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Role of standard antibiotic therapy in Helicobacter pylori associated diseases of stomach...
7. McLean C., Adlington H., Houshian S. Paediatric forearm refractures with retained plates managed with flexible intramedullary nails// Injury. - 2007. - № 8.
8. Park H. W., Yang I. H., Joo S. Y., Park K. B., Kim H. W. Refractures of the upper extremity in children//Yonsei Med. J. - 2007. - № 2.
Yusupbekov Abrorbek Axmedjanovich, Doctor of Medical Sciences, Deputy director, National Cancer Research Center, Republic of Uzbekistan
Mallaev Makhsud Mukhammadievich, Tashkent medical academy, Oncology department, Assistant, Doctor-Oncologist
Ismailova Jadida Akhmedjanovna, National specialized scientific-practical medical center, Doctor
Abdusattorov Ravshan Abduraufovich, Tashkent Medical Academy, Department of General Oncology and Radiation diagnosis, Undergraduate student E-mail: [email protected]
Role of standard antibiotic therapy in Helicobacter pylori associated diseases of stomach in development of stomach MALT lymphoma
Abstract: The discovery of H.pylori and the proof of its leading role in the development of most of gastrointestinal diseases has radically changed the approach to their treatment. Chronic gastritis, peptic ulcer disease, gastric lymphoma associated with H. pylori infection require therapy aimed at killing microbes.The main reason for the ineffectiveness of current treatment program is based on a point mutation of the genome HP and uncontrolled use of modern antimicrobial drugs. Moreover, the literature contains no information on the role of long-term use of ineffective drugs in the occurrence of gastric neoplasms. This fact is the reason for further research in this area. Aim of this research to determine efficiency of antibiotic therapy in antibiotic-resistant forms of Helicobacter pylori in the development of malignancy MALT tumors in gastrointestinal tract. After the study we concluded that long-term use of antibiotics for resistant forms of HP besides ineffective against the disease, contribute to the development of local and general disturbances of the immune status. Availability treatment-resistant forms of HP accelerates proliferation and dysplasia, which leads to the development of neoplasms. Keywords: MALT-lymphoma, helicobacter pylory, stomach neoplazms.
Helicobacter pylori — small, gram-negative, asporous, micro-aerophilic bacteria. Under the influence of the external environment, for example, a change in temperature or pH, long cultivation, Helicobacter pylori starts to change in coccal form. This may be due to the degenerative changes and the transition to an inactive phase, which favors its survival and could be an important factor in the epidemiology and spread of bacteria [1].
In coccal forms impaired enzymatic activity, and they lose their reproductive capacity, becoming resistant to antibacterial agents, they have created good conditions for preservation of bacteria in the bowels. Once in favorable conditions, such forms of H. pylori may be re-transformed into vegetative forms that can colonize in the gastric mucosa.
Helicobacter pylori has the ability to colonize, also it is able to protect themselves from the action of hydrochloric acid. It is equipped with a smooth cell wall — glycocalyx. Glycocalix makes bacteria non-susceptible to antibacterial agents and protects it from the host's immune response. Helicobacter pylori produce urease which neutralizes the hydrochloric acid in gastric juice that creates pH 7 environment around Helicobacter pylori.
In addition, the urease of H. pylori acts as a toxin that formed ammonium ion during the hydrolysis of urea. It damages epithelium which increases the inflammatory reaction by activation of monocytes and neutrophils, stimulation of cytokine secretion, formation of oxygen radicals and nitric oxide, moreover, large subunit urease (UreB) acts as an attractant for leukocytes [2].
There are two types of Helicobacter "stomach" — clinically important type is Helicobacter pylori (as well as H. acinonychis, H. baculiformis, H. bizzozeronii, H. cetorum, H. cynogastricus, H. felis, H. heilmannii, H. mustelae, H. salomonis, H. suis), «entero-hepatic» (H. anseris, H. bilis, H. brantae, H. canis, H. canadensis, H. cholecystus, H. cinaedi, H. equorum, H. fennelliae, H. ganmani, H. hepaticus, H. marmotae, H. mastomyrinus, H. mesocricetorum, H. muridarum, H. pametensis, H. pullorum, H. rodentium, H. salo-monis, H. trogontum, H. typhlonius).
More than 10 types of helicobacter are pathogenic to human body (H. pylori, H. heilmannii, H. cinaedi, H. fennelliae, H. bilis, H. pullorum, H. hepaticus, etc.).
The most clinically important type for human is — Helico-bacter pylori, which according to modern ideas, related to many cases of stomach ulcers, gastritis, MALT tumors and gastric cancer.
The second most important type for human is H. Heilmannii. It usually causes antral gastritis.
According to many authors H.felis is a major factor in the development of gastric cancer. In particular, to address the conciliation meeting Maastricht IV (Part 3. "Preventing gastric cancer and other complications" statement № 1) "... Transgenic expression of IL- 1p of gastric parietal cells leads to the spontaneous development of gastritis, mobilization suppressor cells of myeloid origin and dysplasia. Helicobacter felis infection leads to the progression of neoplasms".
Section 5. Medical science
In addition H. suis also associated with organic lesions of the stomach.
According to the molecular — genetic results, genome of Helicobacter pylori (strain 2965) contains 1,667,867 pair of nucleotides that determine the synthesis of about 1,500 proteins and includes genes, — cagA, vacA, iceA and babA associated with increased pathogenicity of microorganism.
Gene cagA or cytotoxin — associated gene (cytotoxin associated geneA) located in pathogenic island of PAI (pathogenic island) and encodes synthesis of protein — cagA 120 kD. Gene cagA presents not all strains of Helicobacter pylori. Formation of protein cagA associating with peptic ulcer disease, gastric cancer, lymphoma. After adhesion Helicobacter pylori, protein cagA transported to the stomach cells through the secretion system of type IV, which is also encoded pathogenic island.
In different situations the same Helicobacter pylori strain may express different pathogenicity, virulence, due to the genetic characteristics of the individual and the influence of environmental factors.
The reason for the lack of efficacy of many gastroduodenal diseases is increasing resistance to antibiotics of Helicobacter pylori (H. pylori), which is caused by mutations in different genes. The greatest practical importance 23S rRNA have mutations underlying resistance to clarithromycin. According to international consensus Maastricht-3 circuit with a proton pump inhibitor (PPI), clarithromycin and metronidazole is recommended as 1st line therapy.
The discovery of H. pylori and the proof of its leading role in the development of most of gastroduodenal diseases has radically changed the approach to their treatment. Chronic gastritis, peptic ulcer disease, gastric lymphoma associated with H. pylori infection require therapy aimed at killing microbes. In recent years there has been an increase of failures during the 7-day triple schemes of eradication therapy [1; 2; 3]. The main reason for them is the antibiotic resistance of H. pylori. The development of resistance of H. pylori to antibiotics is associated with point mutations of different genes.
Antibiotic resistance — a leading factor in unsuccessful treatment of first and second line. This explains why it is impossible to provide a standardized treatment which can be applied worldwide. In addition, stability is constantly changing due to the overuse of antibiotics to treat other diseases, and as a result of migration.
The widespread use of clarithromycin for the treatment of respiratory tract infections, especially in children, and metronidazole in gynecology and parasitic infections in the developing countries increased primary H. pylori resistance to the two antibiotics. Metronidazole resistance in some areas as high as 100 %. In developed countries, after studies, as a replacement of metronidazole and clarithromycin, fluoroquinolones proposed to which H. pylori still has a relatively low resistance.
Thus, a brief digression digestive information indicates failure of antibiotic eradication therapy in the treatment of resistant forms of HP.
Based on the literature review, we concluded that long-term treatment of resistant forms of HP insensitive antibiotics does not cure the underlying disease.
The main reason for the ineffectiveness of current treatment program is based on a point mutation of the genome HP and uncontrolled use of modern antimicrobial drugs.
Moreover, the literature contains no information on the role of long-term use of ineffective drugs in the occurrence of gastric neoplasms.
This fact is the reason for further research in this area.
Aim of the study: to determine efficiency of antibiotic therapy in antibiotic-resistant forms of Helicobacter pylori in the development of malignancy MALT tumors in gastrointestinal tract.
Material and metods
We studied 20 patients with diagnosis of tumor in the gastrointestinal tract, treated in the period of2012-2015 years at the National cancer center of Uzbekistan and Tashkent city oncology center.
Age ranged from 25-69 years, with an average of 47.1 ± 0.4 years. The men were 14 (60.8 %), 6 women (39.2 %).
All patients had a history of repeated unsuccessful attempts to medical treat various forms of gastritis and/or peptic ulcer disease in different parts of the system of health care.
All patients on admission to hospital conducted comprehensive diagnostic studies, according to the "Standards of diagnosis and treatment of cancer patients," by Ministry of Health. For determining the HP used materials such as gastric juice, blood and biopsies blocks.
The diagnosis was verified by morfological and immunopheno-typic study of biopsies. Helicobacter pylori determined by PCR. Resistance to HP determined by microbiological examination. Biopsies placed in containers such as "Eppendorf" with sterile 20 % glucose solution and stored prior to deliver to the laboratory conditions of the refrigerator at +4 °C. Within 2-4 hours gastrobioptats delivered to the laboratory for inoculation. Seedings processed in accordance with the method of cultivation [4].
For choosing, the question of determining discharged bacterial culture of Helicobacter carried on the basis of a characteristic morphology ofisolated colonies, as well as a set of tests: morphology of culture in the smear, stained by Gram, and the presence of specific biochemical properties (the ability to produce urease). Typical cell H. pylori microscopy were kind of thin curved pale — pink sticks.
The resistance of H. pylori isolates studied using the limiting dilution method, which is based on the detection of the inhibition of microorganism growth on nutrient agar containing defined concentrations of antibiotics. Determines the sensitivity of H. pylori strains to clarithromycin, amoxicillin, levofloxacin, metronidazole and tetracycline. Working concentrations of these antibacterial drugs in the agar were as follows:
• amoxicillin — 0.25; 0.12; 0.06 g/ml;
• clarithromycin — 1.0; 0.5; 0.25; 0.12 g/ml;
• Levofloxacin — 2.0; 10; 0.5 ug/ml;
• Metronidazole — 16; 8; 4 ug/ml;
• Tetracycline — 2.0; 10; 0.5 ug/ml.
For adequate comparison of the results of the control group consist of 20 patients with chronic atrophic gastritis and 20 patients with gastric ulcer.
We examined all patients for detection of HP gastric juice.
Results and discussion
The first group consisted of 20 people, patients with gastric MALT lymphoma.
In all (100 %) of the patients by polymerase chain reaction for the detection of DNA of HP quality in real time is positive.
In the history of all patients conducted eradication treatment for HP. For a long time took antibiotics such as metronidazole, clarithromycin, amoxicillin.
By morphological picture of the tumor resembles visually dense infiltrate of small atypical, mostly dentritlike cells surrounding the "wide belt" pre-existing reactive follicles with light centers of breeding and propagating interfollicular. Tumor infiltration in most cases located in the mucosa. Often infiltrate seen sporadic reactive follicles that sometimes "stratify" the tumor cells. It is noted the presence of plasma cells and monocytoid B — cells.
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Bacteriological analysis of 20 patients of 1st group in 11 (55 %) patients sensitivity to claritromycin was not observed. To metroni-dazol we observed a low sensitivity (+), sensitivity to amoxicillin was medium (++). For Tetracycline and levofloxacin the sensitivity was high (+++).
6 (30 %) patients in the first group to the low sensitivity of clarithromycin (+). To metronidazol and amoxicillin no sensitivity (-). Tetracycline, we observed an average sensitivity (++) and to levofloxacin high sensitivity (+++).
In 3 (15 %) patients in the same group for metronidazol and claritromitsin sensitivity was not observed. For the rest of the antibiotics: amoxicillin, tetracycline and levofloxacin sensitivity was moderate (++).
2nd group — 20 patients with chronic atrophic gastritis. The average age of 46.5 ± 0.9 years. Patients in this group had a history of chronic hyperacid gastritis. The duration of clinical symptoms until diagnosis is 6-12 months.
In all (100 %) 20 patients by polymerase chain reaction for the detection of DNA of HP quality in real time is positive.
The history of all who had eradication HP treatment. They took antibiotics such as metronidazol, clarithromycin, amoxicillin by the standard of treatment.
By endoscopic study on the background of atrophic gastritis were identified erosive lesions of the mucous membrane. Erosion different polymorphisms in endoscopic picture.
Morphologic study were found degenerative changes in the cells and dysgenerator surface epithelium, continuous inflammatory infiltration of the gastric mucosa and a decrease in the number of normal glands. The epithelium appear fundal cancer among the main and parietal cells. Also found elements of the "restructuring" of the mucosa.
Bacteriological analysis of 20 patients in 9 (45 %) patients to claritromitsin and metronidazol has low sensitivity (+), no sen-sitibility for amoxicillin (-). Tetracycline medium sensitivity (++) and high sensitivity to levofloxacin (+++).
6 (30 %) patients of the second group no sensitivity to clar-ithromycin, metronidazol and amoxycillin (-). Tetracycline and to levofloxatcin we observed high sensitivity (+++).
In 5 (25 %) patients in this group to claritromitsin, metronidazol, amoxicillin and levofloxacin sensitivity was low (+) and tetracycline sensitivity was moderate (++).
3rd group — 20 patients with stomach ulcer. The average age of 46.5 ± 0.9 years. Patients in this group had a history of chronic hyperacid gastritis.
20 (100 %) of 20 patients by polymerase chain reaction for the detection of type DNA HP quality in real time is positive.
The history of all had eradication HP treatment, antibiotics such as metronidazol, clarithromycin, amoxicillin.
Morphologic study was a single ulcer, which has an oval or round in shape and size from a few millimeters to 5-6 cm. Ulcer penetrated the stomach wall at different depths reaching sometimes up to a serous layer. Edge sores facing the esophagus, some implied, and the mucous membrane hangs over the defect. The edge facing the gatekeeper, flat, looks like terraces, steps which are formed by layers of walls — mucosa, submucosal and muscular.
Bacteriological analysis of the 20 patients — 13 (65 %) patients to clarithromycin, metronidasol had an average sensitivity (++) to amoxicillin, tetracycline, and to levofloxacin observed high sensitivity (+++).
In 3 (15 %) patients of the third group to clarithromycin and metronidazol had a high sensitivity (+++). To amoxicillin, tetracycline and levofloxacin observed mild sensitivity (++).
In 4 (20 %) patients in this group to claritromicin, amoxicillin, tetracycline and levofloxacin has high sensitivity (+++). Metronidazol, we observed a low sensitivity (+).
Conclusions
1. Long-term use of antibiotics for resistant forms of HP besides ineffective against the disease, contribute to the development of local and general disturbances of the immune status. Availability treatment-resistant forms of HP accelerates proliferation and dysplasia, which leads to the development of neoplasms.
2. Antibiotic-resistant form of HP, unlike other forms of family HP, a chemical mutation may increase the pathogenicity.
3. Antibiotic-resistant form of the HP continuously irritate lymphatic tissue and the use of eradication therapy in non-susceptible strains of HP causes an allergic reaction of the mucous membranes and lymph tissues of the gastrointestinal tract. This reduces the barrier protection of the stomach wall and HP directly stimulates lymphatic layer.
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Mamajonov Bakhodir Solijonovich, Assistant of the department of traumatology, orthopaedics, field surgery, neurosurgery and medicine of catastrophes Andijan state medical institute, Andijan E-mail: [email protected]
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