≡× MENU

• Water supply
• Pumps
• Water purification
• Wells
• Filters

A combination of a year of effective eradication regimens. Schemes for the eradication of helicobacter pylori. Indications for eradication of Helicobacter pylori

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

Modern trends in the eradication of Helicobacter pylori in peptic ulcer disease

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

Pharmacological suppression of gastric acid secretion has traditionally been the most rational approach to successfully treating ulcers. At the same time, ulcers initially healed with antisecretory therapy tend to recur after stopping treatment. This trend changes clearly after Helicobacter pylori eradication. 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 is still not fully defined. The use of monotherapy and dual therapy does not make it possible to achieve an effective result in more than 90% of patients. Triplet therapy based on the use of bismuth (bismuth, tetracycline and metronidazole) is highly effective if the H. pylori strain is sensitive to metronidazole and the patient follows the treatment regimen. However, side effects are common. Triplet therapy, consisting of omeprazole and 2 antimicrobial drugs (clarithromycin and / or amoxicillin and / or metronidazole), as well as quadriplet therapy (bismuth-based triplet therapy plus omeprazole) are highly effective, and patient compliance is facilitated by the shorter course (1 week). According to preliminary data, the effectiveness of the method of treatment is not affected by resistance to imidazole.

H. pylori eradication prevents the complications and recurrence of peptic ulcer disease and is a cost-effective method of choice over 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 less, because 80 out of 100% of patients with gastric ulcer that are not associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) are H. pylori-positive. However, a minority of individuals infected with H. pylori develop peptic ulcer disease. 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 disease.

In a significant percentage of patients with peptic ulcer disease not only of the stomach, but also of the duodenal ulcer, the cause of ulceration is aspirin or other NSAIDs. The causal relationship of NSAIDs with ulceration is assumed in cases where gastritis is not detected histologically in the surrounding mucous membrane.

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

Although H. pylori infection and NSAIDs are “uncomfortable partners” in peptic ulcer disease, preliminary studies have shown that H. pylori eradication does not affect healing or relapse in NSAID-associated peptic ulcer disease. At the same time, patients who are H. pylori-positive, especially smokers, are more likely to develop stomach ulcers 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 disease. This article presents the main directions for the eradication of H. pylori in peptic ulcer disease that is not associated with either Zollinger-Ellison syndrome or NSAIDs.

1. Indications for anti-Helicobacter pylori therapy for peptic ulcer disease

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, preliminarily expressed the wish that treatment for the eradication of H. pylori should be carried out in patients with severe or weakened ulcerative diseases of the duodenum.

In 1994, at a conference of the National Institutes dedicated to the development of the concept of health, it was concluded that antimicrobial therapy should be prescribed to all patients with documented gastric ulcer and duodenal ulcer associated with H. pylori infection, as well as to patients with peptic ulcer disease. manifested against the background of taking NSAIDs, including if the ulcer is diagnosed for the first time. This desire is based on reports from a number of countries, which have shown convincingly that H. pylori eradication promotes faster ulcer healing, a lower recurrence rate and a decrease in complication rates.

Before starting the treatment of peptic ulcer disease using anti-Helicobacter pylori methods, the doctor must document the presence of an ulcer at least once. Endoscopy is currently used to assess dyspeptic symptoms. If a stomach ulcer is found, it is necessary to make a biopsy for further histological examination in order to exclude malignancy. During endoscopy, a mucosal biopsy can also be done. This allows detection of H. pylori infection in 70 out of 90% of patients with gastric ulcer and in> 95% of patients with duodenal ulcers.

Especially for gastric ulcers, H. pylori must be identified 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 being debated, since in reality there is a 100% association with the microorganism.

Culture of mucosal biopsies is traditionally considered the "gold standard", but it is usually used only in research institutions and is the least sensitive diagnostic test (positive test from 85 to 95%). At the same time, it is an advantage that antimicrobial susceptibility test can be performed. This can be very helpful in the case of prior unsuccessful eradication. In the absence of culture samples to detect H. pylori, histology or rapid urease test can be performed, with the sensitivity and specificity being 90% and 95%, respectively.

If endoscopy is not performed, H. pylori can be detected noninvasively by a 13C or 14C labeled urea breath test or serological test. Of course, a positive test does not confirm the diagnosis of peptic ulcer disease, but these tests can be used, for example, in patients who have had documented peptic ulcer disease in the past, and currently do not note symptomatic manifestations of the disease on maintenance therapy with H2-histamine receptor blockers, if they are collected to carry out anti-Helicobacter pylori treatment. Unfortunately, the breath test is not yet available to diagnose H. pylori infection, but we hope that it will become available, especially to confirm a successful anti-H. pylori treatment.

Serologic tests can 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 diagnose active peptic ulcer disease. At the same time, serological tests can be used as a control of the ongoing anti-Helicobacter pylori treatment. A drop containing at least 50% IgG antibodies in titer for 3 to 6 months can confirm H. pylori eradication with sufficient accuracy without the need for invasive diagnostic tests.

2. Eradication of H. pylori

H. pylori is highly susceptible to a range of antibiotics in vitro, although in vivo efficacy is often less encouraging. Many treatment regimens have been used in which from 2 to 4 drugs have been combined. Very often, treatments that were highly effective, according to one center, were ineffective when replicated in other settings. 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 regions and in the mucous membrane layer), and should also enter the gastric mucosa in an active form, penetrating into a layer of mucous membrane either from the lumen or through its own membrane. The combination of drugs should be simple, highly effective, cheap, and free of side effects, and antimicrobial resistance should not increase. Unfortunately, no such drug combination has yet been found, although the researchers are close to their goal.

3. Suggested drug combinations

Monotherapy

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

Clarithromycin has proven to be the most effective monotherapy with eradication rates between 15% and 54% in a small number of patients. However, antimicrobial monotherapy with nitroimidazoles or macrolides increases the risk of developing resistance. Therefore, monotherapy should not be used to eradicate 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) contributes to 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: KBC - bismuth tripotassium dicitrate (colloidal bismuth subcitrate); (Res.) Ќ imidazole-resistant, (Sen.) Ќ imidazole-sensitive.

In a study by Goodwin et al. H. pylori eradication 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 local high prevalence of resistance (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 revealed an alarmingly high percentage (60%) of resistance to H. pylori nitroimidazoles. Currently, clarithromycin resistance is rare (less than 5%). Although in France, where the 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 eradication rates for H. pylori (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 decreases in smokers compared to nonsmokers. 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 with 88% of nonsmokers.

It remains unclear whether PPIs have a direct anti-Helicobacter effect in vivo, or whether they exert antibacterial activity indirectly through potent inhibition of acid production. It is likely that the higher efficacy of a number of antibiotics at neutral pH explains the efficacy of PPIs in combination with these antimicrobial drugs. Changes in the pattern of colonization of H. pylori from the antrum to the zone of the body of the stomach and the tendency of the microbe to migrate from the surface of the stomach to the deeper layers of the gastric fossa can lead to errors in the analyzes, which explains some conflicting literature data on the effectiveness of the effect of the combination of PPI and antimicrobial drugs on the eradication of H. pylori ... In most studies, only antral biopsies are performed after treatment, and thus false negative results from culture and histopathological analyzes can be obtained. In addition, the overgrowth of a number of other bacteria while the patient is being treated with PPI can lead to false negative H. pylori culture results.

Optimal results are obtained when omeprazole is given twice a day and combined with an antibiotic for at least 2 weeks, resulting in an H. pylori eradication rate of between 24 and 93%. If the 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 its acidic stability and low pH solubility. Unlike other macrolides, it is concentrated in the gastric mucosa, and, apparently, this explains its effectiveness in the eradication of H. pylori, which is about 50%, even if it is prescribed as monotherapy. The combination with omeprazole is well tolerated and promotes the eradication of H. pylori in 61–72% of patients.

In the future, if clarithromycin is used more widely for other conditions, resistance to it will develop and its effectiveness will decline.

Triplet therapy

According to published data, combinations of three different drugs have proven to be the most effective. One of the most effective schemes for H. pylori eradication turned out to be a bismuth salt with tetracycline or amoxicillin in combination with an imidazole derivative (metronidazole or tinidazole), which leads to an eradication rate of about 90%. These regimens require taking a large number of tablets, which complicates their careful adherence, in addition, the results are also influenced by sensitivity to imidazole (Table 2).

table 2

Helicobacter pylori eradication rate (triplet therapy)
Treatment regimen	The degree of eradication
KBC + tetracycline (or amoxicillin) + metronidazole (or tinidazole)	96a * 50 (Res.), 85 (Sen.) 0 (Res.), 71 (Sen.) 50 (Res.), 98.4 (Sen.) 68 (Res.), 93 (Sen.)
Ranitidine + Amoxicillin + Metronidazole	89
Omeprazole + clarithromycin + tinidazole	93,2 95
Omeprazole + clarithromycin + amoxicillin	90

Abbreviations: a * - sensitivity to imidazole was not tested, but, according to literature data, it was found to be very low in the studied population; KBC Ќ bismuth tripotassium 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 in nature 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 bismuth tripotassium 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 H. pylori eradication was achieved in 93% of patients, and only 3% of patients were forced to discontinue treatment due to severe side effects (severe diarrhea, nausea with vomiting, severe rash). In a review by Gynstock, it was estimated that side effects were the reason for discontinuation of eradication therapy in 8–12% of patients.

Adequate information about possible side effects, avoiding concomitant alcohol (ethanol) intake, and limiting the course of treatment to 2 weeks will likely contribute to better tolerance of this type of triplet therapy, as well as increase its effectiveness in eradicating H. pylori. A course of treatment for one week is the same in effectiveness as a 2-week course, but patients tolerate the treatment much better.

Henchel et al. reported that eradication of 89% of H. pylori occurs after a combination of 300 mg ranitidine at night for 6 to 10 weeks with 750 mg of amoxicillin 3 times a day and 500 mg of metronidazole 3 times a day, which were prescribed for the first 10 days. At the same time, there is little data in the literature on such a combination and resistance to imidazole can significantly affect the results of such a method if it is used in other parts of the world where such resistance is common.

Newer, more promising and simpler techniques are the use of omeprazole and 2 antimicrobial drugs 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%. There is clearly synergy at the heart of these excellent results. Amoxicillin 1 g twice daily can replace metronidazole in this new triplet regimen without loss of efficacy. In theory, amoxicillin should be preferred if metronidazole resistance is present 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 imidazole resistance is widespread, H. pylori eradication rate was still over 95% with omeprazole. Bell et al. used a 2-week regimen of treatment with omeprazole, amoxicillin and metronidazole. And reported that the rate of eradication of H. pylori was 96.4% in imidazole-sensitive strains.

Quadriplet therapy

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

Table 3

Helicobacter pylori eradication rate (quadriplet therapy)
Treatment regimen	Duration of treatment (in days)	The degree of eradication
KBC + tetracycline + metronidazole + famotidine	12	89a *
	12	97a *
KBC + tetracycline + metronidazole + omeprazole	7	98
KBC + tetracycline + metronidazole + cimetidine (or ranitidine)	7-14	94-95
Bismuth salicylate + tetracycline + metronidazole + ranitidine	14	84,2

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

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

Eradication of H. pylori is largely indicated for all patients with peptic ulcer disease, as it leads to faster healing of the ulcer, reduces the frequency of relapses and reduces the incidence 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 pylori therapy largely depends on the nature of the sensitivity to imidazole / macrolides, as well as on the patient's 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 the correct adherence of the patient to the treatment regimen and the sensitivity of the H. pylori strain to the drugs used, this indicates that other, as yet unknown strains may exist, leading 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 side effects and the presence of metronidazole-resistant strains of H. pylori can significantly affect the effectiveness of treatment. PPI triplet and quadriplet therapy may be even more effective, but the effect of side effects and the presence of metronidazole-resistant strains of H. pylori on cure rates has not yet been established.

Material provided by the representative office of the company "Sanofi" in Ukraine

The Helicobacter pylori infection, discovered in 1982 by Australians B. Marshall and R. Warren, is the culprit of ulcers in various parts of the stomach and intestines. To combat it, the international medical community has developed various eradication therapy regimens.

Dangerous neighbor

At present, there is no doubt about the high degree of association of peptic ulcers with the vital activity of Helicobacter pylori in the gastric mucosa. For treatment, complex eradication therapy is used - these are actions aimed at completely freeing from infection, which minimize the likelihood of recurrence of ulcers.

In the years following the discovery of H. pylori, there were reports that this bacterium is the etiological factor of a number of other diseases: chronic active antral gastritis (type B), atrophic gastritis (type A), non-cardiac cancer, MALT lymphoma, idiopathic iron deficiency anemia , idiopathic thrombocytopenic purpura, and vitamin B12 deficiency anemia. The study of the relationship of the spiral-shaped bacterium with allergic, respiratory and other extragastric diseases continues.

Eradication therapy in children

The need to eradicate H. pylori infection in children has been shown in numerous clinical studies and their meta-analyzes, which served as the basis for the compilation and regular updating of an international consensus document, well known to practicing gastroenterologists as the Maastricht Consensus. Currently, the issues of diagnosis and treatment of Helicobacter-associated diseases are regulated by the fourth Maastricht consensus, adopted in 2010.

In the developed countries of Europe, America and Australia, where since the discovery of the etiological role of H. pylori, methods for the diagnosis and treatment of this infection have been systematically developed and introduced into practice, a decline in the incidence of peptic ulcer and chronic gastritis has been noted. In addition, in these countries, for the first time in decades, there has been a tendency towards a decrease in the incidence of gastric cancer, which is also facilitated by eradication therapy.

Mysterious bacteria

Based on the results of numerous randomized placebo and comparative studies, the efficacy of probiotic agents in various clinical situations, including Helicobacter pylori infection in children, has been determined. However, despite some advances in understanding the effect of probiotics on the H. pylori bacterium, its subtle mechanisms remain poorly understood.

The main inhibitory and bactericidal factor of Lactobacillus is lactic acid, which they produce in large quantities. Lactic acid inhibits the activity of H. pylori urease and is believed to exert its antimicrobial effect by lowering the pH in the lumenal space of the stomach. However, it was found that lactic acid, which is produced by the cells of the gastric mucosa (GSS), promotes the growth of the H. pylori colony. In addition to lactic acid, lactobacilli and some other probiotic strains produce antibacterial peptides.

Complex therapy

The concept of eradication therapy is based on a combination of drugs. PPIs (proton pump inhibitors) block the enzyme urease and the accumulation of energy within H. pylori, and also raise the pH in the stomach lining, creating the conditions for antibacterial drugs to act. Bismuth salts, accumulating in bacteria, interfere with the enzyme system of the pathogen, allowing the child's immune system to more effectively cope with the "invader". Finally, the most diverse group is the group of antibacterial drugs.

Eradication therapy for peptic ulcer disease in children (as in gastritis) often involves the use of nitroimidazoles, macrolides, lactams, tetracycline and nitrofurans. Helicobacter develops resistance to antibacterial components, which reduces the effectiveness of eradication therapy. And the urgency of this problem is growing every decade.

Antibiotic resistance

The development of antibiotic resistance is a common feature of all pathogenic microorganisms. It is an evolutionary mechanism that ensures their survival in changing conditions. H. pylori resistance is subdivided into:

• Primary (a consequence of previous treatment).
• Secondary (acquired mutation of the microorganism, which is "spurred on" by eradication therapy).

Causes of Treatment Resistance

Scientists name the main reasons for the formation of acquired resistance of H. pylori:

• The growth of prescriptions of antibacterial drugs of the same groups for other indications.
• Uncontrolled self-medication with antibiotics in countries where they are sold without a prescription.
• Inadequately prescribed eradication therapy for gastritis or ulcers (prescribing low doses of antibiotics, shortening the course of treatment, incorrect combination in the drug regimen).
• Non-compliance with the doctor's prescriptions by patients.
• Appearance of low quality drugs on the pharmaceutical markets.

As a result of all of the above, the growth of H. pylori resistance reduces the already limited number of antibiotics active against this microorganism.

The problem of antibiotic resistance is especially relevant for children who are shown eradication therapy for peptic ulcer disease. Most often, they are infected with primarily resistant microorganisms from parents and close relatives.

In addition, in the child population, the unjustified use of antibiotics for the treatment of other diseases, most often respiratory infections, is especially widespread, which also contributes to the selection of primarily resistant strains. Violation of the eradication therapy regimen, as in adults, leads to the formation of secondary resistance. The development of pathogen resistance is also associated with mutations in different genes of Helicobacter pylori.

Diagnostics

Eradication therapy in adolescents begins after a comprehensive diagnosis. The primary goal of evaluating a child who has gastrointestinal symptoms is to determine the cause of these symptoms, not just the presence of H. pylori. At the same time, tests for the detection of Helicobacter are not recommended in children with functional abdominal pain. You can consider the feasibility of conducting tests to identify the pathogen:

• in patients with a family history of stomach cancer in a first-degree relative;
• with refractory iron deficiency anemia (if other causes of the disease are excluded).

There is a lack of sufficient practical evidence for the involvement of H. pylori in otitis media, upper respiratory tract infections, periodontitis, food allergies, sudden infant death syndrome, idiopathic thrombocytopenic purpura, and short stature. But there are suspicions.

Diagnostic tests

Eradication therapy for peptic ulcer and gastritis is determined by diagnostic tests. The testing methodology depends on many factors:

• To diagnose Helicobacter during esophagogastroduodenoscopy, it is recommended to biopsy the antrum of the stomach for further histological analysis.
• It is recommended that the initial diagnosis of H. pylori be based on the following findings: positive histological examination and positive urease test (alternatively, positive culture results).
• The C-urease breath test is a reliable, non-invasive method for determining whether H. pylori has been eradicated.
• Stool immunosorbent assay is also a reliable non-invasive test to determine if bacteria have been eradicated.
• Tests based on the detection of antibodies to Helicobacter in serum, whole blood, urine and saliva, on the contrary, are not reliable.

Indications

What are the indications for eradication therapy:

• In the presence of a peptic ulcer and infection with Helicobacter.
• If there is no peptic ulcer disease, and H. pylori infection has been identified based on the results of a study of samples taken using a biopsy, eradication of the pathogen is optional, but possible.

Epidemiology

Determining the level of resistance in a particular country, region or population is a difficult task that requires large material and human resources. It is even more difficult to compare data from different countries due to differences in research methodology. For example, according to the materials of long-term studies in Europe (2003-2011), the resistance of the pathogen to Clarithromycin ranged from 2 to 64% in different countries. According to Russian authors, resistance to Clarithromycin varies from 5.3 to 39%.

Of the drugs that are used in eradication schemes, the least resistance to resistance is formed by amoxicillin, and the greatest - by "Metronidazole". The resistance of H. pylori to Clarithromycin continues to grow.

Problems of using "Metronidazole" and "Furazolidone"

Eradication therapy used to be often carried out with the above drugs. However, the growth of bacteria adaptability to "Metronidazole" sharply reduced the effectiveness of treatment regimens with its use. For this reason, "Metronidazole" is now excluded from treatment regimens in many countries.

An alternative to Metronidazole is nitrofuran preparations, in particular Furazolidone. The eradication efficiency based on it in combination with bismuth is 86%. However, "Furazolidone" is toxic - it is not used in pediatric therapy in many clinics. The disadvantages of "Furazolidone" include hepato-, neuro- and hematotoxicity, suppression of microflora, unsatisfactory organoleptic properties. To achieve the required concentration of the active substance in the body, this drug has to be taken four times a day. These qualities of "Furazolidone" significantly reduce the beneficial effect of the entire treatment regimen and, as a consequence, the effectiveness of eradication.

New generation drug

Many laboratories of pharmaceutical companies are developing drugs that are less toxic, but effective against Helicobacter. A real breakthrough was the drug "Macmiror" containing nifuratel as an active ingredient. A modern alternative to "Furazolidone" was developed and synthesized by the research company Polichem (Italy). "Macmiror" has a wide spectrum of antibacterial, antifungal and antiprotozoal action. Eradication therapy for children has become safer.

The use of "Makmirora" allows you to improve the existing schemes for the eradication of Helicobacter in children, to increase their effectiveness and safety. "Nifuratel" is included in the updated protocols for the treatment of H. pylori - associated chronic gastritis, gastroduodenitis and peptic ulcer disease in children.

The use of the drug "Macmiror" is accompanied by high compliance, since due to the twelve-hour half-life, it can be prescribed twice a day. It is used in children from the age of six, the daily dose in the treatment of giardiasis and in the eradication regimens for Helicobacter is 30 mg per day per kilogram of the child's weight.

Eradication therapy regimens

Examples of first line therapy. One-week triple regimens with bismuth preparation:

• Colloidal bismuth subcitrate (BSC) is supplemented with Amoxicillin (Roxithromycin) or Clarithromycin (Azithromycin) plus Nifuratel (Furazolidone).
• In the second scheme, "Nifuratel" is replaced by "Famotidine" ("Ranitidine"), the rest of the drugs are the same.

One-week triple regimens with proton pump inhibitors:

• Omeprazole (Pantoprazole) is supplemented with amoxicillin or Clarithromycin plus Nifuratel (Furazolidone).
• The same, but "Nifuratel" is replaced by SWR.

Eradication therapy with four components is used as a second-line treatment: KSV works together with Omeprazole (Pantoprazole), Amoxicillin (or Clarithromycin) and Nifuratel (Furazolidone).

Doses

The protocols also regulate the doses of drugs that should be used in eradication regimens in children (daily per kilogram of weight):

• KSV - 48 mg (maximum 480 mg per day).
• Clarithromycin - 7.5 mg (maximum 500 mg).
• "Amoxicillin" - 25 mg (maximum 1 g).
• Roxithromycin - 10 mg (maximum 1 g).
• "Furazolidone" - 10 mg.
• "Nifuratel" - 15 mg.
• Omeprazole - 0.5-0.8 mg (maximum 40 mg).
• "Pantoprazole" - 20-40 mg (excluding weight).
• "Ranitidine" - 2-8 mg (maximum 300 mg).
• Famotidine - 1-2 mg (maximum 40 mg).

Treatment features

What treatment should be used in a given situation:

• Children who are infected with H. pylori and have a family history of stomach cancer in a first-degree relative may be given eradication therapy.
• It is recommended to monitor the prevalence of antibiotic-resistant Helicobacter strains in different regions.
• In regions / populations in which the prevalence of Helicobacter resistance to Clarithromycin is high (> 20%), it is recommended to determine the sensitivity to this antibiotic before starting triple therapy with Clarithromycin.
• The recommended duration of triple therapy is 7-14 days. When considering this issue, cost, adherence and side effects should be considered.
• To assess the results of the eradication therapy performed, it is recommended to apply reliable non-invasive tests 4-8 weeks after treatment.

If it doesn't help

• Esophagogastroduodenoscopy followed by culture and antibiotic susceptibility testing, including alternative ones, if not done before treatment.
• Fluorescence in situ hybridization (FISH) for determination of resistance to "Clarithromycin" using samples taken at the first biopsy and embedded in paraffin, if the determination of susceptibility to this antibiotic was not carried out before treatment.
• Treatment modification: add an antibiotic, prescribe another antibiotic, add bismuth and / or increase the dose, and / or lengthen the duration of therapy.

Conclusion

Eradication therapy is an effective (sometimes the only) means of fighting the most dangerous bacterium Helicobacter pylori, which can provoke ulcers, gastritis, colitis and other gastrointestinal diseases.

Helicobacter pylori(lat. ) is a spiral gram-negative microaerophilic bacterium that infects the mucous membrane of the stomach and duodenum. Sometimes called helicobacter pylori(see Zimmerman Y.S.).

Helicobacter pylori misconceptions

Often, upon detection , patients begin to worry about their eradication (destruction). Availability itself in the gastrointestinal tract is not a reason for immediate therapy with antibiotics or other agents. In Russia, the number of speakers reaches 70% of the population and the overwhelming majority of them do not suffer from any diseases of the gastrointestinal tract. The eradication procedure involves taking two antibiotics (for example, clarithromycin and amoxicillin). In patients with an increased sensitivity to antibiotics, allergic reactions are possible - from antibiotic-associated diarrhea (not a serious illness) to pseudomembranous colitis, the likelihood of which is small, but the percentage of deaths is high. In addition, taking antibiotics negatively affects the "friendly" microflora of the intestines, urinary tract and contributes to the development of resistance to this type of antibiotics. There is evidence that after successful eradication over the next few years, reinfection of the gastric mucosa is most often observed, which after 3 years is 32 ± 11%, after 5 years - 82–87%, and after 7 years - 90.9% (Zimmerman Y.S.).

Until the pain manifests itself, helicobacteriosis should not be treated. Moreover, in children under eight years of age, it is generally not recommended to carry out erosion therapy, because their immunity has not yet been formed, antibodies to are not generated. If they carry out eradication before the age of 8, then in a day, after talking briefly with other children, they will "grab" these bacteria (PL Shcherbakov).

Eradication may be recommended to reduce the risk of stomach cancer. It is known that at least 90% of bile cancer cases are associated with H. pylori infection (Starostin B.D.).

from experimentally monoinfected mice (A), human gastric mucosa (B) and cultured on an agar plate (C). Both isolated from experimentally infected mice and human biopsy is rough, and the flagella tend to stick together. With the exception of the coccoid form, morphology is relatively well preserved in agar culture (C). Scale marks = 1 μm. Source: Stoffel M.H. et al. Distinction of Gastric Helicobacter spp. in Humans and Domestic Pets by Scanning Electron Microscopy / January 2001. DOI: 10.1046 / j.1523-5378.2000.00036.x. Blackwell Science, 1083-4389 / 00 / 232-239. Inc. Volume 5 Number 4 2000.

Helicobacter pylori virulence factors

Several virulence factors are known to allow populate and then persist in the host's body (Skvortsov V.V., Skvortsova E.M.).

• Flagella allow move in gastric juice and mucus layer.
• is able to attach to the plasmolemma of gastric epithelial cells and destroy the components of the cytoskeleton of these cells.
• produces urease and catalase. Urease breaks down the urea contained in the gastric juice, which increases the pH of the immediate environment of the microbe and protects it from the bactericidal action of the acidic environment of the stomach.
• is able to suppress some immune responses, in particular phagocytosis.
• produces adhesins that promote adhesion of bacteria to epithelial cells and impede their phagocytosis by polymorphonuclear leukocytes.

Duodenal ulcer associated with Helicobacter pylori

Main habitat is the mucous membrane of the antrum of the stomach, affected by the inflammatory and atrophic process - gastritis associated with ... For the development of duodenal ulcers associated with , the presence of gastric metaplasia in the mucous membrane of the duodenum is necessary, which in turn is associated with an increase in the acidity of the duodenum. Thus, duodenal ulcer associated with and duodenitis always develop against the background of acid-peptic aggression in the duodenum, i.e. at the same time they are also acid-dependent pathology. In this case, the most important factor in the hypersecretion of hydrochloric acid in the stomach is the direct effect on the secretory process by excessive alkalization of the antrum of the stomach with products of urea hydrolysis by urease produced ... The consequence of excessive alkalinization is hypergastrinemia, which in turn leads to overproduction of hydrochloric acid. Disturbances in the regulation of acid production in patients associated with gastritis is also caused by the process of specific inflammation and its mediators (cytokines and epidermal growth factors) synthesized in the mucous membrane of the antrum in response to infection , especially pronounced in cytotoxic strains. These strains can not only cause severe inflammation in the stomach, but also contribute to the development of destructive processes - ulceration, including in the duodenum in areas of gastric metaplasia. This is facilitated by aggressive factors of the duodenal environment, a decrease in the protective properties of the mucous barrier, impaired microcirculation (including due to ), hereditary predisposition. All these processes lead to the appearance of ulcers (Maev I.V., Samsonov A.A.).

Helicobacter pylori eradication regimens

World Health Organization to active drugs in relation to included metronidazole, tinidazole, colloidal bismuth subcitrate, clarithromycin, amoxicillin and tetracycline (Podgorbunskikh E.I., Maev I.V., Isakov V.A.).

Eradication does not always reach the goal. The very widespread and inappropriate use of common antibacterial agents has led to increased resistance to them. ... The figure on the right (taken from the article of Belousova Yu.B., Karpov O.I., Belousov D.Yu. and Beketov A.S.) shows the dynamics of resistance to metronidazole, clarithromycin and amoxicillin of strains separated from adults (above) and from children (below). It is recognized that in different countries of the world (different regions), it is advisable to use different schemes. Recommendations for eradication are given below. set forth in the Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases adopted by the Scientific Society of Gastroenterologists of Russia in 2010.The choice of the eradication regimen depends on the presence of individual intolerance to specific drugs by patients, as well as the sensitivity of the strains to these drugs. The use of clarithromycin in eradication regimens is possible only in regions where the resistance to it is less than 15–20%. In regions with resistance above 20%, its use is advisable only after determining the sensitivity to clarithromycin by bacteriological method or by polymerase chain reaction.

There are no full-scale studies in Russia establishing the prevalence of clarithromycin-resistant strains H. pylori... However, there are several local studies, in each of which a low level of resistance was established in the terminology of Maastricht IV, and, based on this, in Russian conditions, it is most likely more expedient to use the left side of the scheme, marked in green.

Professional medical publications concerning diseases associated with Helicobacter pylori

• Ivashkin V.T., Maev I.V., Lapina T.L. and other Clinical guidelines of the Russian Gastroenterological Association for the diagnosis and treatment of Helicobacter pylori infection in adults // RZHGGK. 2018. No. 28 (1). S. 55–77.


• Ivashkin V.T., Maev I.V., Lapina T.L., Sheptulin A.A., Trukhmanov A.S., Abdulkhakov R.A. et al. Treatment of Helicobacter pylori infection: mainstream and innovation // Ros Zhurn gastroenterol hepatol coloproctol. 2017. No. 27 (4). S. 4-21.


• Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases (the fifth Moscow agreement) // XIII Congress of the NOGR. March 12, 2013


• Standards for the diagnosis and treatment of acid-dependent and Helicobacter pylori-associated diseases (the fourth Moscow agreement) / Guidelines No. 37 of the Moscow City Health Department. - M .: TsNIIG, 2010 .-- 12 p.


• Zimmerman Ya. S. Peptic ulcer: a critical analysis of the current state of the problem // Experimental and clinical gastroenterology. - 2018 .-- 149 (1). S. 80–89.


• E.A. Kornienko, N.I. Parolova Antibiotic resistance of Helicobacter pylori in children and the choice of therapy // Questions of modern pediatrics. - 2006. - Volume 5. - No. 5. - p. 46-50.


• Zimmerman Ya.S. The problem of the growing resistance of microorganisms to antibacterial therapy and the prospects for the eradication of Helicobacter pylori infection / In the book: Unsolved and controversial problems of modern gastroenterology. - M .: MEDpress-inform, 2013.S. 147-166.


• Diagnostics and treatment of Helicobacter pylori infection - report of the Maastricht IV / Florence conciliation conference // Bulletin of a practical doctor. Special issue 1.2012, pp. 6-22.


• Isakov V.A. Diagnosis and treatment of Helicobacter pylori infection: IV Maastricht Agreement / New guidelines for the diagnosis and treatment of H. pylori infection - Maastricht IV (Florence). Best Clinical Practice. Russian edition. 2012. Issue 2. S.4-23.


• Maev I.V., Samsonov A.A., Andreev D.N., Kochetov S.A., Andreev N.G., Dicheva D.T. Modern aspects of diagnosis and treatment of Helicobacter pylori infection // Medical Council. 2012. No. 8. C. 10-19.



• Rakitin B.V. Information about the conciliatory conference on the diagnosis and treatment of Helicobacter pylori infection "Maastricht V" from M. Lei's report at the 42nd scientific session of the Central Scientific Research Institute of Geology, March 2-3, 2016.


• Maev I.V., Rapoport S.I., Grechushnikov V.B., Samsonov A.A., Sakovich L.V., Afonin B.V., Aivazova R.A. Diagnostic value of breath tests in the diagnosis of Helicobacter pylori infection // Clinical Medicine. 2013. No. 2. P. 29–33.


• Kazyulin A.N., Partsvania-Vinogradova E.V., Dicheva D.T. and other Optimization of anti-Helicobacter pylori therapy in modern clinical practice // Consilium medicum. - 2016. - No. 8. - Volume 18.P. 32-36.


• Malfertheiner P, Megraud F, Morain CAO, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A et al. Management of Helicobacter pylori infection-the Maastricht V / Florence Consensus Report // Gut 2016; 0: 1–25. doi: 10.1136 / gutjnl-2016-312288.


• B. D. Starostin Treatment of Helicobacter rulo infection - Maastricht V / Florentine Consensus Report (translated with comments) // Gastroenterology of St. Petersburg. 2017; (1): 2-22.


• Maev I.V., Andreev D.N., Dicheva D.T. and other Diagnostics and treatment of Helicobacter pillory infection. Consensus provisions Maastricht V (2015) // Archives of Internal Medicine. Clinical guidelines. - No. 2. - 2017. S. 85-94.


• Oganezova I.A., Avalueva E.B. Helicobacter pylori-negative peptic ulcer disease: historical facts and modern realities. Pharmateca. 2017; Gastroenterology / Hepatology: 16-20.

On the site in the literature catalog there is a section "" containing medical professional articles on gastrointestinal diseases associated with.

Eradication of Helicobacter pylori in pregnant and lactating mothers

Eradication Helicobacter pylori according to the Maastricht Consensus II-2000 and III-2005, it is not carried out in pregnant women. Solving the issue of eradication Helicobacter pylori placed after delivery and the end of the breastfeeding period (Rebrov B.A., Komarova E.B.).

Prevalence of Helicobacter pylori in different countries and in Russia

According to the World Gastroenterological Organization ( in developing countries, 2010, WGO) more than half of the world's population are carriers ), while the incidence of infection varies considerably between different countries, as well as within these countries. In general, infection increases with age. In developing countries, infection much more pronounced in young people than in developed countries.

VGO gives the following figures:

Country (region)	Age groups	Infection rate
Europe
Eastern Europe	adults	70 %
Western Europe	adults	30-50 %
Albania	16-64	70,7 %
Bulgaria	1-17	61,7 %
Czech	5-100	42,1 %
Estonia	25-50	69 %
Germany	50-74	48,8 %
Iceland	25-50	36 %
Netherlands	2-4	1,2 %
Serbia	7-18	36,4 %
Sweden	25-50	11 %
North America
Canada	5-18	7,1 %
Canada	50-80	23,1 %
USA and Canada	adults	30 %
Asia
Siberia	5	30 %
Siberia	15-20	63 %
Siberia	adults	85 %
Bangladesh	adults	> 90 %
India	0-4	22 %
India	10-19	87 %
India	adults	88 %
Japan	adults	55-70 %
Australia and Oceania
Australia	adults	20 %

Socioeconomic differences between populations may be responsible for the different infection rates. Infection mainly occurs by oral-oral or fecal-oral routes. Lack of sanitation, safe drinking water, basic hygiene concepts, as well as limited diet and large populations can play a role in the high prevalence of infection.

Russia belongs to countries with a very high prevalence of H. pylori infection. In some regions, for example, in Eastern Siberia, this figure exceeds 90% in both the Mongoloid and Caucasian populations. In Moscow, infection below. According to the Central Research Institute of Gastroenterology, about 60% of the residents of the Eastern Administrative District of Moscow are carriers of Helicobacter. Although in certain groups of the population, Helicobacter is more common. In particular, among the workers of industrial enterprises in Moscow are infected 88 % (

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.

When treating 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 80%. 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 because of them to interrupt the course of drugs prescribed by the gastroenterologist.

Treatment regimens

The therapy regimen should first of all ensure a constant high level of bacterial eradication. The scheme of eradication of Helicobacter pylori is selected 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. Moreover, they are all aimed at achieving a number of tasks, including:

Development of schemes

At the moment, significant results in all of 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 experts in the industry was formed, whose efforts are aimed at sharing knowledge about eradication.

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

• 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.

The fourth option (for elderly patients):

• standard dosage of inhibitors;
• bismuth tripotassium dicitrate;

The fourth option (alternative) is to take bismuth tripotassium dicitrate in standard dosages for 28 days with 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:

• a 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 spread is minimal due to the high efficiency of 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.

Results of the systematic review and meta-analysis

H. pylori infection is the cause of gastric and duodenal ulcers, gastric MALT lymphomas and stomach cancer. Currently, a large number of eradication therapy regimens have been proposed: standard triple therapy with amoxicillin, clarithromycin, and a proton pump inhibitor (PPI); quadrotherapy based on bismuth preparations, sequential and concomitant therapy. One of the current global challenges is the growing resistance to clarithromycin and metronidazole. To overcome this problem, in clinical practice, sequential therapy has increasingly begun to be used, including the appointment of a PPI and amoxicillin at a dose of 1 g 2 times a day for the first five days and a 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 treatment regimen with triple therapy provide encouraging results and suggest the effectiveness of the new eradication regimen.

Target

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

Materials and methods

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

results

Sequential therapy versus 7-day triple therapy.
Sequential therapy was more effective in 22 RCTs (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 of the studies compared the effectiveness of sequential therapy with triple therapy using PPIs, amoxicillin and metronidazole and PPIs, amoxicillin and clarithromycin; sequential therapy was more effective than the first by 15.9% and the second by 24.0%.

Sequential therapy versus 10-day triple therapy.
Fourteen RCTs showed only a slight difference in the effectiveness of the sequential eradication regimen (RR = 1.11, 95% CI: 1.04-1.19).

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

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

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

Sequential therapy against bismuth-based quadrotherapy.
Analysis of the results of 3 RCTs did not show the advantages of one eradication scheme over another (RR = 1.01, 95% CI: 0.95-1.06).

The effectiveness of eradication in 546 patients who received sequential therapy was 86.2%, and in 545 patients who underwent eradication with drugs included in the quadrotherapy - 84.9%.

Sequential therapy against quadrotherapy without bismuth drug.
Six RCTs compared the efficacy of sequential therapy (n = 1039) and quadrotherapy (n = 1031) using PPIs, amoxicillin, clarithromycin, and metronidazole (the duration of therapy 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% when using quadrotherapy and 81.7% when using sequential therapy).

Findings from studies not included in the meta-analysis

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

Among 240 patients in whom the scheme using 1000 mg of levofloxacin per day was used, the percentage of eradication was 90.0%, and among 240 patients who received classical sequential therapy with clarithromycin, the efficacy was 78.7%. The incidence of side effects was approximately the same (24.3% and 24.4%, respectively).

When comparing therapy with levofloxacin 500 mg per day (n = 241) and the classical sequential eradication regimen (n = 240), the efficacy 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 allowed us to conclude that the sequential scheme of eradication using levofloxacin is more effective than the sequential scheme using clarithromycin.

Comparison of 10-day and 14-day sequential eradication regimens.
Two RCTs compared the duration of sequential therapy: 340 patients received 10-day sequential therapy and 340 patients received 14-day therapy. 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 of Helicobacter pylori infection is more effective than the 7-day standard triple therapy and shows similar efficacy when compared with eradication regimens prescribed for more than 10 days and containing more than 2 antimicrobial drugs.