Cure rates greater than 90%-95% should be expected with an antimicrobial therapy for Helicobacter pylori infection. Standard triple therapy does not guarantee these efficacy rates in most settings worldwide anymore. The choice of eradication regimen should be dictated by factors that can predict the outcome: (1) H. pylori susceptibility; (2) patients’ history of prior antibiotic therapy; and (3) local data, either resistance patterns or clinical success. Currently, the preferred first-line choices are 14-day bismuth quadruple and 14-day non-bismuth quadruple concomitant therapy. Bismuth quadruple (if not used previously), fluoroquinolone-, furazolidone- and rifabutin-containing regimens might be effective rescue treatments.
Key points
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Antibiotic resistance is the critical factor responsible for eradication treatment failure. Because of increasing clarithromycin resistance, first-line triple therapy for Helicobacter pylori ( H pylori ) infection is currently ineffective in most settings worldwide.
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Treatment results for infectious diseases are best (>90%–95%) when regimens are reliably used to treat patients with organisms susceptible to the antimicrobials chosen. Most eradication therapies, however, are prescribed empirically.
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The choice of therapy may depend on patient previous antibiotic treatment, local patterns of antibiotic resistance, and drug availability. Currently, the most effective first-line eradication regimens are 14-day bismuth and nonbismuth concomitant quadruple therapies.
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Fluoroquinolone-, furazolidone-, and rifabutin-containing regimens might be effective rescue treatments, as well as bismuth quadruple therapy if not used previously.
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Optimization of all eradication regimens (increased duration, adequate proton pump inhibitor, and antibiotic doses and dosing intervals) is key to maximize their efficacy.
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Besides antibiotic resistance, compliance is a major concern with increasing complex eradication therapies. Probiotics show promise as an adjuvant treatment to reduce side effects and improve adherence to therapy. Whether probiotics can also increase eradication rates should be further elucidated.
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On large variations in H pylori resistance patterns, the golden rule for choice of treatment is only to use what works locally (>90%–95% success) and to closely monitor its effectiveness over time.
Introduction
Thirty years after the transcendental discovery of the originally termed Campylobacter pyloridis as a causative agent for gastritis and peptic ulceration in 1984, Helicobacter pylori (H pylori) remains the most common bacterial infection in humans. It is estimated that approximately 50% of the world’s population is infected; this infection is currently the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. Eradication of H pylori infection has dramatically changed the natural history of peptic ulcer disease. Furthermore, the World Health Organization classified H pylori as a definite carcinogen in 1994 for its established role in the pathogenesis of gastric cancer and gastric mucosa–associated lymphoid tissue lymphoma. Emphasis has been lately made on the importance of primary and secondary gastric cancer prevention, starting with H pylori eradication. In fact, Japan has recently embarked on population-wide H pylori eradication coupled with surveillance targeted to those with significant remaining risk.
Standard triple therapy, consisting of a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, has been (and unfortunately still remains in many settings) the gold standard eradication therapy for H pylori infection over the last 2 decades. However, the efficacy of triple therapy at the present time is seriously challenged in many parts of the world, where eradication rates have declined to unacceptably low levels, largely related to the development of resistance to clarithromycin. Moreover, H pylori resistance to metronidazole is prevalent as well in certain geographic areas (ie, South America, Turkey, Iran, China) and fluoroquinolone resistance is rapidly growing worldwide due to widespread use of levofloxacin for ear, nose and throat, bronchial and urinary tract infections. Failure of H pylori treatment, in addition, selects antibiotic-multiresistant strains, which will be even more difficult to treat. Complicating this scenario, rescue drugs may be unavailable (eg, bismuth, tetracycline, furazolidone) or may lead to severe adverse effects (eg, rifabutin).
This article aims to revisit all practical aspects that should be taken into consideration when choosing an H pylori eradication regimen. Increasing antibiotic resistance coupled with a lack of new therapeutic alternatives can seriously hamper the fight against H pylori infection. Now more than ever, a clear understanding of the interplay between the bacteria, the individual patient, its geographic area, and the drugs selected becomes pivotal to select and optimize the best therapeutic strategy for each patient, maximizing the efficacy of eradication regimens and minimizing treatment failures, selection of resistant strains, and need for step-up antibiotic therapy.
Why Is Helicobacter pylori Difficult to Treat?
The H pylori infection should be treated by means of a combination of acid-suppressive agents and several antibiotics, yet it has proven challenging to cure. Several factors may account for difficulties associated with cure of the infection, including bacteria-, environmental-, host-, and drug-associated variables. All of these factor influencing eradication rates and potential solutions to overcome these obstacles are summarized in Table 1 . By far, the most important factor is the development of H pylori resistance to many antimicrobial agents, especially clarithromycin, metronidazole, and fluoroquinolones. In H pylori infection, resistance usually develops because of the outgrowth of a small existing population of resistant organisms. Clarithromycin must bind to ribosomes in order to kill H pylori . Acquired resistance is associated with failure to bind to ribosomes, such that resistance cannot be overcome by increasing the dose or duration. Likewise, resistance to fluoroquinolones (eg, levofloxacin, moxifloxacin) is not responsive to changes in dose or duration. Metronidazole resistance can be partially overcome by increasing the dose and duration. In contrast, bismuth resistance does not occur and acquired resistance to either amoxicillin or tetracycline is rare in most regions.
| Causes | Mechanisms | Potential Solutions |
|---|---|---|
| Microorganism itself | Phenotypical antibiotic resistance (persistence of nonreplicating microorganisms) High bacterial load | Increasing amoxicillin/metronidazole duration and doses or shortening dosing interval Increasing PPI doses and/or shortening interval dosing Increasing the dose and duration of antibiotic therapy Combining several antibiotics (one of which will probably kill the resistant organisms) Pretreatment with PPI and bismuth, reducing the bacterial load (which would make survival of the minor populations less likely) |
| Gastric environment | Acid gastric pH ( H pylori becomes phenotypically resistant with a pH range between 3 and 6, usually in the mucus. Increasing the pH in this layer to 6 or 7 allows the bacteria to enter the replicative state, where they become susceptible to amoxicillin and clarithromycin.) | Increasing PPI doses and/or shortening interval dosing |
| Antibiotics | Clarithromycin and fluoroquinolone resistance Metronidazole resistance Amoxicillin and clarithromycin require microbial replication to kill microorganisms. | Not responsive to increasing doses or duration Increasing the dose and duration can partially overcome bacterial resistance. Increasing duration of therapy Increasing PPI doses and/or shortening interval dosing |
However, treatment may also fail while the organism remains susceptible to the antibiotic. This treatment failure is most commonly seen with amoxicillin, for which acquired resistance is rare. This form of reversible resistance is termed phenotypical antibiotic resistance , and it is often caused by the presence of nonreplicating population of organisms. Bacteria usually oscillate between a nonreplicating (phenotypically resistant) and replicating state (phenotypically susceptible), during which they cannot and can be eradicated, respectively. As shown in Table 1 , short duration or shortage of antibiotic drugs may limit the presence of antibiotic drugs during susceptibility periods. Furthermore, insufficient acid suppression, keeping acid gastric pH between 3 and 6, may predispose microorganisms to a nonreplicative state; this is a phenotypically resistant state. Additionally, amoxicillin and clarithromycin are effective antibiotics against H pylori provided microbial replication is present.
Another H pylori intrinsic obstacles for eradication regimens might be the high bacterial load of H pylori organisms in the stomach, resulting in an inoculum effect, and the wide variety of niches where the microorganism can reside (intracellularly, mucus layer). Therefore, drug regimens, including PPI and antibiotics doses and dosing intervals, should be specifically designed to target all of these problems (see Table 1 ).
Introduction
Thirty years after the transcendental discovery of the originally termed Campylobacter pyloridis as a causative agent for gastritis and peptic ulceration in 1984, Helicobacter pylori (H pylori) remains the most common bacterial infection in humans. It is estimated that approximately 50% of the world’s population is infected; this infection is currently the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. Eradication of H pylori infection has dramatically changed the natural history of peptic ulcer disease. Furthermore, the World Health Organization classified H pylori as a definite carcinogen in 1994 for its established role in the pathogenesis of gastric cancer and gastric mucosa–associated lymphoid tissue lymphoma. Emphasis has been lately made on the importance of primary and secondary gastric cancer prevention, starting with H pylori eradication. In fact, Japan has recently embarked on population-wide H pylori eradication coupled with surveillance targeted to those with significant remaining risk.
Standard triple therapy, consisting of a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, has been (and unfortunately still remains in many settings) the gold standard eradication therapy for H pylori infection over the last 2 decades. However, the efficacy of triple therapy at the present time is seriously challenged in many parts of the world, where eradication rates have declined to unacceptably low levels, largely related to the development of resistance to clarithromycin. Moreover, H pylori resistance to metronidazole is prevalent as well in certain geographic areas (ie, South America, Turkey, Iran, China) and fluoroquinolone resistance is rapidly growing worldwide due to widespread use of levofloxacin for ear, nose and throat, bronchial and urinary tract infections. Failure of H pylori treatment, in addition, selects antibiotic-multiresistant strains, which will be even more difficult to treat. Complicating this scenario, rescue drugs may be unavailable (eg, bismuth, tetracycline, furazolidone) or may lead to severe adverse effects (eg, rifabutin).
This article aims to revisit all practical aspects that should be taken into consideration when choosing an H pylori eradication regimen. Increasing antibiotic resistance coupled with a lack of new therapeutic alternatives can seriously hamper the fight against H pylori infection. Now more than ever, a clear understanding of the interplay between the bacteria, the individual patient, its geographic area, and the drugs selected becomes pivotal to select and optimize the best therapeutic strategy for each patient, maximizing the efficacy of eradication regimens and minimizing treatment failures, selection of resistant strains, and need for step-up antibiotic therapy.
Why Is Helicobacter pylori Difficult to Treat?
The H pylori infection should be treated by means of a combination of acid-suppressive agents and several antibiotics, yet it has proven challenging to cure. Several factors may account for difficulties associated with cure of the infection, including bacteria-, environmental-, host-, and drug-associated variables. All of these factor influencing eradication rates and potential solutions to overcome these obstacles are summarized in Table 1 . By far, the most important factor is the development of H pylori resistance to many antimicrobial agents, especially clarithromycin, metronidazole, and fluoroquinolones. In H pylori infection, resistance usually develops because of the outgrowth of a small existing population of resistant organisms. Clarithromycin must bind to ribosomes in order to kill H pylori . Acquired resistance is associated with failure to bind to ribosomes, such that resistance cannot be overcome by increasing the dose or duration. Likewise, resistance to fluoroquinolones (eg, levofloxacin, moxifloxacin) is not responsive to changes in dose or duration. Metronidazole resistance can be partially overcome by increasing the dose and duration. In contrast, bismuth resistance does not occur and acquired resistance to either amoxicillin or tetracycline is rare in most regions.
| Causes | Mechanisms | Potential Solutions |
|---|---|---|
| Microorganism itself | Phenotypical antibiotic resistance (persistence of nonreplicating microorganisms) High bacterial load | Increasing amoxicillin/metronidazole duration and doses or shortening dosing interval Increasing PPI doses and/or shortening interval dosing Increasing the dose and duration of antibiotic therapy Combining several antibiotics (one of which will probably kill the resistant organisms) Pretreatment with PPI and bismuth, reducing the bacterial load (which would make survival of the minor populations less likely) |
| Gastric environment | Acid gastric pH ( H pylori becomes phenotypically resistant with a pH range between 3 and 6, usually in the mucus. Increasing the pH in this layer to 6 or 7 allows the bacteria to enter the replicative state, where they become susceptible to amoxicillin and clarithromycin.) | Increasing PPI doses and/or shortening interval dosing |
| Antibiotics | Clarithromycin and fluoroquinolone resistance Metronidazole resistance Amoxicillin and clarithromycin require microbial replication to kill microorganisms. | Not responsive to increasing doses or duration Increasing the dose and duration can partially overcome bacterial resistance. Increasing duration of therapy Increasing PPI doses and/or shortening interval dosing |
However, treatment may also fail while the organism remains susceptible to the antibiotic. This treatment failure is most commonly seen with amoxicillin, for which acquired resistance is rare. This form of reversible resistance is termed phenotypical antibiotic resistance , and it is often caused by the presence of nonreplicating population of organisms. Bacteria usually oscillate between a nonreplicating (phenotypically resistant) and replicating state (phenotypically susceptible), during which they cannot and can be eradicated, respectively. As shown in Table 1 , short duration or shortage of antibiotic drugs may limit the presence of antibiotic drugs during susceptibility periods. Furthermore, insufficient acid suppression, keeping acid gastric pH between 3 and 6, may predispose microorganisms to a nonreplicative state; this is a phenotypically resistant state. Additionally, amoxicillin and clarithromycin are effective antibiotics against H pylori provided microbial replication is present.
Another H pylori intrinsic obstacles for eradication regimens might be the high bacterial load of H pylori organisms in the stomach, resulting in an inoculum effect, and the wide variety of niches where the microorganism can reside (intracellularly, mucus layer). Therefore, drug regimens, including PPI and antibiotics doses and dosing intervals, should be specifically designed to target all of these problems (see Table 1 ).
Choice of therapy
The strongest predictor of H pylori treatment failure using a regimen proven to be effective elsewhere is antimicrobial resistance. From a microbiological standpoint, treatment results are best when regimens are used to treat patients with organisms susceptible to the antimicrobials chosen. Pretreatment susceptibility testing, either by direct culture of the organism from gastric biopsies or indirectly by molecular testing in gastric biopsies/stools, can be used for this purpose. Nonetheless, this strategy is hampered by the wide unavailability of these techniques, besides the need for an invasive procedure (endoscopy), cost, or time consumption. Another choice would be using bismuth quadruple therapy because resistance to tetracycline is negligible and metronidazole resistance can be partially overcome by increasing doses and duration. Nonetheless, this approach is limited to regions where bismuth salts and tetracycline are both available. The launch of Pylera (the 3-in-1 capsule containing bismuth, tetracycline, and metronidazole, therefore, decreasing pill burden and theoretically improving compliance) might be a good therapeutic option where available.
Therefore, one often must choose antibiotic therapy empirically; the best approach is using regimens that have proven to be reliably excellent locally. Considering H pylori is an infectious disease and 100% success might be obtainable, the efficacy of an antimicrobial therapy should be scored as excellent (>95% success), good (>90% success), borderline acceptable (85%–89% success), poor (80%–84% success), or unacceptably low (<80%). The choice should take advantage of knowledge of local resistance patterns, clinical experience, and patient history. The history of patients’ prior antibiotic use and any prior therapies will help identify which antibiotics are likely to be successful and those where resistance is probable. In fact, treatment outcome in a population or a patient can be calculated based on the effectiveness of a regimen for infections with susceptible and with resistant strains coupled with knowledge of the prevalence of resistance (ie, based on formal measurement, clinical experience, or both). The formula and calculations for predicting the outcome of any antimicrobial therapy have been recently reported. The therapeutic expectations for an individual patient with clarithromycin-based therapies (triple, sequential, concomitant) and bismuth quadruple therapy, depending on the rate of clarithromycin and metronidazole resistance, are shown in Table 2 .
| Antimicrobial Prediction | 7-d Triple Therapy | 14-d Triple Therapy | 10-d Sequential Therapy | 14-d Sequential Therapy | 10-d Concomitant Therapy | 14-d Concomitant Therapy | 14-d Bismuth Quadruple Therapy |
|---|---|---|---|---|---|---|---|
| Clarithromycin and metronidazole susceptible (%) | 94 | 97 | 95 | 98 | 94 | 97 | 99 |
| Clarithromycin resistant-metronidazole susceptible (%) | <20 | 50 | 80 | 88 | 94 | 97 | 99 |
| Clarithromycin susceptible-metronidazole resistant (%) | 94 | 97 | 75 | 75 | 94 | 97 | 95 |
| Clarithromycin and metronidazole resistant (%) | <20 | 50 | <20 | <20 | <25 | <50 | 95 |
In this current era of increasing antibiotic resistance, all therapies should be optimized. High-dose PPI therapy (eg, 40 mg of omeprazole or equivalent twice a day) is recommended in order to guarantee effective and prolonged gastric acid suppression. All PPI molecules are metabolized by cytochrome P450 ( CYP ) 2C19 . Four different genotypes have been described: ultrarapid, rapid/extensive, intermediate, and poor metabolizers. The prevalence of CYP2C19 rapid metabolizer genotype has been shown to be highest in Europe and in North America (56%–81%), whereas the proportion is lower (27%–38%) in the Asian population. Plasma PPI levels and intragastric pH levels during PPI treatment are inversely related to the CYP2C19 genotype. Accordingly, several meta-analyses have shown eradication rates are inversely related to the ability to metabolize the PPIs (eg, the ultrarapid and rapid metabolizer groups have lower eradication rate compared with other groups). Therefore, it is conceivable that all patients, especially in Europe and North America, should receive high-dose PPI therapy with a proper dosing interval (twice or more than a day) in order to circumvent the selection of nonreplicative H pylori strains, increase the effectiveness of amoxicillin and clarithromycin, and achieve similar efficacy rates in either rapid and poor CYP2C19 metabolizers (see Table 1 ). Moreover, a 14-day duration is recommended, given the fact it has proven a therapeutic benefit for triple, bismuth quadruple, and nonbismuth quadruple sequential and concomitant therapy.
First-line regimens
Available first-line regimens, with preferred drug doses and dosing intervals, along with caveats for each treatment, are summarized in Table 3 . The preferred empirical choices are currently 14-day bismuth quadruple therapy or 14-day nonbismuth quadruple concomitant or hybrid (sequential-concomitant) therapy, depending on local resistance pattern, clinical experience, and patient history of antibiotic use.
| Eradication Regimens | Preferred Dosages and Dosing Intervals | Caveat |
|---|---|---|
| 14-d Bismuth-containing classic quadruple therapy | Bismuth salts qid PPI (double doses) bid Tetracycline 500 mg qid Nitroimidazole 500 mg tid | Availability Complexity Side effects Compliance |
| 14-d Bismuth-containing quadruple therapy using Pylera | PPI (double doses) bid Pylera 3 pills qid | Availability Cost Relatively low tetracycline doses |
| 14-d Nonbismuth quadruple concomitant therapy | PPI (double doses) bid Amoxicillin 1 g bid Clarithromycin 500 mg bid Nitroimidazole 500 mg bid | Cure rates ≤90% if dual resistance rate ≥15% |
| 14-d Nonbismuth quadruple hybrid therapy |
| Cure rates <90% if dual resistance rate >9% |
| 14-d Nonbismuth quadruple sequential therapy |
| Cure rates <90% if dual resistance rate >5% Not recommended as an empirical therapy |
| 14-d Triple therapy | PPI (double doses) bid Amoxicillin 1 g bid Clarithromycin 500 mg bid | Cure rates <90% if clarithromycin resistance >15% Not recommended as an empirical therapy |
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