- Email: [email protected]
Helicobacter pylori Infection: An Update for the Internist in the Age of Increasing Global Antibiotic Resistance
REVIEW
Helicobacter pylori Infection: An Update for the Internist in the Age of Increasing Global Antibiotic Resistance Osama Siddique, MD,a Anais Ovalle, MD,a Ayesha S. Siddique, MD,b Steven F. Moss, MDa,c a
Department of Medicine, Alpert Medical School of Brown University, Providence, RI; bDepartment of Pathology, Hartford Hospital, Hartford, CT; cDivision of Gastroenterology and Hepatology, Alpert Medical School of Brown University, Providence, RI.
ABSTRACT Helicobacter pylori infects approximately half the world’s population and is especially prevalent in the developing world. H. pylori is an important cause of global ill health due to its known etiological role in peptic ulcer disease, dyspepsia, gastric cancer, lymphoma, and more recently, recognized in iron deficiency anemia and idiopathic thrombocytopenic purpura. Increased antibiotic usage worldwide has led to antibiotic resistance among many bacteria, including H. pylori, resulting in falling success rates of first-line anti-H. pylori therapies. Eradication failures are principally due to resistance to clarithromycin, levofloxacin, and metronidazole. Several new treatment options or modifications of established regimens are now recommended by updated practice guidelines for primary or secondary therapy. Because these updated recommendations were published in the gastroenterological literature, internists and primary care physicians, who commonly manage H. pylori, may be unaware of these advances. In this review, we outline the changing epidemiology of H. pylori, advise on diagnostic test selection for patients not undergoing endoscopy, and highlight current management options in this era of growing antibacterial resistance. Published by Elsevier Inc. • The American Journal of Medicine (2018) 131, 473–479 KEYWORDS: Antibiotic resistance; First-line therapy; Guidelines; Helicobacter pylori; Internist; Management; Therapy
INTRODUCTION Helicobacter pylori remains one of the most common causes of peptic ulcer disease, as well as causing dyspeptic symptoms in patients who are not found to have ulcers at endoscopy (nonulcer or “functional” dyspepsia).1 While gastroenterologists may be most familiar with H. pylori and may be consulted for optimal management, the diagnosis of H. pylori infection is often made by primary care or internal medicine Funding: None. Conflicts of Interest: None. Authorship: OS: Proposed the review topic, collated and reviewed relevant literature, wrote the manuscript first draft, and reviewed subsequent versions. AO: Collated and reviewed articles, co-wrote the manuscript first draft, and reviewed the final version. ASS: Collected and reviewed articles, co-wrote the manuscript, and reviewed the final version. SFM: Proposed the review topic, reviewed references, and revised all versions of the manuscript. Requests for reprints should be addressed to Steven F. Moss, MD, Rhode Island Hospital, 593 Eddy St., APC 414, Providence, RI 02903. E-mail address: [email protected]
0002-9343/$ - see front matter Published by Elsevier Inc. https://doi.org/10.1016/j.amjmed.2017.12.024
physicians, who may not be aware of the variety of diagnostic tests available, and that the treatment for H. pylori is becoming more challenging due to increasing antibiotic resistance. Falling eradication rates have prompted several authorities to recently update their treatment guidelines for empiric first-line and subsequent therapies.2-4 A translation gap exists for the application of knowledge about H. pylori to patient care, especially outside specialist practice. For example, while it is well appreciated that H. pylori testing is indicated in patients on chronic nonsteroidal antiinflammatory drug therapy or with a diagnosis of a gastric mucosa-associated lymphoid tissue lymphoma, <20% of such patients with these conditions were investigated for H. pylori by their physicians, according to some recent reports.5,6 In another study, only 54% of US primary care physicians used a “test and treat” strategy seeking H. pylori as a cause for dyspepsia, and almost half of the primary care physicians chose the inaccurate serology rather than the more accurate stool antigen or urea breath tests that detect active infection.7
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In this review we focus on updating internists and primary care physicians in H. pylori management, because these are the physicians most likely to encounter H. pylori relatively frequently, but who may not be aware of the changing prevalence of antibiotic resistance, the plethora of diagnostics tests available, and the recently updated guidelines on managing H. pylori infections.
also be potential benefits of H. pylori colonization. For example, an inverse relationship has been found between H. pylori and eosinophilic esophagitis, as well as with Barrett’s esophagus and with esophageal adenocarcinoma.22-24
CLINICAL SIGNIFICANCE
DIAGNOSIS Indications for Testing
H. pylori infection should be sought in patients with history of, or active, peptic ulcer disease, those with a low-grade gastric mucosa-associated lymphoid tissue lymphoma, and • H. pylori increases the risk of peptic ulcer in the evaluation of dyspeptic disease and gastric cancer and is also symptoms.2 etiologically linked to idiopathic “funcA “test-and-treat strategy” has tional” dyspepsia, gastric mucosallong been advocated for detecting associated lymphoid tissue lymphoma, and eradicating H. pylori in paunexplained iron-deficiency anemia, and tients with dyspepsia with low idiopathic thrombocytopenic purpura. gastric cancer risk.3 The most recent version of this strategy targets pa• Antibiotic resistance is increasingly tients younger than 60 years with common among H. pylori strains. Recent chronic or frequently recurring epiguidelines support 14-day quadruple gastric pain or discomfort in the therapies over the prior standard of absence of alarm symptoms, such clarithromycin-based triple therapy. as unexplained weight loss, progressive dysphagia, odynophagia, recurrent vomiting, family history of gastrointestinal cancer, and iron deficiency anemia.25 Moreover, if a patient with dyspepsia undergoes endoscopy, H. pylori presence should be evaluated in gastric biopsies, with the intention of treating if present.25 A suitable algorithm for CLINICAL IMPACT internists is shown in Figure 1. It is not recommended to test Since its discovery by Drs. Barry Marshall and Robin Warren, and treat patients for H. pylori who have been diagnosed with H. pylori has been implicated in a number of gastrointestigastroesophageal reflux disease, or in investigating those with nal conditions, including peptic ulcer disease, gastritis, and 1,14 typical retrosternal heartburn symptoms, because H. pylori gastric malignancies. is not implicated as an etiological factor in gastroesophaIn patients with gastric mucosa-associated lymphoid tissue 2 geal reflux disease. lymphoma, eradication of H. pylori induces complete remisSome evidence supports H. pylori testing in patients inision of this malignancy in most cases.15 Eradicating H. pylori tiating chronic nonsteroidal anti-inflammatory drugs or aspirin also helps prevent gastric carcinoma, by 30%-50%, accord16 therapy because H. pylori is synergistic with these medicaing to a recent meta-analysis of randomized clinical trials. tions in causing peptic ulcer disease and its complications.2,3 Studies have also investigated the relationship between auFurthermore, testing is advisable in patients with unextoimmune gastritis and H. pylori, where the treatment of H. plained iron deficiency anemia and adults with immune pylori has resulted in a decrease in the levels of antigastric 17 thrombocytopenic purpura.3 antibodies. In adults with immune thrombocytopenic purpura, platelet counts tend to increase after eradication of H. pylori,18 Diagnostic Tests leading to a recommendation from the American Society of Internists and primary care physicians can easily detect the Hematology to screen for and treat H. pylori in adults who presence of H. pylori via noninvasive testing: serology, urea test positive.19 Certain other extragastric diseases may also be weakly asbreath testing, and stool antigen detection (Figure 2) Serosociated with H. pylori infections; such as rosacea, chronic logic testing is widely available but is no longer recommended idiopathic urticaria, psoriasis, bronchiectasis, chronic obdue to its relatively low sensitivity and high false-positive structive pulmonary disease, Graves disease, diabetes,20 and rates when the background prevalence is low (as it is in the possibly, hepatic encephalopathy in patients with cirrhosis.21 United States).3 In addition, serology can remain positive While there is overwhelming evidence that H. pylori is a long after successful eradication due to antibody persisdefinite cause of serious gastroduodenal disease, there may tence. In contrast, the urea breath and stool tests detect only
EPIDEMIOLOGY
H. pylori has a prevalence of over 50% globally, with especially high rates in Africa, Central America, Central Asia, and Eastern Europe.8 In contrast, it is slowly declining in much of the developed world; Hooi et al8 estimate the prevalence of H. pylori infection in the United States to be around 35%. In North America, H. pylori is most prevalent among African Americans, Hispanic Americans, Native Americans, Alaskan natives, and in patients with lower socioeconomic status.9-13 In developed countries such as the United States, it is much more common in the elderly, due to a birth cohort effect of aging from a time when H. pylori was much more prevalent.
• Helicobacter pylori infection remains a common clinical issue for internists and primary care physicians.
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Figure 1 Algorithm for dyspepsia management. EGD = esophagogastroduodenoscopy; PPI = proton pump inhibitor.
active infection and are highly sensitive, and specific.26 Proton pump inhibitors (PPI), antibiotics, and bismuth-containing compounds reduce the diagnostic yield of the breath and stool tests because they inhibit H. pylori viability. Thus, PPIs should be discontinued for at least 2 weeks, and bismuth and antibiotics should be held for 4 weeks to avoid falsenegative results.3
Figure 2
Invasive strategies rely on endoscopy to acquire gastric biopsies for culture, urease activity, or histopathology. Culture techniques are less sensitive due to the challenges of successfully growing H. pylori colonies in the laboratory. Similar to the noninvasive urea breath test or stool antigen detection, bismuth and antibiotics should be discontinued for 4 weeks and PPI for at least 2 weeks prior to testing.
Diagnostic testing available for H. pylori.
476 Interestingly, the presence of blood in the stomach reduces the sensitivity of urease-based testing and may give falsenegative results in patients with active gastrointestinal bleeding.27 For this reason, and because the rapid urease test is limited by higher interobserver bias, most invasive testing for H. pylori in the United States is through routine histology, with additional immunohistochemistry as necessary.
MANAGEMENT: OLD AND NEW Standard Therapies and the Problems of Antibiotic Resistance The first effective therapy for H. pylori was introduced in the late 1980s, consisting of the combination of bismuth, tetracycline, and metronidazole, all given together for 2 weeks.28 The discovery that acid inhibition improved eradication rates led to a simpler and better-tolerated regimen known as triple therapy (PPI, amoxicillin, and clarithromycin) that became the mainstay of treatment over the last 25 years.29 Because up to 20% of the US population consider themselves to be penicillin allergic (although the overwhelming majority are not truly allergic on skin testing30), metronidazole is often substituted for amoxicillin in triple therapy. Over the last 10-15 years, there has been a marked decline in the success of triple therapy worldwide up to 90% or even less, linked to the emergence of widespread clarithromycin resistance.31 This led to the development of a minimum local resistance threshold of 15%-20%, above which clarithromycin should be avoided in triple therapy.3 Antibiotic resistance is the usual Achilles heel of H. pylori therapies, especially for clarithromycin, metronidazole, and more recently, levofloxacin; rates have increased to over 30% for each in much of the world.32 Indeed, the World Health Organization recently targeted H. pylori as one of the highpriority pathogens for novel antimicrobial drug development.33 In contrast, resistance to amoxicillin, tetracycline, and rifabutin resistance remains, fortunately, rare (under 2% for each, typically). Despite increasing attention paid to the importance of antimicrobial resistance in H. pylori, little is known about resistance patterns in North America. The Duck et al34 attempt to collate national resistance pattern on more than one agent from 1998-2002 reported resistance rates of 25% in metronidazole and 13% in clarithromycin. Over a decade later, researchers at the VA Medical Center in Houston tested about 100 strains, noting a similar resistance of 20% for metronidazole, and an alarming 31% rate for levofloxacin, while the resistance toward clarithromycin had increased to 16%.35 A recent multicenter, retrospective, cohort study revealed clarithromycin resistance in the United States to be rising further, to about 30%.36
Currently Recommended First-Line Therapies Falling eradication rates with standard therapies have prompted changes in recommended first-line therapies recently.2-4 In
The American Journal of Medicine, Vol 131, No 5, May 2018 general, bismuth quadruple therapy (traditional bismuthbased therapy plus a twice-daily PPI, all for 14 days) is now recommended as first-line therapy in the United States. This is consistent with recommendations from other international authorities.2-4 According to the American College of Gastroenterology (ACG) algorithm, other options for firstline therapy should be predicated upon whether the patient is truly allergic to penicillin, and on their previous antibiotic exposure, because this correlates well with likely H. pylori resistance.37 For patients intolerant of bismuth, concomitant therapy is another first-line option. It comprises standard PPI therapy plus a twice-daily nitroimidazole (in the United States, this is typically a twice-daily dosing of a PPI, 500 mg of clarithromycin, 1 g of amoxicillin, and 500 mg metronidazole, all for 14 days. In Europe and Asia, concomitant therapy appears superior to a 14-day triple therapy,38,39 but this regimen has not been well studied in the United States. Other less wellstudied first-line therapy options are included in the ACG guidelines, in case of further drug intolerances or likely resistance.
Second-Line Therapies Because 10%-30% of patients fail primary therapy, what are the second-line treatment options? Again, a proposed algorithm from the ACG guidelines incorporates choices based upon the patient’s previous antibiotic exposure and penicillinallergy status (Figure 3).2 Clarithromycin triple therapy as a repeat second-line therapy should be avoided due to poor pooled eradication rates. 40 If first-line therapy with clarithromycin or bismuth quadruple therapy fails, then levofloxacin triple therapy is an option. Levofloxacin triple therapy, consisting of PPI, amoxicillin and levofloxacin, seems to be an efficacious therapy41 and should be given for 14 days.2,4 However, little is known about levofloxacin-based therapy in the United States, and the recently described 30% levofloxacin resistance rate from Houston is concerning.35 Concomitant therapy as second line in patients who have failed bismuth quadruple is another option, but there are relatively few randomized studies published with this approach, and the duration of therapy has not been well defined.42,43 Bismuth quadruple therapy for 14 days would be a preferred treatment option if a patient received first-line treatment with a clarithromycin-based regimen.2-4 High-dose dual-therapy regimen with amoxicillin (defined as ≥3 g/day, frequency of administration ≥3/day) and a PPI is another option for patients who failed the usual first-line therapy, as H. pylori rarely develops amoxicillin resistance.35 Multiple randomized trials performed on high-dose dual therapy in comparison with salvage therapies give a pooled eradication rate of 78%,2 but again, there are no recent data from the United States. Probiotics are receiving much attention for many diverse conditions. They may have some benefit in H. pylori therapy, reducing side-effects and possibly marginally improving eradication rates with standard therapy.44 However, many of the
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Figure 3 Suggested second-line H. pylori therapies, according to initial (first-line) regimen. This schema takes into account whether or not the patient has previously used quinolones and whether they have verified allergy to penicillin. In each box, the best choice is signified by red font, with other options below. Rif = rifabutin, Clari = Clarithromycin, Bismuth Quad = Bismuth quadruple. Adapted from reference 2.
publications reporting their efficacy are of low quality, with uncertain blinding and utilizing multiple different probiotic components, so it is too early to conclude whether probiotics have a role in H. pylori treatment.
Practical Advice on Management for the Internist: What to Do after Two Failed Eradication Attempts? H. pylori regimens are complex, and they are often given to patients with relatively few or no symptoms. For these reasons, it is important to discuss with the patient why the drugs are being recommended, the need to take all the medicines exactly as prescribed, and to review the likely and possible side effects. Choosing a good primary and secondary regimen is now relatively easy by following the recommendations above. Despite these important first steps, 5%-10% of patients will have persistent infection. When 2 treatments fail, it is likely that compliance was suboptimal or that the H. pylori is now resistant to one or more antibiotics (usually clarithromycin, metronidazole, and levofloxacin). European guidelines recommend determining antibiotic resistance after 2 failed therapies,3 but this is challenging in the United States because resistance testing is not widely available. At this point, we recommend seeking help from a gastroenterology colleague who has interest and expertise in H. pylori infection and may be able to test for antibiotic resistance—either by traditional means or through the emerging availability of molecular testing on gastric or, potentially, stool specimens.45 This local expert can then review what the
patient has received, consider what they know works locally or regionally and, incorporating knowledge on the patient’s actual or perceived resistance, suggest a “salvage” regimen. One of the commonly recommended salvage regimens is 10 days of rifabutin-amoxicillin-PPI, although rifabutin’s use should be balanced against its adverse effects, such as myelotoxicity (almost always reversible), red secretions (patients should be fore-warned!), and its relatively high cost.46 Levofloxacin can also be used as third-line therapy if not previously used. In this scenario, eradication rates from 60% to 86% have been reported,47,48 but if levofloxacin resistance in the United States remains above 30%,35 then rifabutin regimes are likely preferable.
Confirming Eradication Because of falling H. pylori eradication rates, it is now recommended to check for successful eradication in all patients following therapy. This should be done at least 4 weeks after the end of therapy to avoid false-negative results. Urea breath or stool antigen tests are ideal if another endoscopy is not planned.2,3 By this time, the specificity of these tests is around 98%-100%.26 Confirming eradication allows defining success rates in practices and populations. Tracking eradication rates allows the early detection of emerging resistance patterns, prompting changes in future therapy. Confirming eradication with a posttreatment test of cure is considered mandatory to assess for eradication in case of a bleeding peptic ulcer, a gastric mucosa-associated lymphoid tissue lymphoma, and after endoscopic mucosal resection of early gastric cancer.
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FUTURE PERSPECTIVES Falling eradication rates are prompting calls for a more scientific approach to H. pylori therapy and a move away from empiric “guesswork” when selecting regimens. Resistance testing by traditional or molecular methods is likely to become increasingly widespread over the next decade. In this era of growing antimicrobial resistance, disappointingly few novel antibiotics have been developed—either for H. pylori or the many other emerging bacterial threats.33 In the absence of any imminent breakthrough antimicrobial agent for H. pylori, are there any other developments likely to reverse falling eradication rates? One interesting possibility is to incorporate more potent acid-suppressing drugs to substitute for PPIs. Vonoprazan is a new reversible inhibitor of the hydrogen-potassium ATPase or “proton pump,” which produces profound acid suppression. It is now available in Japan and has produced impressively high H. pylori eradication rates in antibiotic combination therapies.49 An H. pylori vaccine has long been considered a pipe dream, but in 2015 an impressive proof of principle was provided by a study from China.50 Three doses of an oral H. pylori recombinant urease fused to an adjuvant were given orally to teenagers, resulting in the prevention of over 70% of expected infections at 1 year. If successful, preventive or even therapeutic H. pylori vaccination could circumvent the whole problem of antibacterial resistance and eliminate H. pyloriassociated disease altogether. In the meantime, the utilization of appropriate diagnostics, adherence to current national guidelines, and the avoidance of H. pylori regimens known to be inferior (such as clarithromycin-based triple therapy) will be necessary to maintain reasonable eradication rates for this common and clinically important bacterium.
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Helicobacter pylori Infection: An Update for the Internist in the Age of Increasing Global Antibiotic Resistance Osama Siddique, MD,a Anais Ovalle, MD,a Ayesha S. Siddique, MD,b Steven F. Moss, MDa,c a
Department of Medicine, Alpert Medical School of Brown University, Providence, RI; bDepartment of Pathology, Hartford Hospital, Hartford, CT; cDivision of Gastroenterology and Hepatology, Alpert Medical School of Brown University, Providence, RI.
ABSTRACT Helicobacter pylori infects approximately half the world’s population and is especially prevalent in the developing world. H. pylori is an important cause of global ill health due to its known etiological role in peptic ulcer disease, dyspepsia, gastric cancer, lymphoma, and more recently, recognized in iron deficiency anemia and idiopathic thrombocytopenic purpura. Increased antibiotic usage worldwide has led to antibiotic resistance among many bacteria, including H. pylori, resulting in falling success rates of first-line anti-H. pylori therapies. Eradication failures are principally due to resistance to clarithromycin, levofloxacin, and metronidazole. Several new treatment options or modifications of established regimens are now recommended by updated practice guidelines for primary or secondary therapy. Because these updated recommendations were published in the gastroenterological literature, internists and primary care physicians, who commonly manage H. pylori, may be unaware of these advances. In this review, we outline the changing epidemiology of H. pylori, advise on diagnostic test selection for patients not undergoing endoscopy, and highlight current management options in this era of growing antibacterial resistance. Published by Elsevier Inc. • The American Journal of Medicine (2018) 131, 473–479 KEYWORDS: Antibiotic resistance; First-line therapy; Guidelines; Helicobacter pylori; Internist; Management; Therapy
INTRODUCTION Helicobacter pylori remains one of the most common causes of peptic ulcer disease, as well as causing dyspeptic symptoms in patients who are not found to have ulcers at endoscopy (nonulcer or “functional” dyspepsia).1 While gastroenterologists may be most familiar with H. pylori and may be consulted for optimal management, the diagnosis of H. pylori infection is often made by primary care or internal medicine Funding: None. Conflicts of Interest: None. Authorship: OS: Proposed the review topic, collated and reviewed relevant literature, wrote the manuscript first draft, and reviewed subsequent versions. AO: Collated and reviewed articles, co-wrote the manuscript first draft, and reviewed the final version. ASS: Collected and reviewed articles, co-wrote the manuscript, and reviewed the final version. SFM: Proposed the review topic, reviewed references, and revised all versions of the manuscript. Requests for reprints should be addressed to Steven F. Moss, MD, Rhode Island Hospital, 593 Eddy St., APC 414, Providence, RI 02903. E-mail address: [email protected]
0002-9343/$ - see front matter Published by Elsevier Inc. https://doi.org/10.1016/j.amjmed.2017.12.024
physicians, who may not be aware of the variety of diagnostic tests available, and that the treatment for H. pylori is becoming more challenging due to increasing antibiotic resistance. Falling eradication rates have prompted several authorities to recently update their treatment guidelines for empiric first-line and subsequent therapies.2-4 A translation gap exists for the application of knowledge about H. pylori to patient care, especially outside specialist practice. For example, while it is well appreciated that H. pylori testing is indicated in patients on chronic nonsteroidal antiinflammatory drug therapy or with a diagnosis of a gastric mucosa-associated lymphoid tissue lymphoma, <20% of such patients with these conditions were investigated for H. pylori by their physicians, according to some recent reports.5,6 In another study, only 54% of US primary care physicians used a “test and treat” strategy seeking H. pylori as a cause for dyspepsia, and almost half of the primary care physicians chose the inaccurate serology rather than the more accurate stool antigen or urea breath tests that detect active infection.7
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In this review we focus on updating internists and primary care physicians in H. pylori management, because these are the physicians most likely to encounter H. pylori relatively frequently, but who may not be aware of the changing prevalence of antibiotic resistance, the plethora of diagnostics tests available, and the recently updated guidelines on managing H. pylori infections.
also be potential benefits of H. pylori colonization. For example, an inverse relationship has been found between H. pylori and eosinophilic esophagitis, as well as with Barrett’s esophagus and with esophageal adenocarcinoma.22-24
CLINICAL SIGNIFICANCE
DIAGNOSIS Indications for Testing
H. pylori infection should be sought in patients with history of, or active, peptic ulcer disease, those with a low-grade gastric mucosa-associated lymphoid tissue lymphoma, and • H. pylori increases the risk of peptic ulcer in the evaluation of dyspeptic disease and gastric cancer and is also symptoms.2 etiologically linked to idiopathic “funcA “test-and-treat strategy” has tional” dyspepsia, gastric mucosallong been advocated for detecting associated lymphoid tissue lymphoma, and eradicating H. pylori in paunexplained iron-deficiency anemia, and tients with dyspepsia with low idiopathic thrombocytopenic purpura. gastric cancer risk.3 The most recent version of this strategy targets pa• Antibiotic resistance is increasingly tients younger than 60 years with common among H. pylori strains. Recent chronic or frequently recurring epiguidelines support 14-day quadruple gastric pain or discomfort in the therapies over the prior standard of absence of alarm symptoms, such clarithromycin-based triple therapy. as unexplained weight loss, progressive dysphagia, odynophagia, recurrent vomiting, family history of gastrointestinal cancer, and iron deficiency anemia.25 Moreover, if a patient with dyspepsia undergoes endoscopy, H. pylori presence should be evaluated in gastric biopsies, with the intention of treating if present.25 A suitable algorithm for CLINICAL IMPACT internists is shown in Figure 1. It is not recommended to test Since its discovery by Drs. Barry Marshall and Robin Warren, and treat patients for H. pylori who have been diagnosed with H. pylori has been implicated in a number of gastrointestigastroesophageal reflux disease, or in investigating those with nal conditions, including peptic ulcer disease, gastritis, and 1,14 typical retrosternal heartburn symptoms, because H. pylori gastric malignancies. is not implicated as an etiological factor in gastroesophaIn patients with gastric mucosa-associated lymphoid tissue 2 geal reflux disease. lymphoma, eradication of H. pylori induces complete remisSome evidence supports H. pylori testing in patients inision of this malignancy in most cases.15 Eradicating H. pylori tiating chronic nonsteroidal anti-inflammatory drugs or aspirin also helps prevent gastric carcinoma, by 30%-50%, accord16 therapy because H. pylori is synergistic with these medicaing to a recent meta-analysis of randomized clinical trials. tions in causing peptic ulcer disease and its complications.2,3 Studies have also investigated the relationship between auFurthermore, testing is advisable in patients with unextoimmune gastritis and H. pylori, where the treatment of H. plained iron deficiency anemia and adults with immune pylori has resulted in a decrease in the levels of antigastric 17 thrombocytopenic purpura.3 antibodies. In adults with immune thrombocytopenic purpura, platelet counts tend to increase after eradication of H. pylori,18 Diagnostic Tests leading to a recommendation from the American Society of Internists and primary care physicians can easily detect the Hematology to screen for and treat H. pylori in adults who presence of H. pylori via noninvasive testing: serology, urea test positive.19 Certain other extragastric diseases may also be weakly asbreath testing, and stool antigen detection (Figure 2) Serosociated with H. pylori infections; such as rosacea, chronic logic testing is widely available but is no longer recommended idiopathic urticaria, psoriasis, bronchiectasis, chronic obdue to its relatively low sensitivity and high false-positive structive pulmonary disease, Graves disease, diabetes,20 and rates when the background prevalence is low (as it is in the possibly, hepatic encephalopathy in patients with cirrhosis.21 United States).3 In addition, serology can remain positive While there is overwhelming evidence that H. pylori is a long after successful eradication due to antibody persisdefinite cause of serious gastroduodenal disease, there may tence. In contrast, the urea breath and stool tests detect only
EPIDEMIOLOGY
H. pylori has a prevalence of over 50% globally, with especially high rates in Africa, Central America, Central Asia, and Eastern Europe.8 In contrast, it is slowly declining in much of the developed world; Hooi et al8 estimate the prevalence of H. pylori infection in the United States to be around 35%. In North America, H. pylori is most prevalent among African Americans, Hispanic Americans, Native Americans, Alaskan natives, and in patients with lower socioeconomic status.9-13 In developed countries such as the United States, it is much more common in the elderly, due to a birth cohort effect of aging from a time when H. pylori was much more prevalent.
• Helicobacter pylori infection remains a common clinical issue for internists and primary care physicians.
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Figure 1 Algorithm for dyspepsia management. EGD = esophagogastroduodenoscopy; PPI = proton pump inhibitor.
active infection and are highly sensitive, and specific.26 Proton pump inhibitors (PPI), antibiotics, and bismuth-containing compounds reduce the diagnostic yield of the breath and stool tests because they inhibit H. pylori viability. Thus, PPIs should be discontinued for at least 2 weeks, and bismuth and antibiotics should be held for 4 weeks to avoid falsenegative results.3
Figure 2
Invasive strategies rely on endoscopy to acquire gastric biopsies for culture, urease activity, or histopathology. Culture techniques are less sensitive due to the challenges of successfully growing H. pylori colonies in the laboratory. Similar to the noninvasive urea breath test or stool antigen detection, bismuth and antibiotics should be discontinued for 4 weeks and PPI for at least 2 weeks prior to testing.
Diagnostic testing available for H. pylori.
476 Interestingly, the presence of blood in the stomach reduces the sensitivity of urease-based testing and may give falsenegative results in patients with active gastrointestinal bleeding.27 For this reason, and because the rapid urease test is limited by higher interobserver bias, most invasive testing for H. pylori in the United States is through routine histology, with additional immunohistochemistry as necessary.
MANAGEMENT: OLD AND NEW Standard Therapies and the Problems of Antibiotic Resistance The first effective therapy for H. pylori was introduced in the late 1980s, consisting of the combination of bismuth, tetracycline, and metronidazole, all given together for 2 weeks.28 The discovery that acid inhibition improved eradication rates led to a simpler and better-tolerated regimen known as triple therapy (PPI, amoxicillin, and clarithromycin) that became the mainstay of treatment over the last 25 years.29 Because up to 20% of the US population consider themselves to be penicillin allergic (although the overwhelming majority are not truly allergic on skin testing30), metronidazole is often substituted for amoxicillin in triple therapy. Over the last 10-15 years, there has been a marked decline in the success of triple therapy worldwide up to 90% or even less, linked to the emergence of widespread clarithromycin resistance.31 This led to the development of a minimum local resistance threshold of 15%-20%, above which clarithromycin should be avoided in triple therapy.3 Antibiotic resistance is the usual Achilles heel of H. pylori therapies, especially for clarithromycin, metronidazole, and more recently, levofloxacin; rates have increased to over 30% for each in much of the world.32 Indeed, the World Health Organization recently targeted H. pylori as one of the highpriority pathogens for novel antimicrobial drug development.33 In contrast, resistance to amoxicillin, tetracycline, and rifabutin resistance remains, fortunately, rare (under 2% for each, typically). Despite increasing attention paid to the importance of antimicrobial resistance in H. pylori, little is known about resistance patterns in North America. The Duck et al34 attempt to collate national resistance pattern on more than one agent from 1998-2002 reported resistance rates of 25% in metronidazole and 13% in clarithromycin. Over a decade later, researchers at the VA Medical Center in Houston tested about 100 strains, noting a similar resistance of 20% for metronidazole, and an alarming 31% rate for levofloxacin, while the resistance toward clarithromycin had increased to 16%.35 A recent multicenter, retrospective, cohort study revealed clarithromycin resistance in the United States to be rising further, to about 30%.36
Currently Recommended First-Line Therapies Falling eradication rates with standard therapies have prompted changes in recommended first-line therapies recently.2-4 In
The American Journal of Medicine, Vol 131, No 5, May 2018 general, bismuth quadruple therapy (traditional bismuthbased therapy plus a twice-daily PPI, all for 14 days) is now recommended as first-line therapy in the United States. This is consistent with recommendations from other international authorities.2-4 According to the American College of Gastroenterology (ACG) algorithm, other options for firstline therapy should be predicated upon whether the patient is truly allergic to penicillin, and on their previous antibiotic exposure, because this correlates well with likely H. pylori resistance.37 For patients intolerant of bismuth, concomitant therapy is another first-line option. It comprises standard PPI therapy plus a twice-daily nitroimidazole (in the United States, this is typically a twice-daily dosing of a PPI, 500 mg of clarithromycin, 1 g of amoxicillin, and 500 mg metronidazole, all for 14 days. In Europe and Asia, concomitant therapy appears superior to a 14-day triple therapy,38,39 but this regimen has not been well studied in the United States. Other less wellstudied first-line therapy options are included in the ACG guidelines, in case of further drug intolerances or likely resistance.
Second-Line Therapies Because 10%-30% of patients fail primary therapy, what are the second-line treatment options? Again, a proposed algorithm from the ACG guidelines incorporates choices based upon the patient’s previous antibiotic exposure and penicillinallergy status (Figure 3).2 Clarithromycin triple therapy as a repeat second-line therapy should be avoided due to poor pooled eradication rates. 40 If first-line therapy with clarithromycin or bismuth quadruple therapy fails, then levofloxacin triple therapy is an option. Levofloxacin triple therapy, consisting of PPI, amoxicillin and levofloxacin, seems to be an efficacious therapy41 and should be given for 14 days.2,4 However, little is known about levofloxacin-based therapy in the United States, and the recently described 30% levofloxacin resistance rate from Houston is concerning.35 Concomitant therapy as second line in patients who have failed bismuth quadruple is another option, but there are relatively few randomized studies published with this approach, and the duration of therapy has not been well defined.42,43 Bismuth quadruple therapy for 14 days would be a preferred treatment option if a patient received first-line treatment with a clarithromycin-based regimen.2-4 High-dose dual-therapy regimen with amoxicillin (defined as ≥3 g/day, frequency of administration ≥3/day) and a PPI is another option for patients who failed the usual first-line therapy, as H. pylori rarely develops amoxicillin resistance.35 Multiple randomized trials performed on high-dose dual therapy in comparison with salvage therapies give a pooled eradication rate of 78%,2 but again, there are no recent data from the United States. Probiotics are receiving much attention for many diverse conditions. They may have some benefit in H. pylori therapy, reducing side-effects and possibly marginally improving eradication rates with standard therapy.44 However, many of the
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Figure 3 Suggested second-line H. pylori therapies, according to initial (first-line) regimen. This schema takes into account whether or not the patient has previously used quinolones and whether they have verified allergy to penicillin. In each box, the best choice is signified by red font, with other options below. Rif = rifabutin, Clari = Clarithromycin, Bismuth Quad = Bismuth quadruple. Adapted from reference 2.
publications reporting their efficacy are of low quality, with uncertain blinding and utilizing multiple different probiotic components, so it is too early to conclude whether probiotics have a role in H. pylori treatment.
Practical Advice on Management for the Internist: What to Do after Two Failed Eradication Attempts? H. pylori regimens are complex, and they are often given to patients with relatively few or no symptoms. For these reasons, it is important to discuss with the patient why the drugs are being recommended, the need to take all the medicines exactly as prescribed, and to review the likely and possible side effects. Choosing a good primary and secondary regimen is now relatively easy by following the recommendations above. Despite these important first steps, 5%-10% of patients will have persistent infection. When 2 treatments fail, it is likely that compliance was suboptimal or that the H. pylori is now resistant to one or more antibiotics (usually clarithromycin, metronidazole, and levofloxacin). European guidelines recommend determining antibiotic resistance after 2 failed therapies,3 but this is challenging in the United States because resistance testing is not widely available. At this point, we recommend seeking help from a gastroenterology colleague who has interest and expertise in H. pylori infection and may be able to test for antibiotic resistance—either by traditional means or through the emerging availability of molecular testing on gastric or, potentially, stool specimens.45 This local expert can then review what the
patient has received, consider what they know works locally or regionally and, incorporating knowledge on the patient’s actual or perceived resistance, suggest a “salvage” regimen. One of the commonly recommended salvage regimens is 10 days of rifabutin-amoxicillin-PPI, although rifabutin’s use should be balanced against its adverse effects, such as myelotoxicity (almost always reversible), red secretions (patients should be fore-warned!), and its relatively high cost.46 Levofloxacin can also be used as third-line therapy if not previously used. In this scenario, eradication rates from 60% to 86% have been reported,47,48 but if levofloxacin resistance in the United States remains above 30%,35 then rifabutin regimes are likely preferable.
Confirming Eradication Because of falling H. pylori eradication rates, it is now recommended to check for successful eradication in all patients following therapy. This should be done at least 4 weeks after the end of therapy to avoid false-negative results. Urea breath or stool antigen tests are ideal if another endoscopy is not planned.2,3 By this time, the specificity of these tests is around 98%-100%.26 Confirming eradication allows defining success rates in practices and populations. Tracking eradication rates allows the early detection of emerging resistance patterns, prompting changes in future therapy. Confirming eradication with a posttreatment test of cure is considered mandatory to assess for eradication in case of a bleeding peptic ulcer, a gastric mucosa-associated lymphoid tissue lymphoma, and after endoscopic mucosal resection of early gastric cancer.
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FUTURE PERSPECTIVES Falling eradication rates are prompting calls for a more scientific approach to H. pylori therapy and a move away from empiric “guesswork” when selecting regimens. Resistance testing by traditional or molecular methods is likely to become increasingly widespread over the next decade. In this era of growing antimicrobial resistance, disappointingly few novel antibiotics have been developed—either for H. pylori or the many other emerging bacterial threats.33 In the absence of any imminent breakthrough antimicrobial agent for H. pylori, are there any other developments likely to reverse falling eradication rates? One interesting possibility is to incorporate more potent acid-suppressing drugs to substitute for PPIs. Vonoprazan is a new reversible inhibitor of the hydrogen-potassium ATPase or “proton pump,” which produces profound acid suppression. It is now available in Japan and has produced impressively high H. pylori eradication rates in antibiotic combination therapies.49 An H. pylori vaccine has long been considered a pipe dream, but in 2015 an impressive proof of principle was provided by a study from China.50 Three doses of an oral H. pylori recombinant urease fused to an adjuvant were given orally to teenagers, resulting in the prevention of over 70% of expected infections at 1 year. If successful, preventive or even therapeutic H. pylori vaccination could circumvent the whole problem of antibacterial resistance and eliminate H. pyloriassociated disease altogether. In the meantime, the utilization of appropriate diagnostics, adherence to current national guidelines, and the avoidance of H. pylori regimens known to be inferior (such as clarithromycin-based triple therapy) will be necessary to maintain reasonable eradication rates for this common and clinically important bacterium.
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