–14 days is a recommended first-line option and is useful for patients who have penicillin allergy or prior macrolide exposure.

Given the increasing antibiotic resistance, clarithromycin triple therapy (including a PPI, clarithromycin, and amoxicillin or metronidazole) for 14 days can be considered if clarithromycin resistance is known to be < 15% and the patient has no prior macrolide exposure for more than 2 weeks. Additional first-line therapies include concomitant therapy (including a PPI, clarithromycin, amoxicillin, and a nitroimidazole for 10–14 days), sequential therapy (including a PPI and amoxicillin for 5–7 days, then a PPI, clarithromycin, and a nitroimidazole for 5–7 days), and hybrid therapy (including a PPI and amoxicillin for 7 days, then a PPI, amoxicillin, clarithromycin, and a nitroimidazole for 7 days). ^[1]

In terms of fluoroquinolone-based therapies, options for first-line regimens include levofloxacin triple therapy (including a PPI, levofloxacin, and amoxicillin for 10–14 days) and fluoroquinolone sequential therapy (including a PPI and amoxicillin for 5–7 days, then a PPI, fluoroquinolone, and nitroimidazole for 5–7 days). ^[1]  

Overall, factors influencing eradication failure include antibiotic resistance, nonadherence in the setting of complex drug regimens, inadequate acid suppression, and genetic factors (such as CYP2C19). ^[3] With regard to antibiotic resistance, rates are higher for levofloxacin, clarithromycin, and metronidazole compared with tetracycline, amoxicillin, and rifabutin, which have resistance rates < 2%. ^[3] Of note, metronidazole (1.5-2g daily in divided doses) combined with bismuth therapy improves eradication rates despite its higher resistance rate.

Additionally, barriers to medication adherence can influence eradication failure, including difficulty with dosing regimens and side effects from medications. In terms of optimizing acid suppression, the goal is an intragastric pH of 6 to 8 as decreased pH reduces the half-lives of some antibiotics, including amoxicillin and clarithromycin. For this reason, regimens include increased PPI dosing or potassium-competitive acid blocker use along with increased and more frequent dosing of antibiotics, such as amoxicillin, to improve eradication rates. Additionally, the presence of CYP2C19 can affect the metabolism of early generation PPIs, such as lansoprazole and omeprazole, leading to higher rates of eradication failure.

When managing patients with a refractory H pylori infection, it is important to consider antibiotic selection, drug allergies (such as to penicillin), and duration of therapy. Antibiotics that were previously used should be avoided and local antimicrobial resistance data should be utilized if available. ^[1] Additionally, after 2 failed treatment regimens despite adherence, H pylori susceptibility testing should be considered through endoscopic evaluation with gastric biopsies. In cases of ongoing refractory infections, management should involve shared decision-making, weighing potential benefits of H pylori eradication with adverse effects from repeat antibiotic exposure and high-dose acid suppression, such as in the elderly population. For patients with refractory infections and a penicillin allergy, an allergy referral should be considered. 

For those initially treated with clarithromycin-based therapies, bismuth quadruple therapy or levofloxacin salvage regimens for 14 days are the preferred next line. On the other hand, if patients initially were treated with bismuth quadruple therapy, clarithromycin, or levofloxacin-containing salvages regimens should be considered. Additional salvage regimens to consider include rifabutin triple therapy (including a PPI, amoxicillin, and rifabutin for 10 days) and high-dose dual therapy (including a high-dose PPI, such as esomeprazole 20 mg 4 times a day, and amoxicillin, at least 2 g divided in 3 or 4 doses per day, for 14 days). ^[1] The latter optimizes acid suppression and avoids low trough levels of amoxicillin. ^[3]