A.A. Sheptulin
Elena Alexandrovna Poluektova, doctor, candidate of medical sciences:
- Now the message “Maastricht-IV. Modern eradication schemes ", Arkady Alexandrovich Sheptulin.
Arkady Alexandrovich Sheptulin, professor, doctor of medical sciences:
- Good afternoon, dear colleagues. In order to better imagine what the Maastricht-IV conciliation meeting brought new, let us 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 resection of the stomach for early cancer, these are the closest relatives of patients with stomach cancer and the patient's desire in those cases if he has no contraindications for this ...
The Maastricht III Consensus addressed three controversial issues concerning the relationship between pyloric helicobacter and diseases such as functional dyspepsia, gastropathy associated with nonsteroidal anti-inflammatory drugs, and the relationship of pyloric helicobacter to a wide range of non-gastroenterological diseases.
As for functional dyspepsia, a meta-analysis of a large number of works carried out quite a long time ago showed that the effectiveness of eradication in relation to the elimination of dyspepsia symptoms is low. The NNT index is 17: 17 patients need to be treated in order for one patient to get rid of complaints. Nevertheless, what Tatyana Lvovna spoke about was the importance of pyloric helicobacter in the development of stomach cancer, as well as the fact that pyloric helicobacter is the main risk factor for the development of peptic ulcer disease in countries with high contamination - and we, unfortunately, to such We refer to countries - with functional dyspepsia, it is advisable to determine the infection of pyloric helicobacter and, with positive results, to carry out eradication.
As for NSAID-associated gastropathy, it was found that the risk of developing NSAID gastropathy in H. Pilori-positive patients is higher than in H. Pilori-negative patients, which reduces the risk of ulcers and erosions of the stomach in patients receiving NSAIDs. Before starting to take NSAIDs, it is advisable to investigate the presence of this infection and, if confirmed, to carry out its eradication. But a very important remark is that only the eradication of pyloric helicobacter is not enough to prevent the onset of NVPV gastropathy. Therefore, if the patient also has additional risk factors for NVPV-gastropathy - old age, a history of peptic ulcer disease, concomitant use of corticosteroids or anticoagulants - then, in addition to eradication, a cover of proton pump inhibitors must be prescribed.
If we take a wide range of non-gastroenterological diseases, then only two nosological forms are associated with infection of pyloric helicobacter: this is immune thrombocytopenia - there is a cross of antibodies to pyloric helicobacter 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, first of all ischemic disease heart, there is currently no convincing evidence for the connection of these diseases with infection of the pyloric helicobacter.
The Maastricht-III consensus defined the main provisions for the diagnosis of pyloric helicobacter infection. If the patient does not undergo esophagogastroduodenoscopy, then for the diagnosis of this infection it is preferable to use a urease breath test, determination of pyloric helicobacter antigen in feces or a serological method. Most often, we determine the presence of pyloric helicobacter at the time of gastroduodenoscopy: say, a patient has an ulcer or erosion. Here, a fast urease test is usually used for diagnosis.
It is best to use a breath urease test to monitor eradication. If it is impossible to conduct it, examine the pyloric helicobacter antigen in the feces. It is very important that current antisecretory therapy reduces the detection rate of pyloric Helicobacter antigen in feces and the rate of positive breath test results.
And it is important that the definition of pyloric helicobacter strains - in particular, the cagA-strain, vacA-strain and others - does not play any role in deciding on the treatment of patients. If any strain of pyloric helicobacter is detected, if the patient is on the list of indications for eradication, it is carried out.
In terms of treatment, the Maastricht III consensus defined first-line, second-line and back-up therapy.
The scheme of the first line - the standard triple therapy, which Tatyana Lvovna has already mentioned - includes proton pump blockers in a double dose. This is Rabeprazole, but we used to write Pariet because we had no other drugs. Tatyana Lvovna said that now we already have other analogues of Rabeprazole, in particular, Ontaym - in combination with Clarithromycin and Amoxicillin. This regimen is prescribed if the resistance to Clarithromycin in the given region does not exceed 20%.
As for the second-line regimen, double-dose proton pump blockers are used - Tetracycline, Metronidazole and bismuth preparations. It was emphasized that this scheme is also effective in the case of Metronidazole-resistant patients.
Also, the Maastricht-III consensus found that the effectiveness for a 14-day course of eradication is about 10% higher on average than a seven-day course.
Finally, if first- and second-line regimens are ineffective, there are several options available to the clinician for further action. This is to increase the dose of Amoxicillin to three grams per day in combination with doubled more - here not 4 times a day, but four times - say, if this is the same Rabeprazole, this is not 40 milligrams, but 80 milligrams per day for 14 days ...
It was proposed to replace Metronidazole in quadrotherapy schemes with Furazolidone, to use the antibiotics Rifabutin or Levofloxacin in combination with proton pump blockers and Amoxicillin. The best option for a backup scheme is an individual selection of antibiotics after determining the sensitivity of the inoculated 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 an 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 effectsrelated to drug interactions. The effect of Rabeprazole develops more rapidly and is more pronounced. Rabeprazole is more effective than other proton pump inhibitors in inhibiting the growth of pyloric Helicobacter. 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 has the lowest minimum inhibitory concentration in all eradication regimens with Metronidazole, Amoxicillin, Clarithromycin, that is, it is most active against pyloric helicobacter in comparison with 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 mucus and mucin production, providing mucosal protection. And here is the slide that Tatyana Lvovna already showed: Ontaym is a new form, a new variant, a new analogue of Rabeprazole - in its pharmacodynamic and pharmacogenetic properties it is completely analogous to Pariet.
What has changed over the years since the adoption of the Maastricht III consensus? First, two new eradication regimens have become widespread: sequential therapy and the so-called concomitant (concomitant). What is the meaning of these schemes? The main challenge is to overcome the rapidly growing Clarithromycin resistance. The sequential scheme involves two five-day courses: at the beginning with a combination of proton pump inhibitors and Amoxicillin, the second five days - 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, in the United States of America, so now this scheme is indeed considered highly effective.
As for the concomitant eradication regimen, this is a quadrotherapy regimen with an additional antibacterial drug. This is quadrotherapy without bismuth preparations. This is the standard triple therapy, to which another is added antibacterial drug... Most often it is Metronidazole. You can see that the effectiveness of concomitant therapy is also high, reaching 90%.
The use of schemes with Levofloxacin has become widespread. In the beginning, a daily dose of 500 milligrams was used, now it is 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 was the conclusion of the Maastricht IV consensus? You see: 45 experts from 26 countries discussed various provisions - indications for eradication, diagnosis and treatment, prevention and screening of cancer. A decision was considered adopted if more than 70% of those present voted for it, and you see three issues that were discussed.
So, with regard to functional dyspepsia. In general, in relation to the testimony, nothing, probably, new in comparison with the "Maastricht-III" was positioned. In countries with a high prevalence of pyloric helicobacter infection, patients with functional dyspepsia are shown eradication. Here, in parentheses, I write the diagnosis "chronic gastritis with clinical symptoms", because in our country the majority of doctors, especially general practitioners, still use the clinical diagnosis of "chronic gastritis".
It was reaffirmed that the eradication of pyloric helicobacter does not cause GERD, does not exacerbate GERD, and does not affect the effectiveness of its treatment. However, it has been noted that there is a negative correlation between infection with pyloric helicobacter, 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 established that pyloric helicobacter increases the risk of developing NSAID gastropathy, therefore, patients who receive these drugs for a long time are shown eradication. Eradication can reduce the severity of atrophy in the fundic stomach, which is very important in terms of cancer prevention, but does not affect the severity of intestinal metaplasia.
If we talk about diagnosis, then the two main tests - the urease test and the determination of the antigen in the stool - are equivalent in their accuracy. As for the serological method, this is the only method, the results of which are not affected by the dissemination of the pyloric helicobacter (I mean the degree), the presence of mucosal atrophy, the intake of antisecretory drugs and antibiotics. But it was specially emphasized that in order to obtain accurate results, it is necessary to determine antibodies of only the immunoglobulin G class.
If the patient is receiving proton pump inhibitors, they should be discontinued two weeks before testing. If proton pump inhibitors cannot be canceled, then the serological method should be used. As for the microbiological method, the culture of microorganisms must be obtained from patients with ineffective treatment for individual selection of drugs.
The new thing that was introduced into the diagnosis by the Maastricht-IV position is the introduction of molecular methods into clinical practice. For example, a different real-time chain reaction that is used to detect Clarithromycin resistance.
The Maastricht IV Consensus has reduced the number of eradication regimens that can now be applied. What is left behind? This is a standard triple regimen (7 or more days), this is a sequential regimen (10 days), this is a quadrotherapy regimen with bismuth preparations (also 10 days), this is a concomitant regimen we talked about (10 days) and the only backup regimen with Levofloxacin ( also lasting at least 10 days).
How to apply these schemes? The use of the regimens is determined by the indicators of resistance to Clarithromycin in the region. If resistance does not exceed 10%, then standard triple therapy can be prescribed as a first-line regimen without prior testing. If the indicators of resistance to Clarithromycin range from 10 to 50%, then it is necessary to conduct preliminary testing for sensitivity to this antibiotic.
What do we see in Western Europe? The same sensitivity in Austria and Hungary shows that the 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 carried out in St. Petersburg, Smolensk, Nizhny Novgorod and Novosibirsk have shown that resistance to Clarithromycin in our country is less than 10%. This means that we are following the guidelines for regions with low Clarithromycin resistance. In this case, standard triple therapy remains the first-line regimen. Sequential therapy or quadrotherapy with bismuth preparations can be applied. As a second-line regimen, a quadrotherapy regimen with bismuth preparations or triple therapy with Levofloxacin. And the third-line scheme is based on individual antibiotic susceptibility testing.
It was again confirmed that doubling the dose of proton pump inhibitors can increase its efficiency by about 5%. For the first time, it was officially announced that the use together with antibiotics in eradication regimens of probiotics as adjuvant therapy can increase the effectiveness. We have previously widely prescribed probiotics, in particular Enterol, but mainly with the aim of reducing the risk of side effects, intestinal disorders. But it turned out that it is possible in this way to increase the effectiveness of eradication.
Efficiency control, as before, should be carried out 4 weeks after eradication, using a urease breath test or stool antigen determination.
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 relapse after surgical treatment. But the best results are achieved when eradication is carried out to 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 the resistance to Clarithromycin in Russia does not exceed 10%, the standard triple therapy remains the first-line regimen. There are measures that can improve its effectiveness: an increase in the dose of proton pump inhibitors, an increase in the duration of treatment and the addition of bismuth preparations, in particular tripotassium dicitrate.
As a variant of the first-line eradication scheme, 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 the standard triple therapy scheme and quadrotherapy with bismuth tripotassium dicitrate.
So, once again summing up that the first-line scheme in our country is standard triple therapy and quadrotherapy with bismuth preparations, the second-line scheme is quadrotherapy with bismuth preparations and triple therapy with Levofloxacin, and the third-line scheme is selected individually, taking into account the results of determining antibiotic resistance.
Thus, to summarize, we can say that the main indications for the eradication of pyloric helicobacter infection remain the same. The choice of the eradication scheme depends on the level of resistance of pyloric helicobacter strains to Clarithromycin. The main schemes of eradication are currently the standard triple scheme, the scheme of quadrotherapy with bismuth tripotassium dicitrate. As for sequential and concomitant therapy, you have noticed that we do not recommend them in our Russian recommendations yet, since we have no experience of the effectiveness of this scheme in our country. When we get the first results, then we will discuss the place of these schemes.
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STRATEGY TEST-TREATMENT
- A test treatment strategy can be used for unexamined dyspepsia in populations with a high prevalence (\u003e 20%). This approach is based on a local risk / benefit ratio and is not applicable to patients with anxiety symptoms, elderly people with an increased risk of cancer (1a, A).
- The main non-invasive tests used for the test-treatment strategy are the breath urease test and the determination of monoclonal antigens in the stool. Certain validated serological tests can also be used (2a, B).
Acidity and functional dyspepsia
- Helicobacter pylori eradication causes long-term relief of dyspepsia in 1 in 12 patients infected with Helicobacter pylori and functional dyspepsia and is superior to other treatments (1a, A).
- Helicobacter pylori infection can increase or decrease secretion depending on the prevalence of inflammation in the stomach (2b, B).
Helicobacter pylori and gastroesophageal reflux disease
- Helicobacter pylori infection does not affect the severity, frequency of symptoms, and the effectiveness of therapy for gastroesophageal reflux disease. Helicobacter pylori eradication does not lead to an exacerbation of gastroesophageal reflux disease and does not affect the effectiveness of treatment (1a, A).
- Epidemiological studies demonstrate an inverse relationship between the prevalence of Helicobacter pylori on the one hand, the severity of gastroesophageal reflux disease and the incidence of esophageal adenocarcinoma, on the other (2a, B).
Helicobacter pylori, aspirin, and nonsteroidal anti-inflammatory drugs
- Helicobacter pylori is associated with an increased risk of complicated and uncomplicated gastroduodenal ulcers in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin (2a, B).
Helicobacter pylori eradication reduces the risk of complicated and uncomplicated gastroduodenal ulcers associated with NSAIDs and low-dose aspirin (1b, A).
- Helicobacter pylori eradication is helpful before starting NSAID therapy. Eradication is required in case of a history of peptic ulcer disease (1b, A).
Eradication of Helicobacter pylori alone does not reduce the incidence of gastroduodenal ulcers in patients already receiving long-term NSAIDs. In this case, continued treatment with proton pump inhibitors (PPIs) and eradication of Helicobacter pylori are required (1b, A).
- A Helicobacter pylori test should be performed in patients with a history of gastroduodenal ulcer who are taking aspirin. The long-term incidence of ulcer bleeding is low in eradication patients, even in the absence of gastroprotective treatment (2b, B).
Helicobacter pylori and proton pump inhibitors
10a. Long-term treatment PPIs in patients with Helicobacter pylori are associated with the development of gastritis, predominantly of the body of the stomach. The process of loss of specialized glands is accelerated, leading to atrophic gastritis (1c, A).
10b. Eradication of Helicobacter pylori in patients receiving long-term PPIs leads to a cure for gastritis and prevents the progression of atrophic gastritis. However, there is no evidence that the risk is reduced (1b, A).
Intestinal metaplasia guidelines
11a. Evidence is accumulating that gastric body function improves after Helicobacter pylori eradication. However, how much this is related to regression of atrophic gastritis remains unclear (2a, B).
11b. There is no evidence that eradication of Helicobacter pylori leads to regression of intestinal metoplasia (2a, B).
Helicobacter pylori and MALT lymphoma
- Helicobacter pylori eradication is the first-line treatment for low-grade borderline lymphoma (1b, A).
Extragastric Disease Regulations
- There is evidence for the etiological role of Helicobacter pylori in unexplained iron deficiency, idiopathic thrombocytopenia and vitamin B12 deficiency. In these situations, it is necessary to identify and treat Helicobacter pylori (for iron deficiency anemia - 1a, A, for idiopathic thrombocytopenia - 1b, A, for vitamin B12 deficiency - 3b, B).
The available evidence does not clearly identify a causal relationship between Helicobacter pylori and other extragastric diseases, including cardiovascular and neurological diseases.
- It has been proven that Helicobacter pylori does not have a protective effect against bronchial asthma and atopy, obesity and related diseases, and that the eradication of Helicobacter pylori causes or worsens these diseases.
- In patients with the presence of Helicobacter pylori, eradication of Helicobacter pylori improves the bioavailability of thyroxine and L-dopa (2b, B).
TREATMENT OF HELICOBACTER PYLORI INFECTION
Diagnostic non-invasive tests
- The diagnostic accuracy of detecting Helicobacter pylori antigens in feces, validated by a monoclonal laboratory test, is equal to the urease breath test (1a, A).
- Not all serological tests are created equal. Due to the variable accuracy of various commercial tests, only validated IgG serological tests should be used (1b, B).
- Validated serological tests can be used with recent antimicrobial and antisecretory drugs, ulcerative bleeding, atrophy, and gastric cancer (1b, B).
- In patients treated with PPIs:
1) if possible, PPIs should be discontinued 2 weeks before testing by culture, rapid urease test, urease breath test, or fecal Helicobacter pylori antigens (1b, A).
2) If this is not possible, a validated IgG serological test may be performed (2b, B). Endoscopic strategy
- 1) It is important to determine culture and standard antimicrobial susceptibility in regions or populations with high clarithromycin resistance before initiating first-line therapy if a standard clarithromycin-containing regimen is used.
Culture and standard antimicrobial susceptibility tests should be performed in all regions before second-line therapy, for another reason, or when second-line therapy has failed (5, D).
2) If standard susceptibility testing is not possible, a molecular test can be used to determine H. pylori and clarithromycin and / or fluoroquinolone resistance on gastric biopsy (1b, A).
- 1) If H. pylori is isolated from gastric biopsies, a susceptibility test should include metronidazole (1b, A).
2) If clarithromycin susceptibility is determined by a molecular test, additional culture determination of metronidazole resistance is not warranted (5, D).
- Triple therapy with PPIs and clarithromycin should be abandoned without a preliminary study of sensitivity to clarithromycin if the level of clarithromycin resistance in the region is more than 15-20% (5, D).
- In regions with low clarithromycin resistance, clarithromycin regimens are recommended as the first line of empiric therapy. An alternative is the appointment of quadrotherapy with a bismuth preparation (1a, A).
- Prescribing a high dose PPI (twice daily) increases the effectiveness of triple therapy (1b, A).
- An increase in the duration of triple therapy with PPIs and clarithromycin from 7 to 10-14 days increases the rate of successful eradication by 5% (1a, A).
- The effectiveness of the “PPI + clarithromycin + metronidazole” and “PPI + clarithromycin + amoxicillin” regimens is the same (1a, A).
- Some pro- and prebiotics are showing promising results as adjunctive therapy that can reduce side effects (5th).
- PPI-clarithromycin-containing regimens should not be tailored to the patient's characteristics, except for the dose (5, d).
Second line therapy
- 1) After an ineffective regimen with PPI and clarithromycin, it is recommended to prescribe quadrotherapy with bismuth or triple therapy with levofloxacin (1a, A).
Third line therapy
Areas of high clarithromycin resistance, first-line therapy
- In regions with high clarithromycin resistance, bismuth quadruple therapy is recommended as the first line of empiric therapy. If this scheme cannot be implemented, sequential therapy or quadrotherapy without bismuth preparation is recommended (1a, A).
Regions with high clarithromycin resistance, second to third line therapy
- 1) In regions with high clarithromycin resistance, after the failure of quadrotherapy with bismuth, it is recommended to prescribe triple therapy with levofloxacin (5th).
2) The growing level of resistance to levofloxacin should be considered (2b, B).
- After ineffective second-line therapy, treatment should be based on antibiotic susceptibility tests, if possible (4, A).
With penicillin
- In patients allergic to penicillin in regions with low clarithromycin resistance, the combination PPI + clarithromycin + metronidazole may be prescribed as first-line therapy.
In regions with high clarithromycin resistance, quadrotherapy with bismuth is preferred (2c, B).
CONTROL OF THERAPY
- Urease breath test and laboratory validated monoclonal test for Helicobacter pylori antigens in stool are recommended as non-invasive tests to assess the success of eradication therapy. Serology is not used (1a, A).
- To determine successful eradication of H. pylori, the interval after completion of therapy should be at least 4 weeks (2b, B).
- 1) In case of uncomplicated duodenal ulcer after treatment with Helicobacter pylori, continued PPI treatment is not recommended (1a, A).
2) In case of gastric ulcer and complicated duodenal ulcer, it is recommended to continue PPI (1b, A).
- Eradication therapy for bleeding ulcers should begin from the moment feeding is resumed through the mouth (1b, A).
PREVENTION OF CANCER AND OTHER COMPLICATIONS
- Helicobacter pylori infection is the most persistent risk factor for stomach cancer. Elimination of Helicobacter pylori is the most promising strategy for reducing the incidence of gastric cancer (1a, A).
- There is strong evidence that Helicobacter pylori infection has a direct mutagenic effect in animal models and cell lines (C).
- The risk of developing stomach cancer is influenced by bacterial virulent factors, but there are no specific markers of bacterial virulence that can be recommended for clinical practice (1a, A).
- The risk of developing stomach cancer is influenced by host genetic factors, but there are no specific markers for genetic testing that can be recommended for clinical practice at present (1b, A).
- The influence of environmental factors is inferior to the influence of Helicobacter pylori infection on the risk of gastric cancer (1a, A).
- Histopathological changes at the morphological level indicate that:
1) stomach cancer rarely develops in the absence of chronic gastritis;
2) the prevalence and severity of gastritis, together with atrophy, are associated with the development of cancer (2b, A).
- Mechanisms at the functional level indicate that:
1) atrophic gastritis of the body of the stomach causes hypochlorhydria;
2) hypochlorhydria promotes the growth of non-Helicobacter pylori organisms that are capable of producing metabolites with carcinogenic potential (2c, A).
- Helicobacter pylori eradication eliminates the inflammatory response and slows down and may stop the progression of atrophy. In some cases, atrophy may be reduced (1a, A).
- There is strong evidence that eradication of Helicobacter pylori reduces the risk of gastric cancer (1c, A).
- The risk of stomach cancer can be more effectively reduced with eradication therapy before precancerous conditions develop (1a, A).
- Helicobacter pylori eradication for the prevention of gastric cancer is economically justified in certain high-risk groups (3, B).
- Helicobacter pylori eradication brings additional clinical and economic benefits in addition to gastric cancer prevention (1a-4 for various diseases).
- The Helicobacter pylori screening treatment strategy should be used in groups at significant risk of gastric cancer (2c, A).
- Validated serologic tests for Helicobacter pylori and markers of atrophy (eg, pepsinogens) are the best available tests to identify individuals at high risk of gastric cancer (1a, B).
- Risk stratification of patients with gastric precancerous conditions is useful and can be based on the severity and extent of the injury (2b, B).
- Helicobacter pylori eradication for the prevention of stomach cancer can be used in the following cases:
- first-degree relatives of family members with stomach cancer;
- patients with previous gastric cancer who underwent endoscopic treatment or subtotal;
- patients with severe pangastritis, gastritis, predominantly of the body of the stomach, severe atrophy;
- patients with chronic gastritis and low acidity for more than 1 year;
- patients with severe environmental risk factors for stomach cancer (heavy smoking, high exposure to dust, coal, quartz, cement, and / or working in a quarry);
- Helicobacter pylori-positive patient with fear of gastric cancer (1a-4).
- Helicobacter pylori eradication for the prevention of gastric cancer should be carried out in high-risk populations (1c, A).
- Factors to consider when developing prevention strategies should include:
- the incidence of gastric cancer in a given population;
- the likelihood of a change in the frequency of cancer if the intervention is not carried out;
- availability of conditions in primary health care and other logistics;
- the likelihood of adherence to a given population;
- availability of resources;
- the possibility of repeated testing and treatment if eradication is ineffective (A).
- The combination of antibiotics is selected according to the local characteristics of resistance (2b, B).
- Vaccination may be the best choice for eliminating Helicobacter pylori infection in a population. Serious efforts are needed to develop a vaccine (4, A).
21: (a) Precancerous conditions high risk require endoscopic control.
(b) Prospective studies are needed to assess the optimal control interval (2c, A).
The article was prepared and edited by: surgeonOn March 3, 2016, within the framework of the 42nd scientific session of the Central Scientific Research Institute of Geology and Research "Principles of Evidence-Based Medicine in Clinical Practice", the Round Table "Recommendations of Experts on the Diagnosis and Treatment of Diseases Associated with Helicobacter pylori and Real Clinical Practice: Is It Great?"
This is one of the first, if not the first, public appearance in Russia with information about the conciliatory conference on the diagnosis and treatment of Helicobacter pylori infection - Maastricht V, held in October 2015 in Florence (Italy). The conference materials have not yet been published, so any information about the decisions made is extremely interesting.
The previous consensus conference "Diagnosis and treatment of Helicobacter pylori infection: Maastricht IV" was also held in Florence in November 2010, and the final text of the agreement was not published until May 2012.
Marcis Leja participated as an expert in both of these conferences.
The report was made in Russian. The text from the slides is presented below in frames.
As noted by Marcis Leja, a number of Maastricht V provisions echo the Kyoto Global Consensus on Helicobacter pylori-associated gastritis.
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Risk Stratification - Kyoto Consensus:
Sugano et al. Gut. 2015 |
Marcis Leja says a new European association has been created Cancer Control Joint Action (CanCon) - Collaborative Action for Cancer Control, www .cancercontrol.eu.
Russian organizations have not yet joined this association.
On May 28, 2015, Riga hosted CanCon - Gastric cancer screening working group meeting. From Russia, D.S. Bordin. The possibilities of monitoring gastric cancer and the risks associated with mass eradication of H. pylori were discussed.
Marcis Leja noted that according to the results of the Riga meeting, it was decided not to carry out mass monitoring of stomach cancer and mass eradication of H. pylori in Latvia. This decision does not comply with European recommendations, but Latvia is not yet ready to follow these recommendations.
Conciliation participantsconferences on the diagnosis and treatment of Helicobacter pylori infection - "Maastricht V "(Florence, 2015)
Only 30 years have passed since the discovery of Helicobacter pylori in 1982, but over these three decades, approaches to the diagnosis, therapy and prevention of a number of diseases of the gastrointestinal tract have been fundamentally revised. It should be noted that the study of the use of antibiotics and chemotherapy drugs for the eradication of H. pylori in terms of the dynamics and drama of its development is much superior to other areas of application of antimicrobial therapy. This is primarily due to the fact that already at the beginning of the development of the concept of H. pylori eradication, it was clear that a relatively simple and short course of antimicrobial therapy could prevent the development of a number of serious gastrointestinal diseases. In the following decades, during the 80-90s, the arsenal of antimicrobial drugs used for eradication was replenished with new drugs, and the main direction of research was the development and comparison of the effectiveness of various combinations and dosage regimens of antibiotics in eradication regimens.
However, the beginning of the new century was marked by the emergence of a problem that has long been identified in the treatment of other infections - the problem of the development of H. pylori resistance to antimicrobial drugs. The first studies describing the presence of H. pylori resistance to metronidazole were published already in the late 1980s, but they did not attract significant attention of clinicians due to their small effect on treatment outcomes. The first isolated cases of resistance to macrolides were recorded in the early 90s of the twentieth century and were often accompanied by clinical ineffectiveness of eradication therapy. As a rule, these were cases of secondary H. pylori resistance during azithromycin therapy. However, in the late 90s, a problem was clearly identified that radically changed the approaches to the choice of eradication regimens - the development of resistance to one of the main drugs included in the eradication regimens - clarithromycin.
Currently, the population level of resistance (the frequency of isolation of resistant strains in the population) is one of the defining criteria for choosing a particular eradication scheme and forms the basis of the Maastricht recommendations of the 4th revision, published in this issue of the Bulletin.
The active use of data on antibiotic resistance to predict the effectiveness of antibiotic therapy and optimize treatment regimens is possible only if sufficient data have been accumulated on the correlation between the population level of antibiotic resistance and a decrease in the effectiveness of therapy. In the field of anti-helicobacter therapy, such a correlation has been well studied, both in the analysis of the individual resistance of H. pylori (the value of the MIC of H. pylori in individual patients) and in the analysis of population resistance - the level of prevalence of resistant strains of H. pylori in the population. Obviously, it is for this reason that a significant part of the statements regarding the choice of specific eradication regimens in the Maastricht IV manual, one way or another, is based on or takes into account data on H. pylori resistance to antibiotics (statements 8, 14, 15, 16, 17, 18).
It should be taken into account that the effect of H. pylori resistance on the effectiveness of antimicrobial drugs of different groups used in eradication regimens manifests itself to varying degrees (Table 1).
Tab. 1. Clinical significance antibiotic resistance of H. pylori for various drugs used in eradication regimens
The largest amount of data on the effect on the effectiveness of therapy has been accumulated in relation to the resistance of H. pylori to macrolides, primarily to clarithromycin. Research results show that with an increase in clarithromycin MIC for H. pylori above 0.5 mg / L, and especially\u003e 2-4 mg / L, there is a sharp decrease in the frequency of eradication (Fig. 1).
Figure: 1. Decrease in the frequency of eradication during eradication according to the three-component scheme in the case of an increase in H. pylori MIC. According to various studies
A similar pattern was found for fluoroquinlones. It has been shown that with an increase in the MIC of levofloxacin to H. pylori from 1 mg / ml, the frequency of eradication decreases from 84.1 to 50%, and when the MIC changes from 8 mg / ml, the frequency of eradication decreases from 82.3 to 0% ...
The situation is somewhat different with the resistance of H. pylori to metronidazole. Despite the fairly wide distribution of resistant strains in the population, H. pylori resistance to metronidazole does not have such a dramatic effect on the frequency of eradication, as in the case of macrolides and fluoroquinolones. The frequency of eradication in the regimens of 3-component therapy of infection caused by metronidazole-resistant strains is reduced by no more than 25%. Moreover, the use of high doses and the prolongation of the course of metronidazole therapy allows maintaining an acceptable level of clinical efficacy.
In the last decade, a significant step forward has been made in the antimicrobial therapy of H. pylori infection, associated with the active introduction of molecular diagnostics methods (PCR, real-time PCR, sequencing, DNA hybridization, etc.). These methods make it possible to quickly, within a few hours, identify the determinants of antibiotic resistance and adjust therapy. The use of genotyping makes it possible to actually switch to the “gold standard” of antimicrobial therapy - the choice of a therapy regimen based on the pathogen resistance profile. It has been established that already now the sensitivity of genotypic methods in predicting the effectiveness of eradication is about 90% for levofloxacin and 60-70% for clarithromycin, and the specificity for both classes of antibiotics exceeds 97%. For genotypic determination of clarithromycin resistance, detection of the A21420 or A21430 mutations in the 23s subunit of the H. pylori ribosome is most often used, in particular, by the TaqMan real-time PCR method. When isolating strains in which the A21420 substitution is present, the MIC of H. pylori increases to 32-256 mg / L, and the effectiveness of the three-component eradication scheme decreases to 57.1%, when the A21430 substitution is detected, the MIC rises to 4-128 mg / L, and the eradication efficiency is reduced to 30.7%.
Thus, data on the phenotypic and (or) genotypic resistance of H. pylori are the most important tool for predicting the effectiveness of anti-Helicobacter pylori therapy and choosing an eradication regimen. The guideline under discussion emphasizes that the main reason for the decrease in the effectiveness of eradication regimens is the increase in resistance to clarithromycin, and therefore it is unjustified to prescribe a three-way regimen, including clarithromycin, in regions where the level of resistance exceeds 15-20% (Statement 7, Part 2). however, in regions where clarithromycin resistance is low, the clarithromycin regimen is the recommended first-line empiric therapy (Statement 8, Part 2).
In this regard, the data obtained in epidemiological studies on monitoring H. pylori resistance are of great importance in choosing the optimal eradication regimen. Of the large multicenter studies, due primarily to their geographical location, the III European multicenter study of antibiotic resistance of H. pylori, conducted in 2008-2009, is of great interest. ... The study included 2204 strains from 32 European centers in 18 EU countries (1 center per 10 million inhabitants), 50-100 H. pylori strains were presented from each center. Determination of sensitivity to clarithromycin, amoxicillin, levofloxacin, metronidazole, tetracycline, rifabutin was carried out by the method of E-tests (Fig. 2).
Figure: 2. Frequency of isolation of resistant strains of H. pylori. in Europe 2008-2009
As can be seen from the figure, the level of H. pylori resistance to amoxicillin, tetracycline and rifabutin was predictably low - about 1%; the level of resistance to metronidazole was also expectedly high - 34.9%. Of greatest clinical interest are the data on H. pylori resistance to clarithromycin, which averaged 17.5% in Europe. H. pylori resistance to levofloxacin was also quite high - 14.1%. Interestingly, the study confirmed the presence of significant regional differences in the geography of H. pylori resistance, which were also determined in earlier studies, namely, a lower level of resistance in the northern countries (Norway, Denmark, Germany, etc.) compared to the “eastern” ( Czech Republic, Hungary, etc.) and "southern" (Italy, Portugal, Greece, etc.), for clarithromycin and levofloxacin: 8%, 20.9%, 24.3% and 6.4%, 12.3%, 14.2%, respectively (Fig. 3).
Figure: 3. Frequency of isolation of resistant strains of H. pylori in different regions of the EU
Obviously, when interpreting the data obtained in Europe in relation to the Russian Federation, it is justified to use that part of them that describes the stability in the central and eastern regions of the EU. However, it is more reasonable to use data directly obtained in domestic studies. At present, the prevalence of clarithromycin-resistant strains is of greatest practical interest (Table 2).
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Tab. 2. The frequency of isolation of clarithromycin-resistant strains of H. pylori in the Russian Federation according to different authors
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Undoubtedly, the number and volume of studies performed in the Russian Federation on the sensitivity of H. pylori to antimicrobial drugs are still insufficient and, probably, do not fully reflect the existing picture. At the same time, the analysis of the collected data allows us to draw two conclusions - 1) H. pylori resistance to clarithromycin in the Russian Federation, as in most countries of the world, has been growing since the 90s of the last century;
2) the level of H. pylori resistance to clarithromycin in the Russian Federation is high and amounts to 25-35%. This level of resilience is consistent with data from the European study mentioned above for countries in the east of the EU.
In the context of the discussion of the Maastricht IV guidelines, it is of interest to analyze the potential causes of the increase in the population resistance of H. pylori to clarithromycin. In a recently published study by F. Megraud et al. For the first time, an attempt was made to answer this question using two epidemiological approaches - a comparison of data on population resistance of H. pylori in different EU countries and data on the consumption of antimicrobial drugs. Interestingly, no correlation was found between the consumption of macrolides with a short (erythromycin) and medium (clarithromycin) half-life and an increase in H. pylori resistance. At the same time, a significant correlation was established between an increase in the frequency of macrolide-resistant strains and the consumption of macrolides with a long half-life (azithromycin).
Thus, the induction of clarithromycin resistance occurs indirectly through an increase in azithromycin consumption, probably to a greater extent due to prescriptions for respiratory infections. In any case, the share of antibiotic consumption for respiratory infections in the EU is 54.6%, while for gastrointestinal infections - only 0.9% of the total amount of antibiotics consumed. It should be emphasized that in the Russian Federation the situation is largely similar to the EU, and the growth rate of consumption of macrolides with a long half-life in the Russian Federation is even higher than in most EU countries (Fig. 4).
Figure: 4. Dynamics of growth in consumption of macrolides in the Russian Federation. DDD (Defined Daily Dose) per 1000 population per day. Macrolides with long t1 / 2 - azithromycin, medium t1 / 2 - roxithromycin, josamycin, clarithromycin, with a short
Requirements for antimicrobial drugs used in the eradication of H. pylori are not limited to the presence of high activity against H. pylori in vitro. Equally important are the ability to create sufficiently high (higher than the MIC for H. pylori) concentrations in the gastric mucosa, the presence of an oral form, a high safety profile, a low frequency of administration, and an acceptable price.
When choosing certain drugs for inclusion in eradication regimens, the pharmacokinetic parameters of antimicrobial drugs are often taken into account, but at the same time, one can often come across the opinion that an antibiotic does not have to create high systemic concentrations in order to eradicate H. pylori - due to localization bacteria in the stomach lining. This is a fundamentally incorrect position based on an insufficient understanding of the pharmacokinetics of antimicrobial drugs. When taken orally, antimicrobial drugs are in the lumen of the stomach for no more than 1-1.5 hours, after which they are absorbed in the duodenum. In turn, systemic antibiotic concentrations above the MIC of H. pylori are maintained, as a rule, during the entire period between doses of the drug. The accumulation of antimicrobial drugs in the gastric mucosa occurs during the distribution phase from the systemic circulation. In this regard, the concentration of the antimicrobial drug in the gastric mucosa is directly proportional to the concentration in the blood serum, which, in turn, depends on the bioavailability of the drug. Thus, in eradication schemes, those drugs that have a higher bioavailability have an advantage, for example, amoxicillin is used for eradication, and not ampicillin, which has a similar activity, but is less absorbed from the gastrointestinal tract. The only exception that confirms the rule is bismuth preparations, which realize their anti-Helicobacter potential similarly to antiseptics - by direct contact with bacteria, creating very high local concentrations and the rapid development of a bactericidal effect.
With the peculiarities of the pharmacokinetics of antibiotics, another important point is associated with anti-Helicobacter pylori therapy - the mandatory use of antisecretory drugs. Their use can significantly improve the accumulation of antibiotics in the gastric mucosa and increase the stability of drugs. It is known that some drugs, such as clarithromycin, penetrate worse into the gastric mucosa with an increase in acidity.
In a number of antibiotics (macrolides, fluoroquinolones) in an acidic environment, the activity against H. pylori decreases (Table 3).
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Tab. 3. Change in IPC 90 various antimicrobials against wild strains of H. pylori at different pH values
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Some antibiotics, in particular clarithromycin, show lower stability at low pH values. There is direct and indirect evidence, discussed in detail in the updated Maastricht IV guidelines, that high-dose proton pump inhibitors (PPIs) increase the success rate of H. pylori infection. Thus, the data above explains the rationale for using high doses of PPIs twice daily in the guidance (Statement 9, Part 2).
Natural in vitro activity against H. pylori is possessed by a significant number of antimicrobial drugs - many beta-lactams, macrolides, tetracyclines, aminoglycosides, fenicols, fosfomycin, rifamycins, fluoroquinolones, nitroimidazoles, nitrofurans, bismuth preparations. However, not all of the listed drugs and classes of antibiotics have found application in H. pylori eradication regimens. This is due to the peculiarities of pharmacokinetics, the safety profile of antimicrobial drugs, and other reasons.
Among the beta-lactam antibiotics, the only drug that fully meets the established requirements is amoxicillin. This antibiotic has a number of unique properties that make it a first-line drug in eradication regimens. First of all, this is a high activity against H. pylori, which is realized due to binding to penicillin-binding proteins (PBP) and disruption of the synthesis of the microbial wall. An extremely important feature of amoxicillin is the absence of clinically significant resistance to this antibiotic in H. pylori. Over the entire observation period, isolated reports on the isolation of resistant strains have been published, and their prevalence in the population does not exceed 1%. A more frequent mechanism of resistance is the modification of the -PSB target, for example, due to the mutation Ser-414-AKO; strains producing beta-lactamases of the TEM-1 family are less common.
Metronidazole, a representative of the nitroimidazole class, is one of the first chemotherapy drugs used to eradicate H. pylori. The mechanism of the antibacterial action of metronidazole is not fully understood. Shown to be damaging to bacterial DNA. Resistance is realized by mutation of the hexA gene, which encodes the synthesis of an oxygen-independent nitroreductase, which is responsible for the activation of nitroimidazoles inside the bacterial cell. Less commonly, resistance develops due to mutations in the frA flavin reductase genes and the functioning of the To1C efflux. Interestingly, resistance of H. pylori to metronidazole does not have the same pronounced effect on treatment outcomes as resistance to macrolides or fluoroquinolones. An increase in the dose of metronidazole, an increase in the duration of therapy, and a combination with bismuth preparations make it possible to overcome the resistance of H. pylori to this drug.
Tetracycline suppresses protein synthesis by binding to the s30 subunit of RNA and has a bacteriostatic effect on H. pylori. Despite the fact that doxycycline is a later and more advanced antibiotic in many respects, the clinical efficacy of tetracycline in eradication regimens is much higher. Replacing tetracycline with doxycycline resulted in decreased efficacy. The frequency of isolation of strains resistant to tetracycline is low and amounts to
From the group of macrolide drugs, clarithromycin is the basic anti-helicobacter drug. Little experience has been accumulated with azithromycin, but its effectiveness is significantly inferior to clarithromycin. In connection with the growth of H. pylori resistance to clarithromycin and a corresponding decrease in the rate of successful eradication, attempts are being made to use other members of the macrolide class in the therapy regimens for H. pylori infection. Thus, in the study by Liu (2000), two eradication schemes were compared: the first, including bismuth tripotassium dicitrate, furazolidone, josamycin and famotidine, and the second, bismuth tripotassium dicitrate, clarithromycin and furazolidone. The frequency of eradication was slightly higher in the josamycin group compared with the clarithromycin group - 95% and 88%, but the differences were not significant.
In recent years, fluoroquinolones have attracted the close attention of scientists and practitioners as drugs with anti-Helicobacter activity. The pharmacodynamics of fluoroquinolones is due to the binding of drugs to H. pylori DNA gyrase, which leads to a disruption in the process of topological transitions in the bacterial DNA molecule. All fluoroquinolones are to some extent active against H. pylori, but newer generation drugs are more active. The activity of fluoroquinolones in vitro against H. pylori is distributed as follows: sitafloxacin\u003e garnofloxacin\u003e levofloxacin ~ moxifloxacin ~ ciprofloxacin. It should be noted that the clinical significance of the different in vitro activity of fluoroquinolones against H. pylori has not been established. At the same time, with the development of H. pylori resistance to one of the fluoroquinolones, cross-resistance to other drugs in this group is noted. Moreover, fluoroquinolones are characterized by the rapid development of antibiotic resistance during both therapy and the spread of resistance in the population. In eradication regimens, the most well studied regimens containing levofloxacin. In the instructions for the use of fluoroquinolones in the Russian Federation, there is currently no indication for "H. pylori eradication".
Nitrofurans have limited use in H. pylori eradication regimens. The most studied drug is furazolidone. The effectiveness of Helicobacter pylori therapy when this drug is included in the eradication regimens is 78-81%. In the Russian Federation, in the official instructions for furazolidone there is no indication for "eradication of H. pylori", however, experience has been accumulated in the use of another drug from the nitrofuran group - nifuratel. The mechanism of action of nitrofurans is associated with a violation of the cellular respiration of bacteria, the Krebs cycle, inhibition of certain bacterial enzymes (pyruvate-flavodoxin-oxidoreductase,
1-oxoglutarate reductase). The pharmacodynamic feature of nitrofurans is a low resistance induction potential.
Bismuth preparations, due to the peculiarities of pharmacodynamics and pharmacokinetics, occupy a special place in the regimens of anti-Helicobacter pylori therapy. Bismuth preparations have been used in medicine for over 300 years,
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Tab. 4. Comparison of the features of the action of systemic antibiotics and antiseptics on bacterial cells |
the first experience of their use for dyspepsia was obtained in 1786. The features of bismuth preparations include: 1) a multicomponent mechanism of action against H. pylori; 2) practically absence of H. pylori resistance; 3) the presence of "non-antibiotic effects" that have a potentiating effect in diseases of the stomach - enveloping, cytoprotective, anti-inflammatory;
1) the ability to potentiate the action of other antimicrobial drugs.
The antibacterial effect of bismuth preparations, in contrast to antibiotics, is realized due to the local "antiseptic-like" action. When bismuth preparations come into contact with H. pylori, the synthesis of ATP, proteins of the bacterial wall is suppressed, bacterial adhesion, the synthesis of bacterial protease, phospholipase and urease are disrupted, the extracellular bacterial glycocalyx is damaged. Recent studies have shown that one of the mechanisms of H. pylori damage is the modification of the metabolism of iron and nickel in a bacterial cell.