Maastricht – IV: modern eradication schemes. Choice of proton pump inhibitor during Helicobacter pylori eradication therapy. Maastricht V Kazan State Medical University

The next XXIVth meeting of the International Working Group on Helicobacter pylori and related bacteria in chronic inflammatory processes of the digestive tract and gastric cancer - XXIVth International Workshop on Helicobacter and related bacteria in chronic digestive inflammation and gastric cancer - was held in Dublin (Ireland) on September 11-13 2011. A number of reports and speeches were devoted to the most pressing problems for the international Helicobacter pylori community - the growing resistance of the infection to clarithromycin and levofloxacin, new approaches to the diagnosis and treatment of Helicobacter pylori infection. Report by Dr. F.Megraud
(INSERM U853 & Universite de Bordeaux, Bordeaux, France) entitled “Management of Helicobacter pylori infection Maastricht-4” was based on the main Statements of the recent Maastricht Agreements. Based on this report, as well as references to the Approvals of the Maastricht Agreements, which were present in the report of T.L. Lapina (Clinic of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology named after V.Kh. Vasilenko MMA named after I.M. Sechenov) at the 4th Ukrainian Gastroweek one can almost come close to the content of “The Fourth Maastricht”. Selected presentation slides and key Statements (Provisions) are published below:

Regulations on FD :
3. HP eradication causes complete and long-term symptom relief in 1 in 12 patients with HP and FD, with superiority compared to all other treatments.
4. HP can increase or decrease secretion depending on the pattern of inflammation in the stomach.

GERD Regulations :
5. H. pylori does not affect the severity, frequency of symptoms, or effectiveness of therapy for GERD.
6. Epidemiological studies demonstrate a negative association between the prevalence of HP and GERD and esophageal adenocarcinoma.

NSAID Regulations :
7. HP increases the risk of complicated and uncomplicated gastroduodenal ulcers in users of NSAIDs. HP eradication reduces this risk.
8. HP eradication is especially indicated for patients with a history of ulcerative disease.
9. Eradication of HP does not in itself eliminate the risk of ulceration.

Regulations on intestinal metaplasia :
11. After HP eradication, the functional capabilities of the gastric body improve, but the extent to which this is related to regression of atrophy remains controversial.
11b. Convincing evidence that eradication of HP leads to regression of CM has not yet been obtained.

Regulations on extra-gastric diseases :
13. There is evidence of a connection between HP and IDA, ITP and vitamin B12 YES.
There is still insufficient evidence linking HP with other life-threatening diseases, including cardiovascular and neurological ones.
14. It has been proven that HP does not have a protective effect against asthma and atopy, obesity and related diseases.
15. In an HP (+) patient, eradication of HP improves the bioavailability of thyroxine.

Statement 1:
The diagnostic accuracy of the antigen stool test is equal to the UDT when the former is validated with a monoclonal laboratory test.
- Level of evidence: 1a
- Grade of recommendation: A

Statement 2:
Not all serological tests are equal. Due to variability in the accuracy of different commercial tests, only validated IgG serological tests should be used.
- Level of evidence: 1b
- Grade of recommendation: B

Statement 3:
Validated serology can be used to guide decisions about prescribing antimicrobial and antisecretory drugs for ulcer bleeding, atrophy and gastric tumors.
- Level of evidence: 1b
- Grade of recommendation: B
* expert opinion (5D)

Statement 4:
In patients treated with PPIs
1) If possible, PPI use should be stopped for 2 weeks before testing by culture, histology, rapid urease test, UDT or stool test.
- Level of evidence: 1b
- Grade of recommendation: A
2) If this is not possible, validated serology can be performed.
- Level of evidence: 2b
- Grade of recommendation: B

Statement 5:
1) It is important to determine cultural and standard sensitivity to antimicrobial drugs:
- before prescribing first-line therapy, if a standard clarithromycin regimen containing triple therapy is taken into account in regions where the population has high resistance to clarithromycin.
- before second-line therapy in all regions, when endoscopy is performed for another reason, and
- mainly in case of failure of second-line therapy.
- Evidence level: 5
- Grade of recommendation: D
2) If a standard determination of susceptibility is not possible, a molecular genetic test can be used to determine H. pylori and resistance to clarithromycin and/or fluorquinol directly on the biopsy material.
- Level of evidence: 1b
- Grade of recommendation: A

Statement 6:
1) If H. pylori is isolated from gastric biopsies, antibiotic susceptibility testing and metronidazole testing should be performed.
-Level of Evidence: 1b
-Grade of recommendation:A
2) If susceptibility to clarithromycin is determined molecularly genetically, additional cultural determination of resistance to metronidazole is not justified.
-Level of Evidence: 5
-Grade of recommendation:D

Statement 7:
Triple therapy with a PPI and clarithromycin (without prior testing of sensitivity to clarithromycin) should be abandoned if the level of resistance to clarithromycin in the region is more than 15-20%.
- Evidence level: 5
- Grade of recommendation: D.

Statement 8:
In regions with low levels of clarithromycin resistance, clarithromycin-containing regimens are recommended as first-line empirical therapy. An alternative is to prescribe quadruple therapy with a bismuth preparation.

- Grade of recommendation: A.

How to improve the results of standard triple therapy?

Statement 9:
Prescribing a high dose of PPI (twice daily) increases the effectiveness of triple therapy.
- Level of evidence: 1b
- Grade of recommendation: A.
Statement 10:
Increasing the duration of triple therapy with PPI and clarithromycin from 7 to 10-14 days increases the rate of successful eradication by 5%, which should be taken into account.
- Level of evidence: 1a.
- Grade of recommendation: A.
Statement 11:
The effectiveness of the “PPI - clarithromycin + metronidazole” and “PPI + clarithromycin + amoxicillin” regimens is equivalent.
- Level of evidence: 1a.
- Grade of recommendation: A.

How to improve results?
Statement 12:
Certain pro- and prebiotics show promising results as adjuvant therapy and reduce side effects.
Statement 13:
Standard regimens do not need to be tailored to the patient's characteristics other than the dose.

Second line therapy
Statement 14:
1) After an ineffective regimen with a PPI and clarithromycin, quadruple therapy with bismuth or triple therapy with levofloxacin is recommended.
- Level of evidence: 1a.
- Grade of recommendation: A.

- Level of evidence: 2b.
- Grade of recommendation: B.

Third line therapy
Statement 15:
After failure of second-line therapy, treatment should be guided by antibiotic susceptibility testing whenever possible.
- Level of evidence: 1c
- Grade of recommendation: A.

Regions with high levels of clarithromycin resistance
Statement 16:
In regions with high levels of clarithromycin resistance, bismuth quadruple therapy is recommended as first-line empirical therapy. If this regimen cannot be implemented, sequential therapy or quadruple therapy without bismuth is recommended.
- Level of evidence: 1a.
- Grade of recommendation: A.

Calculation of the effectiveness of various eradication therapy regimens with clarithromycin depending on resistance to clarithromycin
Resistance to clarithromycin 10% 30%
Standard triple therapy 83% 69%
Sequential therapy 92% 87%

Second and third line therapy
Statement 14b.:
1) In regions with high resistance to clarithromycin, after failure of quadruple therapy with a bismuth drug, triple therapy with levofloxacin is recommended.
- Level of evidence: 5.
- Grade of recommendation: D.
2) Increasing levels of resistance to levofloxacin should be taken into account.

- Grade of recommendation: B.
Statement 15b.:
After failure of second-line therapy, subsequent treatment should be determined by antibiotic susceptibility testing.
- Level of evidence: 1c.
- Grade of recommendation: A.

If you are allergic to penicillin
Statement 17:
In regions with low resistance to clarithromycin - PPI+K+M
In regions with high resistance to clarithromycin - quadruple therapy with bismuth - PPI + B + M + T.
- Level of evidence: 2C.
- Grade of recommendation: B.

Statement 18:
Both the UBT (urease breath test) and the laboratory validated monoclonal stool test are recommended as non-invasive tests to determine the success of eradication therapy. Serology is not needed.
- Level of evidence: 1a.
- Grade of recommendation: A.

Control of therapy
Statement 19:
To determine successful eradication of H. pylori, the interval after completion of eradication therapy should be at least 4 weeks.
- Level of evidence: 2b.
- Grade of recommendation: B.

Special Recommendations
Statement 20:
1) In uncomplicated DU, continued PPI treatment is not recommended.
- Level of evidence: 1A.
- Grade of recommendation: A.
2) In case of ulcerative stomach and complicated DU, continuation of PPI is recommended.

- Grade of recommendation: A.
Statement 21 :
Eradication therapy for bleeding from ulcers should begin from the moment of reintroduction of oral nutrition.
- Level of evidence: 1b.

Sheptulin A.A.

Elena Aleksandrovna Poluektova, doctor, candidate of medical sciences:

– Now the message “Maastricht-IV. Modern eradication schemes,” Arkady Aleksandrovich Sheptulin.

Arkady Aleksandrovich Sheptulin, professor, doctor of medical sciences:

– Good afternoon, dear colleagues. In order to better imagine what new things the Maastricht-IV conciliation meeting brought, let’s very briefly, very quickly recall the main provisions of the previous Maastricht-III consensus.

The Maastricht III consensus, first of all, determined the main indications for eradication therapy. You know them well: this is a peptic ulcer, this is MALT lymphoma of the stomach, this is atrophic gastritis, this is a condition after gastrectomy for early cancer, these are the closest relatives of patients with stomach cancer and the desire of the patient himself in cases where he has no contraindications for this .

The Maastricht III Consensus addressed three controversial issues regarding the relationship between Helicobacter pylorus and diseases such as functional dyspepsia, gastropathy associated with non-steroidal anti-inflammatory drugs, and the relationship of Helicobacter pylorus with a wide range of non-gastroenterological diseases.

As for functional dyspepsia, a meta-analysis of a large number of studies conducted quite a long time ago showed that the effectiveness of eradication in eliminating the symptoms of dyspepsia is low. The NNT indicator is 17: we need to treat 17 patients so that one patient’s complaints disappear. However, what Tatyana Lvovna spoke about was the importance of Helicobacter pyloric in the development of stomach cancer, as well as the fact that Helicobacter pylorus is the main risk factor for the development of peptic ulcers in countries with high contamination rates - and we, unfortunately, are among such We relate to countries - in case of functional dyspepsia, it is advisable to determine the infection of Helicobacter pyloricus and, if the results are positive, to carry out eradication.

As for NSAID-associated gastropathy, it has been established that the risk of developing NSAID gastropathy in H. Pilori-positive patients is higher than in H. Pilori-negative patients, and that eradication reduces the risk of developing gastric ulcers and erosions in patients receiving NSAIDs. Before starting to take NSAIDs, it is advisable to investigate the presence of this infection and, if confirmed, eradicate it. But a very important note is that eradication of Helicobacter pyloricus alone is not enough to prevent the occurrence of NSAID gastropathy. Therefore, if the patient has additional risk factors for NSAID gastropathy - old age, a history of peptic ulcer disease, simultaneous use of corticosteroids or anticoagulants - then in addition to eradication, cover with proton pump inhibitors is necessarily prescribed.

If we take a wide range of non-gastroenterological diseases, then only two nosological forms are associated with Helicobacter pyloric infection: immune thrombocytopenia - there is a crossover of antibodies to Helicobacter pyloric and antibodies to platelets - and iron deficiency anemia, but in cases where the examination did not reveal others causes of iron deficiency anemia, in particular bleeding.

As for other diseases, primarily coronary heart disease, there is currently no convincing evidence to link these diseases with Helicobacter pyloric infection.

The Maastricht III consensus defined the main provisions regarding the diagnosis of Helicobacter pyloric infection. If the patient does not undergo esophagogastroduodenoscopy, then to diagnose this infection it is preferable to use a urease breath test, determination of Helicobacter pyloric antigen in stool, or a serological method. Most often, we determine the presence of Helicobacter pyloricus at the time of gastroduodenoscopy: say, a patient has an ulcer or erosion. Here, a rapid urease test is usually used for diagnosis.

To monitor eradication, it is best to use the urease breath test. If this is not possible, examine the Helicobacter pyloric antigen in the stool. Importantly, current antisecretory therapy reduces the detection rate of Helicobacter pyloric antigen in stool and the rate of positive breath test results.

And it is important that the determination of Helicobacter pyloric strains - in particular, the cagA strain, vacA strain and others - does not play any role in deciding the issue of treating patients. If any strain of Helicobacter pyloric is detected, if the patient is included in the list of indications for eradication, it is carried out.

As for treatment, the Maastricht III consensus determined the first-line, second-line and reserve therapy regimen.

The first-line regimen - standard triple therapy, Tatyana Lvovna has already spoken about it - includes proton pump blockers in a double dose. This is Rabeprazole, but before we wrote Pariet because we had no other drugs. Tatyana Lvovna said that now we already have other analogues of Rabeprazole, and in particular, Ontime - in combination with Clarithromycin and Amoxicillin. This regimen is prescribed if resistance to Clarithromycin in a given region does not exceed 20%.

As for the second-line regimen, proton pump blockers are used here in a double dose - Tetracycline, Metronidazole and bismuth preparations. It was specifically emphasized that this regimen is also effective in cases of Metronidazole-resistant patients.

Also, the Maastricht III consensus found that the effectiveness of a 14-day eradication course is approximately 10% higher on average than a seven-day course.

Finally, if first- and second-line regimens are ineffective, the physician has several options at his disposal for further action. This is to increase the dose of Amoxicillin to three grams per day in combination with an even doubled dose - here it’s not 4 times a day, but four times - say, if it’s the same Rabeprazole, it’s not 40 milligrams, but 80 milligrams per day for 14 days .

It was proposed to replace Metronidazole in quadruple therapy regimens with Furazolidone and use the antibiotics Rifabutin or Levofloxacin in combination with proton pump blockers and Amoxicillin. The best option for a backup regimen is an individual selection of antibiotics after determining the sensitivity of the cultured microorganisms.

What is the role of proton pump inhibitors in eradication regimens? First of all, they have an independent anti-Helicobacter effect: by reducing the volume of gastric secretion, they increase the concentration of antibiotics in the gastric juice, and, most importantly, create the optimal pH for the action of antibiotics.

Tatyana Lvovna has already spoken about the importance of Rabeprazole. According to the recommendations of the Russian Gastroenterological Association, back in 2000, Rabeprazole was recognized as the most preferable for the treatment of patients with peptic ulcer disease. What are its advantages: unlike other proton pump inhibitors, it does not interact with the cytochrome P450 system in the liver, and accordingly, all possible side effects associated with drug interactions are removed. The effect of Rabeprazole develops more quickly and is more pronounced. Rabeprazole is more effective than other proton pump inhibitors in inhibiting the growth of Helicobacter pyloricus. And it was shown at one time that a seven-day course of eradication with Rabeprazole is more effective than a ten-day course of eradication with Omeprazole.

It is shown here that Rabeprazole in all eradication regimens with Metronidazole, Amoxicillin, Clarithromycin has the lowest minimum inhibitory concentration, that is, it is most active against Helicobacter pyloricus compared to other proton pump inhibitors.

It is shown here that the minimum inhibitory concentration of Rabeprazole is 64 times less than that of Omeprazole. In addition, Rabeprazole enhances the production of mucus and mucin, providing protection to the mucous membrane. And here is the slide that Tatyana Lvovna already showed: Ontime is a new form, a new variant, a new analogue of Rabeprazole - in its pharmacodynamic and pharmacogenetic properties it is completely similar to Pariet.

What has changed in the years since the Maastricht III consensus was adopted? Firstly, two new eradication schemes have become widespread: sequential therapy and the so-called concomitant therapy. What is the point of these schemes? The main challenge is to overcome the rapidly growing resistance to Clarithromycin. The sequential scheme involves two five-day courses: at the beginning with a combination of proton pump inhibitors and Amoxicillin, the second five days is a combination of proton pump inhibitors with Clarithromycin and Metronidazole.

At first, the results of this scheme were perceived with distrust by the gastroenterology community, if only because all the work came from Italy, so there was no confirmation. But by 2011, similar results were obtained in European countries and the United States of America, so at present this scheme is truly considered highly effective.

As for the concomitant eradication regimen, this is a quadruple therapy regimen with an additional antibacterial drug. This is quadruple therapy without bismuth preparations. This is a standard triple therapy, to which another antibacterial drug is added. Most often it is Metronidazole. You see that the effectiveness of concomitant therapy is also high and reaches 90%.

The use of regimens with Levofloxacin has become widespread. In the beginning, a daily dose of 500 milligrams was used, currently - 1000 milligrams. Levofloxacin was prescribed instead of Clarithromycin in standard and sequential therapy regimens. However, the rapidly growing resistance to Levofloxacin immediately turned out to be a serious problem.

So, what did the Maastricht IV consensus come to? You see: 45 experts from 26 countries discussed various provisions - indications for eradication, diagnosis and treatment, cancer prevention and screening. A decision was considered adopted if more than 70% of those present voted for it, and you see three issues that were discussed.

So, as for functional dyspepsia. In general, in relation to the indications, probably nothing new was positioned in comparison with Maastricht-III. In countries with a high prevalence of Helicobacter pyloric infection, eradication is indicated for patients with functional dyspepsia. Here I write the diagnosis “chronic gastritis with clinical symptoms” in parentheses, because in our country most doctors, especially general practitioners, still use the clinical diagnosis “chronic gastritis”.

It was reconfirmed that eradication of Helicobacter pyloricus is not a cause of GERD, does not cause exacerbation of GERD, and does not affect the effectiveness of its treatment. However, it has been noted that there is a negative correlation between Helicobacter pyloricus infection, GERD, Barrett's esophagus and the development of esophageal adenocarcinoma.

As for non-gastroenterological diseases, eradication, as we have already said, is carried out in patients with autoimmune idiopathic thrombocytopenia and idiopathic iron deficiency anemia. Eradication may be effective for B12 deficiency anemia, but the level of evidence is still low.

Like the Maastricht-III consensus, Maastricht-IV found that Helicobacter pyloric increases the risk of developing NSAID gastropathy, therefore eradication is indicated for patients receiving these drugs for a long time. Eradication can reduce the severity of atrophy in the fundus of the stomach, which is very important in terms of cancer prevention, but does not affect the severity of intestinal metaplasia.

When it comes to diagnostics, the two main tests—the urease test and stool antigen testing—are equivalent in accuracy. As for the serological method, this is the only method whose results are not affected by the contamination of Helicobacter pyloricus (I mean the degree), the presence of mucosal atrophy, or the use of antisecretory drugs and antibiotics. But it was specifically emphasized that in order to obtain accurate results, it is necessary to determine only antibodies of the immunoglobulin G class.

If the patient is receiving proton pump inhibitors, they should be stopped two weeks before testing. If proton pump inhibitors cannot be discontinued, then a serological method must be used. As for the microbiological method, a culture of microorganisms must be obtained from patients with ineffective treatment for individual selection of drugs.

The new thing introduced into diagnostics by the Maastricht-IV provision is the introduction of molecular methods into clinical practice. For example, various real-time chain reactions, which are used to detect resistance to Clarithromycin.

The Maastricht IV consensus has reduced the number of eradication regimens that can currently be used. What's left? This is a standard triple regimen (7 or more days), this is a sequential regimen (10 days), this is a quadruple therapy regimen with bismuth preparations (also 10 days), this is the accompanying regimen that we talked about (10 days) and the only reserve regimen with Levofloxacin ( also lasting at least 10 days).

How to apply these schemes? The use of regimens is determined by clarithromycin resistance rates in a given region. If resistance does not exceed 10%, then standard triple therapy can be prescribed as a first-line regimen without prior testing. If resistance rates to Clarithromycin range from 10 to 50%, then preliminary testing for sensitivity to this antibiotic is necessary.

What do we see in Western European countries? The same sensitivity in Austria and Hungary shows that these two countries were once one country. But at the same time, we see very low sustainability rates in, say, Ireland and Germany.

As for our country, you see: various studies conducted in St. Petersburg, Smolensk, Nizhny Novgorod and Novosibirsk showed that resistance to Clarithromycin in our country is less than 10%. This means that we use recommendations for regions with low clarithromycin resistance. In this case, standard triple therapy remains the first-line regimen. Sequential therapy or quadruple therapy with bismuth preparations can be used. As a second-line regimen - a quadruple therapy regimen with bismuth drugs or triple therapy with Levofloxacin. And the third-line regimen is based on individual determination of sensitivity to antibiotics.

It was again confirmed that doubling the dose of proton pump inhibitors increases its effectiveness by approximately 5%. For the first time, it was officially stated that the use of probiotics together with antibiotics in eradication regimens as adjuvant therapy can increase effectiveness. We have previously widely prescribed probiotics, in particular Enterol, but mainly to reduce the risk of side effects and intestinal disorders. But it turned out that it is possible to increase the effectiveness of eradication in this way.

Monitoring of effectiveness, as before, must be carried out 4 weeks after eradication, using a urease breath test or determination of antigen in stool.

As for the connection between pyloric Helicobacter and stomach cancer, Tatyana Lvovna spoke about this in great detail, that eradication prevents the development of stomach cancer and its recurrence after surgical treatment. But the best results are achieved when eradication is carried out before severe atrophy and intestinal metaplasia.

Tatyana Lvovna has already spoken about the recommendations of the Russian Gastroenterological Association, made on the basis of Maastricht-IV, taking into account the specifics of our country. Considering that resistance to Clarithromycin in Russia does not exceed 10%, standard triple therapy remains the first-line regimen. There are measures that can increase its effectiveness: increasing the dose of proton pump inhibitors, increasing the duration of treatment and adding bismuth preparations, in particular tripotassium dicitrate.

As a variant of the first-line eradication regimen, classical four-component therapy can be used. This regimen can also be used as a second-line treatment regimen when standard triple therapy is ineffective. And triple therapy with Levofloxacin can be prescribed after an unsuccessful attempt at eradication with a standard triple therapy regimen and quadruple therapy with bismuth tripotassium dicitrate.

So, to summarize once again, the first-line regimen in our country is standard triple therapy and quadruple therapy with bismuth preparations, the second-line regimen is quadruple therapy with bismuth preparations and triple therapy with Levofloxacin, and the third-line regimen is selected individually, taking into account the results of determining antibiotic resistance.

Thus, to summarize, we can say that the main indications for eradication of Helicobacter pyloric infection remain the same. The choice of eradication regimen depends on the level of resistance of Helicobacter pyloric strains to Clarithromycin. The main eradication regimens at present are the standard triple regimen and the quadruple therapy regimen with bismuth tripotassium dicitrate. As for sequential and concomitant therapy, you noticed that we do not yet recommend them in our Russian recommendations, since we have no experience of the effectiveness of this regimen in our country. When we get the first results, then we will discuss the place of these schemes.

(0)

02.04.2017

Over the past few years, gastroenterologists around the world have been awaiting updated guidelines for the diagnosis and treatment of infection. Helicobacter pylori (HP). In 2016, the V Conciliation Conference was held in Florence; 43 experts from 24 countries took part in its work. This time, 5 working groups were formed that considered topical issues in the main areas: indications for therapy, diagnosis, treatment, prevention, HP and gastric microbiota.

Until now, the main provisions of these recommendations were available only in electronic form on the Gut magazine website. The final version of the Maastricht V/Florence conciliation document was published in the January issue of this authoritative international publication. We invite practicing gastroenterologists to familiarize themselves with its summary.

Working group 1: Indications for treatment/relationships

Statement 1. HP-associated gastritis is an infectious disease regardless of symptoms and complications.

Level of Evidence (LE): 1B; degree of validity of the recommendation (SOR): A.

Statement 2. The “test and treat” strategy is optimal for unstudied dyspepsia. This approach can be adjusted based on regional prevalence HP, cost/effectiveness ratios; it is not used in patients with the so-called. anxiety symptoms and elderly patients.

UD: high; SOR: strong.

Statement 3. The feasibility of using a strategy involving endoscopic examination in patients with dyspeptic complaints should be considered, especially if the prevalence of HP in the population is low.

Statement 4. HP-associated gastritis can cause both an increase and a decrease in the secretion of hydrochloric acid. Treatment may completely or partially reverse these effects.

UD: high; SOR: weak.

Statement 5. HP-associated gastritis is a separate nosological entity that can provoke the appearance of dyspeptic complaints in some patients. Eradication HP helps relieve symptoms of dyspepsia for a long time in approximately 10% of patients compared with placebo or acid suppressive therapy.

UD: average; SOR: strong.

Statement 6. The wording “ HP-associated gastritis” up to objective confirmation of the diagnosis, in this case a diagnosis of functional dyspepsia can be made.

UD: high; SOR: strong.

Statement 7. Taking aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of developing peptic ulcers in people infected with HP. Anticoagulants (aspirin, coumarins, newer oral anticoagulants) increase the likelihood of bleeding in patients with peptic ulcers.

UD: high; SOR: strong.

Statement 8. Patients with a history of peptic ulcers who are taking aspirin and NSAIDs should be evaluated for HP.

UD: average; SOR: strong.

Statement 9. Long-term therapy with proton pump inhibitors (PPIs) alters topography HP- associated gastritis. Eradication HP helps cure gastritis in people taking PPIs for a long time.

UD: low; SOR: strong.

Statement 10. There is evidence linking HP with iron deficiency anemia of unknown etiology, idiopathic thrombocytopenic purpura, vitamin B12 deficiency. For these diseases, research should be carried out to identify HP and prescribe eradication therapy.

UD: very low; SOR: weak.

Statement 11. Positive and negative relationships between HP and various extragastroduodenal pathologies. A cause-and-effect relationship between the associations has not been proven.

UD: average; SOP: average.

Statement 12. Eradication HP is the first-line therapy for MALToma localized in the stomach.

UD: average; SOR: strong.

2nd working group: Diagnostics

Statement 1. The urease breath test is a well-studied and most commonly recommended non-invasive test method in the context of the test and treat strategy. Antigen detection may also be used HP in stool using monoclonal antibodies (fecal antigen test). Serological tests should only be used after their diagnostic accuracy has been confirmed (validation). Therefore, it is advisable to avoid the use of rapid (“office”) serological tests with whole blood.

UD: 2a; SOR: V.

Statement 2. PPIs should be discontinued at least 2 weeks before testing for the presence of HP. Antibiotics and bismuth preparations should be discontinued at least 4 weeks before the examination.

UD: 2b; SOR: V.

Statement 3. In clinical practice, if there are indications for endoscopy and no contraindications for taking a biopsy, a rapid urease test is recommended as a first-line diagnostic test. If the result is positive, treatment can be started immediately.
One biopsy should be obtained from the body of the stomach and another from the antrum. The rapid urease test should not be used to confirm the effectiveness of eradication. HP after treatment.

UD: 2b; SOR: V.

Statement 4. For diagnostics HP-associated gastritis requires a minimum standard biopsy: two biopsies from the antrum (on the greater and lesser curvature, 3 cm proximal to the pylorus) and two biopsies from the middle of the body of the stomach. An additional biopsy from the gastric notch area is recommended to diagnose precancerous changes.

UD: 2b; SOR: V.

Statement 5. In most cases the infection HP can be diagnosed by examining gastric biopsies using histochemical staining alone. In cases of chronic (active) gastritis, in which HP not determined histochemically; immunohistochemical detection method can be used as an auxiliary test HP. If histology is normal, immunohistochemical staining should not be performed.

UD: 2b; SOR: A.

Statement 6. It is recommended to test clarithromycin susceptibility when a standard clarithromycin eradication regimen is being considered as first-line therapy, except in populations or regions with proven low levels of clarithromycin resistance (<15%). Этот тест может быть выполнен с использованием стандартной методики (антибиотикограммы) после культурального исследования или при помощи молекулярного тестирования непосредственно в гастробиоптате.

UD: very low; SOR: weak.

Statement 7. If endoscopic examination is performed after first-line therapy has failed, culture and standard antibiotic susceptibility testing are recommended to guide therapy, unless bismuth quadruple therapy is planned.

UD: low; SOR: strong.

Statement 8. Highly accurate, locally validated serological tests can be used for non-invasive diagnosis HP.

UD: 2a; SOR: V.

Statement 9. According to available data, serological determination of pepsinogen levels is considered the most effective non-invasive test to study the status (atrophic vs non-atrophic) of the gastric mucosa. The pepsinogen I/pepsinogen II ratio cannot be used as a biomarker for gastric neoplasia.

UD: 2a; SOR: A.

Statement 10. Urease breath test is the best way to confirm eradication HP, an alternative to this method is the monoclonal fecal antigen test. These studies should be performed 4 weeks (minimum) after completion of eradication therapy.

UD: high; SOR: strong.

Statement 11. Eradication HP leads to a significant reduction in the severity of gastritis and gastric atrophy, but not intestinal metaplasia.

UD: average; SOR: strong.

3rd working group: Treatment

Statement 1. Resistance is increasing in most countries of the world HP to antibacterial drugs.

UD: average; SOR: strong.

Statement 2. A three-component regimen with a PPI and clarithromycin should not be used without prior antibiotic susceptibility testing in regions where the level of clarithromycin resistance exceeds 15%.

UD: very low; SOR: weak.

Statement 3. For any treatment regimen, the level of eradication can be predicted if the effectiveness of treatment of sensitive and resistant strains is known, as well as the level of resistance in the population.

In patients who have previously taken one of the key antibiotics, it is recommended to determine the probable antibiotic resistance (despite the low level of resistance in the population). The results obtained after determining sensitivity allow us to achieve significant progress both at the population and individual levels.

UD: low; SOR: strong.

Statement 4. In regions with high (>15%) resistance to clarithromycin, quadruple therapy with bismuth or simultaneous quadruple therapy without bismuth (PPI, amoxicillin, clarithromycin, nitroimidazole) is recommended. In areas with high dual resistance to clarithromycin and metronidazole, a quadruple bismuth regimen is recommended as first-line therapy (Figure).

UD: low; SOR: strong.

Statement 5. The duration of bismuth quadruple therapy should be increased to 14 days, unless a 10-day regimen has proven regionally effective.

UD: very low; SOR: weak.

Statement 6. Resistance to clarithromycin neutralizes the effectiveness of triple and sequential therapy, resistance to metronidazole reduces the effectiveness of sequential therapy, double resistance to clarithromycin and metronidazole negatively affects the effectiveness of sequential, hybrid and simultaneous therapy.

UD: average; SOR: strong.

Statement 7. At present, preference should be given not to a four-component regimen without bismuth, but to simultaneous therapy (parallel PPIs, amoxicillin, clarithromycin, nitroimidazole), because it is the most effective way to overcome antibiotic resistance.

UD: average; SOR: strong.

UD: very low; SOR: weak.

Statement 9. In regions with low levels of clarithromycin resistance, the recommended empirical first-line regimen is a three-drug regimen. Quadruple therapy with bismuth is considered an alternative treatment method.

UD: high; SOR: strong.

Statement 10. The use of PPIs in high doses (2 times a day) increases the effectiveness of triple therapy. Prescription of esomeprazole and rabeprazole may be preferable in Europe and North America, where the number of rapid metabolizers of PPIs is quite large.

UD: low; SOR: weak.

Statement 11. The duration of triple therapy with a PPI and clarithromycin should be extended to 14 days, unless shorter regimens have proven regionally effective.

UD: low; SOR: weak.

Statement 12. If quadruple therapy with bismuth is ineffective, a three- or four-component regimen with a fluoroquinolone may be recommended. In case of high resistance to fluoroquinolones, an alternative may be a combination of bismuth with other antibiotics or rifabutin.

UD: very low; SOR: weak.

Statement 13. If triple therapy with a PPI and clarithromycin is ineffective, a four-component regimen with bismuth or a three-/quadruple regimen with a fluoroquinolone is recommended as second-line therapy.

UD: low; SOR: weak.

Statement 14. If a four-component regimen without bismuth is ineffective, quadruple therapy with a bismuth drug or a three-/quadruple regimen with a fluoroquinolone is recommended.

UD: very low; SOR: weak.

Statement 15. In case of ineffectiveness of second-line therapy, it is recommended to conduct a cultural study to determine sensitivity to antibiotics or molecular determination of the resistance genotype for subsequent correction of therapy.

UD: very low; SOR: weak.

Statement 16. In case of ineffectiveness of first-line (using clarithromycin) and second-line (quadruple regimen with bismuth) therapy, it is recommended to use a treatment regimen with a fluoroquinolone. In regions with proven high levels of resistance to fluoroquinolones, the advisability of prescribing bismuth in combination with various antibiotics or salvage therapy with rifabutin should be considered.

UD: very low; SOR: weak.

Statement 17. In case of ineffectiveness of therapy of the first (three- or four-component regimen without bismuth) and second (regime with fluoroquinolone) line, it is recommended to prescribe quadruple therapy with a bismuth drug.

UD: very low; SOR: weak.

Statement 18. In case of ineffectiveness of first-line therapy (quadruple therapy with bismuth) and second line (fluoroquinolone regimen), it is recommended to use a three-/four-component regimen with clarithromycin. An alternative option may be to prescribe a bismuth drug in combination with various antibiotics.

UD: very low; SOR: weak.

Statement 19. In patients allergic to penicillin drugs in areas with low resistance to clarithromycin, a combination of PPI/clarithromycin/metronidazole may be prescribed as first-line therapy; in areas with high resistance to clarithromycin, preference should be given to quadruple therapy with a bismuth preparation.

UD: very low; SOR: weak.

Statement 20. Salvage therapy: A fluoroquinolone regimen can be used as second-line empiric salvage therapy in the presence of penicillin allergy.

UD: very low; SOR: weak.

Working Group 4: Prevention/Public Health

Statement 1. Hp infection is considered the main etiological factor of gastric cancer.

UD: 1a; SOR: A.

Statement 2. Infection HP is also a risk factor for neoplastic lesions of the proximal stomach, provided that adenocarcinoma of the esophagus and esophagogastric junction is completely excluded.

UD: 2s; SOR: V.

Statement 3. Eradication HP reduces the risk of developing stomach cancer.

UD: low; SOP: average.

Statement 4. The influence of environmental factors is of secondary importance compared to the influence of infection HP.

UD: 2a; SOR: A.

Statement 5. Eradication HP eliminates the inflammatory process, and early treatment prevents the progression of precancerous conditions.

UD: 1b; SOR: V.

Statement 6. Eradication HP promotes the reverse development of gastric atrophy in the absence of intestinal metaplasia, and also prevents the progression of pretumor changes into neoplastic pathology in many patients.

UD: 1b; SOR: V.

Statement 7. The risk of developing gastric cancer is reduced more effectively if eradication therapy is carried out before the development of atrophy and intestinal metaplasia.

UD: 2b; SOR: V.

Statement 8. Eradication HP for the purpose of preventing gastric cancer, it is cost-effective in populations with a high risk of developing this pathology.

UD: average; SOR: strong.

Statement 9. In addition to the prevention of stomach cancer, eradication HP provides additional clinical and economic benefits; its feasibility should be considered in all populations.

UD: low; SOR: weak.

Statement 10. In populations at high risk of developing gastric cancer, a screen and treat strategy is recommended. HP.

UD: average; SOR: strong.

Statement 11. In populations at moderate to low risk of developing gastric cancer, a screen-and-treat strategy should be considered. HP- associated gastritis.

UD: low; SOR: weak.

UD: average; SOR: strong.

Statement 13. Endoscopic screening should be considered as an alternative option in populations and individuals at high risk of developing gastric cancer.

UD: very low; SOR: weak.

Statement 14. The progression of pretumor changes (atrophy/intestinal metaplasia) requires dynamic endoscopic monitoring.

UD: very low; SOP: average.

Statement 15. Public awareness campaigns on gastric cancer prevention should be encouraged.

UD: D; SOR: A.

Statement 16. Mass eradication using a screen-and-treat strategy and the administration of widely used antibiotics may provoke the emergence of additional resistance and selection pressure on pathogens other than HP.

UD: 1b; SOR: A.

Statement 17. An effective vaccine against HP, will probably be one of the best preventive measures against this bacterium.

UD: 1b; SOR: A.

5th working group: HP and gastric microbiota

Statement 1. Except HP The gastric microbiota contains other microorganisms.

UD: 2s; SOR: V.

Statement 2. Composition of healthy gastric microbiota and mode of interaction HP with these microorganisms have not been fully studied.

UD: 5; SOR: V.

Statement 3. Other components of the gastric microbiota may play a significant role in the development of Hp-associated diseases.

UD: low; SOR: weak.

Statement 4. Strains Helicobacter, different from HP, can cause stomach diseases in humans.

UD: 2s; SOR: V.

Statement 5. Eradication HP may have a negative impact on the state of healthy intestinal microbiota, causing short-term clinical consequences.

UD: 2s; SOR: V.

Statement 6. Patients with an undeveloped or unstable gut microbiota should undergo eradication therapy cautiously HP to avoid long-term clinical consequences.

UD: 2s; SOR: V.

Statement 7. Eradication HP with the use of antibacterial drugs can cause the emergence of components of the intestinal microbiota that are resistant to antibiotics.

UD: 2s; SOR: V.

Statement 8. Additional studies are needed to examine the long-term effects of eradication therapy on the composition of the intestinal microbiota.

UD: 2s; SOR: V.

Statement 9. Only a few probiotics have proven their ability to effectively reduce the severity of gastrointestinal side effects caused by eradication therapy HP. Specific probiotic strains should be selected only based on proven clinical effectiveness.

06.01.2020 Gastroenterology Leaked bowel syndrome: etiology, pathogenesis and treatment

National scientific-practical conference with international participation “Inflammatory and functional diseases of the intestines”, which took place on November 21-22 in Kiev, attracted a large audience of experts from Ukraine and abroad zha. During the visit, participants will be able to get acquainted with current views on the diagnosis and treatment of the most widespread pathologies of the intestinal tract (CTT). ...

03.01.2020 Gastroenterology The condition of the subslantum in patients with metabolic disorders

The pace of everyday life leads to the early onset of metabolic disorders, which most often develop as a result of insulin resistance (IR), and in fact, patients not only with obvious risk factors for the development of the disease are treated before treatment. b, and with pathological conditions that have already developed. A metabolically abnormal phenotype is formed as a result of factors such as low or daily physical activity, smoking, obesity, dyslipidemia, stress....

02.01.2020 Gastroenterology Inflammatory and functional diseases of the intestines: in the center of respect – abdominal pain syndrome

At the end of the meeting, local doctors and international specialists in gastroenterology presented a current look at the problems of treatment of the most widespread diseases of the intestinal tract (GCT). The audience was particularly impressed by the evidence that the management of functional intestinal diseases followed the principles of evidence-based medicine....

A review article devoted to one of the leading problems of gastroenterology - the choice of a proton pump inhibitor (PPI) in order to increase the effectiveness of Helicobacter pylori eradication therapy. Based on the analysis of the results of experimental and clinical studies, it was concluded that rabeprazole has a number of distinctive features among other PPIs, which determine the high feasibility of its choice for successful eradication therapy. Among them - the maximum effect after the first dose; the dose of rabeprazole is lower compared to the doses of other PPIs (highest pharmacological activity); rabeprazole more reliably suppresses the secretion of hydrochloric acid, because its destruction in the liver does not depend on the presence of polymorphisms of the cytP450 gene, and the effects of rabeprazole are predictable; rabeprazole is safe for patients taking multiple medications at the same time; rabeprazole has a number of pleiotropic effects. A significant argument in favor of prescribing generics has always been their lower cost compared to the cost of the original drug, but they do not always have the proper biological, pharmaceutical and therapeutic equivalence to the original drug. Currently, doctors and their patients are offered Razo®, produced by Dr. Reddy's, a generic rabeprazole that combines the high clinical effectiveness of the original drug, safety of use, economic accessibility and high production standards in accordance with GMP criteria, registered FDA Orange Book Category AB.

Keywords: eradication of H. pylori, proton pump inhibitors, rabeprazole, generic, Razo®.

For quotation: Kazyulin A.N., Goncharenko A.Yu. Choice of proton pump inhibitor during Helicobacter pylori eradication therapy. Maastricht V // Russian Journal of Journalism. 2017. No. 10. pp. 712-717

The choice of proton pump inhibitor in the eradication therapy of Helicobacter pylori infection. Maastricht V
Kazyulin A.N., Goncharenko A.Yu.

Moscow State Medical Dental University named after A.I. Evdokimov

The review is devoted to one of the main problems in gastroenterology - the choice of proton pump inhibitor (PPI) in order to increase the effectiveness of eradication therapy of Helicobacter pylori. Based on the analysis of the results of experimental and clinical studies, it has been concluded that rabeprazole has a number of distinctive features among the other PPIs that determine the high feasibility of its choice for successful eradication therapy. Among them - the maximum effect after the first intake; the dose of rabeprazole is lower in comparison with the doses of other PPIs (the highest pharmacological activity); rabeprazole reliably suppresses the secretion of hydrochloric acid, because its destruction in the liver does not depend on the presence of polymorphisms of the cytP450 gene, and the effects of rabeprazole are predictable; rabeprazole is safe for patients taking several drugs at the same time; rabeprazole has a number of pleiotropic effects. The lower cost of generics compared to the cost of the original drug has always been an important reason for their appointment, but they do not always have the proper biological, pharmaceutical and therapeutic equivalence to the original drug. At present, doctors and their patients are offered the Razo® generic rabeprazole produced by Dr Reddy's®, which combines the high clinical efficacy of the original drug, safety of use, economic accessibility and high production culture in accordance with GMP criteria, registered FDA in the "Orange Book" in the AB category.

Key words: H. pylori eradication, proton pump inhibitors, rabeprazole, generic, Razo®.
For citation: Kazyulin A.N., Goncharenko A.Yu. The choice of proton pump inhibitor in the eradication therapy of Helicobacter pylori infection. Maastricht V // RMJ. 2017. No. 10. P. 712–717.

An article devoted to the problem of choosing a proton pump inhibitor

Literature

1. Maev I.V., Samsonov A.A., Andreev D.N. Stomach diseases. M.: GEOTAR-Media, 2015. 976 p. .
2. Maev I.V., Samsonov A.A., Andreev D.N. Helicobacter pylori infection. M.: GEOTAR-Media, 2016. 256 p. .
3. Maev I.V., Andreev D.N., Kucheryavyi Yu.A., Dicheva D.T., Zaborovsky A.V., Partsvania-Vinogradova E.V. Diagnosis and treatment of Helicobacter pylori infection: provisions of the Maastricht V consensus (2015) // Archives of Internal Medicine. 2017. No. 2. pp. 85–94.
4. Kalinin A.V. Chronic gastritis. Gastroenterology and hepatology: diagnosis and treatment. M.: Miklos, 2007. pp. 59–92.
5. Ford A.C., Axon A.T. Epidemiology of Helicobacter pylori infection and public health implications // Helicobacter. 2010. Vol. 15(1). P. 1–6.
6. Tonkic A., Tonkic M., Lehours P., Megraud F. Epidemiology and diagnosis of Helicobacter pylori infection // Helicobacter. 2012. Vol. 17(1). P. 1–8.
7. Lazebnik L.B., Vasiliev Yu.V., Shcherbakov P.L. and others. Helicobacter pylori: prevalence, diagnosis and treatment // Experimental and clinical gastroenterology. 2010. No. 2. P. 3–7.
8. German S.V., Zykova I.E., Modestova A.V., Ermakov N.V. Prevalence of H. pylori infection among the population of Moscow // Ros. magazine gastroenterology, hepatology, coloproctology. 2010. No. 2. pp. 25–30.
9. Baryshnikova N.V., Tkachenko E.I., Uspensky Yu.P. Modern aspects of the problem of Helicobacter pylori-associated diseases // Gastroenterology. Diseases of adults / under general. ed. L.B. Lazebnik, P.L. Shcherbakova. M.: MK, 2011. P. 103.
10. Tsukanov V.V., Khomenko O.V., Rzhavicheva O.S. et al. Prevalence of Helicobacter pylori and GERD in Mongoloids and Caucasians of Eastern Siberia // Ros. magazine gastroenterology, hepatology, coloproctology. 2009. No. 19(3). pp. 38–41.
11. Ivashkin V.T., Sheptulin A.A., Lapina T.A. Chronic gastritis caused by Helicobacter pylori infection: diagnosis, clinical significance, prognosis. A manual for doctors. RGA. M., 2009. 23 p. .
12. Loranskaya I.D., Rakitskaya L.G., Mamedova L.D. Problems of treatment of Helicobacter pylori infection // RMZh. 2013. No. 31. pp. 1638–1641.
13. Malfertheiner P., Megraud F., O’Morain C.A. et al. on behalf of the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection—the Maastricht V. Florence Consensus Report // Gut. 2017. Vol. 66(1). P. 6–30.
14. Kucheryavyi Yu.A., Barkalova E.V. The severity of the acid-suppressive effect of proton pump inhibitors and the effectiveness of modern eradication regimens // Farmateka. 2013. No. 10. pp. 11–17.
15. Scott D., Weeks D., Melchers K. et al. The life and death of Helicobacter pylori // Gut 1998. Vol. 43(1). P. 56–60.
16. Sugimoto M., Furuta T., Shirai N. et al. Evidence that the degree and duration of acid suppression are related to Helicobacter pylori eradication by triple therapy // Helicobacter. 2007. Vol. 12(4). P. 317–323.
17. Kazyulin A.N., Samsonov A.A., Pavleeva E.E. Features of choosing a proton pump inhibitor for the treatment of acid-related diseases in a clinician’s practice // Consilium Medicum. 2014. No. 08. pp. 9–13.
18. Maev I.V., Andreev D.N., Dicheva D.E., Goncharenko A.Yu. Pharmacotherapeutic aspects of the use of proton pump inhibitors // Medical Bulletin of the Ministry of Internal Affairs. 2013. No. 3(64). pp. 9–14.
19. Maev I.V., Andreev D.N., Goncharenko A.Yu., Dicheva D.T. Proton pump inhibitors as a basis for the treatment of acid-related diseases // Reference. polyclinic doctor 2013. No. 7–8. pp. 42–44.
20. Blume H., Donat F., Warnke A., Schug B.S. Pharmacokinetic drug interactions involving proton pump inhibitors // RMJ. 2009. No. 9. P. 622.
21. Samsonov A.A. Proton pump inhibitors are the drugs of choice in the treatment of acid-related diseases // Pharmateka. 2007. No. 6. P. 10–15.
22. Zakharova N.V., Bakulin I.G., Simanenkov V.I., Maslygina A.A. Review of recommendations of the fifth Maastricht/Florence consensus on the diagnosis and treatment of Helicobacter pylori infection // Farmateka. 2016. No. 5. P. 8–26.
23. Villoria A., Garcia P., Calvet X. et al. Meta-analysis: high-dose proton pump inhibitors vs. standard dose in triple therapy for Helicobacter pylori eradication // Aliment Pharmacol Ther. 2008. Vol. 28. P. 868–877.
24. Vallve M., Vergara M., Gisbert J.P. et al. Single vs. double dose of a proton pump inhibitor in triple therapy for Helicobacter pylori eradication: a meta-analysis // Aliment Pharmacol Ther. 2002. Vol. 16. P. 1149–1156.
25. Molina-Infante J., Gisbert J.P. Optimizing clarithromycin-containing therapy for Helicobacter pylori in the era of antibiotic resistance // World J Gastroenterol. 2014. Vol. 20. P. 10338–10347.
26. Furuta T., Ohashi K., Kamata T. et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer // Ann Intern Med. 1998. Vol. 129. P. 1027–1030.
27. Sharara A.I. Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication // Expert Rev Anti Infect Ther. 2005. Vol. 3. P. 863–870.
28. De Francesco V., Ierardi E., Hassan C. et al. Helicobacter pylori therapy: present and future // World J Gastrointest Pharmacol Ther. 2012. Vol. 3. P. 68–73.
29. Tang H.L., Li Y., Hu Y.F. et al. Effects of CYP2C19 loss-of-function variants on the eradication of H. pylori infection in patients treated with proton pump inhibitor-based triple therapy regimens: a meta-analysis of randomized clinical trials // PLoS One. 2013. Vol. 8. P. e62162.
30. Padol S., Yuan Y., Thabane M. et al. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis // Am J Gastroenterol. 2006. Vol. 101. P. 1467–1475.
31. Zhao F., Wang J., Yang Y. et al. Effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis // Helicobacter. 2008. Vol. 13. P. 532–541.
32. McNicholl A.G., Linares P.M., Nyssen O.P. et al. Meta-analysis: esomeprazole or rabeprazole vs. first-generation pump inhibitors in the treatment of Helicobacter pylori infection // Aliment Pharmacol Ther. 2012. Vol. 36. P. 414–425.
33. Lopina O.D., Maev I.V. Family of proton pump inhibitors of the gastric mucosa // Kharkiv Surgical School. 2004. No. 4. P. 123.
34. Maev I.V., Trukhmanov A.S. Clinical and functional assessment of the effectiveness of rabeprazole, omeprazole and esomeprazole in patients with non-erosive reflux disease associated with bronchial asthma // RZHGGK. 2004. No. 5. pp. 22–30.
35. Ivashkin V.T. and others. Prevention and treatment of chronic diseases of the upper gastrointestinal tract / 2nd ed., revised and additional. M.: MEDpress-inform, 2013. 152 p. .
36. Ohning G.V., Walsh J.H., Pisegna J.R. et al. Rabeprazole is superior to omeprazole for the inhibition of peptone meal-stimulated gastric acid secretion in Helicobacter pylori-negative subjects // Aliment Pharmacol Ther. 2003. Vol. 17(9). P. 1109–1114.
37. Pantoflickova D., Dorta G., Ravic M. et al. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors // Aliment Pharmacol Ther. 2003. Vol. 17(12). P. 1507–1514.
38. Maliti R., Jaida J., Israel P.L. Rabeprazole and esomeprazole in mild-to-moderate erosive gastroesophageal reflux disease: A comparative study of efficacy and safety // J. Pharmacol. Pharmacother. 2011. Vol. 2(3). P. 150–157.
39. Kareva E.N. Rabeprazole through the prism of “metabolism - effectiveness” // RMJ. 2016. No. 17. pp. 1172–1176.
40. Pasechnikov V.D. Keys to choosing the optimal proton pump inhibitor for the treatment of acid-dependent diseases // RZHGGK. 2004. No. 3. pp. 32–39.
41. Marelli S., Pace F. Rabeprazole for the treatment of acid-related disorders // Expert Rev Gastroent Hepatol. 2012. Vol. 6(4). P. 423–435.
42. Bardhun K. Intermittent and On-Demand Use of Proton Pump Inhibitor in the Management of Symptomatic Gastroesophagcal Reflux Disease // Amer. J. Gastroenterol. 2003. Vol. 98. P. 40–48.
43. Ishizaki T., Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole // Aliment Pharmacol Ther. 1999. Vol. 13(3). P. 27–36.
44. Horn J. Review article: relationship between the metabolism and efficacy of proton pump inhibitors - focus on rabeprazole // Aliment Pharmacol Ther. 2004. Vol. 20(6). P. 11–19.
45. Adachi K., Katsube T., Kawamura A. et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Aliment // Pharmacol. Ther. 2000. No. 14(10). P. 1259–1266.
46. ​​Maev I.V., Andreev D.N., Dicheva D.T. Possibilities for optimizing eradication therapy for Helicobacter pylori infection in modern clinical practice // Ther. archive. 2017. No. 2. pp. 84–90.
47. Horai Y., Kimura M., Furuie H. et al. Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP 2C19 genotypes // Aliment Pharmacol Ther. 2001. Vol. 15(6). P. 793–803.
48. Kita T., Sakaeda T., Baba T. et al. Different contribution of CYP 2C19 in the in vitro metabolism of three proton pump inhibitors // Biol Pharm Bull. 2003. Vol. 26(3). P. 386–390.
49. Goldstein J.A. Clinical relevance of genetic polymorphisms in the human CYP 2C subfamily // Br J Clin Pharmacol. 2001. Vol. 52(4). P. 349–355.
50. Desta Z., Zhao X., Shin J.G., Flockhart D.A. Clinical significance of the cytochrome P450 2C19 genetic polymorphism // Clin Pharmacokinet. 2002. Vol. 41(12). P. 913–958.
51. Lin C.J., Yang J.C., Uang Y.S. et al. Time dependent amplified pharmacokinetic and pharmacodynamics responses of rabeprazole in cytochrome P450 2C19 poor metabolizers // Pharmacotherapy. 2003. Vol. 23(6). P. 711–719.
52. Saitoh T., Fukushima Y., Otsuka H. et al. Effects of rabeprazole, lansoprazole and omeprazole on intragastric pH in CYP 2C19 extensive metabolizers // Aliment Pharmacol Ther. 2002. Vol. 16(10). P. 1811–1817.
53. Andersson T., Hassan-Alin M., Hasselgren G. et al. Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole // Clin Pharmacokinet. 2001. Vol. 40(6). P. 411–426.
54. Zvyaga T., Chang S.Y., Chen C. et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19 // Drug Metab Dispos. 2012. Vol. 40(9). P. 1698–1711.
55. McGowan C.C., Cover T.L., Blaser M.J. The proton pump inhibitor omeprazole inhibits acid survival of Helicobacter pylori by a ureaseindependent mechanism // Gastroenterology. 1994. Vol. 107. P. 1573–1578.
56. Tsutsui N., Taneike I., Ohara T. et al. A Novel Action of the Proton Pump Inhibitor Rabeprazole and Its Thioether Derivative against the Motility of Helicobacter pylori // Antimicrobial agents and chemotherapy. 2000. Vol. 44(11). P. 3069–3073.
57. Ohara T., Goshi S., Taneike I. et al. Inhibitory action of a novel proton pump inhibitor, rabeprazole, and its thioether derivative against the growth and motility of clarithromycin-resistant Helicobacter pylori // Helicobacter. 2001. Vol. 6(2). P. 125–129.
58. Osipenko M.F., Lopina O.D., Estulin D.G. Pleiotropic effects of rabeprazole // RMJ. 2014. No. 20. P. 1468.
59. Heo J., Jeon S.W. Optimal treatment strategy for Helicobacter pylori: Era of antibiotic resistance // World J Gastroenterol. 2014. Vol. 20(19). P. 5654–5659.
60. Yamamoto T., Sanaka M., Anjiki H. et al. No Relationship between Plasma Desacyl-Ghrelin Levels and Rabeprazole-Related Delay in Gastric Emptying Controlled Study in Healthy Volunteers // Drugs R D. 2008. Vol. 9(5). P. 345–348.
61. Takahashi Y., Amano Y., Yuki T. et al. Influence of acid suppressants Ott gastric emptying: cross-over analysis in healthy volunteers // J Gastroenterol Hepatol. 2006. Vol. 21. P. 1664–1668.
62. Sanaka M., Yamamoto T., Kuyama Y. Does Rabeprazole Enhance Distension-Induced Gastric Accommodation? // Dig Dis Sci. 2009. Vol. 54. P. 416–418.
63. Zhang Z., Liu Z.Q., Zheng P.Y. et al. Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori // World J Gastroenterol. 2010. Vol. 16(10). P. 1279–1284.
64. Watanabe T., Higuchi K., Tominaga K. et al. Cytoprotective effect of rabeprazole against ethanol-induced gastric mucosal damage: possible involvement of nitric oxide: possible involvement of nitric oxide // Drug. Exptl. Clin. Res. 2000. Vol. 26(2). P. 41–45.
65. Khlynov I.B., Chikunova M.V. The importance of the mucous-bicarbonate barrier of the stomach in acid-dependent diseases // Breast Cancer. 2016. No. 7. pp. 1125–1129.
66. Skoczylas T., Sarosiek I., Sostarich S. et al. Significant Enhancement of Gastric Mucin Content After Rabeprazole Administration Its Potential Clinical Significance in Acid-Related Disorders // Digestive Diseases and Sciences. 2003. Vol. 48(2). P. 322–328.
67. Jaworski T., Sarosiek I., Sostarich S. et al. Restorative impact of rabeprazole on gastric mucus and mucin production impairment during naproxen administration: its potential clinical signi-cance // Dig. Dis. Sci. 2005. Vol. 50. P. 357–365.
68. Federal Law of the Russian Federation of April 12, 2010 No. 61-FZ “On the circulation of medicines” // Russian newspaper. 2010. P. 5157.
69. Andreev D.N., Dicheva D.T. Rational antisecretory therapy of gastroesophageal reflux disease // Reference. polyclinic doctor 2013. No. 12. pp. 21–24.
70. Tarlovskaya I.E. Generics and original drugs: the view of a practical doctor // Healthy Ukraine. 2011. No. 2. P. 34–35.
71. Meshkovsky A.P. The place of generics in drug supply // Farmateka. 2003. No. 3. pp. 103–104.

A.G.Evdokimova, L.V.Zhukolenko, G.S.Slobodkina, A.V.Tomova
MGMSU named after. A.I.Evdokimova, Moscow
City Clinical Hospital No. 52, Moscow

The article discusses European guidelines for H. pylori eradication. The expansion of indications for eradication therapy, the increase in resistance to antibiotics used, as well as an increase in doses of proton pump inhibitors are emphasized.
Key words: peptic ulcer, eradication, recommendations.

Current treatment of Helicobacter-associated disorders (according to the IV Maastricht Consensus, 2010)

A.G.Evdokimova, L.V.Zhukolenko, G.S.Slobodkina, A.V.Tomova
A.I.Evdokimov MSMSU, Moscow
City Hospital No. 52, Moscow

The article discusses current guidelines on the eradication of H. pylori. Paper spotlights widening of indications for the eradication, increase in bacterial resistance level to antibiotics, and increasing of proton pump inhibitors doses.
Keywords: peptic ulcer, eradication, guidelines.

About the author:
Evdokimova Anna Grigorievna – Doctor of Medical Sciences, Professor, Department of Therapy No. 1, Faculty of Postgraduate Education, Moscow State Medical and Dental University. A.I.Evdokimova

In 1983, Australian researchers B. Marshall and R. Warren independently isolated a microorganism from a biopsy specimen of a patient with chronic antral gastritis, later named Helicobacter pylori (H. pylori). This discovery marked the beginning of a new branch of development of gastroenterology, forced the world medical community to reconsider a number of provisions on the pathology of the gastroduodenal zone and identify a group of Helicobacter-associated diseases. According to modern concepts, H. pylori is an important link in the etiopathogenetic development of chronic gastritis type B, gastric and duodenal ulcers, MALT lymphoma and non-cardiac gastric cancer. In order to study the pathogenesis of H. pylori-associated diseases, the European Helicobacter pylori Study Group (EHSG) was created in 1987, under the patronage of which consensus conferences were held with the participation of leading experts in this field of research, Clinical data were summarized and discussed, recommendations for the diagnosis and treatment of H. pylori were created.
The first recommendations were developed in the city of Maastricht in 1996, and therefore received their name - the “First Maastricht Consensus”. As new data on H. pylori is obtained, every five years, the document regulating the tactics and strategy for managing patients suffering from Helicobacter-associated diseases is revised. By tradition, all conciliation meetings, regardless of where they were held, began to be called the Maastricht Consensus. Under the auspices of the EHSG, conferences were held and recommendations were developed Maastricht II (2000) and Maastricht III (2005). The last revision of the recommendations took place in 2010 in the city of Florence (Maastricht IV). The full text of the recommendations was published in February 2012 in the journal Gut, in English. The translation of the recommendations into Russian (in full) can be found in the additional issue of the “Bulletin of a Practitioner”.
44 experts from 24 countries took part in the IV conciliation conference. The working group considered three blocks of problems related to H. pylori infection:
clinical scenarios and indications for treatment of H. pylori infection;
diagnostic tests and treatment of infection;
prevention of stomach cancer and other complications.
Recommendations are based on modern and reliable data (according to the developed classes and levels of evidence-based medicine, formulated at consensus conferences).

Clinical scenarios and indications for treatment of H. pylori infection
Indications for the diagnosis and treatment of H. pylori infection (Maastricht-III and Maastricht-IV) included the following pathological conditions:
dyspepsia of unspecified etiology (uninvestigated dyspepsia);
functional dyspepsia (FD);
gastroesophageal reflux disease (GERD);
NSAID gastropathy;
extragastrointestinal diseases associated with Helicobacter pylori infection.
Consensus (III and IV) distinguished the concepts of examined and unexamined dyspepsia. For untested dyspepsia, a test and treat strategy has been recommended in areas with a high prevalence of H. pylori infection (above 20%) in young patients without the presence of so-called “alarm” symptoms. This strategy involves the use of non-invasive tests to detect H. pylori infection: urease breath test or stool antigen testing using monoclonal antibodies. The clinical effect is achieved at a minimum of cost (endoscopic examination is excluded), without psychological and physiological discomfort for the patient.
For FD, eradication therapy is recognized as the optimal and effective treatment method and is recommended for all infected patients. H. pylori eradication was determined to produce complete and long-lasting relief of FD symptoms in 1 in 12 patients, with benefit compared to other treatments. It was emphasized that infection with H. pylori can cause both an increase and a decrease in the level of acidity of gastric juice, depending on the nature of the inflammatory process of the mucous membrane.
Regarding the treatment tactics for patients with GERD associated with H. pylori, the recommendations remain almost the same. H. pylori infection does not have a significant impact on the severity of the course, recurrence of symptoms and the effectiveness of treatment.
The new consensus document noted a negative association between the prevalence of H. pylori and the severity of GERD, as well as the incidence of Barrett's esophagus and esophageal adenocarcinoma.
The materials of the III Maastricht Agreement indicate a synergistic damaging effect of H. pylori and non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa. The IV Maastricht Agreement recommends that all patients requiring long-term use of NSAIDs, selective cyclooxygenase-2 inhibitors or acetylsalicylic acid be diagnosed and treated for H. pylori infection. In addition, the need for long-term use of proton pump inhibitors (PPIs) in this category of patients along with anti-Helicobacter therapy was emphasized.
The issue of the effect of anti-Helicobacter therapy on atrophy and intestinal metaplasia of the mucosa was discussed. A meta-analysis of 12 studies involving 2658 patients showed that eradication of H. pylori during atrophy significantly improves the condition of the mucous membrane of the body, but not the antrum, and does not affect intestinal metaplasia.
Eradication therapy is the first-line treatment for low-grade gastric lymphoma (MALT lymphoma). In the early stages of MALT lymphoma development (stages I–II), anti-Helicobacter therapy leads to a cure in 60–80% of cases. If there is a translocation, this type of treatment is not effective; additional alternative methods are required.
With regard to extragastrointestinal diseases, there is evidence of a connection between Helicobacter pylori infection and the development of iron deficiency anemia of unspecified etiology (in 40% of cases), idiopathic thrombocytopenic purpura (in 50% of cases) and vitamin B12 deficiency.
Available data do not suggest that there is a clear link between other diseases, including cardiovascular diseases and neurological diseases. A relationship between H. pylori and a number of neurological diseases has been revealed: stroke, Alzheimer's disease, Parkinson's disease. However, the data obtained are insufficient to establish a clear causal relationship or interaction with treatment.
A negative association has been demonstrated between H. pylori infection and the prevalence of certain diseases, such as asthma, obesity and allergies in childhood.
It has been established that in some patients infected with H. pylori, eradication increases the bioavailability of drugs, in particular thyroxine and L-dopa.

Diagnostic tests and treatment for H. pylori infection
Recent consensuses have addressed the concept and criteria for the primary diagnosis of Helicobacter pylori infection. Priority was given to non-invasive methods, primarily the urea breath test and stool antigen testing using monoclonal antibodies, and their virtual equivalence was emphasized. In some cases (taking antibiotics, PPIs, gastrointestinal bleeding, atrophy of the gastric mucosa, stomach cancer) associated with a decrease in bacterial load, it is possible to use serological methods for determining H. pylori. The IV Maastricht Agreement emphasizes the great variability of antigens used in commercial serological test systems and recommends only standardized tests for the determination of Ig-G antibodies.
Taking PPIs can cause false-positive results for all diagnostic methods (except serological). In connection with the above, it is recommended to stop taking PPIs two weeks before performing cultural studies. If it is impossible to discontinue medications, priority is given to serological tests with the determination of Ig-G antibodies.
Maastricht III (2005) recommended the use of the following combination as first-line anti-Helicobacter therapy:
Standard dose PPI;
(omeprazole – 20 mg, lansoprazole – 30 mg, rabeprazole – 20 mg, or esomeprozole – 20 mg);
clarithromycin (CLR) 500 mg;
amoxicillin (AMK) 1000 mg or metronidazole (MTP) 500 mg
All drugs were prescribed 2 times a day, lasting at least 10–14 days.
As second-line therapy (quad therapy):
bismuth tripotassium dicitrate (BCM) 120 mg 4 times a day;
tetracycline (TTP) 500 mg 4 times a day;
metronidazole (MTP) 500 mg 3 times a day;
Standard dose PPI.
In some cases, quadruple therapy was allowed to be used as first-line therapy.
The IV Maastricht Consensus proposed various approaches to prescribing therapy, depending on the resistance of the microorganism to clarithromycin (CLR). These recommendations are based on data from more than one hundred meta-analyses of the effectiveness of various anti-Helicobacter therapy regimens conducted from 1992 to 2010. . With resistance to CLR, the effectiveness of the standard three-component eradication regimen (including CLR) is significantly reduced and amounts to no more than 10–30%. In the absence of an effect on primary therapy, when choosing a second line of therapy during endoscopy, a standard determination of sensitivity to antibiotics is necessary, which is associated with a high probability of resistance to antibacterial drugs. In the absence of response to second-line therapy, antibiotic sensitivity testing is performed in all cases. The culture method for identifying the sensitivity of H. pylori to CLR is recommended in regions where the frequency of resistance of H. pylori strains exceeds 15–20%. At the same time, it was noted that if a cultural sensitivity study is impossible, to determine resistance to CLR, as well as fluoroquinolone antibiotics, it is advisable to use molecular methods for determining sensitivity directly in biopsy specimens.
Thus, the IV Maastricht Consensus somewhat expanded the indications for determining the sensitivity of H. pylori to antibacterial drugs:
Before prescribing standard triple therapy in regions with high CPR resistance (above 15–20%).
Before prescribing second-line therapy during endoscopic examination in all regions.
In case of failure of second line therapy.
In accordance with the new recommendations, the choice of anti-Helicobacter therapy regimen is dictated by the level of HP resistance to antibacterial drugs in a given region.
I. If resistance to CLR does not exceed 15–20%, then standard triple therapy can be used as first-line therapy:
PPI + CLR + AMK or PPI + CLR + MTP or
standard quadruple therapy with bismuth preparation: PPI + MTP + TTP + VSM.
Currently, schemes with AMK and MTP are considered equivalent. The dosages of the drugs remain the same. An innovation of the IV Maastricht Agreement is the introduction of regulated treatment regimens for patients with allergies to penicillin drugs. In such cases, the regimen with AUB is excluded; triple therapy with levofloxacin is possible: PPI + CPR + levofloxacin.
As a second-line therapy, standard quadruple therapy with bismuth is used (PPI + MTP + TTP + VSM). If it is ineffective, an individual selection of the drug is carried out based on the sensitivity of H. pylori to antibacterial drugs - third-line therapy (table).
II. In regions with high resistance to CPR, only therapy with a bismuth drug - quadruple therapy (PPI + MTP + TTP + VSM) is recommended as first-line therapy. In countries where this drug is not available (France), sequential eradication therapy should be considered as an alternative therapy:
PPI+AMK 5 days, then PPI+CLR+MTP 5 days or
quadruple therapy that does not contain bismuth preparations: PPI + CPR + ABA + MTP.
Sequential anti-Helicobacter therapy was not discussed in previous consensuses, but a series of successful studies in recent years allowed its inclusion in the latest recommendations. Consecutive administration of antibacterial drugs – overcoming the resistance of H. pylori to CLR and reducing side effects from the use of antibacterial drugs.
Triple therapy with levofloxacin is recommended as second-line therapy: PPI + levofloxacin + AMK.
If there is no effect, to continue treatment, it is necessary to determine the sensitivity of H. pylori to antibacterial drugs (see table). Consensus materials emphasize the rapid growth of levofloxacin-resistant strains of H. pylori.
The 2010 consensus showed that prolongation of triple therapy from 7 to 10–14 days increases the eradication rate by an average of 5%, and not by 12%, as previously thought.
To assess the effectiveness of anti-Helicobacter therapy, standard non-invasive tests are used (urea breath test and stool test for the presence of antigens using monoclonal antibodies); serological methods are not recommended. The result of eradication is determined at least 4 weeks after the end of treatment.
It has been argued that high-dose PPIs (twice daily) increase the effectiveness of triple therapy by 8%.
It has been noted that the inclusion of certain types of probiotics and prebiotics in standard triple therapy significantly reduces the incidence of side effects from the use of antibacterial drugs, but this issue requires further study.
The expert council of the latest consensus for the first time clearly regulated the indications and duration of acid suppressive therapy. In uncomplicated duodenal ulcers, the use of PPIs after eradication is not recommended. On the contrary, in case of gastric ulcer and complicated duodenal ulcer, continued treatment with PPI is indicated. In case of ulcer bleeding, eradication therapy is recommended to begin immediately after resumption of oral nutrition, to reduce the frequency of recurrent bleeding.

Prevention of stomach cancer and other complications
Prevalence of stomach cancer in the population and high mortality (about one million people per year) as a result of the disease.
Some researchers estimate that infection with H. pylori increases the risk of developing stomach cancer by about six times. Currently, the pathogenetic relationship between gastric cancer and H. pylori is the subject of numerous studies in the field of genetics, morphology and pathophysiology. According to the III Maastricht Consensus, pathogenic carcinogens are usually classified as bacterial virulence factors, family history, autoimmune pathology, nutritional factors, and socio-economic factors. Maastricht IV expanded these provisions. There is now evidence of a direct mutagenic effect of H. pylori in cell lines and animal models. However, a specific genetic marker recommended for use in clinical practice has not yet been found.
One of the pressing issues is the possibility of preventing and inhibiting paroneoplastic processes in the gastric mucosa (atrophy and intestinal metaplasia) through anti-Helicobacter therapy. A recent meta-analysis showed that atrophy can regress, but only in the body of the stomach. Intestinal metaplasia is an irreversible process.
The latest consensus highlights cases when eradication should be carried out to prevent the development of gastric cancer:
diagnosis of stomach cancer in first-degree relatives;
patients with a history of gastric neoplasm who underwent endoscopic examination or subtotal gastrectomy;
patients suffering from high-risk gastritis;
patients with chronic suppression of gastric acid production (more than a year);
patients with external risk factors for stomach cancer (smoking, exposure to dust, coal, quartz);
H. pylori-positive patients fearing gastric cancer
It has been accepted that it is necessary to develop a vaccine, since vaccination may be the optimal way to eliminate H. pylori infection in a population.

Conclusion
Thus, the history of European recommendations for the diagnosis and treatment of H. pylori infection goes back more than 15 years. The latter period was marked by a number of significant additions:
Noteworthy is the expansion of indications for eradication therapy.
The growth of resistance to CLR dictates the need for rational use of drugs, the need to improve and integrate new regimens. Use of quadruple therapy and sequential therapy as first-line therapy. New treatment regimens using levofloxacin have been introduced for patients with allergies to penicillin drugs, and a therapy option is also being considered for regions where bismuth drugs are not available. The use of drugs with a low level of resistance to H. pylori: bismuth drugs, TTP, AMK.
It is recommended to use high-dose PPIs in first-line triple therapy protocols.
The position of supporters of the prevention of gastric cancer through eradication therapy has significantly strengthened.

Literature
1. Maev I.V., Samsonov A.A., Andreev D.N., Kochetov S.A. The evolution of ideas about the diagnosis and treatment of Helicobacter pylori infection (based on the Maastricht IV consensus, Florence, 2010). Bulletin of a practical doctor. Special issue. 2012; 1:23–30.
2. Mubarakshina O.A., Shcherbova Z.R. Modern approaches to the treatment of diseases associated with Helicobacter pylori. Medical Bulletin. 2012; 27 (604): 14.
3. Pimanov S.I., Leya M., Makarenko E.V.. Recommendations of the Maastricht-4 consensus on the diagnosis and treatment of Helicobacter pylori infection: discussion at the European Gastroenterology Week. Consilium medicum. 2012; 8 (14): 11–21.
4. Malfertheiner P., Megraud F., O`Morain C. et al. Management of Helicobacter Pylori infection – Maastricht IV / Florence Consensus Report Gut. 2012; 61:646–64.
5. Malfertheiner P., Megraud F., O`Morian C.A., Atherton J., Axon A.T.R., Bazzoli F., Gensini G.F., Gisbert J.P., Graham D.Y., Rokkas T., El-Omar E.M., Kuipers E.J., European Helicobacter Pylori study group (European Helicobacter Pylori Study Group, EHSG) Diagnosis and treatment of Helicobacter pylori infection - report from the Maastricht IV consensus conference. Florence. Bulletin of a practical doctor. Special issue. 2012;1: 6–22.
6. Rafalsky V.V. Recommendations Maastricht IV: choosing an eradication regimen in an era of increasing antibiotic resistance. Bulletin of a practical doctor. Special issue. 2012; 1:24–36.
7. Glupczinski Y. European multicenter study on H. pylori susceptibility. Helicobacter pylori from basic research to clinical issues. Villars-sur-Ollon, Switzerland; 2011.
8. Graham D.Y., Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010; 59(8):1143–53.
9. Megraud F. Antimicrobial resistance and Approaches to Treatment. In: Sutton P., Mitchell H.M., ed. Helicobacter pylori in the 21st Century. Wallingford, UK: CABI; 2010.
10. Megraud F., Coenen S., Versporten A., Kist M., Lopez-Brea M., Hirschl A.M. et al. Helicobacter Pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut. 2012; doi: 11.1136/gutjnl-2012-302254.
11. Tkachenko E.I. Baryshnikova N.V., Denisova E.V. and others. Epidemiological study of Helicobacter pylori resistance to clarithromycin in residents of St. Petersburg with peptic ulcer disease. Experimental and clinical gastroenterology. 2009; 5:73–76.
12. Kornienko E.A., Suvorov A.N., Tkachenko E.I., Uspensky Yu.P., Baryshnikova N.V. Critical increase in Helicobacter pylori resistance to clarithromycin in pediatric and adult gastroenterological practice. Directory of a polyclinic doctor. 2010; 12:54–56.
13. Asaka M., Sepulveda A.R., Sugiyama T., Graham D.Y. Gastric Cancer. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001. Chapter
14. Calvet X, Lario S, Ramirez-Lazaro M.J. et al. Accuracy of monoclonal stool tests for determining cure of Helicobacter pylori infection after treatment. Helicobacter. 2010; 15: 201–205.
15. Maev I.V., Golubev N.N. Principles of diagnosis and rational pharmacotherapy of chronic gastritis. Rus. honey. magazine Diseases of the digestive system. 2010; 28:1702–1706.