Version July 2025
INTRODUCTION —
The management of chronic infection with Helicobacter pylori continues to evolve since its first recognition as the main cause of peptic ulcer disease and gastric cancer over 40 years ago. Current regimens to eradicate H. pylori generally include one to three antimicrobials plus a potent gastric acid suppression agent, such as a proton pump inhibitor or a potassium-competitive acid blocker.
Selecting a treatment regimen is challenging given increasing rates of H. pylori antibiotic resistance, limited data on local H. pylori antibiotic resistance rates and their impact on eradication outcomes, and a paucity of high-quality clinical trials, particularly in diverse North American populations [1,2]. Moreover, patient adherence to therapy is undermined by the complexity of H. pylori treatment regimens, their high pill burdens, and frequent side effects. Availability and cost of certain component medications of H. pylori treatment (eg, tetracycline) as well as prepackaged combination therapies have also led to heterogeneous prescribing practices in the United States. All of these factors have contributed to decreasing success rates of H. pylori eradication [3,4].
This topic reviews how to select and administer H. pylori regimens for initial treatment and the treatment of persistent H. pylori infection. The epidemiology, clinical manifestations, and diagnosis of H. pylori infection are discussed separately. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults" and "Helicobacter pylori: Epidemiology, pathophysiology, and overview of disease associations".)
PRETREATMENT CONSIDERATIONS
Whom to treat — All patients who test positive for active H. pylori infection (ie, have a positive nonserologic test) should be offered treatment. We typically do not test individuals with contraindications to treatment (eg, pregnancy) or for whom the risks of treatment outweigh the perceived benefits (eg, limited life expectancy) (table 1). (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
Pretreatment counseling — Pretreatment counseling is important to address potential patient barriers to treatment adherence and maximize the likelihood of successful H. pylori eradication. We counsel patients that H. pylori eradication is associated with peptic ulcer healing, reduces the likelihood of ulcer recurrence, reduces the risk of gastric cancer, and, in symptomatic individuals, may improve or resolve dyspepsia symptoms. We emphasize that completing the entire treatment course and not skipping medication doses maximizes the chance of H. pylori eradication and avoids the need for salvage treatment, which is generally associated with lower rates of eradication success.
We also inform patients about the appropriate timing and administration of medications and their expected side effects [5]. Because H. pylori regimens require taking multiple pills several times daily for 10 to 14 days, clinicians should provide advice on how and when to take the medications and use pill dispensers or visual aids, particularly for individuals with limited health literacy [6]. We discuss common side effects, such as a black tongue and/or stool with bismuth and gastrointestinal upset with antibiotics. We encourage patients to notify us if they are unable to tolerate treatment due to side effects and provide medications to treat side effects (eg, antiemetics) when needed. (See 'Adverse effects' below.)
INITIAL MANAGEMENT
Selecting a regimen — First-line regimens for the initial treatment of H. pylori infection include "optimized" bismuth quadruple therapy (BQT), low-dose rifabutin triple therapy, vonoprazan dual therapy, and vonoprazan triple therapy (table 2). Optimized BQT is the preferred option for empiric first-line therapy in North America. When selecting a treatment regimen for H. pylori infection, we consider local antibiotic resistance patterns and rates of H. pylori eradication; the patient's previous antibiotic exposures, allergies, medication intolerances, and possible drug-drug interactions; regimen cost; and ease of administration. Although combination medication capsules simplify pill regimens, they are expensive, and payors may not cover them [6].
Empiric therapy refers to therapy that is selected without knowledge of H. pylori's antibiotic resistance profile as determined through molecular or culture-based antibiotic susceptibility profiling. Susceptibility-guided therapy refers to the selection of a treatment regimen based on knowledge of the antibiotic susceptibility profile. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
The following approach is consistent with guidelines on the treatment of H. pylori infection from the American College of Gastroenterology and others [7-9].
Avoid empiric treatment containing clarithromycin or levofloxacin — We do not use regimens that contain clarithromycin or levofloxacin for empiric therapy in treatment-naïve individuals in the United States and other areas with high rates of H. pylori resistance to these antibiotics. In the United States, H. pylori rates of resistance to clarithromycin exceed 20 to 30 percent and are steadily increasing [10,11]. Similarly, nearly 40 percent of H. pylori strains in the United States are resistant to levofloxacin.
H. pylori regimens with eradication rates lower than 85 percent should generally be avoided for empiric treatment. H. pylori eradication rates with clarithromycin-containing regimens have declined over the past 20 years and are now below 70 percent overall and only 30 percent in those with documented clarithromycin-resistant H. pylori strains [10,11]. Regimens that include clarithromycin or levofloxacin should only be used in patients whose H. pylori strains demonstrate susceptibility to these antibiotics based on antimicrobial susceptibility testing. (See 'Prior treatment with more than one regimen' below.)
Bismuth quadruple therapy preferred — For empiric treatment of H. pylori infection in treatment-naïve individuals, we suggest optimized BQT rather than other regimens (table 2). Optimized BQT is the preferred regimen in areas with high or unknown rates of H. pylori resistance to clarithromycin and can be used in patients with and without penicillin allergy. Although optimized BQT has not been directly compared with low-dose rifabutin triple therapy or vonoprazan-based regimens, it is highly effective for H. pylori eradication in "real-world" populations, including the United States.
●Dose and administration – Optimized BQT consists of a 10- to 14-day treatment course that includes a proton pump inhibitor (PPI) twice daily, high doses of bismuth subsalicylate, tetracycline, and metronidazole 500 mg three or four times daily (table 2) [12]. Preferred options for optimized BQT include a fixed-dose combination antibiotic capsule (Pylera) as a 10-day course or a 14-day course of the three antimicrobials as individual pills. These regimens are combined with a twice-daily PPI that is prescribed separately and taken 30 to 60 minutes before meals on an empty stomach to maximize acid suppression. (See 'Gastric acid suppression' below.)
Clinicians should not substitute doxycycline for tetracycline because this significantly decreases rates of treatment success [13]. Appropriate metronidazole dosing (1.5 to 2 g total daily dose) and the addition of sufficiently dosed bismuth are typically sufficient to overcome in vitro metronidazole resistance. (See 'Attention to resistance patterns' below.)
Combination pills are simpler to take but likely more expensive than BQT component therapy (ie, using the four medications prescribed separately). We prefer Pylera or component antibiotic therapy to Helidac because Helidac only delivers 1 g of metronidazole daily. In the United States, Helidac and Pylera are approved by the US Food and Drug Administration (FDA) for the treatment of H. pylori. Details regarding specific BQT treatment regimens appear in a table (table 2).
●Efficacy – BQT eradicates H. pylori infection in approximately 85 percent of cases in routine clinical practice [3,13-16]. Optimized BQT is likely the most efficacious regimen in areas with high or unknown rates of H. pylori resistance to clarithromycin, such as the United States. In a systematic review of 30 studies of 6282 participants, the efficacy of BQT was 90 percent as a first-line empiric treatment when it was given as Pylera plus a PPI [17]. By contrast, rates of H. pylori eradication are significantly lower with regimens that contain clarithromycin, given high rates of clarithromycin resistance. (See 'Avoid empiric treatment containing clarithromycin or levofloxacin' above.)
Few trials have directly evaluated the comparative efficacy of optimized BQT, low-dose rifabutin triple therapy, and vonoprazan-based regimens. Most studies were conducted outside of the United States and cannot necessarily be extrapolated to United States populations. These include the following:
•Two meta-analyses reported comparable rates of H. pylori eradication with vonoprazan-amoxicillin dual therapy versus bismuth-containing regimens; however, the latter differed from optimized BQT, and some contained clarithromycin [18,19].
•In a randomized, open-label trial of 300 participants in China, BQT was comparable to vonoprazan (20 mg twice daily) plus tetracycline (500 mg three times daily) for 14 days for eradicating H. pylori infection (89.3 percent, 95% CI 83-93.6 percent, versus 92 percent, 95% CI 86.1-95.6 percent) [20]. Participants in the vonoprazan-tetracycline group had lower rates of treatment-related adverse events (14 versus 48 percent) and treatment discontinuation due to adverse events (2 versus 8.7 percent), compared with those assigned to BQT. However, the doses of bismuth, tetracycline, and metronidazole were lower than those for optimized BQT, and it is unclear if these data can be extrapolated to patients in the United States.
●Side effects – Side effects with BQT are very common, but they are usually mild and rarely cause treatment discontinuation [21,22]. Common side effects include diarrhea, nausea, metallic taste, and black tongue and/or stool.
Although all H. pylori regimens cause side effects, these may be more common with BQT [21]. In a meta-analysis of six trials, vonoprazan-amoxicillin dual therapy had lower rates of side effects than BQT (16 versus 40 percent) [18]. We counsel patients to expect side effects and provide anticipatory guidance and medications to treat symptoms if needed (eg, ondansetron for nausea). (See 'Pretreatment counseling' above.)
●Rationale for empiric treatment – We prefer an empiric treatment approach for the management of treatment-naïve patients rather than performing antimicrobial susceptibility testing if the local H. pylori eradication rate with optimized BQT is 85 percent or higher. Empiric treatment with BQT appears comparable to selecting a regimen based on the results of antimicrobial susceptibility testing [12]. In the United States, tetracycline resistance is low (approximately 1 percent), and although rates of in vitro metronidazole resistance approximate 40 percent [23], they do not correlate well with treatment failure if metronidazole is used in conjunction with bismuth and taken at doses of 1.5 to 2 g daily (three to four divided doses) [12]. (See 'Attention to resistance patterns' below.)
Alternative first-line regimens — Low-dose rifabutin triple therapy and vonoprazan dual or triple therapy are alternative first-line treatment regimens for treatment-naïve individuals with H. pylori infection, especially if local eradication rates with optimized BQT are less than 85 percent.
Rifabutin triple therapy — Low-dose rifabutin triple therapy is an alternative first-line option for treatment-naïve individuals. We reserve its use for select patients in whom optimized BTQ is not an option. Low-dose rifabutin triple therapy demonstrates high rates of H. pylori eradication, and its dosing schedule may be easier to take than that of BQT. However, it is expensive, and rifabutin is a World Health Organization (WHO) watchlist antibiotic, meaning that it should be used cautiously and monitored to avoid overuse and preserve its effectiveness [24].
●Dosing and administration – Low-dose rifabutin triple therapy consists of a 14-day course of rifabutin 50 mg, amoxicillin 1 g, and omeprazole 40 mg three times daily, which is available as the combination pill Talicia (table 2). Patients should take Talicia with food three times daily.
We prefer Talicia over prescribing rifabutin, amoxicillin, and omeprazole separately (ie, "component therapy"). Talicia contains a low dose of rifabutin (50 mg three times daily) that may contribute to efficacy while minimizing systemic exposure to rifabutin [25]. The efficacy of other rifabutin-based regimens for treating H. pylori has not been evaluated in United States populations, and only a 150 mg dose of rifabutin is available in the United States. Pharmacokinetic studies indicate that rifabutin 50 mg three times daily achieves the most consistent intragastric concentrations, compared with other dosing schedules (ie, 150 mg or 300 mg once daily or 150 mg twice daily).
●Side effects – Common side effects with low-dose rifabutin triple therapy include diarrhea, headache, nausea, and chromaturia [26,27]. Data from randomized trials suggest that serious adverse effects are uncommon (<1 percent) [26,27]. Although rifabutin can induce myelosuppression, this has not been observed in trials of low-dose rifabutin triple therapy. A review of observational studies using higher rifabutin doses reported reversible leukopenia in one patient (0.2 percent) [28].
We assess patients for potential drug-drug interactions before initiating rifabutin. This can be done with the UpToDate drug interactions program. Rifabutin induces the hepatic enzyme cytochrome P450 (CYP) 3A4 and may decrease the serum concentration and clinical efficacy of various medications (eg, atorvastatin, tamoxifen, tacrolimus).
In countries where tuberculosis is endemic, rifabutin is a less preferred option given its WHO watchlist status and theoretical potential to induce cross-resistance to rifampin. However, rifampin cross-resistance has not been substantiated with the short duration of rifabutin used in H. pylori therapy.
●Efficacy – Although the comparative efficacy between rifabutin triple therapy and BQT has not been studied, low-dose rifabutin triple therapy demonstrates high efficacy and is superior to dual therapy with amoxicillin plus a PPI. Data supporting its efficacy include the following:
•In a randomized trial enrolling 455 treatment-naïve, non-Asian participants in the United States, low-dose rifabutin triple therapy resulted in higher H. pylori eradication rates than dual therapy with amoxicillin plus a high-dose PPI (83.8 percent [95% CI 78.4-88.0 percent] versus 57.7 percent [95% CI 51.2-64.0 percent]) [26].
•A second randomized trial reported an eradication rate of 89 percent with low-dose rifabutin triple therapy [27].
•In a pooled analysis of observational studies that included 500 participants undergoing treatment for H. pylori infection in Europe, treatment success with rifabutin-containing regimens was 73 percent in treatment-naïve participants [28]. None of these studies evaluated low-dose rifabutin triple therapy.
Vonoprazan-containing regimens — Vonoprazan-based regimens are alternative first-line options for the initial treatment of H. pylori infection [29]. Vonoprazan-based regimens offer a lower pill burden and less complex regimen compared with BQT and, possibly, fewer side effects. However, these regimens have not been directly compared with optimized BQT, may have lower efficacy than optimized BQT, and are generally more costly. (See 'Bismuth quadruple therapy preferred' above.)
●Dosing and administration – Two vonoprazan-based regimens are FDA-approved combination pills for first-line therapy: dual therapy (Voquezna Dual Pak, vonoprazan-amoxicillin) and triple therapy (Voquezna Triple Pak, vonoprazan-amoxicillin-clarithromycin) (table 2). In the United States and other countries with high rates of clarithromycin resistance, we reserve vonoprazan triple therapy for scenarios where clarithromycin susceptibility is confirmed [9,23,30].
Vonoprazan is a potassium-competitive acid blocker (PCAB). PCABs produce more rapid and potent acid suppression than that achieved with lansoprazole and possibly other PPIs [31,32]. Unlike PPIs, PCABs can be taken with or without food without impacting efficacy. PCABs also bypass metabolism by CYP2C19, so their clearance is not affected by CYP2C19 extensive metabolizer polymorphisms. (See 'Gastric acid suppression' below and "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Potassium-competitive acid inhibitors'.)
●Efficacy – Vonoprazan-based regimens appear superior to PPI-based regimens. Data regarding their efficacy include the following:
•Vonoprazan-based regimens versus PPI-based triple therapy – Vonoprazan dual and triple therapy likely have superior efficacy for H. pylori eradication, compared with PPI-based triple therapy. In a meta-analysis of eight trials (seven from East Asia) that included 2956 treatment-naïve participants, vonoprazan dual and triple therapy regimens achieved higher H. pylori eradication rates compared with PPI-based regimens (84 versus 73 percent; relative risk [RR] 1.14; 95% CI 1.08-1.21) [29]. In subgroup analysis, vonoprazan dual therapy achieved higher eradication rates than PPI-based triple therapy (76 versus 67 percent; RR 1.13; 95% CI 1.04-1.23). A subsequent network meta-analysis reported similar results [33].
However, it is unclear if these results can be extrapolated to patients in the United States and Europe because the single randomized trial in these populations found H. pylori eradication rates below 85 percent [10]. In this trial of 1046 treatment-naïve patients from the United States and Europe, vonoprazan triple and dual therapy achieved a higher frequency of H. pylori eradication compared with PPI-based triple therapy with lansoprazole, amoxicillin, and clarithromycin (80.8 and 77.2 percent versus 68.5 percent; difference 12.3 percent, 95% CI 5.7-18.8; and difference 8.7 percent, 95% CI 1.9-15.4) [10]. Differences in eradication rates between vonoprazan dual and triple therapy versus the lansoprazole-based regimen were greater in the subset of participants with clarithromycin-resistant H. pylori strains (66 and 70 percent versus 32 percent).
Further studies in Western populations are warranted that compare the efficacy of PCAB-based regimens with other regimens, including optimized BQT and regimens that contain second-generation PPIs (eg, esomeprazole, rabeprazole) or first-generation PPIs (eg, omeprazole, lansoprazole) at higher doses.
•Dual versus triple vonoprazan-based regimens – Vonoprazan-amoxicillin (dual therapy) appears to have comparable efficacy for H. pylori eradication compared with vonoprazan-amoxicillin-clarithromycin (triple therapy). In the above-described trial of 1046 treatment-naïve participants, vonoprazan dual and triple therapy demonstrated H. pylori eradication rates of 77.2 and 80.8 percent [10]. Their efficacy was similar (69.6 versus 65.8 percent) in the subset of participants with clarithromycin-resistant H. pylori strains, further supporting that clarithromycin should only be used in patients with demonstrated susceptibility.
•Other vonoprazan-based regimens – Other vonoprazan-based regimens have demonstrated efficacy in China but have not yet been studied in Western populations [20]. (See 'Bismuth quadruple therapy preferred' above.)
Duration of therapy — The recommended duration of initial H. pylori treatment regimens is 14 days, except for the fixed-dose combination pill Pylera, which is a 10-day regimen (table 2) [7,8,34]. Treatment courses that are shorter than 10 days are not recommended in North America because they are associated with higher rates of treatment failure [7].
Adverse effects — Side effects occur in 25 to 50 percent of patients who take multidrug H. pylori regimens; however, they rarely lead to treatment cessation. In a large, retrospective analysis of patients treated for H. pylori in Europe, 23 percent of participants reported at least one side effect, but only 1.3 percent discontinued treatment due to an adverse effect [21]. The most common side effects were taste disturbance (7 percent), diarrhea (7 percent), nausea (6 percent), and abdominal pain (3 percent). BQT was the most poorly tolerated regimen, causing side effects in 37 percent of participants.
The side effects of individual drugs are discussed separately:
●Vonoprazan (see "Antiulcer medications: Mechanism of action, pharmacology, and side effects", section on 'Potassium-competitive acid inhibitors')
●Tetracycline (see "Tetracyclines", section on 'Adverse reactions')
●Metronidazole (see "Metronidazole: An overview", section on 'Toxicity')
●Beta-lactam antibiotics (see "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Adverse effects')
●Rifabutin (see "Rifamycins (rifampin, rifabutin, rifapentine)", section on 'Adverse effects')
Ensuring treatment success — In addition to pretreatment counseling (see 'Pretreatment counseling' above), key considerations that inform regimen selection and ensure treatment success include attention to local patterns of H. pylori antibiotic resistance and adequate gastric acid suppression.
Attention to resistance patterns — Because antibiotic resistance is a leading cause of H. pylori treatment failure, clinicians should develop an awareness of local H. pylori resistance patterns. Although initial treatment for H. pylori is usually empiric, clinicians should use pretreatment antimicrobial susceptibility information if available. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
Infection with H. pylori strains that are resistant to antibiotics decreases the likelihood of successful H. pylori eradication, with the exception of metronidazole resistance. In vitro H. pylori resistance to clarithromycin and levofloxacin is strongly associated with H. pylori eradication failure when these antibiotics are used. In the United States, rates of H. pylori resistance to clarithromycin or levofloxacin exceed 20 percent and are increasing [10,11]. In contrast, resistance rates for amoxicillin, rifabutin, and tetracycline are consistently below 5 percent [23].
Although in vitro metronidazole resistance is common, it does not correlate well with H. pylori treatment failure when metronidazole is combined with bismuth and used in sufficiently high doses (1.5 to 2 g total daily dose) [23,35]. (See 'Bismuth quadruple therapy preferred' above.)
Gastric acid suppression — Adequate, sustained gastric acid suppression is an important component of H. pylori eradication. Regimens to treat H. pylori should include an agent that achieves and maintains potent gastric acid suppression, specifically a PPI or PCAB, such as vonoprazan. To achieve this, we prescribe a PPI twice daily (eg, rabeprazole 20 mg twice daily) 30 minutes prior to meals or PCAB twice daily (eg, vonoprazan 20 mg twice daily), which can be dosed independent of mealtime [7,36] (see 'Vonoprazan-containing regimens' above). We prefer higher-potency second-generation PPIs, such as esomeprazole or rabeprazole, and avoid the lower-potency first-generation PPIs (eg, lansoprazole, pantoprazole) if possible. Doses of acid-suppressive medications appear in a table (table 2).
●Antibiotic efficacy – Adequate, sustained gastric acid suppression may enhance the efficacy of some antibiotics. Gastric acid inhibition promotes H. pylori replication, making the bacteria more susceptible to antibiotics that rely on bacterial replication (eg, amoxicillin, clarithromycin). The concentrations of some antibiotics, such as amoxicillin and clarithromycin, are also higher in gastric tissue and the mucus layer with PPI administration; the relative impact of this on in vivo H. pylori eradication is not fully known [37-40].
●CYP2C19 metabolizer status – CYP2C19 metabolizer status can affect gastric acid suppression and the likelihood of H. pylori eradication when first-generation PPIs are used. These include omeprazole, lansoprazole, and pantoprazole, which are heavily metabolized by CYP2C19, and their metabolism and plasma concentrations vary with different CYP2C19 genetic polymorphisms. Extensive (rapid or ultrarapid) metabolizers typically have lower plasma concentrations of these medications. In Western populations, the prevalence of CYP2C19 extensive metabolizers is approximately 30 percent [41].
In a large meta-analysis, individuals who were extensive CYP2C19 metabolizers had higher odds of H. pylori eradication failure when given the first-generation PPIs omeprazole, pantoprazole, or lansoprazole as part of their treatment regimen, compared with intermediate, normal, or poor metabolizers [38]. By contrast, eradication failure was independent of CYP2C19 phenotype in patients who were given the second-generation PPIs rabeprazole or esomeprazole, which either bypass or are not heavily metabolized by CYP2C19 [42]. Guidelines from the Clinical Pharmacogenetics Implementation Consortium recommend that individuals with known CYP2C19 extensive metabolizer status receive esomeprazole or rabeprazole or, if given omeprazole, lansoprazole, or pantoprazole, have the dose increased by 50 to 100 percent [42].
Screening for gastric cancer — The question of whether adults with H. pylori infection should undergo screening for gastric cancer is discussed separately. (See "Gastric cancer screening", section on 'What is the role of gastric cancer screening in patients with Helicobacter pylori infection?'.)
CONFIRMATION OF ERADICATION ("TEST OF CURE") —
It is important to confirm eradication of H. pylori infection in all patients because symptom improvement/resolution or persistence does not correlate with H. pylori treatment success [9,43].
●Timing of test of cure and recommendations regarding interfering medications – Test of cure should be performed at least four weeks after H. pylori treatment completion and at least two weeks after stopping acid suppression medications (eg, proton pump inhibitors or potassium-competitive acid blockers). Although these drugs can lead to false-negative results on histology, urea breath testing, and urease testing, their impact on the accuracy of stool H. pylori antigen is less clear. Patients with symptoms of dyspepsia or reflux can take histamine 2 receptor antagonists and antacids (eg, calcium carbonate) because these do not significantly impact the sensitivity of nonserologic H. pylori diagnostic tests.
●Choice of test – Diagnostic options for confirming eradication include urea breath test, fecal antigen test, and biopsy during upper endoscopy. The choice of test is similar to that for individuals undergoing initial testing for H. pylori and depends on the need for an upper endoscopy (eg, follow-up of bleeding peptic ulcer) and local availability. H. pylori serologic tests are not appropriate diagnostic tests of cure because serology does not reliably distinguish between active and past infection and antibody levels do not fall predictably following successful eradication [9,44]. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
●Rationale – Confirming the eradication of H. pylori infection is important given increasing H. pylori resistance to antibiotics and decreasing H. pylori eradication success rates [7,34]. In aggregate, test results can also provide information about local patterns of treatment efficacy. (See 'Attention to resistance patterns' above.)
PERSISTENT H. PYLORI INFECTION
Treatment failure
●Frequency – Initial treatment fails to eradicate H. pylori infection in at least 15 to 20 percent of individuals, and the likelihood of failure increases with each round of treatment. Rates of treatment failure with the use of clarithromycin- or levofloxacin-based regimens are higher in populations where local H. pylori resistance rates to these antibiotics exceed 15 percent [7]. (See 'Bismuth quadruple therapy preferred' above.)
●Common causes – The most common causes of H. pylori treatment failure include antibiotic resistance of the patient's H. pylori strain, treatment nonadherence, insufficient dosing or frequency of prescribed medications, and inadequate gastric acid suppression [43] (see 'Ensuring treatment success' above and 'Pretreatment counseling' above). Careful discussion with the patient may provide important insights about specific problems experienced with prior treatment, such as financial challenges, side effects, or language and knowledge gaps. Addressing these problems may lessen the chances of treatment failures with subsequent regimens [6].
Selecting a regimen for salvage therapy — "Salvage" therapy refers to any regimen used to treat persistent H. pylori infection following an initial treatment course that failed. Because persistent, or "refractory," infection places patients at ongoing risk of H. pylori-related complications, all those with persistent infection should receive treatment (see "Helicobacter pylori: Epidemiology, pathophysiology, and overview of disease associations", section on 'Clinical manifestations and disease associations'). Our approach is similar to that described in 2024 guidelines from the American College of Gastroenterology [9].
Key considerations — Specific measures in the setting of persistent H. pylori infection include selecting a different treatment regimen, optimized acid suppression, and, for select patients, antimicrobial susceptibility testing (see 'Prior treatment with more than one regimen' below). Other key considerations for selecting a salvage regimen are the same as those used in selecting the initial regimen. (See 'Ensuring treatment success' above.)
●Select a different regimen – In individuals with persistent H. pylori infection, we use an alternative therapeutic regimen with a different combination of antibiotics than the patient previously took (algorithm 1) [3,7]. Patients who received bismuth quadruple therapy (BQT) that was not optimized (eg, insufficient dose of metronidazole or substitution of doxycycline for tetracycline) should receive optimized BQT (see 'Prior treatment with a single regimen' below and 'Prior treatment with more than one regimen' below). Salvage therapy should not include clarithromycin or levofloxacin unless antibiotic susceptibility testing demonstrates H. pylori susceptibility to these antibiotics.
●Optimize acid suppression – To ensure that insufficient gastric acid suppression is not a factor, we typically use high-dose proton pump inhibitors (PPIs; double the standard dose twice daily), more potent PPIs (eg, esomeprazole or rabeprazole), or vonoprazan, especially with regimens that contain antibiotics that are more prone to the effects of gastric acid (eg, amoxicillin and clarithromycin) (table 3) [36,43,45]. Thrice-daily high-dose PPI options (eg, omeprazole 40 mg thrice daily or esomeprazole 40 mg thrice daily) can be used in amoxicillin-containing salvage therapy regimens (eg, rifabutin triple therapy and high-dose PPI dual therapy). (See 'Gastric acid suppression' above.)
Prior treatment with a single regimen — The choice of a salvage regimen depends on prior treatment regimens, the presence of a true penicillin allergy, and knowledge of H. pylori antibiotic susceptibility profile (algorithm 1). In patients with persistent H. pylori infection after a single round of treatment, salvage regimens are similar to those used in treatment-naïve patients and include optimized BQT, rifabutin triple therapy, and vonoprazan-amoxicillin dual regimens (table 3).
No prior bismuth quadruple therapy — Individuals who have not previously received a BQT regimen should receive optimized BQT. Optimized BQT consists of a 14-day treatment course that includes a PPI twice daily, high doses of bismuth subsalicylate, tetracycline, and metronidazole 500 mg three or four times daily [12]. Pylera plus a twice-daily PPI for 10 days can also be used in these patients [9]. PPIs should be given 30 minutes prior to meals. (See 'Bismuth quadruple therapy preferred' above.)
The efficacy of BQT in treating individuals with persistent H. pylori infection appears comparable to that of BQT as an initial treatment. Based on a systematic review of 30 studies of 6282 participants, the efficacy of BQT was 89 percent as a second-line treatment when it was given as Pylera plus a PPI [17]. A subsequent systematic review of 24 studies in European countries reported similar results [46]. (See 'Bismuth quadruple therapy preferred' above.)
Prior bismuth quadruple therapy
●Patients who took "suboptimal" BQT – In patients who previously took BQT, we evaluate whether they received a lower-than-recommended dose of metronidazole (<1.5 g daily) or doxycycline as a substitute for tetracycline. If either of these conditions are met, the patient should undergo retreatment with optimized BQT. (See 'No prior bismuth quadruple therapy' above.)
●Patients who took optimized BQT
•Without penicillin allergy – In patients without penicillin allergy who previously took optimized BQT, we typically use rifabutin triple therapy, vonoprazan-amoxicillin dual therapy, or high-dose PPI dual therapy (table 3). Rifabutin triple therapy options include low-dose rifabutin therapy (ie, Talicia) or component therapy using rifabutin 150 mg twice daily. Few clinical data exist to guide regimen selection in these patients. However, each of these regimens includes high-potency acid suppression, and resistance to rifabutin and amoxicillin rarely exists in the United States.
•With penicillin allergy – Because most salvage regimens other than BQT contain amoxicillin, it is important to confirm the presence of a true penicillin allergy. In those who report a prior allergy to penicillin, we obtain additional information about the specific reaction and antibiotic that provoked it. If uncertainty remains, we refer the patient for allergy testing [43]. In most cases, penicillin allergy can be delisted, and an amoxicillin-containing regimen can be used [47].
In patients with a true penicillin allergy, we suggest antimicrobial susceptibility testing to inform regimen selection (table 3 and algorithm 1). This approach is similar to that in patients who have undergone more than one prior treatment course for H. pylori infection. (See 'Prior treatment with more than one regimen' below.)
Susceptibility testing of H. pylori and its efficacy are discussed separately. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
Prior treatment with more than one regimen — In patients with H. pylori infection that persists after two distinct courses of treatment, we suggest selecting a regimen that is tailored to the results of antimicrobial susceptibility testing (algorithm 1 and table 3). An alternative approach consists of empiric treatment based on the patient's prior H. pylori treatment regimens and past antibiotic exposures, allergies, and intolerances. Ideally, regimen selection should occur in consultation with a gastroenterologist experienced in treating H. pylori.
Our approach to antimicrobial susceptibility testing of H. pylori strains is discussed separately. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
●Specific regimens – Antimicrobial susceptibility testing enables clinicians to select regimens containing clarithromycin and levofloxacin for patients whose H. pylori strains are susceptible to these antibiotics in addition to other salvage regimens (algorithm 1 and table 3). We only use regimens with clarithromycin or levofloxacin when the H. pylori strain has known susceptibility since H. pylori resistance to macrolides and fluoroquinolones is common [7].
•Clarithromycin triple therapy – Although triple regimens containing clarithromycin and a PPI were the most common H. pylori treatment options for decades [3,48], rising rates of clarithromycin resistance worldwide have caused eradication rates to decline [1,30]. Overall, H. pylori eradication rates are less than 70 percent and only up to 30 percent in patients with demonstrated clarithromycin resistance (table 3) [10,11]. (See 'Avoid empiric treatment containing clarithromycin or levofloxacin' above.)
•Levofloxacin triple therapy – Levofloxacin-containing regimens are a treatment of last resort. They should be used only in patients whose H. pylori strain has been refractory to initial management and has demonstrated sensitivity to levofloxacin (table 3). Rates of H. pylori resistance to levofloxacin are over 35 percent in the United States. Furthermore, levofloxacin-related toxicities, such as tendon damage and peripheral neuropathy, have led to a black box warning from the US Food and Drug Administration [23,30].
•Metronidazole triple therapy – Triple therapy with metronidazole, amoxicillin, and a high-dose PPI is also an option for individuals with H. pylori strains that are resistant to clarithromycin but sensitive to metronidazole (table 3). We typically add bismuth to this regimen to maximize the susceptibility of H. pylori to metronidazole.
•Other regimens – Various combination regimens that include clarithromycin and/or levofloxacin and/or amoxicillin and acid-suppressive medications have been studied outside of the United States. They include "hybrid," "sequential," "concomitant," and "reverse hybrid" regimens and have generally been used in first-line therapy. These have not been widely studied in the United States, and their complex dosing instructions may undermine patient adherence.
●Efficacy of a tailored approach – Although robust evidence does not exist to support antimicrobial susceptibility testing for guiding salvage regimen choice, we prefer this approach given increasing levels of H. pylori resistance to macrolide and quinolone antibiotics and based on considerations of antimicrobial stewardship [7-9,12,34]. Meta-analyses have failed to demonstrate the superiority of salvage regimen selection based on antimicrobial susceptibility testing compared with empiric BQT. One meta-analysis of salvage therapies for H. pylori infection showed comparable eradication success with tailored and empiric approaches in analyses that included all studies (relative risk [RR] 1.09, 95% CI 0.97-1.22) and were limited to randomized trials (RR 1.15, 95% CI 0.97-1.36) [49]. A second meta-analysis reported similar results [50]. However, the strength of these conclusions was limited by variable trial quality, high heterogeneity, and imprecision [49,50].
ADJUVANT THERAPIES WITH UNCLEAR ROLE —
Several potential adjuvant therapies for H. pylori have been evaluated, but additional studies are needed to support their use.
Probiotics may have an inhibitory effect on H. pylori and may reduce antibiotic side effects, thereby potentially improving patients' ability to adhere to the full treatment course. In a meta-analysis of 40 trials in patients with H. pylori infection, adjuvant probiotics increased rates of H. pylori treatment success and reduced the incidence of side effects [51]. However, many included studies were at high risk of bias due to a lack of blinding and inadequate allocation concealment. Significant variability in probiotic type and antibiotic regimens also limited the certainty of the results. Nearly all studies were from Europe and Asia.
TREATMENT DURING PREGNANCY AND LACTATION —
In pregnant persons with H. pylori infection, we defer treatment of H. pylori until after delivery and breastfeeding are completed because most antimicrobials used to treat H. pylori (eg, bismuth, metronidazole, and levofloxacin) are contraindicated in pregnancy and nursing [52]. Although some evidence suggests that H. pylori can cause severe nausea and vomiting in pregnancy, including hyperemesis gravidarum [53], we do not feel that the evidence is sufficiently strong to support H. pylori eradication therapy during pregnancy, considering the potential risks. (See "Initial management of gastroesophageal reflux disease in adults", section on 'Patients who are pregnant or breastfeeding' and "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Helicobacter pylori".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: H. pylori infection (The Basics)" and "Patient education: Gastritis (The Basics)")
●Beyond the Basics topic (see "Patient education: Helicobacter pylori infection and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Whom to treat – All patients with evidence of active infection with Helicobacter pylori should be offered treatment (table 1). (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
●Initial management
•Pretreatment counseling – We counsel all individuals about the rationale for treatment, the importance of regimen adherence, and the management of common side effects. (See 'Pretreatment counseling' above.)
•Key considerations – Key considerations that inform regimen selection include attention to local patterns of H. pylori antibiotic resistance and adequate gastric acid suppression. We also consider regimen cost and ease of administration and the patient's previous antibiotic exposures, allergies, and medication intolerances. (See 'Ensuring treatment success' above.)
•Avoid empiric treatment with clarithromycin and levofloxacin – We do not use regimens that contain clarithromycin and levofloxacin for empiric treatment. These regimens result in lower rates of H. pylori eradication in the United States and other areas with high rates of H. pylori resistance to clarithromycin and levofloxacin. (See 'Avoid empiric treatment containing clarithromycin or levofloxacin' above.)
•BQT preferred – In treatment-naïve individuals with H. pylori infection, we suggest empiric treatment with optimized bismuth quadruple therapy (BQT) (table 2) (Grade 2C). Optimized BQT consists of a 10- to 14-day treatment course that includes high doses of bismuth subsalicylate, metronidazole 500 mg three or four times daily, tetracycline, and a proton pump inhibitor (PPI) twice daily.
Low-dose rifabutin triple therapy and vonoprazan-amoxicillin dual therapy are reasonable alternatives. (See 'Bismuth quadruple therapy preferred' above and 'Alternative first-line regimens' above.)
●Confirmation of eradication – All patients should undergo testing to confirm H. pylori eradication. We typically perform either a urea breath test, fecal antigen test, or upper endoscopy at least four weeks after completion of treatment and withhold PPIs or potassium-competitive acid blockers for two weeks prior to testing. (See 'Confirmation of eradication ("test of cure")' above and "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
●Persistent H. pylori infection – All individuals whose H. pylori infection persists after initial management require retreatment with a salvage regimen that differs from prior antibiotic regimens and includes potent acid suppression. (See 'Key considerations' above.)
•Prior treatment with a single regimen – For those who have undergone one prior course of H. pylori treatment, we select a salvage regimen based on the patient's prior treatment regimens and the existence of a penicillin allergy (algorithm 1 and table 3). (See 'Prior treatment with a single regimen' above.)
-No prior BQT – Patients who have not previously undergone treatment with BQT or have taken a suboptimal BQT regimen should receive optimized BQT. (See 'No prior bismuth quadruple therapy' above.)
-Prior BQT – In patients whose previous treatment included optimized BQT, we typically select vonoprazan-amoxicillin dual therapy or rifabutin triple therapy in those without a penicillin allergy.
In patients with a penicillin allergy whose previous treatment included optimized BQT, we suggest salvage regimen selection based on the results of antimicrobial susceptibility testing (Grade 2C). (See 'Prior bismuth quadruple therapy' above.)
•Prior treatment with multiple regimens – For those who have undergone two or more treatment courses, we suggest selecting a salvage regimen based on the results of antimicrobial susceptibility testing (Grade 2C). (See 'Prior treatment with more than one regimen' above and "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
ACKNOWLEDGMENT —
We are saddened by the death of Mark Feldman, MD, who passed away in March 2024. UpToDate gratefully acknowledges Dr. Feldman's role as a Section Editor on this topic and his dedicated and longstanding involvement with the UpToDate program.
