What is triple therapy used to treat

Regimens for eradication of Helicobacter pylori infection are typically chosen empirically, on the basis of regional bacterial resistance patterns, local recommendations, and drug availability. [1]  Therapy for H pylori infection has undergone major changes, based on application of the principles of antimicrobial stewardship and increased availability of susceptibility testing. Common initial choices for empiric treatment include a 14-day bismuth-based quadruple therapy or rifabutin-based triple therapy. However, clinicians should use regimens shown to be highly effective locally. [2] In addition, health care providers should ask their patients about any prior antibiotic use or exposure, and take that information into consideration in the choice of a treatment regimen. [3]  

The following regimens are described below [4] :

• Triple therapy

• Non-bismuth quadruple therapy

• Bismuth-based therapy

• Levofloxacin-containing therapy

• Concomitant bismuth- and levofloxacin-containing therapy

• Second-line therapy

• Rescue or third-line therapy

Triple therapy

Proton pump inhibitor (PPI)–based triple therapy for Hpylori infection remains an option for first-line therapy in areas of low (< 15%) clarithromycin resistance [5] and consists of the following:

• PPI (eg, omeprazole 20 mg BID, lansoprazole 30 mg BID, esomeprazole 40 mg QD, pantoprazole 40 mg QD, rabeprazole 20 mg BID) [3, 6] plus

• Clarithromycin 500 mg BID [6] (first-line and continues to be recommended in areas where H pylori clarithromycin resistance is less than 15% and in patients without previous macrolide exposure [3] ​) or metronidazole 500 mg BID [6] (when clarithromycin resistance is increasing) [7, 8]  plus

• Amoxicillin 1000 mg BID [6] or  metronidazole 500 mg BID [9] (if not already selected) 

Prepackaged versions of those peptic ulcer disease combination regimens (PUD Combos) include the following:

A rifabutin-based triple-therapy regimen consists of the following three agents given together every 8 hours for 14 days [10] :

• Amoxicillin 1 g plus

• Omeprazole 40 mg plus

• Rifabutin 50 mg

This regimen is available prepackaged as Talicia. The US Food and Drug Administration (FDA) approved Talicia for treatment of H pylori infection in 2019, based in part on results of two phase III studies that showed eradication rates of 84.1% and 90.3%. [11, 10]

The first potassium-competitive acid blocker (PCAB)–based therapy was approved by the FDA in May 2022 and consists of triple therapy for 14 days with the following [12] :

• plus Vonoprazan (PCAB) 20 mg BID

• Amoxicillin 1000 mg BID plus

• Clarithromycin 500 mg BID

This regimen is available as Voquezna Triple Pak.

Duration

A Cochrane meta-analysis of 55 studies concluded that 14 days is the optimal duration of triple therapy, achieving an H pylori eradication rate of 81.9%, whereas 7 days attains an eradication rate of only 72.9%. [13] In more recent studies, however, the eradication rate with 14-day triple therapy is not significantly different from that with 10-day sequential therapy (amoxicillin and a PPI for 5 days followed by a PPI, clarithromycin and metronidazole for another 5 days) [14]  or 10-day concomitant nonbismuth quadruple therapy. [15]

Non-bismuth quadruple therapy

Non-bismuth quadruple therapy may be given sequentially or concomitantly. [4]

Sequential therapy 

Sequential therapy (a suggested first-line option [3] ) is superior to standard triple therapy, according to two systematic reviews, [16, 17] and consists of the following:

1. PPI plus amoxicillin for 5-7 days (eg, pantoprazole 40 mg BID and amoxicillin 1 g BID for 7 days [18] ), then

2. PPI plus 2 other antibiotics for the next 5-7 days; clarithromycin and metronidazole are the antibiotics usually chosen, but levofloxacin-based regimens (see below) [16, 19, 20] and tetracycline-based regimens (eg, pantoprazole 40 mg BID, tetracycline 500 mg QID, and metronidazole 500 mg BID) [18] are superior to 14-day triple therapy, based on a meta-analysis of 21 trials [16]

Eradication rates with different durations of sequential therapy are as follows:

• [21, 22]

  14 days: 90.7-92.5% eradication rates

• [3, 6, 21]

  10 days: 87% eradication rate

Concomitant therapy

Concomitant therapy (an alternative first-line option [3] ) consists of the following (using dosages similar to those in triple therapy; or all drugs BID in one study):

• PPI plus

• Amoxicillin plus

• Clarithromycin (1 g modified-release tablet QD in one study) plus

• Metronidazole (500 mg TID in one study)

Duration of concomitant therapy is 10-14 days. [3, 23, 24]

Concomitant therapy is better for clarithromycin-resistant strains, [23, 5] and 14 days of concomitant therapy is superior to 14-day triple therapy, with cure rates of ≥90%. [25, 26, 27, 28]

Hybrid therapy

Hybrid therapy is a combination of sequential and concomitant therapy, [4, 29, 30] as follows:

1. PPI plus amoxicillin for 3-7 days (the latter recommended as another suggested first-line option in the 2017 American College of Gastroenterology guideline [3] ), then

2. PPI plus amoxicillin plus 2 other antibiotics (usually, clarithromycin and metronidazole) for 7 days

There is evidence that the eradication rates with 10-day, 12-day, and 14-day regimens are comparable, at 95.0%, 95.1%, and 93.4%, respectively. This suggests that the optimal duration of hybrid therapy is 12 days, since high rates of eradication are still achieved.

When compared with 14 days of bismuth-containing quadruple therapy, a 14-day hybrid therapy regimen (7 days of dual therapy with pantoprazole plus amoxicillin, followed by 7 days of quadruple therapy with pantoprazole plus amoxicillin, clarithromycin, and metronidazole) showed comparable drug adherence and eradication rates, but with a significantly lower rate of adverse effects (15.7%, versus 55.5% with bismuth-containing quadruple therapy; P < 0.001). [31]

Reverse hybrid therapy

Reverse hybrid therapy is a combination of sequential and concomitant therapy, using the same drugs as hybrid therapy but in reverse sequence, [30]  as follows:

1. PPI plus amoxicillin plus 2 other antibiotics (usually, clarithromycin and metronidazole) for 7 days then
2. PPI plus amoxicillin for 3–7 days

The eradication rate achieved with 12 days of reverse hybrid therapy is similar to that with 12 days of hybrid therapy (95.7% vs. 95.1%, respectively). Fourteen-day reverse hybrid therapy as first-line treatment has equivalent efficacy but less adverse effects than 14-day concomitant therapy, according to a randomized, controlled trial from Taiwan. [32]

Novel concomitant therapy

Novel concomitant therapy consists of the following agents, which are given for 10 days [33] :

• PPI (eg, rabeprazole 20 mg TID) plus

• Amoxicillin 1 g TID for 10 days (or, if penicillin allergic, bismuth subcitrate 240 mg QID plus

• plus Rifabutin 150 mg BID
• Ciprofloxacin 500 mg BID

A small randomized trial in Taiwan reported that 14-day high-dose dual therapy with esomeprazole (40 mg TID) and amoxicillin (750 mg QID) as first-line treatment yielded an eradication rate similar to that of a 7-day non-bismuth quadruple therapy. [34]

Bismuth-based therapy

Bismuth-based therapy is an alternative first-line therapy (in areas with high clarithromycin and metronidazole resistance, and in patients with prior macrolide exposure or penicillin-allergic) [5, 3]  or second-line therapy (see below). [4] It consists of the following:

1. PPI or H2 receptor antagonist (eg, lansoprazole 30 mg BID [15] or ranitidine 150 mg BID [6] ) plus
2. Bismuth subsalicylate 525 mg QID [6]  (or bismuth tripotassium dicitrate 300 mg QID [15] ) plus
3. Metronidazole 250 mg QID [6]  or 500 mg TID [15]  (or levofloxacin 500 mg QD) [35]  plus
4. Tetracycline 500 mg QID [6]

Duration is 10-14 days. [3, 6, 36, 15] The eradication rate was 90.4% for 10 days of bismuth quadruple therapy, while extending therapy to 14 days achieved an eradication rate of 97.1% [36]

Chinese researchers reported that the following regimen provides effective first-line treatment in a population with high antibiotic resistance [37] :

• Rabeprazole 10 mg BID  plus

• Bismuth potassium citrate 220 mg BID  plus

• Amoxicillin 1000 mg BID  plus

• Clarithromycin 500 mg BID

Duration is 10 days. Rabeprazole and bismuth were given 30 min before the morning and evening meals. Antibiotics were given 30 min after the morning and evening meals. [37]

Researchers in Turkey, however, reported that a 14-day regimen of lansoprazole 30 mg BID, amoxicillin 1000 mg BID, clarithromycin 500 mg BID, bismuth subsalicylate 600 mg BID was not significantly superior to a 7-day regimen (81.4% vs. 80%). [38]

Levofloxacin-containing therapy

This is an alternative first-line regimen [19, 39] and consists of a PPI plus amoxicillin 1 g BID plus levofloxacin 500 mg QD. [6]

Duration options are as follows:

• [19, 39, 40]

  7 days (eradication rates of up to 80.9%)

• [3, 6, 41]

  10 days (eradication rates of up to 83.1%)

• [3]

  10-14 days is recommended by the 2017 American College of Gastroenterology guidelines

Sequential therapy, an alternative first-line regimen, is as follows (eradication rates of up to 86.5%): [42, 19, 16, 3]

1. PPI (esomeprazole 20 mg or 40 mg BID) plus amoxicillin (1 g BID) for 5-7 days, then
2. PPI (esomeprazole 20 mg or 40 mg BID) plus levofloxacin (250 mg or 500 mg BID) plus a nitroimidazole antibiotic (eg, tinidazole 500 mg BID) for 5-7 days

A randomized trial investigated the role of bismuth in levofloxacin-containing 14-day sequential therapy, and concluded that adding bismuth did not significantly improve eradication rates (85.2% vs. 82.6%).

Concomitant therapy, another alternative first-line regimen, is as follows (eradication rates of up to 96.5%) [43] :

• PPI (esomeprazole 40 mg BID) plus amoxicillin (1 g BID) plus levofloxacin (500 mg QD) plus another antibiotic (eg, tinidazole 500 mg BID) for 5 days

Concomitant bismuth- and levofloxacin-containing therapy

A group of Chinese researchers reported that the following regimen also provided satisfactory eradication rates in a population with high antibiotic resistance:

• Esomeprazole 20 mg BID plus

• Levofloxacin 500 mg BID plus

• Bismuth 220 mg BID plus

• Amoxicillin 1000 mg BID or cefuroxime 500 mg BID

Duration: 14 days.  Eradication rates were not significantly different between the amoxicillin and cefuroxime groups (83.5% vs 81%). [44]

An open-label, randomized trial conducted in China reported acceptable eradication rates even for the following 1-week bismuth-containing regimen:

• Esomeprazole 20 mg BID plus

• Colloidal bismuth pectin 200 mg BID plus

• Amoxicillin 1000 mg BID plus

• Levofloxacin 500 mg OD or clarithromycin 500 mg BID

The above levofloxacin-based concomitant quadruple regimen demonstrated a higher eradication rate (86.66% vs 76.22%). [45]

Second-line therapy

Second-line therapy [4, 46] should avoid repeating first-line regimens that were already used, and should incorporate at least one different antibiotic. Bismuth-based therapy or levofloxacin-containing triple therapy [46] can be used (same regimens as above, if not used previously).

In a meta-analysis of 115 heterogeneous studies, per protocol analysis showed that quadruple therapies have better cure rate than triple (83% vs 76%) and 14-day quadruple treatment than 7-day regimens (91% vs 81%). [47]

Rescue or third-line therapy

Before initiating rescue/third-line therapy, send ulcer biopsy specimen for culture and antimicrobial susceptibility testing. [4, 46, 5]  It is essential to avoid antimicrobials that have previously been used. The preferred treatments for patients who have received a clarithromycin-containing first-line regimen are bismuth quadruple therapy or levofloxacin-salvage combination therapy. In general, clarithromycin triple therapy is not recommended for salvage treatment. [3]

Salvage regimens

Bismuth-based quadruple therapy is used for 14 days and comprises the following (eradication rates for all combinations below were above 90%) [48] :

• PPI (lansoprazole 30 mg BID) plus

• Bismuth potassium citrate 220 mg BID plus

• Tetracycline 500 mg QID or amoxicillin 1 g TID plus

• Tetracycline 500 mg QID (if not already selected) or metronidazole 400 mg QID

For patients who already received bismuth quadruple therapy as first-line treatment, clarithromycin or levofloxacin-containing salvage regimens are preferred. [3]

Levofloxacin-based sequential therapy is superior to clarithromycin- and tetracycline-based therapies and consists of the following (eradication rates of up to 92.2%, as long as the H pylori was susceptible to levofloxacin): [20]

1. PPI (esomeprazole 40 mg BID) + amoxicillin (1 g BID) for 7 days, then
2. PPI (esomeprazole 40 mg BID) + metronidazole (500 mg BID) + levofloxacin (250 mg or 500 mg BID, with the former surprisingly achieving higher cure rates [16] ) for another 7 days

Other salvage regimens that can be recommended are the following [3] :

1. Triple therapy (which includes levofloxacin) is also a recommended salvage regimen (see above)
2. Concomitant therapy as described above
3. 14-day rifabutin triple salvage regimen (PPI plus amoxicillin plus rifabutin)
4. High-dose dual therapy (PPI plus amoxicillin for 14 days)

Pooled eradication rates for rifabutin triple therapy were 79%, 66%, and 70% as a second-, third-, and fourth/fifth-line regimen, respectively, according to a meta-analysis of cohort studies. [49]

Adjuvant therapies

More conclusive evidence is needed to support the role of the following as potential adjuvant therapies:

• [50]

  Probiotics

• [51]

  Statins