Helicobacter pylori infection medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: ; Joseph Nasr, M.D.[2];Yamuna Kondapally, M.B.B.S[3] Fahad Hasan, M.D.[4]

Overview

Scanning electron microscopic (SEM) image revealing some of the ultrastructural morphology exhibited by a number of Gram-negative, Helicobacter spp.

Helicobacter pylori (H. pylori) is a gram-negative, microaerophilic, spiral-shaped bacterium that colonizes the gastric mucosa and is formally recognized as an infectious disease in the International Classification of Diseases, 11th Revision (ICD-11). It is the most prevalent chronic bacterial infection worldwide, with an estimated global prevalence that declined from 58.2% during 1980-1990 to 43.1% during 2011-2020. In North America, the prevalence remains substantial at approximately 30%-40%, with infection disproportionately affecting non-White racial and ethnic groups, immigrants from endemic regions, and individuals living in crowded or poor sanitary conditions.

H. pylori infection is a leading cause of peptic ulcer disease, functional dyspepsia, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. It is classified as a Group 1 carcinogen by the International Agency for Research on Cancer and remains the primary infectious cause of cancer death globally. Transmission occurs primarily through close household contact, including oral-oral, gastric-oral, and fecal-oral routes, with acquisition usually occurring during childhood.

Indications for treatment of H. pylori infection include past or present duodenal and/or gastric ulcer, with or without complications, following resection of gastric cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, atrophic gastritis, dyspepsia, patients with first-degree relatives with gastric cancer, and patient preference. Factors involved in choosing treatment regimens include prevalence of H. pylori infection, prevalence of gastric cancer, resistance to antibiotics, availability of bismuth, availability of endoscopy and H. pylori tests, ethnicity, drug allergies and tolerance, previous treatments and outcome, adverse effects, local treatment effectiveness, and recommended dosages and treatment duration.

The 2024 American College of Gastroenterology (ACG) Clinical Practice Guideline and the 2022 Maastricht VI/Florence Consensus Report represent the most current major North American and international frameworks for the diagnosis and treatment of H. pylori infection.

Epidemiology

Approximately 4.4 billion individuals were estimated to be infected with H. pylori worldwide in 2015. Global prevalence has declined over time, but remains high in many low-resource settings. In the systematic review by Hooi et al., Africa had the highest pooled prevalence at 70.1%, whereas Oceania had the lowest pooled prevalence at 24.4%. A subsequent systematic review covering 1980-2022 confirmed a declining global trend, while also documenting persistent geographic and socioeconomic disparities.

In the United States, a Veterans Health Administration cohort from 1999-2018 found an overall H. pylori prevalence of 25.8% among 913,328 individuals tested. Prevalence differed substantially by race and ethnicity: 20.1% in non-Hispanic White individuals, 36.7% in Hispanic individuals, and 40.2% in Black individuals. Disparities are especially notable among Hispanic and non-Hispanic Black individuals in parts of the southern United States, including Texas, New Mexico, and the Southeast. Globally, prevalence is modestly higher in men than women, with an odds ratio of 1.12 (95% CI, 1.09-1.15).

Transmission usually occurs in early childhood. Intrafamilial person-to-person transmission, including vertical and horizontal household spread, is considered important. Community transmission may occur in resource-limited settings with crowded living conditions, poor sanitation, or contaminated food and water. Immigrants from high-prevalence regions generally have higher infection prevalence, which may decline in subsequent generations. H. pylori has coevolved with humans for more than 100,000 years, and bacterial subpopulations mirror human migration patterns.

Principal clinical sequelae include dyspepsia, peptic ulcer disease, and gastric adenocarcinoma. Additional recognized associations include gastric MALT lymphoma, iron deficiency anemia, and immune thrombocytopenic purpura.

Pathophysiology

H. pylori colonizes the gastric mucus layer and produces chronic active gastritis in virtually all infected individuals. The organism survives in an acidic gastric environment through urease production, motility, epithelial adhesion, immune evasion, and toxin-mediated epithelial injury.

Colonization and Survival

Urease is essential for survival in gastric acid. It catalyzes urea into ammonia and carbon dioxide, creating a relatively alkaline microenvironment that allows H. pylori to survive at gastric pH levels that may be as low as 1.5. Flagella provide motility and allow the organism to penetrate the gastric mucus layer. Adhesins, including BabA and OipA, facilitate attachment to gastric epithelial cells and influence inflammatory response and disease risk.

Virulence Factors

Virulence factor	Mechanism	Clinical relevance
Urease	Converts urea into ammonia and carbon dioxide, buffering gastric acid.	Essential for gastric survival and colonization.
Flagella	Provide motility through the gastric mucus layer.	Facilitates colonization near the gastric epithelium.
BabA and OipA adhesins	Promote epithelial attachment.	Associated with enhanced colonization and inflammatory response.
CagA and cag pathogenicity island	Type IV secretion system translocates CagA into host cells, altering signaling, polarity, and proliferation.	Associated with more severe gastritis, ulcer disease, gastric cancer, and MALT lymphoma.
VacA	Causes epithelial vacuolation, apoptosis, mitochondrial dysfunction, and immune modulation.	s1/m1 genotype is associated with higher virulence.
HtrA protease	Cleaves E-cadherin and disrupts epithelial junctions.	Promotes barrier disruption and tissue injury.

The cag pathogenicity island is an approximately 40-kb genomic island encoding about 31 genes, including a type IV secretion system. This system translocates CagA, a 120-160 kDa immunodominant oncoprotein, into gastric epithelial cells. CagA undergoes tyrosine phosphorylation at EPIYA motifs, activates SHP-2 phosphatase, and disrupts cellular signaling pathways involved in proliferation, cytoskeletal organization, and epithelial polarity. CagA-positive strains induce stronger IL-8 production, NF-kB activation, neutrophil recruitment, and gastric inflammation. East Asian EPIYA-D motifs and multiple EPIYA-C motifs are associated with higher gastric cancer risk.

VacA is present in all H. pylori strains but is functionally expressed in only a subset depending on allelic variation. VacA causes vacuolar degeneration of epithelial cells, promotes apoptosis, disrupts mitochondrial function, and modulates immune responses. Allelic variation includes signal-region types s1a, s1b, and s2 and mid-region types m1 and m2; the s1/m1 genotype is associated with greatest virulence.

Host Response and Tissue Injury

H. pylori induces chronic active gastritis characterized by neutrophil, lymphocyte, and plasma cell infiltration. The immune response is paradoxically Th1-biased and inflammatory, but fails to eradicate the noninvasive organism, leading to persistent tissue damage. Functional polymorphisms in host cytokine genes, including IL-1 beta, TNF-alpha, and IL-10, may influence the magnitude of inflammation and disease outcome.

Mechanisms of tissue injury include VacA-mediated epithelial disruption, impairment of mucosal hydrophobicity by phospholipases, Fas-mediated apoptosis, HtrA-mediated cleavage of E-cadherin, generation of reactive oxygen species, and oxidative DNA damage.

Natural History

H. pylori infection is usually acquired during childhood through intrafamilial transmission. Without treatment, infection persists lifelong in most individuals, and chronic active gastritis develops in nearly all infected individuals.

The natural history of gastric carcinogenesis is often described by the Correa cascade: normal gastric mucosa progresses to chronic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and finally gastric adenocarcinoma. This process usually requires decades. Chronic H. pylori-related gastritis is the dominant risk factor for noncardia gastric adenocarcinoma, with an attributable risk estimated at 75%-89%.

Gastritis pattern	Acid output	Main clinical risk
Antral-predominant gastritis	Increased or preserved acid output	Higher risk of duodenal ulcer
Corpus-predominant atrophic gastritis	Reduced acid output	Higher risk of gastric ulcer, atrophy, intestinal metaplasia, and gastric cancer
Pangastritis	Variable	Mixed ulcer and cancer risk depending on severity and distribution

Only a minority of infected individuals develop clinically important complications. Approximately 15%-20% of infected individuals develop peptic ulcer disease during life, and only about 3% develop gastric cancer. Localized gastric MALT lymphoma is rare but strongly associated with H. pylori infection, and eradication therapy can induce remission in many localized cases.

Diagnosis

Diagnosis of H. pylori infection may be established by non-invasive or invasive testing. The 2024 ACG guideline emphasizes the principle that if a patient is tested and found positive, the patient should be treated and eradication should be confirmed.

Testing Algorithm

Clinical indication to test for H. pylori

Is upper endoscopy clinically indicated?

Yes

No

Use biopsy-based testing: histology, rapid urease test, culture, or molecular testing

Use non-invasive testing: 13C-urea breath test or monoclonal stool antigen test

If positive: treat and confirm eradication

If positive: treat and confirm eradication

Non-Invasive Tests

The urea breath test and monoclonal stool antigen test are preferred non-invasive tests for active infection. Proton pump inhibitors should be discontinued for at least 2 weeks before non-serologic testing, and antibiotics and bismuth should be discontinued for at least 4 weeks before testing.

Test	Sensitivity	Specificity	Advantages	Limitations
13C-urea breath test	94%-100%	93%-100%	Preferred non-invasive test; detects active infection through urease activity; useful for diagnosis and test of cure.	Requires PPI hold for at least 2 weeks and antibiotic/bismuth hold for at least 4 weeks.
Monoclonal stool antigen test	Approximately 94%	Approximately 97%	Reliable, cost-effective, detects active infection; laboratory-based monoclonal assays preferred.	Requires PPI hold for at least 2 weeks; stool collection may be less acceptable to some patients.
Serology IgG	Approximately 85%	Approximately 79%	May remain useful when other tests are falsely negative, such as active upper GI bleeding, recent PPI or antibiotic use, gastric atrophy, or gastric MALT lymphoma.	Cannot distinguish active from prior infection; not useful for test of cure; not preferred in low-prevalence settings.

The urea breath test requires ingestion of labeled urea. If H. pylori is present, urease releases labeled carbon dioxide, which is measured in exhaled breath. Serology should not be used to confirm eradication because antibodies may remain elevated for months to years after cure.

Invasive Tests

Invasive tests require upper endoscopy with gastric sampling and are preferred when endoscopy is clinically indicated for alarm features, bleeding, gastric ulcer, suspected malignancy, refractory disease, or need for antimicrobial susceptibility testing.

Test	Sensitivity	Specificity	Advantages	Limitations
Rapid urease test	67%-95%	93%-100%	Rapid biopsy-based test; inexpensive; detects urease activity.	False negatives occur with PPI use, antibiotics, bismuth, bleeding, atrophy, or low bacterial density.
Histology	70%-90%	Approximately 90%	Allows assessment of gastritis, atrophy, intestinal metaplasia, dysplasia, and malignancy.	Requires endoscopy and adequate sampling from antrum and corpus.
Culture	Approximately 45%	Approximately 98%	Allows phenotypic antibiotic susceptibility testing.	Technically difficult, slow, and not widely available.
Molecular testing / PCR / NAAT	Variable; stool PCR sensitivity approximately 88.6%-92.8% in studies	High for specific mutations	Detects organism and clarithromycin resistance mutations from biopsy or stool.	Availability, cost, and mutation coverage vary by platform.

Multiple biopsies from different gastric sites, including antrum and corpus, improve diagnostic yield and allow assessment of premalignant histology. In acute upper gastrointestinal bleeding, 25%-55% of H. pylori tests may yield false-negative results, and repeat testing after recovery is recommended when initial testing is negative but clinical suspicion remains high.

Medical Therapy

Indications for treatment of H. pylori infection include:

• Past or present duodenal and/or gastric ulcer, with or without complications
• Following resection of gastric cancer
• Gastric mucosa-associated lymphoid tissue (MALT) lymphoma
• Atrophic gastritis
• Dyspepsia (uninvestigated dyspepsia in patients under 60 years old; test-and-treat strategy)
• Functional dyspepsia
• Patients with first-degree relatives with gastric cancer
• Adult household members of individuals with a positive non-serological test for H. pylori
• Patients on long-term non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin
• Patients with unexplained iron deficiency anemia
• Patients with immune thrombocytopenic purpura
• Patients with premalignant lesions (atrophic gastritis, intestinal metaplasia, dysplasia) or history of early gastric cancer resection
• Immigrants from high-gastric-cancer-incidence regions
• Individuals with hereditary cancer syndromes associated with elevated gastric cancer risk
• Patient preference

Factors involved in choosing treatment regimens include:

• Prevalence of H. pylori infection
• Prevalence of gastric cancer
• Resistance to antibiotics
• Availability of bismuth
• Cost of tests
• Availability of endoscopy and H. pylori tests
• Availability of antibiotic susceptibility testing
• Ethnicity
• Drug allergies and tolerance
• Previous treatments and outcome
• Ease of administration
• Adverse effects
• Effectiveness of local treatment
• Recommended dosages and treatment duration
• CYP2C19 metabolizer status

The 2024 ACG guideline emphasizes that the decision to test for and treat H. pylori should be viewed as a single, unified decision: if a patient is tested and found positive, eradication therapy should be offered, and confirmation of eradication must always follow.

Antibiotic Susceptibility Testing

Because H. pylori infection is now treated as an infectious disease, treatment should be guided by likely or actual antibiotic susceptibility whenever possible. Clarithromycin resistance in North America is approximately 22.2%-31.5%, and levofloxacin resistance is approximately 37.6%; therefore, empiric clarithromycin- and levofloxacin-containing regimens should not be used without susceptibility data.

Method	Specimen	Advantages	Limitations
Culture-based phenotypic testing	Gastric biopsy	Directly measures antibiotic growth inhibition.	Requires endoscopy, special transport, technical expertise, and viable organisms; culture success may be low in routine practice.
PCR / NAAT	Gastric biopsy or stool	Detects H. pylori and clarithromycin resistance mutations; may avoid endoscopy when stool-based.	Resistance targets vary by assay; may not detect all resistance mechanisms.
Next-generation sequencing	Gastric biopsy or stool	Can evaluate multiple resistance genes and heteroresistance; higher DNA yield than culture.	Availability, cost, and interpretation vary.

Antibiotic susceptibility testing should be considered when therapy choice remains unclear after reviewing previous H. pylori treatments, past antibiotic exposure, and penicillin allergy status; before using clarithromycin- or levofloxacin-containing regimens; and after two or more treatment failures. Stool-based molecular testing is preferred when endoscopy is otherwise unnecessary.

First-Line Regimens for Helicobacter pylori Eradication

Rising rates of antibiotic resistance have fundamentally changed the approach to empiric first-line therapy. The 2024 ACG guideline has removed PPI-clarithromycin triple therapy as an empiric first-line recommendation and has designated optimized bismuth quadruple therapy (BQT) for 14 days as the preferred first-line regimen when antibiotic susceptibility is unknown. Clarithromycin-containing and levofloxacin-containing regimens must be avoided in the absence of demonstrated susceptibility to the respective antibiotic.

Antimicrobial susceptibility testing, via culture, molecular testing, or next-generation sequencing on gastric biopsy or stool specimens, should be used whenever the choice of therapy remains unclear after consideration of prior treatment history, prior antibiotic exposure, and penicillin allergy status.

All empiric regimens should be administered for 14 days.

Regimen	Duration	Approximate eradication rate	Comments
Optimized Bismuth Quadruple Therapy (BQT) — recommended first-line regimen Standard-dose PPI b.i.d. + bismuth subcitrate or subsalicylate q.i.d. + tetracycline 500 mg q.i.d. + metronidazole 500 mg t.i.d. or q.i.d.	14 days	90%-95%	Preferred first-line regimen for treatment-naive patients with unknown susceptibility profile per 2024 ACG guideline and 2022 Maastricht VI consensus. Doxycycline must not be substituted for tetracycline; substitution is associated with approximately 10%-17% lower eradication rates. Tetracycline 500 mg q.i.d. is the required component of optimized BQT.
Rifabutin Triple Therapy (Talicia) omeprazole 40 mg / amoxicillin 1,000 mg / rifabutin 50 mg all q8h	14 days	83.8%-89.4% (mITT)	FDA-approved all-in-one capsule. The ERADICATE Hp trial demonstrated modified ITT eradication of 89.4%. The ERADICATE Hp2 trial confirmed ITT superiority versus active comparator (83.8% vs. 57.7%). Contains amoxicillin; avoid in confirmed penicillin allergy.
Vonoprazan Dual Therapy vonoprazan 20 mg b.i.d. + amoxicillin 1 g t.i.d. or per labeling	14 days	77.2% (ITT, overall population)	Potassium-competitive acid blocker-based regimen. In PHALCON-HP, overall ITT eradication was 77.2% versus 68.5% with lansoprazole triple therapy; among clarithromycin-resistant strains, 69.6% versus 31.9%. Not subject to CYP2C19 polymorphism.
Vonoprazan Triple Therapy vonoprazan 20 mg b.i.d. + amoxicillin 1 g b.i.d. + clarithromycin 500 mg b.i.d.	14 days	80.8% (ITT, overall population)	In PHALCON-HP, overall ITT eradication was 80.8% versus 68.5% with lansoprazole triple therapy; among clarithromycin-resistant strains, 65.8% versus 31.9%. Use should still account for clarithromycin resistance and prior macrolide exposure.
PPI-Clarithromycin Triple Therapy Standard-dose PPI b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1,000 mg b.i.d.	14 days	70%-85% where susceptible	Removed as empiric first-line therapy by the 2024 ACG guideline because of clarithromycin resistance. Reserved for patients with documented clarithromycin susceptibility and no prior macrolide exposure.
PPI + Clarithromycin + Metronidazole	14 days	70%-85% where susceptible	Not recommended empirically. Consider only in penicillin-allergic patients with documented clarithromycin susceptibility when BQT is not tolerated.

PPI = proton pump inhibitor; b.i.d. = twice daily; t.i.d. = three times daily; q.i.d. = four times daily; q8h = every 8 hours; ITT = intention-to-treat; mITT = modified intention-to-treat.

Concomitant Therapy

Concomitant therapy, also called PAMC therapy, consists of a PPI plus amoxicillin, metronidazole, and clarithromycin, all given simultaneously for 14 days. It differs from sequential therapy, in which antibiotics are administered in phases, and from hybrid therapy, which combines a dual-therapy lead-in phase with a quadruple-therapy phase.

The 2024 ACG guideline removed concomitant therapy as a preferred empiric first-line recommendation because of rising dual clarithromycin and metronidazole resistance. The 2022 Maastricht VI consensus retains concomitant therapy as a first-line option in regions where bismuth is unavailable and dual clarithromycin/metronidazole resistance is low.

Susceptibility-Guided Therapy

When antibiotic susceptibility testing is available, therapy should be tailored to the susceptibility profile:

Susceptibility profile	Recommended regimen
Clarithromycin-susceptible and metronidazole-susceptible	PPI + clarithromycin + amoxicillin for 14 days; or concomitant therapy for 14 days where appropriate.
Clarithromycin-resistant	Optimized BQT or rifabutin triple therapy for 14 days.
Levofloxacin-susceptible in salvage context	Levofloxacin triple or quadruple therapy for 14 days; use only after confirmed susceptibility.
Multidrug-resistant or multiple treatment failures	Culture- or molecular-guided therapy; specialist referral recommended.

Predictors of H. pylori Treatment Outcome

Predictors of treatment failure include:

• Poor adherence
• Antibiotic resistance, especially clarithromycin or levofloxacin resistance
• Prior antibiotic exposure
• CYP2C19 ultra-rapid metabolism when PPI-based regimens are used
• Smoking
• High bacterial load
• Prior treatment failure

CYP2C19 polymorphisms may influence treatment outcomes when regimens containing PPIs are used, because they affect PPI clearance and gastric acid suppression. Vonoprazan is not subject to this polymorphism and may offer more consistent acid suppression regardless of metabolizer status.

Drug Adverse Effects and Prescribing Considerations

Drug	Side effects	Recommendations
Proton pump inhibitors	Headache, diarrhea	PPIs should be taken 30-60 minutes before eating. CYP2C19 ultra-rapid metabolizers may have reduced efficacy; consider higher doses or vonoprazan.
Vonoprazan	Diarrhea, dysgeusia, vulvovaginal candidiasis, abdominal pain, headache	Not subject to CYP2C19 polymorphism; provides more profound and durable acid suppression than PPIs.
Clarithromycin	GI upset, headache, altered taste, QT prolongation	Avoid empirically. Use only when susceptibility is confirmed. Consider interactions with CYP3A4-metabolized drugs, including selected statins.
Amoxicillin	GI upset, headache, diarrhea, allergic reactions	Avoid in confirmed penicillin allergy. Primary resistance remains uncommon.
Metronidazole	Metallic taste, dyspepsia, disulfiram-like reaction with alcohol	Resistance may be partly overcome by higher doses and 14-day optimized BQT.
Tetracycline	GI upset, photosensitivity	Required component of optimized BQT. Do not substitute doxycycline for tetracycline in optimized BQT. Avoid in pregnancy and in children under 8 years.
Bismuth compounds	Dark tongue, dark stool, nausea, GI upset	Bismuth subsalicylate contains salicylate; avoid in salicylate allergy. Stop at least 4 weeks before test of cure.
Rifabutin	Diarrhea, headache, chromaturia, abdominal tenderness, dizziness	Myelotoxicity not reported at Talicia dose in pivotal trials; consider photosensitivity and reproductive counseling.
Levofloxacin	GI upset, QT prolongation, tendinopathy, tendon rupture, neuropathy, CNS effects, myasthenia gravis exacerbation	Fluoroquinolones carry FDA boxed warnings for disabling and potentially irreversible serious adverse reactions. Use only when susceptibility is confirmed. Stop immediately if serious tendon, neurologic, CNS, or myasthenia symptoms occur.

Salvage Therapy for Persistent H. pylori Infection

In patients with persistent H. pylori infection, every effort should be made to avoid antibiotics that have been previously taken by the patient. Per the 2024 ACG guideline, antibiotic susceptibility testing is strongly encouraged before initiating any salvage regimen, particularly after two or more treatment failures.

Regimen	Duration	Approximate eradication rate	Comments
Optimized BQT, if not previously used	14 days	90%-95%	Preferred salvage regimen for treatment-experienced patients who have not previously received optimized BQT and for whom susceptibility is unknown.
Rifabutin triple therapy	14 days	83.8%-89.4%	Suggested when optimized BQT has previously failed or cannot be used. Contains amoxicillin; avoid in confirmed penicillin allergy.
Levofloxacin-based triple therapy	10-14 days	Up to 87% where susceptible	Use only when levofloxacin susceptibility has been confirmed. Empiric use is inappropriate where resistance is high.
High-dose PPI-amoxicillin dual therapy	14 days	Approximately 89% per protocol in selected Asian second-line studies	Second-line option in settings with high fluoroquinolone resistance; Western data remain more limited.

Other Alternative Antibiotics

Rifabutin

• Rifabutin is FDA-approved as part of Talicia (rifabutin 50 mg / amoxicillin 1,000 mg / omeprazole 40 mg, q8h for 14 days) for treatment of H. pylori infection and is suggested by the 2024 ACG guideline as an alternative to optimized BQT for selected treatment-naive and treatment-experienced patients.
• High-dose rifabutin may be considered as later-line salvage therapy in patients who have failed multiple prior courses.

Furazolidone

• Furazolidone is used as an alternative to clarithromycin, metronidazole, or amoxicillin in some developing countries where it remains available.
• It is not currently used in the United States.
• Side effects include nausea, vomiting, headache, and malaise.

Levofloxacin

• Levofloxacin-based therapy can be used as second- or third-line therapy only when levofloxacin susceptibility has been confirmed. Given levofloxacin resistance rates in North America, empiric use is no longer appropriate per the 2024 ACG guideline.

Special Populations

Population	Recommendation
Penicillin allergy	BQT does not contain penicillin and remains a first-line option. Rifabutin triple therapy and vonoprazan-based regimens contain amoxicillin and should be avoided in confirmed penicillin allergy. Allergy evaluation is recommended when BQT has failed or is not tolerated.
Pregnancy	Eradication is generally deferred until after delivery. Tetracycline-containing regimens are contraindicated. Treatment should be individualized after risk-benefit discussion.
Hepatic impairment	Regimen selection should account for hepatic disease severity and product labeling. Severe hepatic impairment may limit use of some multidrug regimens.
Children and adolescents	Susceptibility-guided therapy is preferred. Tetracycline should not be given to children under 8 years because of tooth discoloration risk. The 13C-UBT is safe and reliable for post-treatment testing in children aged 3 years or older.
CYP2C19 ultra-rapid metabolizers	Rapid PPI metabolism may reduce eradication rates. Higher PPI doses or vonoprazan may be considered.

Probiotics as Adjunctive Therapy

Current evidence is insufficient to recommend routine probiotic use to improve eradication efficacy or tolerability. Some meta-analyses suggest modest benefit and fewer side effects when probiotics are used with BQT, but optimal strain, dose, and duration remain uncertain.

H. pylori Treatment Options in Developing Countries

H. pylori infection remains highly prevalent in low- and middle-income countries, where access to vonoprazan, rifabutin, and antimicrobial susceptibility testing may be limited. Treatment choices are guided by local antibiotic resistance patterns, drug availability, cost, and feasibility, in alignment with the World Gastroenterology Organisation Global Guideline and the Maastricht VI/Florence Consensus.

Therapy type	Regimen / role
Optimized BQT	PPI b.i.d. + bismuth q.i.d. + tetracycline 500 mg q.i.d. + metronidazole 500 mg t.i.d. or q.i.d. for 14 days. Preferred when bismuth and tetracycline are available.
Standard triple therapy	PPI + amoxicillin + clarithromycin for 7-14 days. Acceptable only where locally verified clarithromycin resistance remains below 15%.
Concomitant therapy	PPI + clarithromycin + metronidazole + amoxicillin for 14 days. Option where bismuth is unavailable and dual resistance is low.
Sequential therapy	PPI + amoxicillin followed by PPI + clarithromycin + metronidazole or tinidazole. Not preferred where clarithromycin resistance is high.
Hybrid therapy	PPI + amoxicillin lead-in followed by PPI + amoxicillin + clarithromycin + metronidazole. May have high eradication rates in selected regions.
Furazolidone-containing regimens	Used in some developing countries where available; not used in the United States.

The Maastricht VI consensus recommends that empiric regimens should not be relied upon when local eradication rates are expected to fall below 85%; local resistance surveillance is essential to guide regimen selection.

Testing to Prove Eradication After Antibiotic Therapy

Confirmation of eradication is mandatory for all patients treated for H. pylori infection, as symptom resolution is a poor surrogate for cure and persistent infection predicts ulcer recurrence and ongoing gastric cancer risk.

Indications for testing to prove eradication after antibiotic therapy include:

• All patients treated for H. pylori infection
• Any patient with an H. pylori-associated ulcer
• Individuals with persistent dyspeptic symptoms after test-and-treat strategy
• Patients with H. pylori-associated MALT lymphoma
• Individuals who have undergone resection of early gastric cancer

Pre-test requirements:

• Discontinue all antibiotics and bismuth for at least 4 weeks before testing
• Discontinue PPIs for at least 2 weeks before testing
• Discontinue PCABs, such as vonoprazan, for at least 2 weeks before testing

Test	Sensitivity	Specificity	Notes
13C-urea breath test	94.7%-97%	95%-100%	Preferred non-invasive test of cure; detects viable organism urease activity.
Validated monoclonal stool antigen test	>90%-95%	>90%-95%	Reliable and cost-effective alternative; laboratory-based monoclonal assay preferred.
Biopsy-based testing by upper endoscopy	Variable	Variable	Reserved for patients requiring repeat endoscopy or susceptibility testing.
Serology IgG	Not applicable	Not applicable	Not recommended for test of cure because antibodies remain elevated after eradication.

Test of cure should be performed at least 4 weeks after completion of therapy. In the setting of bleeding peptic ulcer disease, testing may be delayed to 4-8 weeks after the bleeding episode to allow mucosal recovery. A positive test of cure confirms persistent infection and requires a second eradication attempt using a non-cross-resistant regimen, ideally guided by antibiotic susceptibility testing.

Gastric Cancer Prevention

Eradication of H. pylori reduces gastric cancer risk. Meta-analyses demonstrate approximately 46% reduction in gastric adenocarcinoma incidence with eradication therapy, with risk ratio 0.54 and number needed to treat of approximately 72. A 2025 meta-analysis confirmed benefit in healthy H. pylori-positive individuals and in patients after resection of gastric neoplasia.

The benefit of eradication is greatest before development of premalignant gastric conditions. Mild to moderate atrophic gastritis may be reversible after eradication, whereas patients with advanced atrophy, extensive intestinal metaplasia, or dysplasia remain at increased risk and may require endoscopic surveillance even after cure.

Increased-risk population	Rationale
First-degree relatives of patients with gastric cancer	Familial clustering and shared environmental or genetic risk.
Immigrants from high-incidence regions	Higher background prevalence and gastric cancer incidence.
Hispanic, Black, East Asian, Native American, and Alaska Native populations	Higher observed gastric cancer risk in several U.S. datasets.
Atrophic gastritis, intestinal metaplasia, or dysplasia	Premalignant histology increases cancer risk.
Prior gastric neoplasia resection	Increased metachronous cancer risk.
Hereditary cancer syndromes	Includes CDH1-related hereditary diffuse gastric cancer, Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, and juvenile polyposis.

The 2025 Taipei Global Consensus II recommends offering eradication therapy to all infected adults, prioritizing screening in high-risk populations and using 13C-UBT or monoclonal stool antigen testing as preferred non-invasive tests. Family-based test-and-treat strategies may improve eradication and reduce recurrence compared with treating only the index patient.

Reinfection and Recrudescence

Recurrence refers to reappearance of H. pylori after confirmed eradication and includes recrudescence and reinfection. Recrudescence refers to reappearance of the original strain after an initially false-negative post-treatment test, whereas reinfection refers to acquisition of a new strain after true eradication.

A global meta-analysis including 132 studies and 53,934 patient-years estimated an annual recurrence rate of 4.3%. Recurrence was inversely related to the Human Development Index: 3.1% in very high-HDI settings, 6.2% in high-HDI settings, and 10.9% in medium- or low-HDI settings. In studies using DNA fingerprinting, annual reinfection and recrudescence rates were approximately 3.1% and 2.2%, respectively.

Recrudescence is more common in the first year after therapy, whereas reinfection becomes more important later. In developed countries, reinfection rates are often approximately 1.5%-3% per year, while substantially higher rates have been reported in low-resource settings and parts of Latin America.

Risk factors for recurrence include low socioeconomic development, poor sanitation, high local prevalence, number of children in the household, poor medication adherence, low education level, family history of gastric cancer, and residence in high-prevalence regions. The 2024 ACG guideline recommends testing adult household members of individuals with a positive non-serologic H. pylori test.

Extraintestinal Associations

H. pylori is associated with selected extraintestinal conditions, especially iron deficiency anemia, immune thrombocytopenic purpura, and vitamin B12 deficiency. These associations do not imply that H. pylori is the only cause, but they support testing and treatment in appropriate unexplained cases.

Condition	Proposed mechanisms	Clinical implication
Iron deficiency anemia	Iron competition, achlorhydria reducing iron absorption, chronic gastritis, occult blood loss, hepcidin-mediated impaired iron mobilization.	Recognized indication for H. pylori testing and treatment when otherwise unexplained.
Immune thrombocytopenic purpura	Molecular mimicry between H. pylori antigens, including CagA, and platelet surface glycoproteins.	Eradication can increase platelet count in some patients; response varies geographically and ethnically.
Vitamin B12 deficiency	Chronic gastritis and atrophy impair intrinsic factor production and vitamin B12 absorption.	Eradication may improve vitamin B12 levels in selected patients.