Results of a systematic review and meta-analysis

H. pylori infection is the cause of gastric and duodenal ulcers, gastric MALT lymphomas, and gastric cancer. Currently, a large number of eradication therapy regimens have been proposed: standard triple therapy with amoxicillin, clarithromycin and a proton pump inhibitor (PPI); bismuth-based quadruple therapy, sequential and concomitant therapy. One of the global problems at the moment is the growing resistance to clarithromycin and metronidazole. To overcome this problem, sequential therapy has become increasingly used in clinical practice, including the appointment of a PPI and amoxicillin at a dose of 1 g 2 times a day for the first five days, and for the subsequent five days - PPI, clarithromycin 500 mg 2 times a day and a drug from group of nitromidazoles at a dose of 500 mg 2 times a day. Recent studies comparing this regimen with triple therapy provide encouraging results and suggest the effectiveness of the new eradication regimen.

Target

Compare sequential eradication therapy with other H. pylori eradication regimens.

Materials and methods

The study included randomized controlled trials (RCTs) found by searching databases such as Medline (from 1950 to May 2013), Embase (from 1980 to May 2013) and Cochrane Central Register of Controlled Trials (to May 2013), comparing sequential therapy with other eradication regimens in patients over 18 years of age.

results

Sequential therapy versus 7-day triple therapy.
According to the results of 22 RCTs, sequential therapy was more effective (RR = 1.21, 95% CI: 1.17-1.25). A total of 2449 patients who received sequential therapy were compared with 2566 who received 7-day triple therapy, the eradication efficiency was 86.5% (95% CI: 82.9-89.7%) and 71.5 ( 95% CI: 68.4-74.5% respectively.

One study compared the effectiveness of sequential therapy with triple therapy using PPI, amoxicillin and metronidazole and PPI, amoxicillin and clarithromycin, sequential therapy was 15.9% more effective than the first and 24.0% more than the second.

Sequential therapy versus 10-day triple therapy.
Based on the results of 14 RCTs, only a small difference in the effectiveness of the sequential eradication regimen was shown (RR = 1.11, 95% CI: 1.04-1.19).

In total, 1368 patients were included in the study, who were treated with the components of a sequential regimen and 1376 patients in whom eradication was carried out using a 10-day triple therapy, the effectiveness was 84.3% and 75.3%, respectively.

Sequential therapy versus 14-day triple therapy.
The results of 7 studies suggest no difference in efficacy when comparing the above two regimens (RR=1.00, 95% CI: 0.94-1.06).

The effectiveness of the sequential regimen of therapy in 1224 patients was 80.8%, and in the group of patients (n=1227) using 14-day triple therapy - 81.3%.

Sequential therapy versus bismuth-based quadruple therapy.
An analysis of the results of 3 RCTs showed no advantage of one eradication regimen over another (RR=1.01, 95% CI: 0.95-1.06).

The effectiveness of eradication in 546 patients who used sequential therapy was 86.2%, and in 545 patients who underwent eradication with drugs that are part of quadruple therapy - 84.9%.

Sequential therapy versus quadruple therapy without bismuth drug.
Six RCTs compared sequential therapy (n=1039) and quadruple therapy (n=1031) with PPIs, amoxicillin, clarithromycin, and metronidazole (treatment duration was 10 days in 4 studies and 5 days in 2 studies). Analysis of the results showed that the percentage of eradication with both regimens was the same (81.3% with quadruple therapy and 81.7% with sequential therapy).

Results of studies not included in the meta-analysis

Sequential therapy versus sequential therapy with levofloxacin.
Three studies compared the efficacy of sequential therapy with clarithromycin and sequential therapy in which levofloxacin at a dose of 500 to 1000 mg per day was used instead of clarithromycin.

Among 240 patients treated with a regimen using 1000 mg of levofloxacin per day, the percentage of eradication was 90.0%, and among 240 patients who received classical sequential therapy with clarithromycin, the effectiveness was 78.7%. Frequency side effects was approximately the same (24.3% and 24.4%, respectively).

When comparing therapy using 500 mg per day of levofloxacin (n=241) and the classical sequential eradication scheme (n=240), the effectiveness in the first case was 89.8%, and in the second - 79.5%. The incidence of side effects was 13.8% and 14.3%, respectively. Analysis of the results led to the conclusion that a sequential eradication regimen using levofloxacin is more effective than a sequential regimen using clarithromycin.

Comparison of 10-day and 14-day sequential eradication regimens.
Two RCTs compared the duration of sequential therapy: 340 patients received 10 days of consecutive therapy and 340 patients received 14 days. The effectiveness of the therapy was 87.6% and 89.7%, respectively, which did not prove that an increase in the duration of therapy increases its effectiveness.

Conclusion

The results of the meta-analysis show that the sequential eradication regimen for Helicobacter pylori infection is more effective than the 7-day standard triple therapy and shows similar efficacy when compared with eradication regimens given for more than 10 days and containing more than 2 antimicrobials.

Helicobacter pylori- a pathogenic bacterium, on the conscience of which up to 90% of all registered gastritis and ulcers. Immune to hydrochloric acid, it affects the mucous membranes of the stomach and intestines, causing inflammation of varying severity. To combat diseases provoked by this microorganism, doctors use eradication - a special therapeutic complex of various measures aimed at destroying bacteria and restoring the normal functioning of the gastrointestinal tract. What methods can be used to detect bacterium How is Helicobacter pylori eradication carried out, and what treatment regimens are there?

The patient's complaints and clinical manifestations are often not enough to make a correct diagnosis, since the symptoms characteristic of Helicobacter pylori infection may accompany other gastrointestinal diseases. To confirm or refute the involvement of Helicobacter pylori, specialists conduct a series of examinations, which may include:

• gastroscopy with taking the contents of the stomach for additional analysis;
• breath testing;
• immunological tests;
• clinical and biochemical analyzes blood;
• biopsy;
• PCR technique;
• bakposevy.

All these studies help the doctor to determine the "culprit" of the disease, identify concomitant diseases and choose the most effective and safe treatment regimen.

Helicobacter pylori eradication

For the first time, the destruction of Helicobacter pylori according to a certain scheme was tested by the Australian doctor Berry Marshal, having tested on himself. To do this, he drank a special composition with a pre-isolated culture of this bacterium, waited for inflammation and eliminated it with a combination of bismuth and metronidazole preparations.

Now several standard options for eliminating Helicobacter pylori infection have been developed, each of which the attending physician optimizes in accordance with the characteristics of the course of the disease in a particular patient. In the world practice of gastroenterology, WHO calls for adherence to the recommendations received at Maastricht 2005 - a worldwide consensus in the Netherlands on the diagnosis, management and treatment of diseases associated with the bacteria Helicobacter pylori. The criteria for the effectiveness of the chosen therapy regimen, according to the experts who took part in the congress, are:

• positive result obtained in at least 80% of patients;
• duration of active treatment not exceeding 14 days;
• the use of non-toxic drugs;
• the severity of side effects, not exceeding the benefits of treatment;
• the occurrence of various undesirable effects in no more than 15% of patients;
• lack of resistance to Helicobacter pylori in selected drugs;
• extremely simple terms intake and dosage medicines;
• prolonged action of drugs, which allows to reduce the dosage of the active substance and the number of doses per day;
• interchangeability of medicines if necessary.

First line therapy for Helicobacter pylori

The first line of therapy consists of three drugs, which is why it is also called a three-component one. Several schemes have been developed, each of which is selected only by a full-time specialist in accordance with the anamnesis, the nature of the course of the disease and possible contraindications to the use of these drugs.

Scheme No. 1 involves the use of:

• antibiotic clarithromycin.

• antibiotic amoxicillin or other antibacterial agents (metronidazole, tripochol, nifuratel).

• proton pump inhibitor (omeprazole, pantoprozol and others).

The optimal course of taking medications from this scheme is 7 days, it is this period that is sufficient for the effective destruction of pathogenic microflora. However, with insufficient effectiveness, the course of therapy can be increased to 10–14 days, but no more.

Antibacterial drugs are needed to kill Helicobacter pylori, and proton pump inhibitors act in relation to the acidity of the stomach, regulating the secretory activity of the organ and eliminating unwanted symptoms. In rare cases, if necessary, a fourth component is added at the discretion of the attending physician. But it is recommended to use the same scheme for all countries.

If the first scheme did not work or had an insufficient effect, as well as in case of atrophy of the gastric mucosa, resort to scheme No. 2. Helicobacter pylori treatment this plan includes:

• antibiotic amoxicillin.

• antibiotic clarithromycin or nifuratel (or other antibacterial drugs of a similar spectrum of action).

• bismuth drug.

The duration of the course of therapy is from 10 to 14 days, depending on the severity of the effect of drugs. Eradication control carried out through face-to-face observation and taking tests that help determine the presence and concentration of bacteria in the body, as well as evaluate the effectiveness of treatment.

There is another treatment regimen, which is mainly selected for elderly patients and people whose treatment according to the first two regimens did not bring the desired effect. It includes amoxicillin, clarithromycin and bismuth preparations.

The course is up to 14 days, but in some cases it is possible to increase the period up to 4 weeks, but only under medical supervision. In order to eliminate the effect of "addiction" of the body to drugs, experts recommend conducting the so-called sequential therapy, which distributes the selected drugs "in time". The bottom line is the orderly intake of first a combination of the first antibiotic and proton pump inhibitors, and then the second antibiotic with the same drugs that regulate stomach acidity.

Second line eradication of Helicobacter pylori

Eradication therapy the second line is necessary if the schemes of the first option did not have the desired effect or it was insufficient. Several schemes have also been developed to destroy Helicobacter pylori, each of which already includes four components.

Scheme number 1 implies the reception:

• proton pump inhibitors or dopamine receptor blockers replacing them;
• broad-spectrum antibacterial drugs (metronidazole or trichopolum);
• tetracycline;
• bismuth drug.

Scheme No. 2 includes:

• amoxicillin;
• proton pump inhibitor;
• bismuth preparation;
• one of the nitrofurans.

Therapy Helicobacter pylori according to scheme No. 3 implies the same drugs as in the second plan, but with the replacement of nitrofurans with the antibiotic rifaximin.

All second-line therapeutic regimens against Helicobacter pylori infection are designed for a long course of administration from 10 to 14 days. An increase in this period is highly discouraged due to possible side effects and the development of resistance.

In a situation where the second line of struggle against this bacterium has not brought results, experts are developing a third plan. In this case, drugs are selected more carefully with a test for the sensitivity of Helicobacter pylori to certain antibacterial agents. Bismuth preparation will be mandatory in the treatment regimen.

Folk remedies in eradication therapy

Techniques and formulations based on herbal ingredients have been used successfully for a long time to restore the mucous membranes of the stomach during the eradication of Helicobacter pylori infection. The main thing that a patient who decides to turn to herbal medicine and other similar types of alternative medicine should understand is that the effect and safety of use depends on the correct choice and compatibility of herbal remedies with basic medicines. Therefore, it is necessary to select specific funds only in tandem with the attending physician.

Preventive measures and diet after successful therapy

get rid of helicobacter pylori - does not mean once and for all forget about diseases of the gastrointestinal tract. To prevent possible re-infection with this bacterium or other equally "harmful" microorganisms, it is advisable to carefully observe personal hygiene and regularly undergo preventive examinations.

What can you do yourself to reduce the risk of disease and not treat then an inflamed stomach:

• give up nicotine and avoid passive smoking in every possible way;
• limit alcohol intake as much as possible;
• wash hands before eating, after the street and visiting public places;
• process products thermally;
• do not use other people's personal hygiene products and do not give your items to other people (this provision is also relevant not only for toothbrushes and towels, but also for decorative cosmetics);
• do not try to treat yourself if you suspect any infectious disease.

After eradication, in order to restore the normal functioning of the gastrointestinal tract as soon as possible and further prevent inflammation of the mucous membranes of the stomach, it is recommended to limit the use of:

• fatty, fried, spicy and salty foods;
• smoked meats;
• fatty sauces and oily sweet creams;
• spices and hot seasonings;
• mushrooms;
• sweet muffin;
• strong coffee and tea.

During the period of exacerbation of gastrointestinal diseases, it is undesirable to eat fresh vegetables and fruits.

Marina Pozdeeva about the principles and schemes of anti-Helicobacter therapy

Colonization of Helicobacter pylori on the surface and folds of the gastric mucosa greatly complicates antibiotic therapy. A successful treatment regimen is based on a combination of drugs that prevent the emergence of resistance and overtake the bacterium in different parts of the stomach. Therapy must ensure that even a small population of microorganisms does not remain viable.

Helicobacter pylori eradication therapy includes a complex of several drugs. A common mistake, which often leads to unpredictable results, is the replacement of even one well-studied drug from the standard regimen with another drug of the same group.

Proton pump inhibitors (PPIs)

PPI therapy has proven effective in various clinical studies. Although in vitro PPIs have a direct antibacterial effect on H. pylori, they do not play an important role in the eradication of infection.

The mechanism of PPI synergy when combined with antimicrobials, which increases the clinical efficacy of eradication therapy, has not been fully established. It is assumed that antisecretory drugs of the PPI group can increase the concentration of antimicrobial agents, in particular metronidazole and clarithromycin, in the gastric lumen. PPIs reduce the volume of gastric juice, as a result of which the leaching of antibiotics from the mucosal surface decreases, and the concentration, accordingly, increases. In addition, reducing the volume of hydrochloric acid maintains the stability of antimicrobials.

Bismuth preparations

Bismuth was one of the first drugs to eradicate H. pylori. There is evidence that bismuth has a direct bactericidal effect, although its minimum inhibitory concentration (MIC - the smallest amount of a drug that inhibits the growth of the pathogen) against H. pylori is too high. Like other heavy metals such as zinc and nickel, bismuth compounds reduce the activity of the urease enzyme, which is involved in life cycle H. pylori. In addition, bismuth preparations have local antimicrobial activity, acting directly on the bacterial cell wall and violating its integrity.

Metronidazole

H. pylori is generally very sensitive to metronidazole, whose efficacy is independent of pH. After oral or infusion administration, high concentrations of the drug are achieved in the gastric juice, which makes it possible to achieve the maximum therapeutic effect. Metronidazole is a prodrug that undergoes activation by bacterial nitroreductase during metabolism. Metronidazole causes the helical structure of the H. pylori DNA to be lost, causing the DNA to break and the bacterium to die.

NB! The result of treatment is considered positive if the results of the test for H. pylori, carried out no earlier than 4 weeks after the course of treatment, are negative. Testing before 4 weeks after eradication therapy significantly increases the risk of false negative results. It is preferable to stop taking PPIs two weeks before diagnosis.

Clarithromycin

Clarithromycin, a 14-mer macrolide, is an erythromycin derivative with a similar spectrum of activity and indications for use. However, unlike erythromycin, it is more resistant to acids and has a longer half-life. The results of studies proving that the scheme of triple eradication therapy for Helicobacter pylori using clarithromycin gives a positive result in 90% of cases, led to the widespread use of the antibiotic.

In this regard, in last years an increase in the prevalence of clarithromycin-resistant strains of H. pylori has been documented. There is no evidence that increasing the dose of clarithromycin will overcome the problem of antibiotic resistance to the drug.

Amoxicillin

An antibiotic of the penicillin series, amoxicillin, both structurally and in terms of activity spectrum is very close to ampicillin. Amoxicillin is stable in an acidic environment. The drug inhibits the synthesis of the bacterial cell wall, acts both locally and systemically after absorption into the bloodstream and subsequent penetration into the lumen of the stomach. H. pylori demonstrates good sensitivity to amoxicillin in vitro, but eradication of the bacterium requires complex therapy.

Tetracyclines

The point of application of tetracyclines is the bacterial ribosome. The antibiotic interrupts protein biosynthesis and specifically binds to the 30‑S subunit of the ribosome, eliminating the addition of amino acids to the growing peptide chain. Tetracycline has proven effective against H. pylori in vitro and remains active at low pH.

Indications for eradication therapy

In accordance with the principles adopted in Maastricht in 2000 (the Maastricht 2–2000 Consensus Report), H. pylori eradication is strongly recommended:

• all patients with peptic ulcer;
• patients with low-grade MALT-lymphoma;
• persons with atrophic gastritis;
• after resection for stomach cancer;
• relatives of patients with gastric cancer of the first degree of kinship.

The need for eradication therapy in patients with functional dyspepsia, GERD, as well as those taking non-steroidal anti-inflammatory drugs for a long time remains a subject of discussion. There is no evidence that eradication of H. pylori in such patients affects the course of the disease. However, it is well known that H. pylori patients with non-ulcer dyspepsia and corpus-predominant gastritis are at increased risk of developing gastric adenocarcinoma. Thus, H. pylori eradication should also be recommended in patients with non-ulcer dyspepsia, especially if corpus-predominant gastritis is detected on histology.

The argument against anti-Helicobacter therapy in patients taking NSAIDs is that the body protects the gastric mucosa from damaging effects medicines, increasing the activity of cyclooxygenase and the synthesis of prostaglandin, and PPIs reduce natural protection. Nevertheless, the elimination of H. pylori prior to the appointment of NSAIDs significantly reduces the risk of peptic ulcer during subsequent treatment (a study by American scientists led by Francis K. Chan, published in The Lancet in 1997).

Eradication therapy

Despite the use of combined treatment regimens, 10-20% of patients infected with H. pylori fail to achieve elimination of the pathogen. The best strategy is considered to be the selection of the most effective treatment regimen, however, the possibility of using two or even more sequential regimens should not be ruled out in case of insufficient effectiveness of the therapy of choice.

In the event of an unsuccessful first attempt at eradication of H. pylori, it is recommended to immediately switch to second-line therapy. Seeding for antibiotic susceptibility and switching to rescue regimens is indicated only for those patients in whom second-line therapy also does not lead to eradication of the pathogen.

One of the most effective "rescue regimens" is the combination of a PPI, rifabutin, and amoxicillin (or levofloxacin 500 mg) for 7 days. An Italian study led by Fabrizio Perri and published in Alimentary Pharmacology & Therapeutics in 2000 confirmed that the rifabutin regimen is effective against clarithromycin or metronidazole resistant H. pylori strains. However, the high price of rifabutin limits its widespread use.

NB! To avoid the formation of resistance simultaneously to metronidazole and clarithromycin, these drugs are never combined in one regimen. The effectiveness of this combination is very high, but patients who do not respond to therapy usually develop resistance to both drugs at once (a study by German scientists led by Ulrich Peitz, published in Alimentary Pharmacology & Therapeutics in 2002). And further selection of therapy causes serious difficulties.

Research data confirm that a 10-day salvage regimen of rabeprazole, amoxicillin and levofloxacin is much more effective than standard second-line eradication therapy (study by Italian scientists led by Enrico C Nista, published in Alimentary Pharmacology & Therapeutics in 2003 year).

Helicobacter pylori is a bacterium that can become the causative agent of diseases of the duodenum and stomach. Ulcers, gastritis, duodenitis and even cancerous tumors are often the result of the spread of this microorganism. Due to the special structure of the bacteria, it is possible to penetrate into the mucous membrane and calmly create colonies there.

In the treatment of diseases associated with Helicobacter pylori, it is important to provide a set of measures for the complete destruction of bacteria. It is considered effective only if the probability of recovery approaches the 80% mark. The average duration of such treatment is about two weeks, and the likelihood of side effects should not exceed 15%. Most of them are not serious, that is, it is not necessary to interrupt the course of drugs prescribed by the gastroenterologist because of them.

Treatment regimens

The treatment regimen should primarily provide constant high level eradication of bacteria. Helicobacter pylori eradication scheme is selected in individually depending on the sensitivity of the bacteria and the body's response to the drug.

There are many eradication (elimination) schemes, and their number increases over time. At the same time, all of them are aimed at achieving a number of tasks, including:

Circuit Design

At the moment, significant results in all the above areas have been achieved thanks to the collaboration of scientists and pharmaceutical companies. At the end of the last century, a group of the most influential industry experts was created, whose efforts are aimed at sharing knowledge about eradication.

This has enabled breakthroughs in the development of treatments and more effective trials. The greatest progress was made at the Maastricht conference in 1996. In honor of this event, the complexes for the treatment of Helicobacter pylori were subsequently named.

• amoxicillin (0.5 g 4 times a day or 1 g - 2 times);
• clarithromycin or josamycin or nifuratel (standard doses);
• bismuth tripotassium dicitrate (240 mg twice a day or half the dose - four times).

The above scheme is used only for patients with atrophy of the gastric mucosa.

Fourth option (for elderly patients):

• standard dosage of inhibitors;
• bismuth tripotassium dicitrate;

The fourth option (alternative) consists in taking bismuth tripotassium dicitrate in standard dosages for 28 days with the possible short-term use of inhibitors.

Second line

In the absence of a visible effect, a second line of eradication is used, which makes it possible to increase the effectiveness of the procedure.

Option one:

Option two:

• inhibitors;
• bismuth tripotassium dicitrate;
• preparations of the nitrofuran group;

Option three:

• proton pump inhibitor;
• bismuth tripotassium dicitrate (only 120 mg four times a day);
• rifaximin (0.4 g twice a day).

third line

There is also a third line, but its distribution is minimal due to high efficiency the options listed above. The use of this scheme takes place only in cases where the indications do not allow the use of the first two due to allergic reactions or an unsatisfactory response to treatment.

Catad_tema Peptic ulcer disease - articles

The choice of eradication therapy for helicobacter pylori in case of need for repeated treatment

T. Lapina, candidate of medical sciences,
MMA them. I. M. Sechenova

Treatment for Helicobacter pylori (Hp) infection can be considered detailed: it is standardized in terms of the combination of drugs, their doses and duration of the course. In Russia, this therapy is approved in the relevant standards of medical care and the formulary system. The national recommendations of many European countries and domestic standards for the diagnosis and treatment of Hp are based on algorithms developed under the auspices of the European Group for the Study of this infection. Since the first conferences to develop this consensus were held in Maastricht, the recommendations are called Maastricht (conferences were held in 1996, 2000 and 2005).

Schemes of eradication therapy are strictly regulated, it seems that such treatment should not raise questions. However, the implementation of any standard in practice is not always accompanied by one hundred percent efficiency. Most of the most pressing questions concern the choice of treatment regimen after the failure of the first (and sometimes second and third) attempts.

Why, then, with Hp, a repeated course of eradication therapy is sometimes required (in the English-language literature, the term “second, third-line therapy” is used to refer to it)? As an indicator indicating the optimality of the treatment regimen, all the Maastricht recommendations call 80% Hp eradication. This means that the percentage of eradication of the microorganism according to the criterion of intention-to-treat should be equal to or greater than 80%. This "target" percentage of successful eradication is proposed based on the analysis of data from many clinical studies of various treatment regimens, their availability and tolerability; it also takes into account the characteristics of Hp (the sensitivity of the microorganism to drugs, the characteristics of the habitat). A consistently high kill rate should be easily reproducible with treatment across different populations and different regions and countries.

Of decisive importance is, of course, first-line therapy, which should be aimed at achieving Hp eradication in the maximum number of patients. As a first-line therapy, the Maastricht III recommendations suggest the following three-component treatment regimens (Table 1): proton pump inhibitor at a standard dosage 2 times a day + clarithromycin - 500 mg 2 times a day + amoxicillin - 1000 mg 2 times a day or metronidazole - 400 or 500 mg 2 times a day. Minimum duration triple therapy - 7 days, but it turned out that for this regimen a 14-day course of treatment was more effective (by 12%; 95% confidence interval - CI: 7-17%). However, 7-day triple therapy may be acceptable if local studies show that it is highly effective. The same first-line therapy is recommended for all countries, although in different countries different doses of drugs may be approved.

Table 1 Standard triple therapy regimens for Hp

The four-component treatment regimen includes a proton pump inhibitor at a standard dose 2 times a day + bismuth subsalicylate / tripotassium dicitrate - 120 mg 4 times a day + metronidazole - 500 mg 3 times a day + tetracycline - 500 mg 4 times a day (Table 1). 2). In the Maastricht II recommendations, the four-component regimen was assigned the position of second-line therapy. One of the new provisions of the Maastricht III recommendations is the possibility of using such a regimen in certain clinical situations, as first-line therapy (alternative first-line therapy) .

Table 2. Schemes of four-component eradication therapy for HP

Why have the ideas about optimal first-line therapy in the Maastricht recommendations changed? Why does the search for better treatment regimens never stop? The results of clinical studies of standard triple therapy (proton pump inhibitor + amoxicillin + clarithromycin) in different countries have appeared, according to which “targeted” eradication is not achieved, i.e. it is below 80%. The most significant reason for the decrease in the effectiveness of standard eradication therapy is the resistance of the microorganism to antimicrobial agents. In the Maastricht III recommendations, much attention is paid to the issues of treatment planning depending on the sensitivity of Hp to antibacterial agents. Thus, the combination of proton pump inhibitor + clarithromycin + amoxicillin or metronidazole remains the recommended first-line therapy for populations with a clarithromycin-resistant rate of less than 15–20%. In populations with a metronidazole resistance rate of less than 40%, a proton pump inhibitor + clarithromycin + metronidazole regimen is preferable.

Let us dwell in more detail on the problem of Hp resistance to antibiotics. According to international data, Hp resistance to amoxicillin is either 0 or less than 1%. There are extremely rare reports of the formation of resistance due to mutations in the pbp-1A gene. Thus, resistance to amoxicillin is extremely rare and has no clinical significance. Equally rare is tetracycline resistance, which is not reported at all in many countries. It is caused by a mutation of 3 adjacent nucleotides in the 16S rRNA gene (AGA 926–928→TTC). According to experimental data, if a mutation occurs in only 1 or 2 of these nucleotides, resistance is clinically insignificant; only a triple mutation leads to stable resistance, which can affect treatment outcomes.

Of fundamental importance is the sensitivity of Hp to clarithromycin and metronidazole. The number of resistant Hp strains to clarithromycin, according to a multicenter European study, averages 9.9% (95% CI: 8.3-11.7). Significant differences were found in this indicator: in the Nordic countries, the incidence of resistance to clarithromycin is low (4.2%; 95% CI: 0–10.8%); it is higher in Central and Eastern Europe (9.3%; 95% CI: 0–22%) and highest in southern Europe (18%; 95% CI: 2.1–34.8%) (Fig. 1 ) . The risk of developing resistance to clarithromycin is related to the frequency of macrolide administration in this population. Due to the fact that in a number of European countries macrolides were widely prescribed in pediatric practice for, for example, respiratory diseases, the frequency of resistance of Hp strains to clarithromycin in children is very high, which makes the choice of tactics of eradication therapy a problem.

Rice. 1. The prevalence of Hp strains resistant to macrolides in European countries (according to Glupczynski Y. et al., 2000)

Responsible for resistance to clarithromycin is the mutation of the 23S rDNA gene, which leads to disruption of the spatial configuration of the ribosome. It is recognized that it contributes to the development of cross-resistance to macrolide antibiotics; however, it is not clear whether all macrolides that penetrate the gastric mucosa in different ways can lead to the selection of resistant strains in vivo.

Data on the impact of resistance to clarithromycin on the outcomes of eradication therapy are also different. The maximum of the described effects is as follows: 87.8% of Hp eradication in the presence of sensitive strains, 18.3% in the presence of resistant strains.

The number of Hp strains resistant to metronidazole in Europe and the USA ranges from 20 to 40%. It is known that in developing countries the number of metronidazole-resistant strains is higher. The most important for the selection of resistant strains is the use of metronidazole in the population. The mechanism of metronidazole resistance formation is not completely clear: changes in the rdxA gene are suspected, but the exact mutations are not known.

Observation (1996–2001) of the dynamics of resistance to nitroimidazole derivatives (metronidazole), macrolides (clarithromycin), and β-lactams (amoxicillin) in Hp strains isolated in Moscow showed that it differs from that in Europe (Fig. 2). Thus, in the adult population, the level of primary Hp resistance to metronidazole already in 1996 exceeded the European average (25.5%) and amounted to 36.1%. During 1996–1999 there was an increase in the number of primary resistant strains of Hp to metronidazole, and then it was not detected.

Rice. Fig. 2. Dynamics of resistance (in %) to metronidazole, clarithromycin and amoxicillin in Hp strains isolated from adults in Moscow in 1996–2001. (Kudryavtseva L., 2004)

In contrast to the data obtained in Europe in 1996, where in the adult population the level of primary Hp resistance to macrolides (clarithromycin) was 7.6%, no Hp strains resistant to this antibiotic were identified in Moscow at that time. The relative increase in the number of Hp strains, primarily resistant to clarithromycin, among the adult population for the 1st year of observation was 8%, for the 2nd - 6.4%, for the 3rd - 2.7%. In 2000, the level of Hp resistance to clarithromycin slightly decreased: if in 1999 it was 17.1%, then in 2000 it was 16.6%. In 2001, there was a clear downward trend in this indicator (13.8%).

In 1996, 3 Hp strains resistant to amoxicillin were isolated in Moscow; in the future, such finds were not repeated, and these data can be considered the only ones in the Russian Federation and unique.

The latest available data on the sensitivity of Hp to antibiotics in Moscow refer to 2005: in adults, the number of strains resistant to metronidazole was 54.8%, to clarithromycin - 19.3%; in children, 23.8 and 28.5%, respectively (Kudryavtseva L., 2006: personal communication).

Thus, based on the latest data, unfavorable conditions have developed in Russia for standard triple therapy due to high levels of Hp resistance to both clarithromycin and metronidazole. Nevertheless, the results of domestic clinical studies indicate a greater significance for the outcomes of therapy in our country of resistance to metronidazole than to clarithromycin. The extreme spread of strains resistant to metronidazole greatly limits the use of this antibacterial agent. So, according to V. Ivashkin et al., in a controlled study, the scheme "proton pump inhibitor + amoxicillin + metronidazole" (approved by the Maastricht recommendations I and excluded by their second revision) was successful only in 30% of cases. As for resistance to macrolides, it should be remembered that the contingent of patients from whose biopsy material strains were isolated to determine resistance was special, in particular, there were many inpatients among them. In addition, the analysis of strains obtained from individuals living in different cities of the Russian Federation revealed significant differences. Thus, no Hp strains resistant to clarithromycin were registered in Abakan (Table 3). This suggests that their prevalence outside of Moscow and St. Petersburg is below the average European level.

Table 3. The frequency of Hp antibiotic resistance in different cities of Russia in 2001 (Kudryavtseva L. et al., 2004)

It should not be forgotten that not only the antibacterial components of the treatment regimen, but also proton pump inhibitors provide a high percentage of HP destruction. It has been convincingly proven that without a proton pump inhibitor, when using only 2 of the same antibiotics at the same dosages, Hp eradication is reduced by 20-50%. It is proton pump inhibitors that serve as the basic drugs of the scheme, providing favorable conditions for the implementation of the action of antibiotics by powerful suppression of gastric secretion. If the quality of the proton pump inhibitor is low and it has little effect on intragastric pH, then the percentage of eradication of the microorganism will not reach the “target” threshold. On the other hand, a high anti-Helicobacter effect indicates successful control of gastric secretion by a proton pump inhibitor and the quality of this drug.

A large number of domestic clinical studies have demonstrated the success of standard triple therapy even with its 7-day duration. So, in the work of V. Pasechnikov et al. (2004) patients with exacerbation of duodenal ulcer (92 people) received standard triple therapy for 7 days: Omez® (omeprazole, Dr. Reddy's Laboratories Ltd.) at a dose of 40 mg / day in combination with amoxicillin (2000 mg/day) and clarithromycin (1000 mg/day). Then randomization was carried out: patients of the 1st group continued to receive omeprazole (40 mg/day) for another 2 weeks; patients of the 2nd group did not receive any treatment. Hp eradication was successful in 82.6% of patients (intention-to-treat; per protocol - 91.6%). In the 1st group, it was 84.2% (intention-to-treat; per protocol - 92.8%), in the 2nd group - 82.2% (intention-to-treat; per protocol - 90.2% ). Of fundamental importance is the fact that ulcer healing was achieved in 91.5% of patients who received Omez® monotherapy after an anti-Helicobacter pylori course, and in 93.3% of patients who received only a weekly course of Hp eradication and no further treatment. Thus, in this study, 7-day standard triple therapy contributed to the achievement of the “target” percentage of eradication and, moreover, ulcer healing even without continuing omeprazole monotherapy, which indirectly indicates the effectiveness of the anti-Helicobacter pylori course.

Various attempts are being made to improve the effectiveness of standard triple therapy. Thus, there is evidence that the combination of an anti-Helicobacter regimen with a probiotic leads to an increase in the Hp eradication rate and reduces the incidence of adverse events. Recently, a study was undertaken in Moscow with the addition of the prebiotic lactulose (Normaze) to the standard triple therapy. Omez® (40 mg/day) in combination with amoxicillin (2000 mg/day) and clarithromycin (1000 mg/day) was prescribed for 12 days and in one group of patients it was combined with Normase. Hp eradication in this group was achieved in 85% of cases, in the other - in 90% of cases (the difference is not significant). Despite the fact that lactulose did not contribute to an increase in Hp eradication (the percentage still exceeded the “target” limit), it reduced the frequency of stool disorders and flatulence.

First line therapy - standard triple– has not lost relevance for Russia. The success of Hp eradication depends on the exact observance of this standard by the doctor and the patient. The higher its score, the less likely it is to re-treat. The most reasonable way to increase the effectiveness of standard triple therapy should be recognized as an increase in its duration up to 14 days.

How should second-line therapy be planned when first-line therapy fails? Prescribing antibiotics that the patient has already received should be avoided. This is one of the fundamental (but not universally recognized) postulates on which such planning is based. From the point of view of the experts - authors of the Maastricht III recommendations, the most the right choice in this situation is bismuth quadruple therapy. The authors of the American Guidelines for the Diagnosis and Treatment of Hp came to the same conclusion. In an analysis of several dozen clinical studies using quadruple therapy as second-line therapy, the average eradication rate of the microorganism was 76% (60-100%). This scheme is available, relatively cheap and effective. Its disadvantages include big number tablets and capsules that have to be taken daily (up to 18 pieces per day), a fourfold dosing regimen and relatively often developing adverse events.

Bismuth preparations are not available in some countries, and as second-line regimens the Maastricht III recommendations suggest triple therapy options: proton pump inhibitor and amoxicillin, and tetracycline or metronidazole appear as an antibacterial agent. In Russia, there is no systematized experience in the use of such schemes, although there is evidence of a very low effectiveness of 7-day triple therapy: a proton pump inhibitor + amoxicillin + metronidazole.

In the group of patients with failed standard triple therapy, 12-day treatment with a proton pump inhibitor in combination with amoxicillin and rifabutin (150 mg) led to Hp eradication in 91% of cases, and proven resistance to metronidazole and clarithromycin did not affect the result. The attractive side of the use of rifabutin is the very low probability of formation of Hp resistance to it (described only in isolated cases). The mechanism of resistance formation (cross to all rifamycins) is a point mutation of the rpoB gene. The Maastricht III recommendations insist on the cautious use of this antibiotic, as its widespread use may lead to the selection of resistant strains of Mycobacteria.

Triple therapy with levofloxacin seems convenient to use and quite effective: a proton pump inhibitor at a standard dose twice a day in combination with amoxicillin (2000 mg/day) and levofloxacin (500 mg/day). As a second line therapy after failed standard triple therapy, this regimen has been shown to be highly effective. But with the use of levofloxacin, the problem of developing resistance to quinolones due to a number of mutations in the gyrA gene is associated. In a recently published French study that examined a large number of Hp strains, resistance was found in 17.2% of them. In the work of Italian authors (with a much smaller number of studied strains), resistance to levofloxacin was established in 30.3% of cases; the rate of successful eradication of a microorganism sensitive to this antibiotic is 75% versus 33.3% in the presence of resistance.

In the latest expert recommendations and reviews on this issue, very close attention is paid to the new Hp eradication scheme - sequential therapy. Well sequential therapy takes 10 days: for the first 5 days, a proton pump inhibitor is prescribed at a standard dose twice a day in combination with amoxicillin (2000 mg / day); then for another 5 days - a proton pump inhibitor at a standard dose twice a day in combination with clarithromycin (1000 mg / day) and tinidazole (1000 mg / day). In an Italian study with sequential therapy, Hp eradication (intention-to-treat) was 91 versus 78% in the comparison group (10-day standard triple therapy). In the group of patients infected with strains resistant to clarithromycin, this figure reached 89 versus 29%.

To rule out failure in Hp eradication, standard triple therapy should be administered in full dose and, if possible, for 14 days. The choice of treatment regimens in case of failure of first-line therapy is quite wide and allows taking into account the individual characteristics of the patient.

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