Helicobacter pylori eradication scheme and three lines of therapy for Helicobacter pylori. H. pylori eradication: a modern look at an old problem Combination of effective eradication regimens

The effectiveness of the treatment of the gastrointestinal tract of the patient depends on the eradication process in his body. The bacterium Helicobacter pylori is capable of developing complications of diseases and pathology of the digestive system, so it is necessary to determine an individual approach for their destruction. Bacterial eradication is one of the most important steps in patient care.

The essence of eradication is the use of standard and individual regimens for treating a patient from the bacterium Helicobacter pylori, which are aimed at its complete destruction in the body. The destruction of harmful microorganisms that have settled on the mucous membrane of the stomach or duodenum creates favorable conditions for tissue repair, healing of erosive formations and ulcers, as well as other injuries.

Helicobacter pylori eradication is designed to exclude exacerbation of diseases, as well as their recurrence during the rehabilitation period, when the patient's body is exhausted by a long course of treatment.

Schemes for the eradication of harmful microorganisms, on average, involve therapy for a period of no more than 14 days. This treatment process has a fairly low toxicity. The effectiveness of the use of medications and antibiotics prescribed by a doctor is expressed in a fairly high performance. About 90% of patients after undergoing a re-diagnosis of the gastrointestinal tract are considered healthy, since there are no signs of helicobacteriosis.

Helicobacter pylori eradication includes some features that make this process more versatile in the treatment of the patient. One of the most important features is aimed at improving the convenience of following such a course of treatment.

The use of potent proton pump inhibitors help the body work, and the patient does not have to follow a strict diet. Of course, nutrition should be balanced and many foods should be excluded from the diet. However, this group of drugs allows you to expand the range of products that can be consumed during the treatment period.

Also, the course of treatment duration can be changed under certain conditions. If the patient improves well enough quickly, then 14 days of antibiotic therapy can be replaced by 10 days or weeks.
The use of drugs with combined properties allows you to simultaneously use a smaller amount of them.

Very frequent daily use of drugs of different properties can worsen the patient's condition or neutralize the effect of another. Reducing the number of drugs taken reduces the likelihood of harm to the patient, as well as preventing high levels of chemicals in the blood. The frequency of taking drugs and their dosage can also be changed. Means of prolonged form can be used in smaller quantities, but in this case, the course of treatment can be calculated for a longer period.

Eradication of the bacterium Helicobacter pylori can prevent a number of possible side effects that may occur during treatment with a specific regimen. The correct and individual selection of medications, antibiotics, proton pump inhibitors, H2-histamine receptor blockers can reduce the likelihood of the body not accepting the substances that are in their composition. Also, a wide variety of drugs increases the effectiveness of the course of treatment.

Eradication of dangerous microorganisms Helicobacter pylori, started at an early stage of its development, allows to overcome its resistance to certain antibiotics. The longer the bacterium is produced in the cells of the digestive system, the more resistant it is. This type of microorganism tolerates the acidic environment of the stomach, and during treatment with small doses of antibiotics it can develop partial resistance against them.

The treatment approach can be flexible. If the patient has an individual intolerance to individual components in the standard scheme, then some of them can be replaced with drugs similar in their properties.
All these characteristics make it possible to increase the effective eradication of Helicobacter pylori and to choose an individual approach to the treatment of the patient.

Eradication therapy must meet the basic requirements of the treatment course:

• high effectiveness of drug treatment;
• effective destruction of harmful bacteria in the body;
• low frequency of possible side effects in the patient;
• profitability;
• active influence on ulcerative processes in the gastrointestinal tract and impact on damaged areas;
• low level of influence of most resistant strains on the frequency of the eradication process.

The better these indicators are with a certain treatment regimen, the more effective the process of eradication of Helicobacter pylori bacteria will be.

Eradication therapy may not always have an absolute result. Until today, many discoveries have taken place in medicine and approaches to treatment have also changed.
The effectiveness of therapy has increased, but still cannot guarantee a complete recovery from harmful bacteria. Now eradication by drug methods is divided into 3 levels of therapy. Each subsequent scheme implies an increase in the use of complementary drugs of various effects and antibiotics.

Indications for eradication therapy against Helicobacter pylori.
First of all, therapy is needed with the positive results of diagnosing the patient's body for helicobacteriosis. If this type of bacteria has caused the formation of gastric ulcer, lymphoma, various forms of gastritis.
Therapy may be prescribed if signs of a cancerous tumor are found after gastric resection. And also at the request of the patient himself, if his next of kin were sick with stomach cancer, and only after a detailed consultation with a doctor.

The expediency of carrying out eradication therapy for Helicobacter pylori lies in several aspects.

functional dyspepsia. Dyspepsia during eradication is a reasonable choice for prophylaxis during treatment, which improves the patient's well-being for a significant period of time (or until complete recovery).

Gastroesophageal reflux. If the treatment is aimed at suppressing the production of hydrochloric acid and caustic enzymes by the digestive system, and the process of eradication therapy is not associated with the manifestation of an existing gastroesophageal reflux disease in the body.

The defeat of the gastroduodenal mucosa of the digestive system. If lesions are induced while taking non-steroidal anti-inflammatory drugs, then eradication therapy is necessary. This is due to the fact that the use of non-steroidal anti-inflammatory drugs cannot adequately prevent recurrence of bleeding in patients with ulcerative pathology. Also, such drugs do not accelerate the process of recovery of gastric and duodenal ulcers, they help to alleviate the symptoms of the disease, but do not eliminate the cause of their appearance.

Video “Helicobacter pylori”

Schemes and preparations

The presence of indications for the eradication of Helicobacter pylori bacteria is determined after the diagnosis of the patient.

If signs of the presence of harmful microorganisms or the DNA of these bacteria are found in the patient's gastrointestinal tract, then the doctor needs to make a correct diagnosis and prescribe a treatment regimen for the patient.

Since Helicobacter pylori is present in the organisms of most of the world's population, it is not always at the stage of active development. If a person does not experience exacerbation of symptoms of a disease of the digestive system, then you should not take hasty treatment with antibiotic drugs.

Carrying out diagnostics by various methods allows you to establish with high accuracy the presence of bacteria in the body, the stage of their development and damage to the stomach or duodenum. But only the presence of Helicobacter pylori in the digestive organs is not a sufficient reason to start the eradication of the pathogen.

Sometimes the presence of a bacterium is detected randomly during the analysis of biological material for the presence of pathogens of other diseases.
Without characteristic signs of a disease of the gastrointestinal tract, the treatment of helicobacteriosis is carried out according to a conservative method.

Such a scheme is determined by a gastroenterologist. The doctor prescribes a special diet and diet. Compliance with a number of preventive measures will help prevent the spread of bacteria in the stomach and intestines. In such a situation, therapy with antibiotics and other medications is not considered justified. During the prevention of the digestive system, radical treatment regimens can cause more harm to a person than following conservative methods.

In the absence of symptoms of helicobacteriosis, in addition to the diet and diet, a scheme for the use of prophylactic agents is determined. They are based on natural natural ingredients, and not on pharmacological preparations.
As a conservative therapy, decoctions based on medicinal herbs, the use of honey and propolis, the preparation of various tinctures and tea are used.

If the diagnosis of the patient was carried out purposefully because of his anxiety about a number of certain symptoms, then the probability of detecting a bacterium present in the body is very high. Also, tests are necessary if there are some other indications for the eradication of Helicobacter pylori.

An integrated approach to the diagnosis and study of the biological material of the patient allows the doctor to determine the treatment regimen.

The method of treatment is customized on an individual basis, taking into account all the indications, the results of the analysis and the characteristics of the patient's body.
Helicobacteriosis eradication implies active treatment with antibiotics in all treatment regimens.

First line therapy regimen. Treatment according to this technique is used much more often than other combinations of drugs. The course of first-line treatment is aimed at the simultaneous use of a certain type of antibiotic and a drug that complements it.

The dosage of antibiotics is determined by the attending physician on an individual basis, taking into account all important indicators (weight, age, and others).
So during the eradication of Helicobacter pylori, antibiotics in different combinations can be used.

1 method. It is usually prescribed in the diagnosis of atrophy of the mucous membrane of the gastrointestinal tract. Antibiotics in the standard dosage for an adult.

Amoxicillin - 500 mg for 4 doses during the day or 1 gram for 2 doses in the morning and evening.

Clarithromycin - 500 mg 2 times a day.

Josamycin - 1 gram 2 times a day.

Nifuratel - 400 mg 2 times a day.

Antibiotics should be used with a complementary drug. The method most commonly used is a proton pump inhibitor.

Omeprazole - 20 mg. Lansoprazole - 30 mg. Pantoprazole - 40 mg. Esomeprazole - 20 mg. Rabeprazole - 20 mg. Used 2 times a day.

2 method. Medications that are used in the first method can also be prescribed with the addition of an additional component - bismuth tripotassium dicitrate - 120 mg 4 times a day or a double dosage 2 times a day.
First-line eradication usually resolves within 2 weeks. It is possible to shorten the period.

Second line therapy regimen. The gastroenterologist prescribes such therapy if the previous approach did not give the necessary results.

This technique consists in the use of one antibiotic and two complementary drugs at the same time.

One agent belongs to the group of proton pump inhibitors, and the other to the group of H2-histamine receptor blockers.

Also, for the eradication of second-line helicobacteriosis, antibiotics Tetracycline and Metronidazole can be used - 500 mg 3 times a day.

Among the proton pump inhibitors, the doctor chooses the most appropriate drug: Maalox, Phosphalugel or Almagel.

H2-histamine receptor blockers include Ranitidine, Kvamatel, Roxatidine and Famotidine. One of them must be included in the treatment regimen.

Each treatment method may have a different dosage of antibiotics and their combination with other drugs.

The simultaneous use of these three groups of drugs can increase the effectiveness of the eradication process. Treatment according to this scheme is designed for 10 days.

Scheme of combination therapy. It is prescribed in the event that the tritherapy of helicobacteriosis did not help the patient.

This scheme implies the maximum possible use of medicines (taking into account overdose). Two types of antibiotics and also complementary drugs are prescribed.

All types of antibiotics can be combined at the same time. For example, Tetracycline and Metronidazole, Clarithromycin and Amoxycycline, and other combinations.
The correct selection of a combination of antibiotics will reduce the likelihood of a conflict between the substances that make up their composition, and will also help expand the spectrum of their action.
The use of more medication reduces the course of therapy to 7 days.

E. A. J. Rose and R. W. M. Holst

Current trends in the eradication of Helicobacter pylori in peptic ulcer

Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, The Netherlands

Pharmacological suppression of gastric acid secretion has traditionally been the most rational approach to successful healing of ulcers. At the same time, ulcers initially treated with antisecretory therapy tend to recur after treatment is stopped. This trend clearly changes after the eradication of Helicobacter pylori. Antimicrobial treatment should be given to all patients with documented gastric and duodenal disease associated with H. pylori infection.

The optimal therapeutic regimen for H. pylori eradication has not yet been definitively determined. The use of monotherapy and dual therapy does not make it possible to achieve an effective result in more than 90% of patients. Bismuth-based triplet therapy (bismuth, tetracycline, and metronidazole) is highly effective when the H. pylori strain is sensitive to metronidazole and the patient is on the treatment regimen. However, side effects are common. Triplet therapy consisting of omeprazole and 2 antimicrobials (clarithromycin and/or amoxicillin and/or metronidazole) and quadruplet therapy (bismuth-based triplet therapy plus omeprazole) are highly effective, and patient compliance is improved due to shorter treatment times. course (1 week). According to preliminary data, the effectiveness of the treatment method is not affected by resistance to imidazole.

H. pylori eradication prevents complications and recurrences of peptic ulcer disease and is a cost-effective method of choice compared to long-term acid suppression therapy.

It is now generally accepted that Helicobacter pylori is the primary pathological factor contributing to the onset of gastritis and is highly associated with peptic ulcer disease. Almost all patients with duodenal ulcer have gastritis induced by H. pylori. The relationship between H. pylori infection and gastric ulcer is not much smaller, since 80 out of 100% of patients with nonsteroidal anti-inflammatory drug (NSAID) gastric ulcers are H. pylori-positive. However, a minority of people infected with H. pylori develop peptic ulcers. In this regard, it is obvious that the variability of strains, factors associated with the macroorganism, etc. should also play an important role in the pathogenesis of peptic ulcer.

In a significant percentage of patients with peptic ulcer, not only of the stomach, but also of the duodenum, the cause of ulceration is aspirin or other NSAIDs. A causal relationship of NSAIDs with ulceration is suggested in cases where gastritis is not detected histologically in the surrounding mucosa.

However, if H. pylori-associated gastritis occurs, NSAIDs may be one of the interacting factors in the pathogenesis of ulceration. A clear interaction between H. pylori and NSAIDs, as the most common factors in the pathogenesis of peptic ulcer, is unknown.

Although H. pylori infection and NSAIDs are "uncomfortable partners" in peptic ulcer disease, preliminary studies have shown that H. pylori eradication has no effect on healing or recurrence in NSAID-associated peptic ulcer disease. At the same time, patients who are H. pylori-positive, especially smokers, are more likely to develop gastric ulcer during treatment with NSAIDs.

The rediscovery of H. pylori has had a major impact on our understanding of the pathogenesis and treatment of peptic ulcer. This article presents the main directions for the eradication of H. pylori in peptic ulcer, not associated with either the Zollinger-Ellison syndrome or NSAIDs.

1. Indications for anti-helicobacter therapy for peptic ulcer

The international working group, which met for the first time at the World Congress of Gastroenterology in Sydney in 1990 and again at the European Congress in Athens in 1992, tentatively expressed the wish that H. pylori eradication treatment should be carried out in patients with severe or mild peptic ulcer. diseases of the duodenum.

In 1994, at the National Institutes of Health Concept Conference, it was concluded that antimicrobial therapy should be given to all patients with documented H. pylori-associated gastric and duodenal ulcers, as well as to patients with peptic ulcer disease, manifested while taking NSAIDs, including if the ulcer is diagnosed for the first time. This wish is based on reports from a number of countries showing that eradication of H. pylori results in faster ulcer healing, lower recurrence rates, and reduced morbidity.

Before treating a peptic ulcer with anti-Helicobacter methods, the doctor must document the presence of an ulcer at least once. Currently, endoscopy is used to evaluate dyspeptic symptoms. If a stomach ulcer is detected, biopsies should be performed for further histological examination in order to exclude malignancy. During endoscopy, a mucosal biopsy can also be performed. This makes it possible to detect H. pylori infection in 70 of 90% of patients with gastric ulcers and in > 95% of patients with duodenal ulcers.

Especially in gastric ulcers, H. pylori must be detected before a doctor can prescribe antibiotic treatment.

As for duodenal ulcers, as well as those patients who have indications of a history of duodenal ulcers, the question of the need to identify H. pylori is discussed, since in reality there is a 100% association with the microorganism.

Mucosal biopsy culture has traditionally been considered the "gold standard", but it is usually used only in research settings and is the least sensitive diagnostic test (85 to 95% positive). At the same time, an advantage is the possibility of conducting an antimicrobial susceptibility test. This can be very useful in the case of previous unsuccessful eradications. In the absence of culture samples, histology or a rapid urease test can be performed to detect H. pylori, with sensitivity and specificity of 90% and 95%, respectively.

If endoscopy is not available, H. pylori can be detected non-invasively with a 13C- or 14C-labeled urea breath test or a serological test. Of course, a positive test does not confirm the diagnosis of peptic ulcer, but these tests may be used, for example, in patients who have had a documented peptic ulcer in the past and are currently not symptomatic on maintenance therapy with H2-histamine receptor blockers, if they are going to conduct anti-helicobacter treatment. Unfortunately, the breath test is not yet sufficiently available to diagnose H. pylori infection, but we hope it will become available, especially to confirm successful H. pylori treatment.

Serological tests may also be used to detect H. pylori. The most widely used method is enzyme-linked immunosorbent assay (ELISA), which is cost-effective, has high sensitivity and specificity. However, this non-invasive test only detects H. pylori infection and does not detect active peptic ulcer disease. At the same time, serological tests can be used as a control of ongoing anti-Helicobacter treatment. A drop containing at least 50% IgG antibodies in titer over a period of 3 to 6 months can accurately confirm H. pylori eradication without the need for invasive diagnostic tests.

2. H. pylori eradication

H. pylori is highly sensitive to a number of antibiotics in vitro, although in vivo efficacy is often less encouraging. Many treatment regimens have been used in which 2 to 4 drugs have been combined. Very often, treatments that are highly effective in one center have been found to be ineffective when replicated in other institutions. Sometimes this can be explained by insufficiently accurate detection methods, small sample sizes, or non-compliance with the patient regimen. Moreover, resistance to antibiotics, especially to metronidazole and probably in the future also to clarithromycin, may explain the differences in the results of a number of published studies.

An ideal antimicrobial agent should have a narrow antimicrobial spectrum, be stable and active at acidic pH (stomach) as well as at neutral pH (in the underlying compartments and in the mucosal layer), and should also enter the gastric mucosa in an active form, penetrating into mucosal layer either from the lumen or through its own membrane. The drug combination should be simple, highly effective, cheap, and free from side effects, while resistance to antimicrobial agents should not increase. Unfortunately, such a combination of drugs has not yet been found, although researchers are close to the goal.

3. Suggested drug combinations

Monotherapy

Monotherapy using bismuth compounds or antimicrobials is not very effective. When using monotherapy with amoxicillin or bismuth preparations, eradication of H. pylori can be achieved in no more than 15-20% of cases.

Clarithromycin proved to be the most effective monotherapy, with eradication rates achieved in a small number of patients between 15% and 54%. However, antimicrobial monotherapy using nitroimidazoles or macrolides increases the risk of developing resistance. In this regard, monotherapy should not be used for the eradication of H. pylori.

Dual Therapy

On the other hand, dual therapy is very attractive and promising. The combination of bismuth compounds with an antimicrobial drug (amoxicillin, clarithromycin) promotes the eradication of H. pylori in 40-60% of cases. The combination of a bismuth compound with imidazole (metronidazole, tinidazole) is effective, but largely depends on the sensitivity to imidazole (Table 1).

Abbreviations: KVS - tripotassium bismuth dicitrate (colloidal bismuth subcitrate); (Res.) Ќ imidazole-resistant, (Sen.) Ќ imidazole-sensitive.

In a study by Goodwin et al. eradication of H. pylori was achieved in 91% of patients sensitive to tinidazole, but only in 20% of patients resistant to this drug. Before prescribing imidazole, it is necessary to determine the patient's sensitivity to it, especially if there is a high prevalence of resistance locally (usually caused by the irrational use of these compounds for the treatment of a number of other infections). In France, strains tested in various laboratories showed an alarmingly high percentage (60%) of resistance to H. pylori nitroimidazoles. Currently, resistance to clarithromycin is uncommon (less than 5%). Although in France, where this drug is used more often, resistance is observed in 9.8% of cases.

Proton pump inhibitors (PPIs) such as omeprazole, in combination with either amoxicillin or clarithromycin, have been reported to promote high rates of H. pylori eradication (Table 1). One of the advantages of using the omeprazole-amoxicillin combination is that potential resistance to imidazole is irrelevant, since H. pylori is always sensitive to amoxicillin. Unfortunately, the effectiveness of antibiotics is less in smokers than in non-smokers. According to a study by Unge et al., H. pylori eradication with dual treatment with omeprazole + amoxicillin was achieved in only 33% of smokers compared to 88% in non-smokers.

It remains unclear whether PPIs have a direct anti-Helicobacter effect in vivo, or whether they exhibit antibacterial activity indirectly through potent inhibition of acid production. Probably, the higher efficacy of a number of antibiotics at neutral pH explains the effectiveness of PPIs in combination with these antimicrobials. The change in the nature of H. pylori colonization from the antrum to the body of the stomach and the tendency of the microbe to migrate from the surface of the stomach into the deeper layers of the gastric pits can lead to analytical errors, which explains some conflicting literature data on the effectiveness of the combination of PPIs and antimicrobials on the eradication of H. pylori . In most studies, only antral biopsies are taken after treatment, and thus false-negative culture and histopathological results can be obtained. In addition, overgrowth of a number of other bacteria at the same time that a patient is receiving PPI treatment can lead to false-negative H. pylori cultures.

Optimum results are obtained when omeprazole is given twice daily and combined with an antibiotic for at least 2 weeks, resulting in a H. pylori eradication rate between 24 and 93%. If a PPI is used within the week(s) before starting amoxicillin, the effectiveness is reduced.

The combination of omeprazole and clarithromycin is also effective. Clarithromycin has theoretical advantages over other macrolides due to acid stability and low pH solubility. Unlike other macrolides, it is concentrated in the gastric mucosa, and this probably explains its H. pylori eradication efficiency of about 50%, even when given as monotherapy. The combination with omeprazole is well tolerated and promotes eradication of H. pylori in 61-72% of patients.

In the future, if clarithromycin is used more widely for other diseases, resistance will develop and effectiveness will decrease.

Triplet Therapy

According to published data, combinations of three different drugs were found to be the most effective. One of the most effective H. pylori eradication regimens has been found to be a bismuth salt with tetracycline or amoxicillin in combination with an imidazole derivative (metronidazole or tinidazole), which results in an eradication rate of about 90%. These regimens require a large number of tablets to be taken, which makes them difficult to adhere to carefully, in addition, sensitivity to imidazole also affects the results (Table 2).

Abbreviations: a* - sensitivity to imidazole has not been tested, but, according to the literature, in the studied population turned out to be very low; KVS - tripotassium bismuth dicitrate (colloidal bismuth subcitrate); (Res.) Ќ imidazole-resistant, (Sen.) Ќ imidazole-sensitive.

One of the disadvantages of triplet therapy is the high rate of side effects (20 to 50%). They are usually mild and include loose stools, nausea, headache, burning sensation in the mouth, rash, dizziness, or candidiasis. More serious side effects include diarrhea and pseudomembranous colitis.

At the same time, in one study conducted on 100 patients treated with tripotassium bismuth dicitrate (colloidal bismuth subcitrate) at a dose of 480 mg / day, tetracycline 1000 mg / day. and metronidazole 750 mg/day. within 15 days, it was shown that eradication of H. pylori was achieved in 93% of patients, and only 3% of patients were forced to stop treatment due to severe side effects (severe diarrhea, nausea with vomiting, severe rash). In Ginstock's review, it was estimated that side effects were the reason for discontinuation of treatment aimed at eradication in 8-12% of patients.

Adequate information about possible side effects, avoidance of concomitant alcohol (ethanol) intake and limiting the course of treatment to 2 weeks is likely to improve the tolerability of this type of triplet therapy, as well as increase its effectiveness in H. pylori eradication. The course of treatment for one week is as effective as a 2-week one, but patients tolerate the treatment much better.

Henchel et al. reported 89% eradication of H. pylori after a combination of ranitidine 300 mg at night for 6 to 10 weeks with amoxicillin 750 mg 3 times daily and metronidazole 500 mg 3 times daily for the first 10 days. However, there are few data in the literature on such a combination and resistance to imidazole may significantly affect the results of this method if it is used in other parts of the world where such resistance is common.

Newer, more encouraging and simpler methods are the use of omeprazole and 2 antimicrobials such as amoxicillin, metronidazole and/or clarithromycin. These combinations are simpler and better tolerated than the original "triplet" therapy.

The use of 20 mg of omeprazole once or twice a day, 250 mg of clarithromycin twice a day and 400 mg of metronidazole 2 times a day for 1 week leads to the eradication of H. pylori from 77 to 88%. Obviously, synergistic interaction underlies these excellent results. Amoxicillin 1 g twice daily can replace metronidazole in this new triplet regimen without loss of efficacy. Theoretically, amoxicillin should be preferred if metronidazole resistance exists in the patient or is widespread in the population.

At the same time, the effect of tinidazole resistance on the outcome of treatment with a combination of omeprazole, imidazole (metronidazole or tinidazole) and/or amoxicillin and clarithromycin has not been thoroughly investigated.

However, according to Bazzoli et al. from Italy, where resistance to imidazole is widespread, the H. pylori eradication rate was still over 95% with omeprazole. Bell et al. used a 2-week regimen of omeprazole, amoxicillin and metronidazole. And they reported that the eradication rate of H. pylori was 96.4% in strains sensitive to imidazole.

Quadriplet Therapy

Quadriplet therapy, which is a combination of bismuth compounds, tetracycline (or amoxicillin), metronidazole and PPI, further enhances the effectiveness of standard triplet therapy (Table 3). On average, quadriplet therapy is effective in 95% of patients. Even reducing the duration of treatment from 2 weeks to 1 week did not affect the effectiveness of this treatment. Compared with bismuth-containing triplet therapy, the addition of PPIs leads to an increase in the eradication rate up to 97%. Earlier reports indicate that the addition of omeprazole may overcome metronidazole resistance through an as yet unknown mechanism.

Abbreviations: a* - p=0.015; TO
BC - tripotassium bismuth dicitrate (colloidal bismuth subcitrate).

Practical approaches and recommendations for the treatment of H. pylori infection in peptic ulcer

Eradication of H. pylori is largely indicated in all patients with peptic ulcer, as it leads to more rapid healing of the ulcer, lowers the recurrence rate and reduces the rate of complications.

The physician has a large number of therapeutic regimens at his disposal (Table 4), but the ideal combination of drugs depends on several factors. The result of anti-Helicobacter therapy largely depends on the nature of sensitivity to imidazole / macrolides, as well as on patient compliance with the treatment regimen. Amoxicillin cannot be used in 5–10% of the population due to an allergy to penicillins. Sometimes H. pylori eradication is not achieved despite proper patient adherence to the treatment regimen and the sensitivity of the H. pylori strain to the drugs used, this indicates that there may be other, as yet unknown strains that lead to unsuccessful eradication.

Abbreviations: bid - 2 times a day; tid -3 times a day; quid - 4 times a day.

We recommend bismuth-based triplet therapy, although treatment efficacy can be significantly affected by side effects and the presence of metronidazole-resistant H. pylori strains. PPI triplet and quadruplet therapy may be even more effective, but the effect of side effects and the presence of metronidazole-resistant H. pylori strains on the rate of cure has not yet been established.

The material was provided by the representative office of Sanofi in Ukraine

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 the life cycle of 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 use in gastric juice, high concentrations of the drug are achieved, which allows 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, an increase in the prevalence of clarithromycin-resistant strains of H. pylori has been recorded in recent years. 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, is still a matter of debate. 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 the damaging effects of drugs by increasing cyclooxygenase activity and prostaglandin synthesis, 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 rescue 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 one of the most common infections in the world. These bacteria play a key role in the development of gastritis, peptic ulcer disease, B-cell lymphoma, and stomach cancer. Eradication therapy is considered successful if it provides a cure rate of more than 80%.

Antibiotic resistance

First line therapy

It should be emphasized that in connection with the growth of H. pylori drug resistance to antibiotics, it is advisable to use original proton pump inhibitors (esomeprazole) and original clarithromycin (Klacid) for eradication.

Proton pump inhibitors (PPIs) at the heart of the triple regimen have been the first-line therapy for more than a decade. According to Maastricht III, the traditional first-line treatment of PPIs (twice a day), amoxicillin (1 g twice a day) and clarithromycin (500 mg twice a day) are prescribed for 10 days. A modern meta-analysis demonstrated that 10-day and 14-day triple therapy resulted in a higher eradication rate than 7-day treatment. The XXII annual conference of the European Helicobacter Study Group (EHSG), held in September 2009 in Porto (Portugal), confirmed the leading position of triple therapy for H. pylori eradication.

Maastricht III (2005) recommended a quadruple regimen as an alternative first line therapy. The following drugs are used for treatment according to this scheme: PPI at a standard dose 2 times a day + De-nol (bismuth tripotassium dicitrate) 120 mg 4 times a day + amoxicillin 1000 mg 2 times a day + clarithromycin 500 mg 2 times a day for 10 days. Given the growing resistance to clarithromycin, quadruple therapy currently occupies a leading position.

In 2008, the European H. pylori Study Group recommended sequential therapy as first-line therapy: 5 days - PPI + amoxicillin 1000 mg 2 times a day; then 5 days - PPI + clarithromycin 500 mg 2 times a day + tinidazole 500 mg 2 times a day. Studies show that sequential therapy leads to eradication in 90%, that is, it exceeds the effectiveness of standard triple therapy. The frequency of side effects and lack of compliance is the same as with triple therapy.

In a meta-analysis of 10 clinical trials of 2747 patients, sequential therapy was superior to standard triple therapy in eradicating H. pylori infection in first-time treated patients. The H. pylori eradication rate was 93.4% (91.3-95.5%) with sequential therapy (n = 1363) and 76.9% (71.0-82.8%) with standard triple therapy (n = 1384). Most of the patients included in these studies were Italian, so further international research is needed. The eradication rate in clarithromycin-resistant patients with sequential therapy was 83.3%, triple therapy - 25.9% (odds ratio (OR) 10.21; significant interval (CI) 3.01-34.58; p< 0,001) .

Second line therapy

A European study showed that the combination of a PPI (twice a day) with levofloxacin (500 mg twice a day) and amoxicillin (1 g twice a day) is effective as a second-line therapy and may have fewer side effects than traditional quadruple therapy. The frequency of eradication according to this scheme as a second-line therapy is 77%. The levofloxacin regimen currently occupies a leading position as second-line therapy.

Quadrotherapy (PPI twice a day, bismuth 120 mg four times a day, metronidazole 250 mg four times a day, tetracycline 500 mg four times a day) should not be widely used in Russia due to total resistance to metronidazole.

Third line therapy

XXII Conference of the European H. pylori Study Group (EHSG), held in Porto (Portugal) in September 2009, recommended as a third-line therapy regimen - PPI (twice a day), amoxicillin (1 g twice a day) and rifabutin (150 mg twice daily) for 10 days. Resistance to rifabutin is also possible, and as it is a first-line treatment for tuberculosis, its use should be limited. A recent German study was performed in more than 100 patients with at least one previous eradication failure and H. pylori resistance to metronidazole and clarithromycin. In these patients, triple therapy with esomeprazole (40 mg), moxifloxacin (400 mg) and rifabutin (300 mg once a day) for 7 days gave an eradication rate of 77.7%.

Complementary Therapy

The occurrence of side effects can reduce patient compliance and lead to the emergence of bacterial resistance. This has stimulated a lot of work to find alternative treatments for H. pylori. A recent study showed that the addition of probiotic strains of Bacillus and Streptococcus faecium to therapy increased compliance, reduced the incidence of side effects, and increased the eradication rate. The most studied probiotics are lactic acid-producing bacteria of the genus Lactobacillus. Probiotics play a role in stabilizing the barrier function of the stomach and reducing mucosal inflammation. Some probiotics, such as Lactobacilli and Bifidobacteria, secrete bacteriocins that can inhibit the growth of H. pylori and decrease its adhesion to gastric epitheliocytes. The frequency of eradication with the use of probiotics did not always increase, but the frequency of side effects, especially diarrhea, nausea and taste disturbance, decreased significantly. A large meta-analysis of standard triple therapy with and without probiotics showed a significant reduction in side effects and a slight increase in eradication rates. In a meta-analysis of 8 randomized trials, the rate of H. pylori eradication when combined with triple therapy with lactobacilli was 82.26%, without probiotics - 76.97% (p = 0.01). The overall frequency of side effects did not differ. However, the addition of lactobacilli reduced the incidence of diarrhea, bloating, and taste disturbance. Thus, the use of probiotics (eg, Linex) can increase the frequency of eradication and reduce side effects.

Therapy of the future

Therapeutic vaccination could save millions of lives, be more cost-effective, and have fewer potential complications than antimicrobial prescriptions. The first studies in animal models demonstrated the efficacy of immunization and gave great promise for a human vaccine. However, developing a vaccine against this unique microorganism has proved very difficult. Initially, vaccination was thought to be given orally because H. pylori is a non-invasive pathogen. However, due to the acidic contents of the stomach, finding a vaccine that could pass this environment and remain effective proved problematic. Another difficulty in the development of oral vaccines is the possibility of additional stimulation of the immune system. In human testing of an oral therapeutic vaccine that consisted of recombinant H. pylori apoenzyme urease and heat-labile Escherichia coli toxin, a large number of patients developed diarrhea. However, these patients had a reduced H. pylori bacterial load. Advances in knowledge of the immunogenicity of H. pylori will aid in the development of a commercially available vaccine.

Conclusion

The XXII EHSG Conference (Porto, Portugal, September 2009) continues to recommend 10-day triple therapy as the leading regimen for H. pylori eradication. An alternative to triple therapy is a four-component regimen with PPI, De-nol, amoxicillin and clarithromycin. Antibiotic resistance in H. pylori is a growing problem and should be investigated regionally and internationally. Levofloxacin-based therapy is effective as a second-line therapy with fewer side effects compared to quadruple therapy. Rifabutin regimens are third-line therapy in clinically difficult cases.

Literature

Aebischer T., Schmitt A., Walduck A. K. et al. Helicobacter pylori vaccine development; facing the challenge // Int. J. Med. microbiol. 2005. V. 295, No. 3. P. 343-353.

Bang S. Y., Han D. S., Eun C. S. et al. Changing patterns of antibiotic resistance of Helicobacter pylori in patients with peptic ulcer disease // Korean J. Gastroenterol. 2007. V. 50. P. 356-362.

Boyanova L., Gergova G., Nikolov R. et al. Prevalence and evolution of Helicobacter pylori resistance to 6 antibacterial agents over 12 years and correlation between susceptibility testing methods // Diagn. microbiol. Infect. Dis. 2008. V. 60, No. 2. P. 409-415.

Calvet X., Garcia N., Lopez T. et al. A meta-analysis of shorl versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Helicobacter pylori infection // Aliment. Pharmacol. Ther. 2000. V. 14, No. 4. P. 603-609.

Chisholm S. A., Teare E. L., Davies K. et al. Surveillance of primary antibiotic resistance of Helicobacter pylori at centers in England and Wales over a six-year period (2000-2005) // Euro Surveill. 2007. No. 12. P. E3-E4.

De Francesco V., Zullo A., Hassan C. et al. The prolongation of triple therapy for Helicobacter pylori does not allow reaching a therapeutic outcome of sequential scheme: a prospective, randomized study // Dig. Liver. Dis. 2004. V. 36, No. 3. P. 322-326.

Gatta L., Vakil N., Leandro G. et al. Sequential Therapy or Triple Therapy for Helicobacter pylori Infection: Systematic Review and Meta-Analysis of Randomized Controlled Trials in Adults and Children // Am. J. Gastroenterol. 2009. Oct 20.

Gisbert J. P., Bermejo F., Castro-Fernandez M. et al. H. pylori Study Group of the Association Espanola de Gastroenterologia. Second-line rescue therapy with levofloxacin alter H. pylori treatment failure: a Spanish multicenter study of 300 patients // Am. J. Gastroenterol. 2008. V. 103, No. 1. P. 71-76.

Gisbert J. P., De la Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure // Aliment. Pharmacol. Ther. 2006. V. 23, No. 1. P. 35-44.

Gotteland M., Brunser O., Cruchet S. Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori? Aliment. Pharmacol. Ther. 2006. V. 23, No. 10. P. 1077-1086.

Hu C. T., Wu C. C., Lin C. Y. et al. Resistance rate to antibiotics of Helicobacter pylori isolates in eastern Taiwan // J. Gastroenterol. Hepatol. 2007. V. 22, No. 7. P. 720-723.

Jafri N. S., Hornung C. A., Howden C. W. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment // Ann. Intern. Med. 2008. V. 19, No. 4. P. 243-248.

Kobayashi I., Murakami K., Kato M. et al. Changing antimicrobial susceptibility epidemiology of Helicobacter pylori strains in Japan between 2002 and 2005 // J. Clin. microbiol. 2007. V. 45, No. 10. P. 4006-4010.

Lesbros-Pantoflickova D., Corthesy-Theulaz I., Blum A. L. Helicobacter pylori and probiotics // J. Nutr. 2007. V. 137, No. 8. P. 812S-818S.

Malfertheiner P., Megraud F., O'Morain C. et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report // Gut. 2007. V. 56, No. 7. P. 772-781.

Michetti P., Kreiss C., Kotloff K. L. et al. Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults // Gastroenterology. 1999. V. 116, No. 6. P. 804-812.

Nista E. C., Candelli M., Cremonini F. et al. Bacillus clausii therapy to reduce side-effects of anti-Helicobacter pylori treatment: randomized, double-blind, placebo controlled trial // Aliment. Pharmacol. Ther. 2004. V. 20, No. 6. P. 1181-1188.

O'Connor A., ​​Gisbert J., O'Morain C. Treatment of Helicobacter pylori infection // Helicobacter. 2009. V. 14, Suppl. 1. P. 46-51.

Park S. K., Park D. I., Choi J. S. et al. The effect of probiotics on Helicobacter pylori eradication // Hepatogastroenterology. 2007. V. 54, No. 6. P. 2032-2036.

Vaira D., Zullo A., Vakil N. et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial // Ann. Intern. Med. 2007. V. 146, No. 3. P. 556-563.

Van der Poorten D., Katelaris P. H. The effectiveness of rifabutin triple therapy for patients with difficull-to-eradicate Helicobacter pylori in clinical practice // Aliment. Pharmacol. Ther. 2007. V. 26, No. 7. P. 1537-1542.

Zou J., Dong J., Yu X. Meta-analysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for Helicobacter pylori eradication // Helicobacter. 2009. V. 14, No. 5. P. 97-107.

Zullo A., Pema F., Hassan C. et al. Primary antibiotic resistance in Helicobacter pylori strains isolated in northern and central Italy // Aliment. Pharmacol. Ther. 2007. V. 25, No. 6. P. 1429-1434.

V. V. Tsukanov*,
O. S. Amelchugova*,
P. L. Shcherbakov**, doctor of medical sciences, professor

*Research Institute for Medical Problems of the North, Siberian Branch of the Russian Academy of Medical Sciences, Krasnoyarsk
**Central Research Institute of Gastroenterology, Moscow