Clinical Management of H. pylori Dig Dis 2014;32:275–280 DOI: 10.1159/000358112
Helicobacter pylori Infection – Management from a European Perspective P. Malfertheiner Department of Gastroenterology, Hepatology and Infectious Diseases, University of Magdeburg, Magdeburg, Germany
Abstract Since the first European Consensus Report on Helicobacter pylori management in 1996 and the strong indication for therapy of peptic ulcer disease and other benign gastroduodenal pathologies, the list of indications for therapeutic interventions has been extended to selected extradigestive diseases. Test-and-treat and search-and-treat strategies have been implemented for patients with dyspeptic symptoms and prevention of H. pylori-related complications (gastric cancer included), respectively. Screen and treat strategies are in discussion but are still lacking any structured implementation. For diagnosis of H. pylori, accurate noninvasive and endoscopy-based tests are widely available across Europe, and individual tests are selected according to patient needs and clinical settings. Standard proton pump inhibitor-based triple therapy faces increasing failure rates mainly because of clarithromycin resistance, but alternative first-line options bismuth quadruple, or non-bismuth quadruples in various combinations have emerged as effective first-line alternatives. After treatment failure, defined rescue therapies including individual antibiotic-sensitive testing are recommended.
The prevalence of Helicobacter pylori infection is highly variable among various European countries and even within countries [1–3]. As in many other parts of the world, in Europe there is a general trend of decreasing prevalence of H. pylori with the most significant decrease in the infection in childhood [4]. In the adult population, the prevalence of the infection is still in a range from 20 to 60%, and thus the management of H. pylori-associated diseases continues to pose an important challenge. Apart from general principles in the management of the infection, there are specific needs to be respected in Europe that take into account differences in the prevalence of infection, incidence of H. pylori-related disease manifestations, health care systems, and resources. Finally, therapeutic regimens which include bismuth salts are not available in all European countries. From the perspective of a European consensus therefore the aim is to set an evidence-based general frame to facilitate the clinical management of this frequent infection with diverse clinical outcomes and complications. The European consensus does in no way prevent specific adaptations and fine-tuning of these general recommendations, whenever it becomes necessary in different countries and areas with distinct demands. The aim of this article is to address general aspects of the management of H. pylori infection in Europe.
© 2014 S. Karger AG, Basel © 2014 S. Karger AG, Basel 0257–2753/14/0323–0275$39.50/0 E-Mail [email protected] www.karger.com/ddi
Prof. Dr. med. Peter Malfertheiner Department of Gastroenterology, Hepatology and Infectious Diseases University of Magdeburg Leipziger Strasse 44, DE–39120 Magdeburg (Germany) E-Mail peter.malfertheiner @ med.ovgu.de
Downloaded by: University of Tokyo 157.82.153.40 - 5/20/2015 7:24:24 PM
Key Words Helicobacter pylori · Diagnostic strategies · Treatment options
GI diseases Peptic ulcer (duodenal ∞ gastric), complicated and noncomplicated Functional dyspepsia Dyspepsia (noninvasive test based) Beneficial before starting NSAID treatment Advisable in NSAID and aspirin users Patients with ulcers on NSAIDs, but PPI need to be continued Aspirin users with previous history of gastroduodenal ulcer Chronic atrophic gastritis Following gastric cancer resection, endoscopic resection MALT lymphoma Extradigestive diseases Idiopathic thrombocytopenic purpura Iron deficiency anemia Vitamin B12 deficiency In clinical practice if a patient is tested and found H. pylori positive the consequence should be eradication therapy if no specific contraindication.
The current guidance of H. pylori management is based on the Maastricht-Florence 4 consensus report [5], and some additional projections for the future are made in that context. The current principal challenges in Europe, shared with other parts in the world, are (a) the burden of gastric cancer and (b) the emergent resistance of H. pylori to antibiotics used in conventional eradication regimen. Gastric cancer has a high incidence in certain European regions and demands selective strategies of prevention. The emergence of antibiotic resistance requests new adjustments of H. pylori eradication therapies.
Indications
Indications for treatment of H. pylori-related gastroduodenal pathologies have first been released in the Maastricht I consensus report in 1996 [6] and have since undergone few modifications. Few additions over time have been made, but more importantly a substantially enlarged body of evidence has become available to support the recommendations for who, when and how to treat. Already at the first European consensus in 1996, ‘the wish of patients for being tested and treated’ was included based on expert opinion because public awareness since the mid-90s pointed to H. pylori as the most important 276
Dig Dis 2014;32:275–280 DOI: 10.1159/000358112
risk factor for gastroduodenal pathologies. In the third European Maastricht consensus report [7], indications for H. pylori therapy were for the first time extended to extra-alimentary conditions, and few additions were made in the latest update in 2010 [5] (table 1). The management of MALT lymphoma has been updated and the recommendation is that H. pylori should always be the first step of treatment and include patients with advanced gastric MALT lymphoma. Eradication is worth trying also in H. pylori-negative patients with MALT lymphoma [8]. In young patients with dyspepsia and no alarm symptoms below the age of 45–50 years, a test-and-treat strategy is considered appropriate because of the low prevalence of gastric malignancies in this age group in most European countries (table 2). However, the adoption of this strategy is not uniform, and it is not set in practice all over Europe. In countries with easily accessible endoscopy, a ‘scope and test’ is the recommended strategy for the management of all patients with dyspeptic symptoms, as is the case in the German guidelines [9]. In patients with dyspeptic symptoms undergoing upper gastrointestinal endoscopy, biopsies for histological assessment and H. pylori diagnosis should routinely be taken independent of presence or absence of gross morphologic changes. H. pylori eradication should routinely be offered to patients with dyspeptic symptoms with a positive H. pylori test. A positive urease test is considered sufficient to start the eradication therapy, even if additional management would eventually be required on the basis of the histological findings. The histological assessment is mostly performed according to the Sidney System. In cases of suspected atrophic gastritis, the updated Sidney-Houston criteria are preferred, and gastritis staging systems with special reference to gastric atrophy (OLGA) [10] or intestinal metaplasia (OLGIM) [11] are recommended. The evidence that H. pylori eradication prevents/reduces gastroduodenal ulcers in patients before long-term NSAIDs exposure and prevents the recurrence of ulcer bleeding in patients on low-dose aspirin has led to the implementation of a series of considerate recommendations in the European consensus (table 1). However, persisting high rates of NSAID- and aspirin-induced upper gastrointestinal bleeding indicates evidence that there is room for improvement in the translation of these recommendations. There is great demand for creating more awareness of the potential to prevent ulcers and complications by eradicating H. pylori in patients exposed to gastrolesive medications. Malfertheiner
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Table 1. Who should be treated for H. pylori-related diseases?
Prevention Strategies
Search and treat and screen and treat are strategies with great potential in the prevention of gastric cancer and other H. pylori-related pathologies (table 3). However, at present in Europe the recommendation of search and treat H. pylori for prevention is recommended only in the first-degree family members of patients with gastric cancer. A recent study from Portugal strengthens this recommendation as 20% of asymptomatic subjects from these families presented with preneoplastic conditions [15]. These subjects require eradication and regular followup after successful eradication. Patients with preneoplastic conditions of the mucosa (i.e. atrophy, intestinal metaplasia) should in any case undergo regular endoscopy controls at scheduled intervals [16]. H. pylori Infection – Management from a European Perspective
Table 2. Strategies adopted in Europe – variable among countries
Test (noninvasive) and treat → in young patients (1 year) PPI therapy1 • Strong environmental risk factors for gastric cancer • Fear of gastric cancer Adapted from Malfertheiner et al. [5]. 1 PPI so far only associated with the accelerated development of gastric preneoplastic conditions.
A search-and-treat strategy is also recommended in patients on long-term proton pump inhibitors (PPI) as they accelerate the development of preneoplastic conditions (i.e. gastric atrophic changes) in the presence of H. pylori. In the European consensus report, the commitment to implement prevention strategies in areas/countries also in Europe with moderate to high prevalence of gastric cancer has been recommended, and some initiatives in this respect have been started. The positive association of H. pylori with colon neoplasms [17] and the established clinical benefits obtained with colonoscopy screening for colorectal cancer [18] prompted a European-wide initiative to screen for gastric preneoplastic conditions in the context of screening colonoscopy [19] (table 2).
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Secondary prophylaxis by H. pylori eradication in aspirin users with H. pylori infection and previous ulcer bleeding is recommended based on a positive study conducted in Asia [12]. A similar study is missing in Europe, and no study on primary prophylaxis of acetylsalicylic acid-induced gastroduodenal lesions by H. pylori eradication is available at present. The ongoing claim H. pylori may be protective for the esophagus and beneficial for GERD and GERD complications has been rejected in the European consensus on the basis of available evidence [5]. The role of H. pylori in the pathogenesis of selected systemic diseases [13] has been corroborated by clinical studies in the most recent European consensus. For extragastric diseases causally related with H. pylori (table 1), it is important to emphasize that other possible causes need to be ruled out before starting the eradication therapy. It is also clearly stated in the European consensus that for several other extragastric diseases associated with H. pylori but with insufficient evidence for causality, more research is required, and eradication is not recommended at present. There are several autoimmune, neuroinflammatory and metabolic associations with H. pylori that deserve further investigations. The hygiene theory has been revisited, and H. pylori has been proposed as an ideal ‘surrogate marker’ of poor hygiene in childhood and to be beneficial in the prevention of atopic diseases. Clinical evidence poorly supports this relationship, but experimental studies provided positive findings and stimulate further clinical research in this area [14].
Table 4. Current (proposed) treatment regimens and dosages
Standard triple therapy
PPI, clarithromycin, amoxicillin or metronidazole Standard dose b.i.d., 500 mg b.i.d., 1,000 mg b.i.d. (or 500 mg b.i.d.)
7 – 10 days
Bismuth-containing quadruple therapy
PPI, tetracycline, metronidazole, bismuth (Pylera®) Standard dose b.i.d., 500 mg q.i.d., 125 mg q.i.d., standard dose q.i.d.
10 days
Sequential therapy
Day 1 – 5, PPI, amoxicillin Standard dose b.i.d., 1,000 mg b.i.d. Day 6 – 10, PPI, clarithromycin (levofloxacin), metronidazole Standard dose b.i.d., 500 mg b.i.d. (250 mg b.i.d.), 500 mg b.i.d.
Concomitant therapy
PPI, clarithromycin, amoxicillin or metronidazole Standard dose b.i.d., 500 mg b.i.d., 1,000 mg b.i.d., 500 mg b.i.d.
Hybrid therapy
Day 1 – 7, PPI, amoxicillin Standard dose b.i.d., 1,000 mg b.i.d. Day 8 – 14, PPI, amoxicillin, clarithromycin, metronidazole Standard dose b.i.d., 1,000 mg b.i.d., 500 mg b.i.d., 500 mg b.i.d.
The full spectrum of noninvasive and invasive tests is in use in Europe with different indications and preferences according to the clinical conditions. Among noninvasive tests, both the 13C-UBT and acid stool antigen test are considered equivalent. Both these tests are used as primary diagnostic tools in the test and treat strategy of dyspeptic patients, and they have the primary role for confirmation of the H. pylori eradication success. In all patients undergoing eradication therapy with noncomplicated peptic ulcer, dyspepsia and other nonmalignant pathologies should be tested 4 weeks after eradication by a noninvasive test. Endoscopy-based testing after therapy is demanded in patients with complicated duodenal ulcer and in all cases of gastric ulcer, preneoplastic conditions (severe atrophy), MALT lymphoma and after surgical subtotal gastric resection or endoscopic resection of gastric neoplasia. If endoscopy is carried out for clinical reasons after first-line treatment has failed to eradicate H. pylori, culture with susceptibility testing of antibiotics used in the eradication regimen should be performed. After second-line treatment has failed, therapy should generally be chosen on the basis of antibiotic susceptibility testing. Serology is useful in conditions of recent use of antimicrobials, PPI and in ulcer bleeding. Serology is also appropriate for testing in patients with dyspeptic symptoms if other noninvasive tests are not available. The use of rapid in-office tests is discouraged because of insufficient accuracy. H. pylori serology combined with serum pepsino278
Dig Dis 2014;32:275–280 DOI: 10.1159/000358112
gen I/II and gastrin 17 offers the possibility to identify patients with advanced preneoplastic conditions (i.e. gastric atrophy) [20]. Novel technologies including in situ hybridization methods for clarithromycin and fluoroquinolone resistance on gastric biopsies are new options if standard testing on culture is not possible; however, they are not routinely available as yet.
Treatment
As in other parts of the world, the efficacy of standard triple PPI (clarithromycin-amoxicillin or metronidazole) for H. pylori eradication has significantly dropped also in many European countries with eradication rates below 80%. The increasing resistance of H. pylori to clarithromycin has been identified as the principal reason for treatment failure, and this is not surprising as the most effective individual antibiotic in eradication regimen is clarithromycin. In contrast, resistance to metronidazole, although generally higher than resistance to clarithromycin, has much less impact on H. pylori eradication failure. Based on the prevalence of clarithromycin resistance, recommendations for first-line therapy have been revised, and no clarithromycin-containing regimen is recommended for use in areas where clarithromycin resistance of >15% is reported. The prevalence of clarithromycin resistance is very different in European countries and also within countries [21, 22]. Accordingly, different solutions for Malfertheiner
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Diagnostic Tests
7 – 10 days
Table 5. H. pylori: eradication therapy
algorithm First line
Second line Third line
Regions with low prevalence of CLA resistance
Regions with high prevalence of CLA resistance
PPI-clarithromycinamoxicillin/metronidazole or bismuth quadruple therapy
Bismuth quadruple therapy If not available: quadruple therapy without bismuth (sequential or concomitant therapy) ↓ PPI-levofloxacin/amoxicillin
↓ Bismuth quadruple therapy or PPI-levofloxacin/amoxicillin ↓ ↓ Only based on a susceptibility testing
Adopted from Malfertheiner et al. [5]. CLA = Clarithromycin.
H. pylori Infection – Management from a European Perspective
[28]. In this context, is worth mentioning that for amoxicillin, tetracycline and rifabutin, resistance rates are none or neglectable in Europe. Several studies have been performed in Europe to test for the add-on value of probiotics, and for some of them a positive effect has been shown [29]. The beneficial effect is considered to be obtained by lowering side effects with better adherence of patients to the eradication therapy [5]. The decision of simultaneous administration of a ‘valid’ probiotic with eradication therapy should be on a case-by-case basis taking into account the susceptibility for side effects reported by patients from the experience with prior antibiotic therapy.
Conclusion
Current recommendations for H. pylori eradication are based on good to excellent evidence regarding gastroduodenal pathologies and related symptoms. Associations of H. pylori with extragastric diseases have been identified as an area of important future research activities. Commitment to gastric cancer prevention strategies has the highest priority. Bismuth-based quadruple therapy and various non-bismuth-based quadruples are effective alternatives to standard PPI triple therapies in areas of high antibiotic (i.e. clarithromycin) resistance. Following failure of first-line therapy, an algorithm of successive therapies is advised.
Disclosure Statement P.M. received honoraria from lectures: Abbott, Astra Zeneca, Aptalis and Takeda.
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improving treatment efficacy have been offered in various European regions. In areas with clarithromycin resistance, >15–20% bismuth-based quadruple is recommended as first line. In a European multicenter study, bismuth quadruple (O-BMT = omeprazole, bismuth, metronidazole, tetracycline) has been significantly superior to PPI standard triple containing clarithromycin [23]. In the absence of bismuth-based regimen in some European countries, several non-bismuth-based quadruple sequential, concomitant, or even hybrid therapies have been used successfully [24, 25] (table 4). In clinical studies, the eradication rates of complex non-bismuth quadruple regimen are above 90% [25]. In routine clinical practice, the eradication rate drops below 90% [26]. Antibiotic resistance testing in the individual patient with the selection of the regimen based on antibiotic susceptibility is not recommended as first-line treatment. However, it should be considered in patients undergoing upper gastrointestinal endoscopy for diagnostic purpose. Second-line regimen should be chosen in consideration of the first-line regimen and can either be OBMT or based on levofloxacin-containing regimen (table 5). Levofloxacin has emerged as the antibiotic of choice for second line, either in the absence of bismuth quadruple, or after O-BMT failure. It is worrisome that also levofloxacin resistance is increasing in many European countries [21], and therefore in countries with high levofloxacin resistance it is advisable to test for levofloxacin resistance before its use. In spite of some excellent results of levofloxacin as first line [27], it should never be used in first-line therapy without susceptibility testing. There is a general recommendation to perform antibiotic susceptibility tests after second-line failure (table 5). Rifabutin for third-line combination is an effective option
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Helicobacter pylori Infection – Management from a European Perspective P. Malfertheiner Department of Gastroenterology, Hepatology and Infectious Diseases, University of Magdeburg, Magdeburg, Germany
Abstract Since the first European Consensus Report on Helicobacter pylori management in 1996 and the strong indication for therapy of peptic ulcer disease and other benign gastroduodenal pathologies, the list of indications for therapeutic interventions has been extended to selected extradigestive diseases. Test-and-treat and search-and-treat strategies have been implemented for patients with dyspeptic symptoms and prevention of H. pylori-related complications (gastric cancer included), respectively. Screen and treat strategies are in discussion but are still lacking any structured implementation. For diagnosis of H. pylori, accurate noninvasive and endoscopy-based tests are widely available across Europe, and individual tests are selected according to patient needs and clinical settings. Standard proton pump inhibitor-based triple therapy faces increasing failure rates mainly because of clarithromycin resistance, but alternative first-line options bismuth quadruple, or non-bismuth quadruples in various combinations have emerged as effective first-line alternatives. After treatment failure, defined rescue therapies including individual antibiotic-sensitive testing are recommended.
The prevalence of Helicobacter pylori infection is highly variable among various European countries and even within countries [1–3]. As in many other parts of the world, in Europe there is a general trend of decreasing prevalence of H. pylori with the most significant decrease in the infection in childhood [4]. In the adult population, the prevalence of the infection is still in a range from 20 to 60%, and thus the management of H. pylori-associated diseases continues to pose an important challenge. Apart from general principles in the management of the infection, there are specific needs to be respected in Europe that take into account differences in the prevalence of infection, incidence of H. pylori-related disease manifestations, health care systems, and resources. Finally, therapeutic regimens which include bismuth salts are not available in all European countries. From the perspective of a European consensus therefore the aim is to set an evidence-based general frame to facilitate the clinical management of this frequent infection with diverse clinical outcomes and complications. The European consensus does in no way prevent specific adaptations and fine-tuning of these general recommendations, whenever it becomes necessary in different countries and areas with distinct demands. The aim of this article is to address general aspects of the management of H. pylori infection in Europe.
© 2014 S. Karger AG, Basel © 2014 S. Karger AG, Basel 0257–2753/14/0323–0275$39.50/0 E-Mail [email protected] www.karger.com/ddi
Prof. Dr. med. Peter Malfertheiner Department of Gastroenterology, Hepatology and Infectious Diseases University of Magdeburg Leipziger Strasse 44, DE–39120 Magdeburg (Germany) E-Mail peter.malfertheiner @ med.ovgu.de
Downloaded by: University of Tokyo 157.82.153.40 - 5/20/2015 7:24:24 PM
Key Words Helicobacter pylori · Diagnostic strategies · Treatment options
GI diseases Peptic ulcer (duodenal ∞ gastric), complicated and noncomplicated Functional dyspepsia Dyspepsia (noninvasive test based) Beneficial before starting NSAID treatment Advisable in NSAID and aspirin users Patients with ulcers on NSAIDs, but PPI need to be continued Aspirin users with previous history of gastroduodenal ulcer Chronic atrophic gastritis Following gastric cancer resection, endoscopic resection MALT lymphoma Extradigestive diseases Idiopathic thrombocytopenic purpura Iron deficiency anemia Vitamin B12 deficiency In clinical practice if a patient is tested and found H. pylori positive the consequence should be eradication therapy if no specific contraindication.
The current guidance of H. pylori management is based on the Maastricht-Florence 4 consensus report [5], and some additional projections for the future are made in that context. The current principal challenges in Europe, shared with other parts in the world, are (a) the burden of gastric cancer and (b) the emergent resistance of H. pylori to antibiotics used in conventional eradication regimen. Gastric cancer has a high incidence in certain European regions and demands selective strategies of prevention. The emergence of antibiotic resistance requests new adjustments of H. pylori eradication therapies.
Indications
Indications for treatment of H. pylori-related gastroduodenal pathologies have first been released in the Maastricht I consensus report in 1996 [6] and have since undergone few modifications. Few additions over time have been made, but more importantly a substantially enlarged body of evidence has become available to support the recommendations for who, when and how to treat. Already at the first European consensus in 1996, ‘the wish of patients for being tested and treated’ was included based on expert opinion because public awareness since the mid-90s pointed to H. pylori as the most important 276
Dig Dis 2014;32:275–280 DOI: 10.1159/000358112
risk factor for gastroduodenal pathologies. In the third European Maastricht consensus report [7], indications for H. pylori therapy were for the first time extended to extra-alimentary conditions, and few additions were made in the latest update in 2010 [5] (table 1). The management of MALT lymphoma has been updated and the recommendation is that H. pylori should always be the first step of treatment and include patients with advanced gastric MALT lymphoma. Eradication is worth trying also in H. pylori-negative patients with MALT lymphoma [8]. In young patients with dyspepsia and no alarm symptoms below the age of 45–50 years, a test-and-treat strategy is considered appropriate because of the low prevalence of gastric malignancies in this age group in most European countries (table 2). However, the adoption of this strategy is not uniform, and it is not set in practice all over Europe. In countries with easily accessible endoscopy, a ‘scope and test’ is the recommended strategy for the management of all patients with dyspeptic symptoms, as is the case in the German guidelines [9]. In patients with dyspeptic symptoms undergoing upper gastrointestinal endoscopy, biopsies for histological assessment and H. pylori diagnosis should routinely be taken independent of presence or absence of gross morphologic changes. H. pylori eradication should routinely be offered to patients with dyspeptic symptoms with a positive H. pylori test. A positive urease test is considered sufficient to start the eradication therapy, even if additional management would eventually be required on the basis of the histological findings. The histological assessment is mostly performed according to the Sidney System. In cases of suspected atrophic gastritis, the updated Sidney-Houston criteria are preferred, and gastritis staging systems with special reference to gastric atrophy (OLGA) [10] or intestinal metaplasia (OLGIM) [11] are recommended. The evidence that H. pylori eradication prevents/reduces gastroduodenal ulcers in patients before long-term NSAIDs exposure and prevents the recurrence of ulcer bleeding in patients on low-dose aspirin has led to the implementation of a series of considerate recommendations in the European consensus (table 1). However, persisting high rates of NSAID- and aspirin-induced upper gastrointestinal bleeding indicates evidence that there is room for improvement in the translation of these recommendations. There is great demand for creating more awareness of the potential to prevent ulcers and complications by eradicating H. pylori in patients exposed to gastrolesive medications. Malfertheiner
Downloaded by: University of Tokyo 157.82.153.40 - 5/20/2015 7:24:24 PM
Table 1. Who should be treated for H. pylori-related diseases?
Prevention Strategies
Search and treat and screen and treat are strategies with great potential in the prevention of gastric cancer and other H. pylori-related pathologies (table 3). However, at present in Europe the recommendation of search and treat H. pylori for prevention is recommended only in the first-degree family members of patients with gastric cancer. A recent study from Portugal strengthens this recommendation as 20% of asymptomatic subjects from these families presented with preneoplastic conditions [15]. These subjects require eradication and regular followup after successful eradication. Patients with preneoplastic conditions of the mucosa (i.e. atrophy, intestinal metaplasia) should in any case undergo regular endoscopy controls at scheduled intervals [16]. H. pylori Infection – Management from a European Perspective
Table 2. Strategies adopted in Europe – variable among countries
Test (noninvasive) and treat → in young patients (1 year) PPI therapy1 • Strong environmental risk factors for gastric cancer • Fear of gastric cancer Adapted from Malfertheiner et al. [5]. 1 PPI so far only associated with the accelerated development of gastric preneoplastic conditions.
A search-and-treat strategy is also recommended in patients on long-term proton pump inhibitors (PPI) as they accelerate the development of preneoplastic conditions (i.e. gastric atrophic changes) in the presence of H. pylori. In the European consensus report, the commitment to implement prevention strategies in areas/countries also in Europe with moderate to high prevalence of gastric cancer has been recommended, and some initiatives in this respect have been started. The positive association of H. pylori with colon neoplasms [17] and the established clinical benefits obtained with colonoscopy screening for colorectal cancer [18] prompted a European-wide initiative to screen for gastric preneoplastic conditions in the context of screening colonoscopy [19] (table 2).
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Secondary prophylaxis by H. pylori eradication in aspirin users with H. pylori infection and previous ulcer bleeding is recommended based on a positive study conducted in Asia [12]. A similar study is missing in Europe, and no study on primary prophylaxis of acetylsalicylic acid-induced gastroduodenal lesions by H. pylori eradication is available at present. The ongoing claim H. pylori may be protective for the esophagus and beneficial for GERD and GERD complications has been rejected in the European consensus on the basis of available evidence [5]. The role of H. pylori in the pathogenesis of selected systemic diseases [13] has been corroborated by clinical studies in the most recent European consensus. For extragastric diseases causally related with H. pylori (table 1), it is important to emphasize that other possible causes need to be ruled out before starting the eradication therapy. It is also clearly stated in the European consensus that for several other extragastric diseases associated with H. pylori but with insufficient evidence for causality, more research is required, and eradication is not recommended at present. There are several autoimmune, neuroinflammatory and metabolic associations with H. pylori that deserve further investigations. The hygiene theory has been revisited, and H. pylori has been proposed as an ideal ‘surrogate marker’ of poor hygiene in childhood and to be beneficial in the prevention of atopic diseases. Clinical evidence poorly supports this relationship, but experimental studies provided positive findings and stimulate further clinical research in this area [14].
Table 4. Current (proposed) treatment regimens and dosages
Standard triple therapy
PPI, clarithromycin, amoxicillin or metronidazole Standard dose b.i.d., 500 mg b.i.d., 1,000 mg b.i.d. (or 500 mg b.i.d.)
7 – 10 days
Bismuth-containing quadruple therapy
PPI, tetracycline, metronidazole, bismuth (Pylera®) Standard dose b.i.d., 500 mg q.i.d., 125 mg q.i.d., standard dose q.i.d.
10 days
Sequential therapy
Day 1 – 5, PPI, amoxicillin Standard dose b.i.d., 1,000 mg b.i.d. Day 6 – 10, PPI, clarithromycin (levofloxacin), metronidazole Standard dose b.i.d., 500 mg b.i.d. (250 mg b.i.d.), 500 mg b.i.d.
Concomitant therapy
PPI, clarithromycin, amoxicillin or metronidazole Standard dose b.i.d., 500 mg b.i.d., 1,000 mg b.i.d., 500 mg b.i.d.
Hybrid therapy
Day 1 – 7, PPI, amoxicillin Standard dose b.i.d., 1,000 mg b.i.d. Day 8 – 14, PPI, amoxicillin, clarithromycin, metronidazole Standard dose b.i.d., 1,000 mg b.i.d., 500 mg b.i.d., 500 mg b.i.d.
The full spectrum of noninvasive and invasive tests is in use in Europe with different indications and preferences according to the clinical conditions. Among noninvasive tests, both the 13C-UBT and acid stool antigen test are considered equivalent. Both these tests are used as primary diagnostic tools in the test and treat strategy of dyspeptic patients, and they have the primary role for confirmation of the H. pylori eradication success. In all patients undergoing eradication therapy with noncomplicated peptic ulcer, dyspepsia and other nonmalignant pathologies should be tested 4 weeks after eradication by a noninvasive test. Endoscopy-based testing after therapy is demanded in patients with complicated duodenal ulcer and in all cases of gastric ulcer, preneoplastic conditions (severe atrophy), MALT lymphoma and after surgical subtotal gastric resection or endoscopic resection of gastric neoplasia. If endoscopy is carried out for clinical reasons after first-line treatment has failed to eradicate H. pylori, culture with susceptibility testing of antibiotics used in the eradication regimen should be performed. After second-line treatment has failed, therapy should generally be chosen on the basis of antibiotic susceptibility testing. Serology is useful in conditions of recent use of antimicrobials, PPI and in ulcer bleeding. Serology is also appropriate for testing in patients with dyspeptic symptoms if other noninvasive tests are not available. The use of rapid in-office tests is discouraged because of insufficient accuracy. H. pylori serology combined with serum pepsino278
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gen I/II and gastrin 17 offers the possibility to identify patients with advanced preneoplastic conditions (i.e. gastric atrophy) [20]. Novel technologies including in situ hybridization methods for clarithromycin and fluoroquinolone resistance on gastric biopsies are new options if standard testing on culture is not possible; however, they are not routinely available as yet.
Treatment
As in other parts of the world, the efficacy of standard triple PPI (clarithromycin-amoxicillin or metronidazole) for H. pylori eradication has significantly dropped also in many European countries with eradication rates below 80%. The increasing resistance of H. pylori to clarithromycin has been identified as the principal reason for treatment failure, and this is not surprising as the most effective individual antibiotic in eradication regimen is clarithromycin. In contrast, resistance to metronidazole, although generally higher than resistance to clarithromycin, has much less impact on H. pylori eradication failure. Based on the prevalence of clarithromycin resistance, recommendations for first-line therapy have been revised, and no clarithromycin-containing regimen is recommended for use in areas where clarithromycin resistance of >15% is reported. The prevalence of clarithromycin resistance is very different in European countries and also within countries [21, 22]. Accordingly, different solutions for Malfertheiner
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Diagnostic Tests
7 – 10 days
Table 5. H. pylori: eradication therapy
algorithm First line
Second line Third line
Regions with low prevalence of CLA resistance
Regions with high prevalence of CLA resistance
PPI-clarithromycinamoxicillin/metronidazole or bismuth quadruple therapy
Bismuth quadruple therapy If not available: quadruple therapy without bismuth (sequential or concomitant therapy) ↓ PPI-levofloxacin/amoxicillin
↓ Bismuth quadruple therapy or PPI-levofloxacin/amoxicillin ↓ ↓ Only based on a susceptibility testing
Adopted from Malfertheiner et al. [5]. CLA = Clarithromycin.
H. pylori Infection – Management from a European Perspective
[28]. In this context, is worth mentioning that for amoxicillin, tetracycline and rifabutin, resistance rates are none or neglectable in Europe. Several studies have been performed in Europe to test for the add-on value of probiotics, and for some of them a positive effect has been shown [29]. The beneficial effect is considered to be obtained by lowering side effects with better adherence of patients to the eradication therapy [5]. The decision of simultaneous administration of a ‘valid’ probiotic with eradication therapy should be on a case-by-case basis taking into account the susceptibility for side effects reported by patients from the experience with prior antibiotic therapy.
Conclusion
Current recommendations for H. pylori eradication are based on good to excellent evidence regarding gastroduodenal pathologies and related symptoms. Associations of H. pylori with extragastric diseases have been identified as an area of important future research activities. Commitment to gastric cancer prevention strategies has the highest priority. Bismuth-based quadruple therapy and various non-bismuth-based quadruples are effective alternatives to standard PPI triple therapies in areas of high antibiotic (i.e. clarithromycin) resistance. Following failure of first-line therapy, an algorithm of successive therapies is advised.
Disclosure Statement P.M. received honoraria from lectures: Abbott, Astra Zeneca, Aptalis and Takeda.
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improving treatment efficacy have been offered in various European regions. In areas with clarithromycin resistance, >15–20% bismuth-based quadruple is recommended as first line. In a European multicenter study, bismuth quadruple (O-BMT = omeprazole, bismuth, metronidazole, tetracycline) has been significantly superior to PPI standard triple containing clarithromycin [23]. In the absence of bismuth-based regimen in some European countries, several non-bismuth-based quadruple sequential, concomitant, or even hybrid therapies have been used successfully [24, 25] (table 4). In clinical studies, the eradication rates of complex non-bismuth quadruple regimen are above 90% [25]. In routine clinical practice, the eradication rate drops below 90% [26]. Antibiotic resistance testing in the individual patient with the selection of the regimen based on antibiotic susceptibility is not recommended as first-line treatment. However, it should be considered in patients undergoing upper gastrointestinal endoscopy for diagnostic purpose. Second-line regimen should be chosen in consideration of the first-line regimen and can either be OBMT or based on levofloxacin-containing regimen (table 5). Levofloxacin has emerged as the antibiotic of choice for second line, either in the absence of bismuth quadruple, or after O-BMT failure. It is worrisome that also levofloxacin resistance is increasing in many European countries [21], and therefore in countries with high levofloxacin resistance it is advisable to test for levofloxacin resistance before its use. In spite of some excellent results of levofloxacin as first line [27], it should never be used in first-line therapy without susceptibility testing. There is a general recommendation to perform antibiotic susceptibility tests after second-line failure (table 5). Rifabutin for third-line combination is an effective option
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