A course of anti-Helicobacter therapy. Ecoantibiotics: a new strategy for increasing the effectiveness of anti-Helicobacter therapy and preventing antibiotic-associated diarrhea
Therapy aimed at expelling a person infected with it from the stomach is not the easiest task that a doctor sets for himself.
This is due to the fact that pathogenic microorganisms are extremely reluctant to leave their favorite places of existence - the epithelial cells of the inner lining of the stomach or the submucosa, and drug-resistant strains are formed.
Therefore, the effect on the bacterium must be complex: medication, physiotherapy, nutrition, phytotherapeutic. The main point of application is drug therapy.
The expression “treat Helicobacter pylori infection” is not entirely correct from a medical point of view. Doctors treat diseases caused by this microorganism, but the bacterium itself should be gotten rid of.
The main direction in drug therapy is eradication - a method of destroying an infectious agent with the help of drugs.
In addition to eradication therapy, it is important to correct the impaired acidity of gastric juice, restore the motor and evacuation function of the gastrointestinal tract, stabilize enzymatic activity, and calm inflammatory processes.
All these functions are assigned to specific drugs, which, in combination with proper nutrition, give positive results. The main groups of drugs, medicines and tablets for Helicobacter pylori:
- Antibacterial
- Preparations of bismuth salts
- Proton pump blockers
- M-anticholinergics
- H2-histamine receptor blockers
- Antacids
- Antispasmodics
- Prokinetics
The most common dosage form of drugs is tablets; antacids can be used in the form of suspensions or powders that require dissolution in water.
What antibiotics kill Helicobacter pylori
Antibacterial drugs are the “heavy artillery” that forces the bacteria to desert and leave the patient’s body.
The standards for the treatment of Helicobacter-associated gastric pathologies indicate at least two antibiotics. With significant contamination of the mucous membrane and pronounced clinical manifestations of the disease, it is impossible to do without them.
- Amoxicillin
- Clarithromycin
- Tetracycline
- Metronidazole
- Rifambutin
- Levofloxacin
Rifambutin and levofloxacin are “reserve” drugs; they are not included in standard treatment regimens, but can be used if pathogenic strains develop resistance to common drugs included in the protocols.
Antibacterial drugs have side effects: allergic reactions, dysbacteriosis, nausea. Patients are often afraid to take antimicrobial drugs precisely for this reason.
If you are infected with Helicobacter and have gastric diseases, you should not do this. Taking antibiotics in this case is justified.
Without these medications, the patient risks earning money, and by refusing treatment, he exposes the body to the risk of developing oncopathology of the gastrointestinal tract. Stomach cancer is 3-6 times more likely to occur in patients infected with H. pylori who have not received proper therapy.
How to treat Helicobacter pylori with antibiotics - eradication therapy regimens
Today, 3- and 4-component treatment regimens aimed at destroying the bacteria have been developed and are actively used.
If a patient has a microbe in the stomach, there are symptoms of gastrointestinal damage, and the person has not previously received treatment, therapy is always started with a three-component regimen, which includes:
- Proton pump blocker (lansoprazole, rabeprazole, pantoprazole 20 mg) 2 times a day
- Amoxicillin 1000 mg 2 times a day
- Clarithromycin 500 mg 2 times a day
A 3-component regimen is prescribed when a patient first seeks treatment; elderly, debilitated patients can be individually adjusted to the dosage of medications.
This therapy is prescribed for 7 (minimum) to 14 days. Clinical studies have shown that in some cases, taking drugs for a week is not enough to ensure eradication, and therapy is ineffective.
After two weeks of taking the drugs, on the contrary, the effect of treatment was an order of magnitude higher: in a much larger number of patients, eradication of the pathogen reached 80% or more.
Four-component treatment regimen
If the effect of the 3-component regimen is not achieved, the destruction of the infectious agent has not occurred, the doctor will recommend continuing therapy after a month and a half, consisting of:
- Proton pump blocker (omeprazole, lansoprazole, rabeprazole, pantoprazole 20 mg) 2 times a day
- Preparations of bismuth salts 120 mg 4 times a day
- Metronidachol 500 mg 3 times a day
- Tetracycline 500 mg 4 times a day
This is a 4-component eradication scheme. It is important to ensure that previously used antibacterial drugs are not repeated. If resistance to the above antibiotics is detected, “reserve” medications can be prescribed: levofloxacin, rifambutin.
Despite the developed standards, the doctor, when carrying out eradication, must approach each case and disease individually, taking into account the patient’s age, concomitant pathologies, possible allergic reactions of the body and the resistance of specific strains of bacteria to drugs.
How many days to take antibiotics for Helicobacter pylori
A 3-component regimen is prescribed by a doctor for a period of 7 to 14 days. It is not advisable to take the drugs for less than a week; there will be no effect from such treatment.
The bacterium is difficult to treat and develops resistance to drugs, so more and more evidence is emerging that even a week is not enough to achieve a positive result and get rid of the pathogen. More and more doctors are inclined to extend antibiotic therapy to 10-14 days.
The 4-component regimen is prescribed for a period of two weeks.
The effectiveness of treatment should be assessed using diagnostic and laboratory methods no earlier than 1-1.5 months from the end of taking the drugs.
If eradication is 80% or more of the initial level, or no bacteria are found in the body at all, we can talk about success in treating the disease associated with this pathogen.
More about drugs
Features of taking antibiotics for the treatment of Helicobacter pylori:
- Clarithromycin
This is an antibacterial drug from the macrolide group. Included in the first-line treatment of Helicobacter pylori infection. It is successfully used in gastroenterology, it is able to inhibit the synthesis of the cell wall of Helicobacter pylori, and therefore prevent its reproduction. It is acid-resistant, works effectively at normal and high acidity, and is well absorbed.
Some strains of bacteria exhibit resistance to clarithromycin. In this case, the drug must be replaced with another one to achieve a better therapeutic effect.
- Amoxicillin and metronidazole
Metronidazole or trichopolum is a drug that has a destructive or bactericidal effect on H. pylori. Its activity does not depend on the pH level in the stomach; the drug can be used in both hyper- and hypoacid conditions.
Today, resistance of many Helicobacter strains to metronidazole is very common. If the drug is prescribed together with de-nol, resistance to it develops more slowly.
Amoxicillin is a penicillin antibiotic that blocks the synthesis of microbial cell walls and is well absorbed by the gastric mucosa. More active in a neutral environment than in an acidic environment. Increasing the pH to 4 increases the pharmacological effect of this drug 10 times.
Metronidazole and amoxicillin are first-line drugs, but can also be prescribed in a 4-component treatment regimen.
- Tetracycline
Another antimicrobial agent actively used in eradication therapy of helicobacter pylori. The mechanism of action of tetracycline is to inhibit microbial cell protein synthesis.
The medicine is well absorbed from the gastrointestinal tract. Eating dairy foods slows down its absorption.
- Proton pump blockers
The most common representative of this group is. There are other very effective drugs: lansoprazole, pantoprozole, esomeprazole, rabeprazole).
Medicines suppress the production of hydrochloric acid. Thus, they influence the microbe indirectly: they do not destroy it, but create unfavorable conditions for existence, have a suppressive effect on the infection: they stop bacterial growth and development.
Omeprazole and other representatives of the group, by increasing the pH of the gastric contents, contribute to the better functioning of antibacterial drugs, in particular amoxicillin.
There is evidence that proton pump inhibitors can block the bacterial enzyme urease.
Doctors recommend that after completing the course of treatment with antibiotics, continue taking omeprazole for up to 4-8 weeks. Patients who continue to take proton pump blockers have better mucosal healing processes and a higher percentage of bacterial destruction compared to patients who stopped taking omeprazole after the end of the eradication regimen.
- Antacids and H2 receptor blockers
Most often, the acidity of gastric juice during infection with H. pylori is normal or increased.
In addition to omeprazole, which normalizes pH, antacid drugs (Almagel, phosphalugel, Hefal, Maalox, Rennie) and H2-histamine receptor blockers (famotidine, ranitidine) also have this effect.
The mechanism of action of antacids is to neutralize gastric acid. The active ingredients in these preparations are aluminum and magnesium hydroskides.
The products effectively eliminate the clinical manifestations of “acidism” – heartburn, sour belching. Take them 1-2 hours after meals and at night. Release form: suspensions, or powders, tablets.
You should not combine the use of antacids with antibacterial drugs or bismuth salts, since aluminum and magnesium hydroxides interfere with the absorption of other substances in the gastrointestinal tract.
New generation H2-histamine receptor blockers (famotidine, ranitidine) have virtually no side effects. Their mechanism of action: they inhibit the production of HCL and the production of pepsin, which causes a decrease in acidity. Prescribe tablets after breakfast and before bed.
- Bismuth preparations
This group of drugs, in combination with antibiotics, has a bactericidal effect - it destroys both coccal strains and vegetative forms.
Bismuth salts have many effects that have a positive effect in the complex treatment of diseases caused by Helicobacter:
- Prevents pathogens from attaching to epithelial cells of the gastric mucosa
- Disrupt microbial ATP synthesis
- Block bacteria enzymes
- Promote the destruction of the cell wall of the infectious agent
- Increases the synthesis of protective immunoglobulins, prostaglandins of gastric secretions
- Increases the secretion of bicarbonates and protective mucus
- Reduce the absorption of antibiotics in the gastrointestinal tract, thereby increasing their concentration in the gastric contents
- Provide a reparative, wound-healing effect of the internal gastric wall
- Improves local blood circulation
These pharmacological properties allowed the bismuth drug to occupy its niche in the treatment of helicobacteriosis in combination with two antibiotics. One of the most effective drugs This group is de-nol.
Does de-nol kill Helicobacter or not?
Only in combination with antimicrobial agents does de-nol have a bactericidal effect. If you take this drug separately as monotherapy, such treatment will not have the desired effect.
But in a combined treatment regimen, de-nol fully reveals its therapeutic effects, while simultaneously enhancing the properties of antibacterial drugs.
The combination “de-nol + 2 antibiotics” is extremely effective, and in the case of Helicobacter sensitivity, it allows the microbe to disappear if the tablets are taken for 10-14 days.
How much to drink de-nol for Helicobacter infection
The drug is prescribed 1 tablet 4 times a day for 30 minutes. before meals and at night for a period of at least 21 days, you can take the medicine for up to 8 weeks as recommended by your doctor. You should know that when the drug is prescribed, the stool turns black.
The tablets should be taken with a glass of boiled water, but not with milk, since dairy products reduce the pharmacological effect of the drug. Tablets cannot be combined with juices either.
Antacids slow down the absorption of de-nol, so you should not drink them together.
If side effects occur: diarrhea, nausea, allergic reactions, vomiting, you should stop taking the medication and consult a doctor.
Just twenty years ago, R. Warren and B. Marshall first proved the pathogenic role of the bacteria Helicobacter pylori. The world scientific community appreciated the significance of this discovery for medicine. In 2005, these scientists were awarded Nobel Prize. Today, an indisputable fact is the absolute pathogenicity of H. pylori bacteria for humans and the need for their destruction. This is evidenced by data from many epidemiological and clinical studies.
Prepared by Dmitry Molchanov
thematic issue: GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY
Contamination of the gastric mucosa by these microorganisms is associated with 100% of antral chronic gastritis type B, 95% of duodenal ulcers, 70% of cases of gastric ulcer, as well as atrophic gastritis, MALT lymphoma (B lymphoma) and gastric adenocarcinoma.
In Ukraine, the average level of H. pylori infection among the adult population is supposedly quite high and reaches 70%. It has been absolutely proven that the target organs of H. pylori are the stomach and duodenum, and that it is the mucous membrane of these organs that is affected. The pathological process during infection with H. pylori begins with inflammation of the mucous membranes in the form of antral gastritis B or gastroduodenitis, which are further complicated by cellular metaplasia of the gastric epithelium and its destruction with ulceration. The inflammatory process in the gastric mucosa under the influence of pathogenic factors H. pylori can develop into atrophic gastritis with an increased likelihood of developing gastric adenocarcinoma.
Anti-Helicobacter therapy is a treatment aimed at eradicating H. pylori. It has been proven that after complete elimination of the infection in patients, it is possible to achieve a significant clinical effect: the symptoms of Helicobacter pylori gastritis disappear, healing of ulcers is observed, as a rule, their relapses stop and further complications are prevented. Successful eradication therapy can reduce the incidence of peptic ulcer relapses to 10% per year compared to 70% in infected patients who did not receive anti-Helicobacter pylori therapy. Even gastric MALT lymphomas undergo reverse development after eradication. Anti-Helicobacter therapy is the primary prevention of the development of gastric cancer and the secondary prevention of its recurrence after surgery.
A direct connection between Helicobacter pylori infection and the development of functional dyspepsia and reflux disease has not yet been confirmed, but it has been proven that infection with H. pylori affects the course of these diseases. IN Lately New data have been found on the pathogenetic impact of Helicobacter pylori infection on the human body. A correlation has been shown between H. pylori infection and worsening of the course of coronary heart disease, which is associated with the participation of infection in the pathogenesis of endothelial dysfunction and platelet activation. New data have been obtained on the place of H. pylori in the pathogenesis of thrombocytopenia, food allergies, and acne. With chronic Helicobacter pylori infection, iron deficiency anemia develops because the absorption of iron in the digestive tract is disrupted.
All these new facts served as the reason for the Third Council of the world's leading scientists working on the problem of Helicobacter pylori infection to be held in March 2005. As a result, the Third Maastricht Consensus was developed, which defines approaches to the diagnosis and eradication of H. pylori infection.
The history of the development of anti-Helicobacter therapy went through the stages of the classical triple regimen based on bismuth preparations, the 1st Maastricht consensus, which proposed various options for therapeutic regimens. According to the recommendations of the 2nd Maastricht Consensus, internists and gastroenterologists have been working for the last 5 years.
What are the main differences between the new international agreement on Helicobacter pylori infection and the two previous ones? The answers to this question were given in the report Doctor of Medical Sciences, Professor Galina Dmitrievna Fadeenko, presented at the gastroenterological section of the International Congress on Pharmacotherapy “Faces and Life”.
– So, the III Maastricht Consensus consists of three sections. The first outlines additional aspects of the indications for anti-Helicobacter therapy, based on the recently proven new pathogenic properties of the bacteria H. pylori. The second section suggests ways to further improve the diagnosis of infection based on the developed new methods for its detection. The third section is devoted to the prevention of non-cardiac gastric cancer through the eradication of Helicobacter pylori infection.
According to the new consensus, patients with unexplored functional dyspepsia are subject to mandatory testing for H. pylori infection and eradication therapy. Eradication is also recommended in infected patients with ischemic heart disease, immune-dependent thrombocytopenia, and iron deficiency anemia. Mandatory anti-Helicobacter therapy to prevent gastritis should be prescribed to patients who take non-steroidal anti-inflammatory drugs for a long time. It is also necessary to eradicate H. pylori in infected patients with complicated forms of gastroesophageal reflux disease.
Today, three directions in the diagnosis of Helicobacter pylori infection have been developed and are used in gastroenterological practice:
- examination of biopsy samples of the mucous membrane of the stomach and duodenum (histological and cytological studies, urease test, polymerase chain reaction with biopsy samples);
- immunological studies of peripheral blood, in which specific antibodies to H. pylori are determined;
- non-invasive methods for detecting bacterial antibodies in saliva and urine; antigens in stool (stool antigen test); 13C breath test.
According to the 2nd and 3rd Maastricht consensuses, the “gold standard” for diagnosing Helicobacter pylori infection and confirming the success of eradication was and remains the breath test. But it should be remembered that this method is not recommended for bleeding ulcers, atrophic gastritis, MALT lymphomas, as well as after taking proton pump inhibitors, since the likelihood of obtaining false results increases significantly. In these cases, the method of choice is to determine antibodies in the blood. When conducting extensive epidemiological studies of population infection, preference should be given to non-invasive methods for detecting H. pylori antigens in saliva and urine.
What has changed in anti-Helicobacter therapy regimens?
The new document provides for first-line treatment regimens and backup eradication regimens, as well as so-called salvage therapy, which should be resorted to in rare cases of ineffectiveness of therapy with first-line drugs and reserve agents. Two well-proven triple regimens are offered as first-line therapy: proton pump inhibitor + clarithromycin + amoxicillin or metronidazole. According to the new consensus, three-component combination anti-Helicobacter therapy for up to 14 days increases eradication efficiency by 12%. Moreover, it is not advisable to prescribe clarithromycin in a specific population if there is evidence of H. pylori resistance to this antibiotic exceeding 30%. The same applies to metronidazole and amoxicillin, although resistance to the latter in H. pylori is much less common. In the case of simultaneous resistance of H. pylori to two first-line drugs, it is recommended to immediately begin eradication with a reserve regimen, i.e., use the reserve treatment regimen as the first line. An important issue is the choice of antibacterial drugs that are included in eradication regimens. Particularly noteworthy here is the drug Flemoxin Solutab - a soluble form of amoxicillin with higher (compared to the capsule form) bioavailability and antibacterial activity.
Discussions continue regarding the choice of the optimal proton pump inhibitor. In our clinic, anti-Helicobacter therapy regimens predominantly use rabeprazole. A sustainable effect from its use is registered from the first day of administration. In addition, there is no need for a 2-3-day interval between the administration of rabeprazole and the antibacterial components of eradication therapy; they can be used in combination from the first days. Why is it important? Amoxicillin and clarithromycin exhibit an antibacterial effect against H. pylori only under conditions of pH 5.0 or more; therefore, the simultaneous administration of other proton pump inhibitors with these antibiotics, which have a longer period of onset of maximum acid suppression, can lead to a decrease in % eradication of H. pylori.
Bismuth preparations have a long history of use in anti-Helicobacter therapy regimens. For bismuth, pronounced anti-Helicobacter activity has been proven without the development of bacterial resistance to this substance, as well as cytoprotective properties in relation to the epithelium of the mucous membranes of the digestive tract. Among all bismuth preparations, its colloidal subcitrate, known as De-Nol, occupies a special place. It exhibits anti-Helicobacter activity at any pH value. In addition, primary and secondary resistance of H. pylori to this drug was not recorded, which makes it possible to repeatedly use De-Nol in the same patients in different treatment regimens. Under the influence of the drug, the enzyme systems of H. pylori bacteria are blocked, their mobility and ability to adhere to the epithelium of the gastric mucosa are inhibited, and the resistance of bacteria to immune factors is reduced.
A unique property of De-Nol is its three-level protection of the mucous membrane. The first level is a pre-epithelial film that protects damaged epithelium in foci of destruction during erosions and ulcers from the aggressive effects of hydrochloric acid, pepsin and microbial toxins. The second level is to stimulate epithelial regeneration by fixing epidermal growth factor. In clinical studies, it was shown that in patients taking De-Nol, scarring of ulcerative defects occurred faster and better than in those who were not prescribed the drug. The third postepithelial level of De-Nol’s protection is realized through the prostaglandin mechanism. Thanks to the production of prostaglandins, the trophism of the epithelium improves, which helps eliminate inflammation and rapid healing of mucosal defects. In clinical studies, where De-Nol was used both as an addition to basic drugs and as monotherapy, its positive effect on the healing of ulcers induced by long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) was proven. According to Russian authors, in infected patients with NSAID-induced ulcers under the influence of De-Nol therapy, their healing was achieved on average in 4 weeks, and in 80% of cases eradication of H. pylori was observed.
The effectiveness of anti-Helicobacter therapy directly depends on factors such as the correct choice of treatment regimens and dosage of drugs, adherence and individual susceptibility to therapy of the patients themselves. A large-scale study of the effectiveness of anti-Helicobacter therapy, conducted in Canada, showed that a third of cases of ineffective treatment are associated directly with doctors’ errors. Similar results were obtained by Russian researchers.
Among the main mistakes of therapists and gastroenterologists, one should note the incorrect dosage of drugs, the use of antacids and H2-histamine receptor blockers in anti-Helicobacter therapy regimens, and the use of generic drugs with unproven effectiveness as components of anti-Helicobacter therapy. Once again, I want to emphasize that in order to achieve a guaranteed effect, anti-Helicobacter therapy must be carried out in accordance with international agreement, as well as using such agents, the effectiveness and safety of which have been proven.
Despite certain failures, properly administered anti-Helicobacter therapy has already proven its effectiveness in the treatment and prevention of gastritis, ulcers and stomach cancer throughout the world. In developed countries, the prevalence of peptic ulcer disease is gradually decreasing, which is associated with active identification and treatment of infected individuals. These successes inspired the global Healthy Stomach Campaign, launched in March 2005 with the participation of countries around the world. The initiators of the action, not without reason, believe that a significant contribution to the prevention of stomach diseases is possible through the active identification of persons infected with H. pylori and the provision of adequate anti-Helicobacter therapy to them in accordance with international criteria and standards.
Catad_tema Peptic ulcer - articles
Clarithromycin as an integral component of anti-Helicobacter therapy
Published in the magazine:PHARMATEKA No. 6 - 2009, p. 22-29 I.V. Maev, A.A. Samsonov, N.N. Golubev
MGMSU, Moscow
The article is devoted to the consideration of modern treatment regimens for Helicobacter pylori infection and the place of clarithromycin in them. Current recommendations of the Maastricht international consensus are presented. Possible ways to solve the main problems associated with the increase in H. pylori resistance to antibiotics are discussed. The main reasons for its development are outlined. Particular attention is paid to the prospects for the use of new treatment regimens, in particular the sequential eradication regimen with the inclusion of clarithromycin, and the quality of antibacterial drugs.
Keywords: Helicobacter pylori, eradication, anti-Helicobacter therapy, clarithromycin, microbial resistance, generics
The discovery of Helicobacter pylori infection, the recognition of its important role in the etiopathogenesis of peptic ulcer (PU) of the stomach and duodenum, active chronic antral gastritis (type B), atrophic gastritis, non-cardiac cancer and gastric MALT lymphoma has in many ways fundamentally changed the previously established approaches to prevention and treatment of the listed common diseases of the upper gastrointestinal tract (GIT). In addition to previously widely used cytoprotectors and antisecretory drugs, primarily proton pump inhibitors (PPIs), antibacterial therapy has come to the fore.
The enormous attention paid to Helicobacter pylorus over the past decades has been fully justified by the clinical results obtained. In the countries of Europe, North America and Australia, where effective methods for diagnosing and treating H. Pylori infection were systematically developed and introduced into widespread practice, a significant decrease in the incidence of Helicobacter-associated peptic ulcer and chronic gastritis was noted, as well as a trend towards a decrease in the prevalence of gastric cancer.
Indications and conditions for anti-Helicobacter therapy
To date, a significant number of anti-Helicobacter therapy regimens, varying in composition and duration of treatment, have been proposed, an obligatory component of which are antibiotics. The positive effect of eradication of H. pylori infection on the course and prognosis of associated diseases has been proven in numerous randomized clinical trials and is reflected in meta-analyses of these studies and international consensuses Maastricht I-III.
The main indications for the diagnosis of H. pylori infection and anti-Helicobacter therapy are:
1. Peptic ulcer and duodenum:
2. Cancer prevention of the stomach:
3. Other indications:
- long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (however, eradication therapy is not sufficient to prevent NSAID-associated ulcers);
- long-term use of PPIs (for example, in patients with gastroesophageal reflux disease);
Antibacterial drugs used in anti-Helicobacter therapy regimens should ideally have a limited spectrum of action, stability and activity in any pH environment (acidic, neutral and slightly alkaline). What is important is the ability of the antibiotic to penetrate the mucus layer without reducing the antimicrobial properties either from the lumen of the stomach or from the bloodstream from the lamina propria. The combination of antibacterial drugs should provide high efficiency in eradication of H. pylori, be economically acceptable, free of serious side effects and simple, which is important for maintaining high adherence to treatment. The optimal combination in circuits of components that have a synergistic interaction.
Unfortunately, many reasons limit the choice of antibiotics to include in treatment regimens for H. pylori infection. The main reasons include: the selective effect of the drug, even within one group, on the growth and survival of the microorganism, the presence of antibiotic resistance and side effects of therapy. It is important to take into account not only the mechanisms of action and antibacterial activity of drugs in vitro, but also the real effectiveness of antibiotics against H. pylori in the aggressive environment of the stomach and duodenum, which may differ significantly from laboratory data.
Principles of treatment of H. pylori infection
In general, the principles of treatment of H. pylori infection have not changed significantly over the past ten years. The Third Maastricht Agreement recommended the use of standard combinations of antibiotics with PPIs and bismuth preparations, distinguishing first- and second-line treatment regimens.
Therapy begins with a first-line clarithromycin-based regimen:
It is recommended to extend the duration of treatment from 7 to 14 days, which significantly increases the effectiveness of eradication by 12% compared to a 7-day therapy regimen and reduces the likelihood of developing secondary resistance of H. pylori to clarithromycin. According to our data, a two-week treatment regimen can increase the rate of successful eradication of H. pylori by 13.3%. Moreover, if high-quality “local” studies have proven the effectiveness and cost-effectiveness of a 7-day first-line triple therapy regimen, then the latter can continue to be used in clinical practice.
According to the recommendations of the III Maastricht Agreement, a regimen consisting of a PPI, clarithromycin and metronidazole can be used as first-line therapy. However, the administration of this combination may be justified in cases where the resistance of the most common strains of H. pylori in a given region to metronidazole does not exceed 40%. In Russia, due to the widespread and often uncontrolled use of metronidazole, this threshold has, unfortunately, been overcome and its use as part of a first-line triple eradication regimen is inappropriate.
Speaking about the drugs included in first-line eradication regimens, it is necessary to emphasize the main properties of clarithromycin, which allow it to remain an indispensable component of anti-Helicobacter pylori therapy.
Clarithromycin in anti-Helicobacter therapy regimens
Clarithromycin (Klacid) is a semisynthetic antibiotic of the macrolide group with high activity against H. pylori, the level of which it surpasses all other drugs in this group. Thus, studies comparing eradication therapy regimens with azithromycin and clarithromycin showed that the effectiveness of the latter is almost 30% higher. This circumstance makes it the only macrolide recommended for the treatment of Helicobacter pylori infection.
Clarithromycin has lipophilic properties and penetrates well into tissues and biological fluids, including gastric secretions, creating high and stable concentrations there. Its action is associated with the blockade of protein synthesis due to reversible binding to the 508 subunit of the ribosome and is bacteriostatic. However, when a concentration at the site of infection reaches a concentration 2-4 times higher than the minimum inhibitory concentration, it can also have a bactericidal effect, which may determine its dose-dependent effect in anti-Helicobacter therapy. In addition, clarithromycin has pronounced anti-inflammatory activity due to its ability to inhibit the production of pro-inflammatory cytokines and stimulate the synthesis of anti-inflammatory cytokines.
Clarithromycin is resistant to gastric acid. When taken orally, it is rapidly absorbed from the gastrointestinal tract (the rate of reaching peak plasma concentration is 1.8-2.8 hours). The bioavailability of clarithromycin is 52-55%, and the half-life when taking 500 mg 2 times a day is 7-8 hours. Biotransformation of the drug occurs in the liver with the participation of cytochrome P450.
Given the fact that clarithromycin and amoxicillin are effective against dividing microorganisms, their combination with PPIs is important to ensure antimicrobial activity. In addition, maintaining the pH level in the stomach above 3 with the help of antisecretory drugs sharply inhibits the degradation process of clarithromycin (the half-life in gastric juice at pH 1 is 1, and at pH 7-205 hours), ensuring complete eradication of H. pylori.
An important property of clarithromycin is its synergism with omeprazole, during which the pharmacokinetic interaction of these drugs occurs at the level of cytochrome P450 isoenzymes. Clarithromycin does not affect acid production, but its use in combination with omeprazole causes a significant increase in the degree of alkalization of the stomach compared to the isolated use of PPIs. When clarithromycin and omeprazole are prescribed, the concentration of the latter in the blood and its half-life increase. Similar changes in pharmacokinetics are observed for clarithromycin when taken concomitantly with omeprazole, and a linear increase in the concentration of clarithromycin in the gastric mucosa and gastric mucus is observed. Clarithromycin has also been shown to have synergism with pantoprazole, lansoprazole and esomeprazole.
If first-stage anti-Helicobacter therapy is ineffective (no eradication of H. pylori 6 weeks after complete discontinuation of antibiotics and antisecretory drugs), a four-component second-line anti-Helicobacter therapy regimen is prescribed for 7 days:
It should be borne in mind that the use of bismuth in eradication regimens makes it possible to overcome the resistance of Helicobacter pyloricus to metronidazole.
However, if H. pylori resistance to clarithromycin in the region exceeds 20% or the patient has hypersensitivity to amoxicillin or clarithromycin, the use of a standard four-component bismuth-based regimen as an alternative first-line therapy is justified. Moreover, the efficiency of three- and four-component schemes is approximately the same, amounting to 85 and 87%, respectively. The disadvantages of this treatment option are: it is difficult for patients to take the drugs four times a day, the need to take a significant number of tablets and a greater number of side effects. In the presence of a high level of clarithromycin-resistant H. pylori strains in the region, the use of four-component bismuth-based regimens is significantly more effective than triple therapy. Taking a large number of medications according to a rather complex regimen often significantly reduces the patient’s adherence to treatment, which is the second most common reason for failure of anti-Helicobacter therapy. They tried to solve this problem by creating a complex product containing a bismuth drug, tetracycline and metronidazole in one capsule. Clinical trials on its use in combination with PPIs, conducted in the USA and Europe, showed high results. The percentage of eradication during the 10-day course was 87.7-93.0%. Unfortunately, this drug combination is not registered in Russia.
Resistance of H. pylori to antibiotics
Multicenter studies conducted in Europe have shown varying levels of H. pylori resistance to clarithromycin. In Northern Europe, resistance to this antibiotic is at the level of 5-15%, while in Southern Europe this figure is already 21-28%. In Turkey, resistance to clarithromycin has been reported in 44-48% of cases. In the USA in 1999-2003. the number of patients with Helicobacter-associated diseases contaminated with clarithromycin-resistant strains of the bacterium H. pylori was 10-12%, but in Alaska this figure was at 31%.
At the same time, in Russia, the 20% threshold of resistance to clarithromycin has not yet been overcome, which makes it possible to maintain triple therapy based on clarithromycin as a first-line eradication regimen and recommend it for widespread use for the treatment of diseases associated with H. pylori.
In addition, triple therapy regimens can be used as a second line of eradication, including standard-dose PPIs and amoxicillin (1000 mg 2 times/day) in combination with tetracycline (500 mg four times/day) or furazolidone (200 mg 2 times/day) .
If the use of the first and second line of anti-Helicobacter therapy does not lead to the eradication of H. pylori, further patient management tactics should be chosen after determining the sensitivity of H. pylori to all antibiotics used in eradication regimens.
Despite the availability of the standard recommendations outlined above, based on numerous studies that meet the requirements of evidence-based medicine, an active search for new methods of anti-Helicobacter therapy continues. This is primarily due to a decrease in the effectiveness of first-line therapy, which is caused by a fairly rapid increase in H. pylori resistance to antibiotics. About a third of eradication failures with standard first-line therapy are due to resistance to clarithromycin.
Resistance of H. pylori to antibiotics is divided into primary, which is always a consequence of previous treatment with a macrolide antibiotic for another nosology, and secondary. Secondary resistance is caused by an acquired mutation of the microorganism during eradication therapy.
The main reasons for the development of resistance to clarithromycin:
When determining the sensitivity of H. pylori to antibiotics, the resistance of this bacterium to clarithromycin is of greatest clinical importance. The mechanism of formation of Helicobacter pyloric resistance to clarithromycin is the appearance of mutations that lead to conformational changes in the ribosomes of the bacterial cell, which are the targets of the antibiotic.
The main ways to prevent and overcome H. pylori resistance to antibiotics, in particular to clarithromycin:
Recently, a number of molecular diagnostic methods have been proposed to detect mutations leading to the development of resistance. Among the most promising, noteworthy is the method of determining specific sequences of ribosomal DNA using the polymerase chain reaction, which, in addition to identifying resistance, can also be used as effective method diagnosis of helicobacteriosis by examining stool and biopsy samples of the gastric mucosa. At the same time, the III Maastricht Agreement recommends the use of sensitivity testing to clarithromycin only in case of failure of the second line of anti-Helicobacter pylori therapy or if the prevalence of H. pylori strains resistant to it in a given population exceeds 20%.
Sequential anti-Helicobacter therapy
One of the most promising approaches to eradication is the so-called. sequential therapy proposed in Italy, the most important component of which is clarithromycin. The prerequisites for its creation were data obtained in the mid-90s. last century. Then it was shown that the effectiveness of second-line anti-Helicobacter therapy after a failed first course was higher if 14-day dual therapy with PPI and amoxicillin was prescribed as the first line, and standard 7-day therapy as the second line, than if these the schemes were applied in reverse order.
When prescribing sequential therapy, the course of treatment is divided into two stages. In the first 5 days, the patient receives a PPI at a standard dose 2 times a day and amoxicillin (1000 mg 2 times a day), and for the next 5 days - triple therapy consisting of a PPI, clarithromycin (500 mg 2 times a day) and tinidazole (500 mg 2 times a day). A series of studies were conducted in Italy and Spain, each including at least 100 patients. Promising results with sequential therapy have been shown in both adults and children. The eradication rate with good treatment tolerance was 91-95%. It is important to take into account that these studies were carried out in countries with high levels of H. pylori resistance to clarithromycin.
Of interest are data from a recent meta-analysis that examined the results of ten randomized controlled trials involving 2747 patients. The effectiveness of sequential therapy was compared with a 7- and 10-day standard triple regimen. The rate of successful eradication in the case of a sequential change of antibiotics was 93.4%, and in the case of using the standard regimen - 76.9%. The absolute reduction in the risk of treatment failure with sequential therapy reached 16%. Subgroup analysis demonstrated higher effectiveness of sequential treatment in groups with a high risk of eradication failure (smoking, functional dyspepsia).
Moreover, sequential therapy has been shown to be effective against clarithromycin-resistant H. pylori strains. The success of anti-Helicobacter therapy was achieved in 89% of patients using a sequential regimen and only in 44% of patients receiving standard triple therapy. The real reasons such high performance is not entirely clear. It is assumed that taking amoxicillin reduces the degree of bacterial contamination of the mucous membrane of the upper gastrointestinal tract, thereby increasing the effectiveness of the combination of clarithromycin and tinidazole. It is also possible that amoxicillin, by disrupting the synthesis of the cell wall of H. pylori, prevents the appearance of membrane channels in it, through which the active removal (efflux) of clarithromycin from the microbial cell can occur.
At the same time, no large studies of sequential therapy have been conducted in other countries, including Russia. There is no work yet comparing this new treatment regimen for H. pylori infection with 14-day triple therapy regimens and a bismuth-based quadruple regimen. Further work Studying this promising option for anti-Helicobacter therapy will apparently make it possible to establish the exact place of the sequential regimen in the system of the first and second lines of eradication.
Options for second line eradication
In addition to sequential therapy, various options for second-line eradication are being considered, differing from classical quadruple therapy recommended by the III Maastricht consensus.
Today, if eradication fails, there are three options for further action:
If clarithromycin was included in the first-line regimen, it should not be used in the second stage. Perhaps an exception may be a sequential treatment regimen, the first results of which may indicate the possibility of overcoming resistance to this antibiotic.
As a “rescue” therapy, three potential options for a 10-day treatment regimen are discussed: to PPI (at a standard dosage 2 times a day) and amoxicillin (1000 mg 2 times a day) is added levofloxacin (250 mg 2 times a day) or furazolidone ( 200 mg 2 times a day), or rifabutin (150 mg 2 times a day).
The most studied and promising regimen includes levofloxacin, which, compared to four-component therapy, is better tolerated and leads to successful eradication in 81-87% of cases. However, a 10-day treatment regimen is superior to a 7-day regimen, and a dose of 500 mg is as effective as 1000 mg. Attempts are being made to modify the levofloxacin-based regimen. In a study in which amoxicillin was replaced by tinidazole, the eradication rate with a 7-day second-line regimen was 84%.
The second line of eradication with the inclusion of furazolidone is less studied, but has a low cost compared to other “rescue” schemes. Eradication of H. pylori when used, according to various sources, ranges from 52 to 85%.
Rifabutin regimens are effective in 74-91% of patients, but rifabutin is significantly inferior to levofloxacin as a basis for third-line therapy and can cause a number of serious side effects. In addition, rifabutin is used in the treatment of tuberculosis, and in our country, for obvious reasons, its use as an anti-Helicobacter drug is inappropriate.
The problem of the quality of antibacterial drugs
In addition to H. pylori resistance and low patient adherence to treatment, an important factor that may contribute to the failure of anti-Helicobacter therapy is the quality of drugs included in eradication regimens.
Currently, much attention is paid to the comparison of original drugs and their reproduced copies (generics). An original drug is a medicinal substance synthesized for the first time and undergone a full cycle of preclinical and clinical trials, the active components of which are protected by a patent. A generic is a medicinal product characterized by proven equivalence and therapeutic interchangeability with an original medicinal product of a similar composition, produced without a developer’s license by another manufacturing company. Generics may be released after the patent protection of the original drug has expired.
In this case, three types of equivalence of original and generic pharmacological drugs are distinguished: pharmaceutical equivalence, pharmacokinetic equivalence and clinical therapeutic equivalence.
Pharmaceutical equivalence is the equivalence of drugs in terms of the qualitative and quantitative composition of medicinal components, which is determined by pharmacopoeial tests. It is also important that there are no significant deviations in the composition of the auxiliary components, which can change the quality of the drug, its bioavailability, and sometimes lead to toxic or allergic reactions.
Pharmacokinetic equivalence (bioequivalence) is assessed by determining the rate and extent of absorption of the original drug and the generic when taken in the same doses and dosage forms based on measuring the concentration in body fluids and tissues (bioavailability). However, pharmaceutical equivalence does not necessarily ensure pharmacokinetic equivalence. Relative bioavailability is the relative amount of a drug that reaches the bloodstream (extent of absorption) and the rate at which this process occurs (rate of absorption). Drugs are bioequivalent if they provide the same bioavailability of the drug. However, the bioavailability of generics can often differ significantly (up to 20%) from that of the original drug.
No less important is the therapeutic equivalence of the original drug and the generic, which is determined after clinical comparative studies. Data on the effectiveness and safety of the original drug cannot be completely transferred to its generics.
Especially great importance has a choice of original or generic drug when carrying out antibacterial therapy, in particular eradication of H. pylori infection. Low antimicrobial activity of the drug can lead to a decrease in the clinical effectiveness of therapy and an increase in the prevalence of resistant strains of bacteria. In this regard, an interesting work presents the results of a comparative study of the quality of the original clarithromycin (Klacida, Abbott Laboratories, USA) and 65 of its generics from 18 countries in Europe, Latin America, Asia, Africa and the Pacific region. In 9% of samples, including those from European manufacturers, the clarithromycin content did not meet the standards of the company that developed the original drug (95-105% of the dose indicated on the package). This is especially important when carrying out eradication, since clarithromycin in this case has a clear dose-dependent effectiveness. Of the 50 generics studied in this experiment, 34% showed a lower rate of release of active clarithromycin upon dissolution compared to the original drug. However, most of them met the solubility standards (80% of the drug in 30 minutes) established by Abbott Laboratories for this antibiotic. A significant number (19%) of generics exceeded Abbott's recommended 3% limit for adulterants. At the same time, 30% of drugs exceeded the 0.8% limit for dioxymethylerythromycin A.
A fairly large number of generic drugs are generally not equivalent to the original clarithromycin in vitro. At the same time, the practical significance of these data needs to be clarified when conducting comparative clinical trials.
We must not forget about the possibility of patients purchasing and using counterfeit antibacterial drugs, which, according to WHO, are the most frequently counterfeit group of drugs. In particular, amoxicillin ranks first in the world in terms of frequency of falsification. The consequences of the use of such “medicines” are not only the failure of anti-Helicobacter therapy, the disappointment of patients with the results of treatment and the development of antibiotic resistance, but also the development of serious complications.
Conclusion
Thus, due to its effectiveness and safety, clarithromycin (Klacid) continues to remain an integral part of first-line anti-Helicobacter therapy in Russia. Broad prospects for the use of clarithromycin in both first- and second-line eradication regimens are associated with the further development and implementation of sequential treatment regimens, which, apparently, will overcome the resistance of H. pylori to this antibiotic and increase the effectiveness of treatment even in regions with high antibiotic resistance. LITERATURE
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A gram-negative spiral-shaped flagellated bacterium was found in the mucous membrane of the stomach and duodenum. Helicobacter pylori, which scientists consider one of the possible causes of chronic gastritis and the formation of ulcers. If this pathogen is detected, drugs that have a bactericidal effect are prescribed. Such drugs include: gastroprotector bismuth tripotassium dicitrate (de-nol), proton pump inhibitor omeprazole, antibacterial agent metronidazole (Trichopol), penicillin antibiotics (ampicillin, amoxicillin), tetracyclines (doxycycline), macrolides (clarithromycin).
There are also combination drugs:
pilobact(clarithromycin + omeprazole + tinidazole);
pylorid(ranitidine + denol);
helicocin(amoxicillin + metronidazole).
In the treatment of gastric and duodenal ulcers, combinations of anti-Helicobacter drugs are used. Combinations can be two-component, three-component, four-component.
Examples of combinations:
Two-part – clarithromycin+metronidazole ; denol+spiramycin ; denol + clarithromycin ; denol + doxycycline ; omeprazole + amoxycycline .
Three-part – denol + amoxicillin + metronidazo (or furagin); omeprazole + amoxicillin + clarithromycin; omeprazole + tinidazole + clarithromycin.
Four-part – deno + tetracycline + metronidazole + omeprazole; clarithromycin + amoxicillin + metronidazole + omeprazole.
After a 7-10 day course of therapy, it is necessary to continue treatment with omeprazole for 5-7 weeks, since monotherapy with bismuth preparations has a weak effect.
It should be noted that in some patients it is not possible to obtain eradication of Helicobacter pylori, which indicates the development of resistance (resistance) of this bacterium to drugs. The reasons for the development of resistance are unknown.
Drugs used for disorders of motor function of the stomach and intestines
Emetics
Vomiting is a complex reflex act, in which many muscle groups (stomach, small intestine, diaphragm, abdominal wall, etc.) take part. It occurs when the vomiting center is activated by a wide variety of stimuli. These may be disgusting visual, olfactory or gustatory sensations. Irritation of the vestibular apparatus and interoreceptors of various locations can also cause vomiting. In addition, it has been established that a special chemoreceptor zone, called the trigger zone, is associated with the center of vomiting. It is located at the bottom of the IV ventricle. Stimulation of the trigger zone chemoreceptors leads to stimulation of the vomiting center. It has been established that the neurons of this zone contain dopamine D2 receptors, serotonin receptors, and m-cholinergic receptors.
Chemicals that induce vomiting act on the chemoreceptors of the trigger zone or act peripherally (by reflexively irritating the gastric mucosa).
Emetics are used to remove poisons or food poisoning from the stomach, especially in cases where it is impossible to lavage the stomach (swallowing is impaired; poisoning with mushrooms, berries or other foods that do not pass through the tube; in case of suicide).
Substances that stimulate dopamine receptors in the trigger zone include apomorphine hydrochloride. The central effect of apomorphine is proven by the fact that vomiting occurs immediately after its application to the trigger zone in small quantities. In addition, animal experiments have shown that gagging occurs with parenteral administration of apomorphine, even with complete removal of the gastrointestinal tract.
Apomorphine has very limited use (if gastric lavage or the use of peripheral emetics is difficult for some reason), it is administered subcutaneously. The action occurs within 2-15 minutes. In addition, apomorphine is used in the treatment of alcoholism to develop a negative conditioned reflex to ethyl alcohol. In case of poisoning with substances that depress the vomiting center (for example, anesthetics), apomorphine is ineffective. Apomorphine can cause drowsiness, respiratory depression, arterial hypotension, and allergies.
Peripheral emetics include - table salt solution in warm water (2-4 teaspoon per glass of water) and emetic root syrup (1 teaspoon) containing the alkaloid emetine. These drugs cause vomiting reflexively, irritating the sensory nerves of the gastric mucosa. The effect occurs within 10-15 minutes.
It is not accompanied by CNS depression.
It is impossible to induce vomiting in people who are unconscious, with burns of the stomach with strong acids and alkalis, with peptic ulcers of the stomach and duodenum, lung diseases with possible pulmonary hemorrhage, and severe forms of heart disease.
Antiemetics (antiemetics)
Depending on the origin of vomiting, one or another antiemetic should be prescribed. Nausea and vomiting have different origins: motion sickness (sea sickness, air sickness), that is, vomiting associated with excessive stimulation of the vestibular apparatus; chemotherapy and radiation therapy of oncological diseases; diseases of the gastrointestinal tract, liver and biliary tract; pregnancy, etc.
An active antiemetic agent that inhibits the trigger zone is the drug metoclopramide (Raglan, Cerucal). It blocks dopamine D2 receptors in the trigger zone of the vomiting center, and thereby eliminates nausea and vomiting. Penetrates the BBB and can cause central effects.
In addition to its antiemetic effect, metoclopramide is able to enhance the motility of the stomach and small intestine and accelerate gastric emptying, that is, it has the properties prokinetics. The drug increases the tone of the lower esophageal sphincter. Does not affect the colon. In addition, metoclopramide increases pressure in the gallbladder and bile ducts and reduces the tone of the sphincter of Oddi.
The spectrum of antiemetic action of metoclopramide is similar to antipsychotic drugs. It is used mainly for vomiting and nausea associated with irritation of the mucous membrane of the gastrointestinal tract, for peptic ulcers, gastritis, colitis, cancer of the gastrointestinal tract, for radiation sickness, as well as for delayed evacuation of contents from the stomach and reflux esophagitis. It is ineffective for motion sickness.
Side effects include drowsiness, dizziness, tinnitus, a feeling of lightheadedness and “failures,” dry mouth, cramping abdominal pain, diarrhea, gynecomastia, and convulsions. In large doses, it causes parkinsonism.
The drug is taken orally, administered intravenously and intramuscularly. Do not chew the tablets, wash them down with a small amount of water.
A more modern analogue of metoclopramide is Domperidone (Motilium). It is called a “second generation prokineticist.” Unlike metoclopramide, it does not penetrate the BBB, acts more selectively and does not cause central effects - dizziness, lightheadedness, convulsions, parkinsonism. Used for the same indications as metoclopramide.
Phenothiazine derivatives (etaperazine, triftazine, etc.) and butyrophenone (haloperidol), which block dopamine receptors in the trigger zone of the vomiting center, have pronounced antiemetic activity. They are effective against vomiting caused by substances whose action is directed to the trigger zone (digitalis glycosides, apomorphine, etc.). These drugs also eliminate vomiting that occurs in the postoperative period, with radiation sickness, and toxicosis of pregnant women. They are ineffective for motion sickness.
Phenothiazine derivatives also include a highly active antiemetic drug thiethylperazine(torekan). There is evidence that, in addition to blocking dopamine receptors in the chemoreceptor zone, thiethylperazine has an inhibitory effect directly on the vomiting center. Therefore, it is a more versatile antiemetic. Well tolerated. Sometimes dry mouth, drowsiness, tachycardia, hypotension occur, and with prolonged use - parkinsonism.
Active antiemetics include a number of drugs that block serotonin S 3 receptors (in the central nervous system and in the periphery). One of them is ondansetron(emetron). It is used mainly to prevent or eliminate vomiting associated with tumor chemotherapy or radiation sickness. It is administered orally and intravenously. Well tolerated. Sometimes causes headache, dizziness, constipation. It differs from metoclopramide in that it does not block dopamine receptors and therefore does not cause disturbances in the extrapyramidal system.
This group of drugs includes granisetron(kytril).
People with increased excitability of the vestibular apparatus are recommended to take prophylactic medications containing scopolamine. One of the most common anti-motion sickness medications are Aeron tablets. They are prescribed 30-60 minutes before the start of the journey (by plane, boat). Duration of action is about 6 hours.
For motion sickness, the histamine H1 receptor blockers diprazine and diphenhydramine, which have sedative and anticholinergic properties, are also effective. It is possible that in the mechanism of the antiemetic action of m-anticholinergics and antihistamines, their direct effect on the center of vomiting plays an important role.
Side effects These two groups of substances are drowsiness, dry mouth, and impaired accommodation.
Marina Pozdeeva about the principles and schemes of anti-Helicobacter therapy
Colonization of Helicobacter pylori on the surface and folds of the gastric mucosa significantly complicates antibacterial therapy. A successful treatment regimen is based on a combination of drugs that prevent the emergence of resistance and overtake the bacteria 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 that often leads to unpredictable results is replacing even one well-studied drug from standard scheme to another drug of the same group.
Proton pump inhibitors (PPIs)
PPI therapy has proven effective in various clinical studies. Although PPIs have a direct antibacterial effect on H. pylori in vitro, they do not play an important role in eradicating the infection.
The mechanism by which PPIs synergize when combined with antimicrobials to enhance the clinical efficacy of eradication therapy has not been fully established. It is assumed that antisecretory drugs of the PPI group may help 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 surface of the mucosa 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 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 enzyme urease, 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 disrupting its integrity.
Metronidazole
H. pylori is generally very sensitive to metronidazole, the effectiveness of which is independent of pH. After oral or infusion use, high concentrations of the drug are achieved in the gastric juice, which makes it possible to achieve the maximum therapeutic effect. Metronidazole is a prodrug that undergoes activation by bacterial nitroreductase during metabolism. Metronidazole causes H. pylori to lose its helical DNA structure, causing DNA damage and killing the bacterium.
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. Performing the test 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.
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Clarithromycin
Clarithromycin, a 14-member macrolide, is a derivative of erythromycin with a similar spectrum of activity and indications for use. However, unlike erythromycin, it is more acid resistant and has a longer half-life. The results of studies showing that the triple eradication therapy regimen for Helicobacter pylori using clarithromycin gives a positive result in 90% of cases, led to the widespread use of the antibiotic.
In this regard, in last years An increase in the prevalence of clarithromycin-resistant H. pylori strains has been documented. There is no evidence that increasing the dose of clarithromycin will overcome the problem of antibiotic resistance to the drug.
Amoxicillin
An antibiotic of the penicillin series, amoxicillin is very close to ampicillin both structurally and in terms of its spectrum of activity. Amoxicillin is stable in an acidic environment. The drug inhibits the synthesis of bacterial cell walls and 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 complex therapy is required to eradicate the bacterium.
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 been shown to be effective in vitro against H. pylori and remains active at low pH.
Indications for eradication therapy
According to the Maastricht 2-2000 Consensus Report, H. pylori eradication is strongly recommended:
- all patients with peptic ulcer disease;
- patients with poorly differentiated MALT lymphoma;
- persons with atrophic gastritis;
- after resection for gastric cancer;
- first-degree relatives of patients with stomach cancer.
The need for eradication therapy in patients with functional dyspepsia, GERD, as well as in persons taking non-steroidal anti-inflammatory drugs for a long time remains a subject 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 individuals with H. pylori who have nonulcer dyspepsia and corpus-predominant gastritis are at increased risk of developing gastric adenocarcinoma. Thus, H. pylori eradication should also be recommended for patients with nonulcer dyspepsia, especially if histology reveals corpus-predominant gastritis.
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, while PPIs reduce natural defenses. However, eradication of H. pylori before prescribing NSAIDs significantly reduces the risk of peptic ulcer disease 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 combination treatment regimens, 10–20% of patients infected with H. pylori fail to achieve elimination of the pathogen. The best strategy is to select the most effective treatment regimen, but the possibility of using two or even more sequential regimens should not be ruled out if the treatment of choice is insufficiently effective.
If the first attempt at eradication of H. pylori fails, it is recommended to immediately proceed to second-line therapy. Antibiotic sensitivity testing and switching to salvage therapy regimens are indicated only for those patients in whom second-line therapy will also not lead to eradication of the pathogen.
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One of the most effective “rescue regimens” is a combination of 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 was effective against strains of H. pylori resistant to clarithromycin or metronidazole. However, the high price of rifabutin limits its widespread use.
NB! To avoid the development of resistance to both metronidazole and clarithromycin, these drugs are never combined in the same regimen. The effectiveness of such a combination is very high, but patients who do not respond to therapy usually develop resistance to both drugs at once (a study by German scientists led by Ulrich Peitz, published in Alimentary Pharmacology & Therapeutics in 2002). And further selection of therapy causes serious difficulties.
Research data confirm that a 10-day salvage therapy regimen, including rabeprazole, amoxicillin and levofloxacin, is much more effective than standard second-line eradication therapy (a study by Italian scientists led by Enrico C Nista, published in Alimentary Pharmacology & Therapeutics in 2003 year).