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MACROLIDE RESISTANCE OF H.PYLORI DUE TO ermB GENE DURING H.PYLORI INFECTION IN REAL PRACTICE
K.M. Perfilova* T.Yu. Butina, N.V. Neumoina, I.V. Shutova, I.A. Kuznetsova, T.A. Troshina, T.V. Shmakova, S.N. Levina#
I.N. Blokhina Research Institute of Epidemiology and Microbiology, 71 Malaya Yamskaya St., Nizhny Novgorod, 603950, Russia.
* Corresponding author: kperfilova@yandex.ru
# the authors contributed equally to this work
Abstract. The aim was to study macrolide resistance of erm B-positive H.pylori in patients with newly diagnosed and recurrent helicobacteriosis in Nizhny Novgorod. Materials and methods: PCR detection of H.pylori DNA in gastric juice and biotopes of the mucous membrane of the gastric antrum was performed in 3450 patients with gastroenterological diseases. To identify the ermB gene associated with macrolide resistance, domestic commercial PCR test systems were used. Results: from 2005 to 2023 there was a progressive reduction in visits for gastric and duodenal ulcers. The dynamics of primary and secondary genetic H.pylori macrolide resistance increased continuously from 2011 to 2014 and stabilized thereafter. From 2014 to 2023, the proportion of patients with ermB gene positive H.pylori infection increased approximately 2-fold (to 17.0% in 2018). In patients with a history of eradication therapy, the minimum detection rate of the ermB gene was established in 2011. Since 2012, there has been an increasing detection rate of secondary H.pylori macrolide resistance to 35.4% in 2022. Conclusions: during the observation period, a progressive reduction in the proportion of patients with gastric and duodenal ulcers among patients with gastroenterological diseases was revealed. The study of primary and secondary H.pylori macrolide resistance showed an increase in the detection rate of resistant isolates in Nizhny Novgorod. The study of genetic H.pylori macrolide resistance is necessary when re-identifying in patients with a history of eradication therapy and in patients who took clarithromycin for other reasons for the optimal selection of drugs included in the re-treatment regimen of infection.
Keywords: Helicobacter pylori, macrolide resistance, ulcer disease, clarithromycin, eradication.
List of Abbreviations
DNA - deoxyribonucleic acid NSAIDs - non-steroidal anti-inflammatory drugs
PCR - polymerase chain reaction RNA - ribonucleic acid erm - erythromycin ribosome methylation H.pylori - Helicobacter pylori
Introduction
In recent decades, H.pylori has been one of the most studied causes of the development of gastric pathology (Lee et al., 2016; Maev et al., 2016; Shirani et al., 2023). The use of adequate eradication therapy in H.pylori infected patients is considered as a prevention of gastric and duodenal ulcers and the formation of a number of neoplasms (Amieva & Peek, 2016; Maev et al., 2017; Malfertheiner et al., 2018; Li Y. et al., 2023). The therapy regimens for pathogen eradication include a number of antibacterial drugs
(amoxicillin, metronidazole, clarithromycin, tetracycline, rifabutin, levofloxacin), the effectiveness of which depends on the sensitivity of the microorganism to them (Maev et al., 2014; Sugano et al., 2015; Ivashkin et al., 2018; Ho et al., 2021; Suzuki et al., 2022). In various countries of the world, there has been a decrease in the effectiveness of eradication therapy regimens associated with an increase in the number of H.pylori strains resistant to antibiotics, which is a determining factor in the persistence of infection in patients with gastroduodenal pathology in all the variety of morphological and clinical manifestations of the disease (Graham & Fischbach, 2010; Kalugin et al., 2016; Lazebnik et al., 2017; Bujanda et al., 2021). It is especially important to study H.pylori resistance to clarithromycin and metronidazole, which are most often used to eradicate the microorganism (Isaeva, 2010; Dekhnich et al., 2011; Lee J.W. et al., 2023). Clarithromycin,
which has an antibacterial effect, is also capable of destroying the matrix of microbial biofilms, including the microorganism, that contribute to the development of pathogen immunity to antibiotic therapy and protect it from the immune response of the macroorganism. The main reason for the decrease in the effectiveness of eradication schemes is the growing spread of clarithromycin resistant strains (Tsukanov et al., 2015; Neumoina et al., 2020; Megraud et al.,
2021). According to the 5th and 6th Maastricht Agreements, the use of clarithromycin in the treatment of H. pylori infection is possible if the resistance of the microorganism to this drug in the population is less than 15-20%. In cases where immunity exceeds this indicator, it is not recommended to use a standard three-component eradication course (amoxicillin, clarithromycin and a proton pump inhibitor) (Mal-fertheiner et al., 2017; Malfertheiner et al., 2022; Dekhnich et al., 2011; Bordin & Liwzan,
2022).
H.pylori has two types of antibiotic resistance: natural (genetically determined) and acquired. Antibacterial drugs such as vancomycin, sulfonamides, nalidixic acid, trimethoprim, polmixin, to which H.pylori are resistant by nature, are used to create transport and selective media.
Acquired H.pylori resistance to antibiotics can be primary and secondary (Srisuphanunt et al., 2023; Lin et al., 2023). Primary H.pylori resistance to antibiotics is considered as an adaptive reaction of the microorganism to unfavorable environmental conditions that have arisen in connection with taking antibiotics for infectious diseases not associated with helicobacteriosis. Secondary H.pylori resistance to antibiotics occurs after an unsuccessful course of eradication therapy. Among the reasons for the emergence of acquired resistance of a microorganism, it should be noted the uncontrolled use of antibiotics and inadequately carried out eradication (anti-Helicobacter) therapy (Akhmetova et al., 2018; Tsapkova, 2022; Park et al., 2023; Ha-sanuzzaman et al., 2024).
All mechanisms of antimicrobial resistance can be divided into 5 main groups (Sidorenko 2007; Ivanov et al., 2022).
Action target modification. Resistance occurs as a result of mutations in the structure of the gene responsible for the synthesis of the protein that is the action target of the antibiotic. A target protein with an altered structure loses its ability to bind to the antibiotic.
Antibiotic inactivation occurs due to the synthesis of enzymes that can destroy or modify the antibiotic. This mechanism is realized through the acquisition of the corresponding genes, which are distributed with the participation of mobile elements.
Active efflux or removal. There is «basic» activity of efflux systems which largely determines the level of natural sensitivity of bacteria to antibacterial drugs. However, when the removal is activated, the formation of acquired resistance is noted.
Decreased permeability. Transport of hy-drophilic antimicrobial drugs into the microbial cell occurs through porin channels. When the structure of porin channels is disrupted or they are lost, the efficiency of antibiotic transport is sharply reduced, which manifests itself in the formation of resistance to several classes of drugs.
Target protection. The target protection mechanism is implemented in two ways. The first is due to synthesis of proteins which bind to the target and modify it. The second is a metabolic shunt, i.e. the production of alternative targets by bacterial cells that are resistant to the inhibitory effect of the antibiotic. They bind to the antibiotic and make it impossible for it to hit real targets.
Currently, several mechanisms of macrolide resistance formation have been described: target modification (ribosome methylation, mutations in ribosomal RNA, mutations in riboso-mal proteins L4, L16, L22), active removal of antibiotics from bacteria, enzymatic inactivation. 20 mutations that determine H.pylori resistance to clarithromycin have been described (Binmaeil et al., 2021; Tsapkova et al., 2022; Ng et al., 2023; Srisuphanunt et al., 2023). The largest number of papers are devoted to the study of nucleotide substitutions in the binding sites of antibiotics with the large bacterial ribosome subunit (structural changes in 23S-riboso-mal RNA under the action of the erythromycin
resistance methylase enzyme, most often at positions 2142 and 2143). In this case, cross-resistance to all macrolides is observed (Redondo et al., 2018; Kakiuchi et al.., 2022; Cho et al., 2023; Kim et al., 2023). For the genotypic determination of resistance to clarithromycin, as a rule, the detection of mutations A2142G or A2143G in the 23S ribosome subunit of H.pylori is used, in particular, by TaqMan real-time PCR. When isolating strains that have a A2142G replacement, the minimum inhibitory concentration (MIC) of the antibiotic increases to 32-256 mg/l, and the effectiveness of the three-component eradication regime decreases to 57.1%. When A2143G replacement is detected, the MIC increases to 4-128 mg/l, and the effectiveness of eradication decreases to 30.7% (Graham & Fischbach, 2010; Malfertheiner et al., 2018; Maev et al., 2020; Megraud et al., 2021; Neumoina et al., 2020; Tsapkova et al., 2022). The main target of macrolide antibiotics is the 50S subunit of the bacterial ribosome. In most bacteria, resistance results from methyla-tion of 23S-ribosomal RNA. Methylation is carried out by the methylase enzyme, which is encoded by the erm gene and determines a high level of macrolide resistance. This gene is associated with transposons and can be localized on both plasmids and chromosomes. The erythromycin resistance gene ermB has been found in many gram-positive bacteria. The presence of the ermB gene leads to the formation of phenotypic resistance to clarithro-mycin, erythromycin, clindamycin, erythro-mycin (Malfertheiner et al., 2018; Bushueva et all., 2023). The presence of the erm gene is associated with erythromycin resistance of streptococci, pneumococci, ureaplasmas, and some other microorganisms (Gospodaryk et al., 2022; Bushueva 2023).
Studies of H.pylori resistance to macrolides due to the presence of the erm gene have not been found in the available literature. This work is the first devoted to the study of the resistance of this microorganism to antibiotics of the macrolide group. The results of the study of the phenotypic and genotypic resistance of H.pylori are an important tool for predicting the effectiveness of antichelicobacter therapy and choosing an eradication regimen.
The aim of the research was to study H.pylori macrolide resistance due to the presence of the ermB gene in patients with newly diagnosed and recurrent helicobacteriosis in Nizhny Novgorod.
Materials and Methods
The structure of the reasons for hospitaliza-tion in the clinic of the I.N. Blokhina Research Institute of Epidemiology and Microbiology was analyzed over 19 years. In 3450 patients aged from 18 to 69 years (average age 48.8 ± 6.1 years) with various types of gastroenterological diseases, PCR detection of H.pylori DNA was performed in gastric juice and bio-topes of the mucous membrane of the gastric antrum. To identify mutations in the genome of bacteria responsible for the development of resistance to macrolides (ErmB - gene - 23S RNA methylase), a commercial PCR test of the Erythropol systems manufactured by «Lytech» Co. Ltd., Moscow, were used. Statistical analysis was performed using the Stat Soft Statistica 6.0 application package and statistical functions of Excel program and standard formulas (Re-brova, 2002).
The work was carried out in compliance with the standards of biomedical ethics, in accordance with the standards of the Declaration of Helsinki of the World Medical Association and Good Clinical Practice. Voluntary informed consent was obtained from all patients of the clinic for examination and use of the results in scientific work. This research was approved by the Ethics Committee of the I.N. Blokhina Research Institute of Epidemiology and Microbiology September 13, 2021, protocol No 2.
Results
In the course of many years of scientific work, morbidity was monitored based on the data from patients with diseases of the upper gastrointestinal tract. From 2005 to 2023, progressive decrease in the proportion of visits for gastric and duodenal ulcers was noted (Fig. 1). In 2006, the proportion of hospitalized patients with erosive and ulcerative pathology was the largest and amounted to 41.3%. In 2023, this figure was significantly lower, at 2.6%. Among
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2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023
Fig. 1. The proportion of patients with erosive and ulcerative pathology in dynamics (according to the data of the Nizhny Novgorod Research Institute of Epidemiology and Microbiology)
patients with exacerbation of peptic ulcer disease, the vast majority were diagnosed for the first time. During 2020-2023, there were no requests from patients with relapse of chronic H.pylori associated peptic ulcer disease. There has been a more than 10-fold decrease in the incidence of H.pylori associated gastric and duodenal ulcers over the past 19 years. It should be noted that there is an increase in the number of requests for gastropathy associated with the use of NSAIDs. These conditions had some features of the endoscopic picture and manifested themselves both in the form of non-destructive pangastritis, gastroduodenitis, and in the form of hemorrhagic and erosive gastritis, duodenitis, and multiple superficial ulcers. Some patients had a combined etiology of the disease -an association with both H.pylori and the use of NSAIDs. The H.pylori detection rate for erosive ulcerative lesions of the stomach and duodenum remained high from 92.9 to 66.6% in different years, which required eradication therapy.
The phenomena of functional dyspepsia were clinically diagnosed in all patients. An endoscopic examination confirmed the presence of an inflammatory process of varying severity and prevalence in all examined patients with the main diagnosis of exacerbation of ulcerative disease of the stomach and duodenum, chronic pancreatitis, chronic cholecystitis, and gastroesophageal reflux disease. Long-term studies (from 2011 to 2023) revealed a trend towards a decrease in H.pylori prevalence in patients with gastroenterological diseases without significantly significant differences in dynamics in the examined groups according to nosological forms (Fig. 2). It should be noted that throughout the entire observation period, the detection rate of H.pylori DNA in patients with exacerbation of peptic ulcer disease was significantly higher than in patients with exacerbation of gastroesophageal reflux disease.
To determine the tactics for choosing empirical treatment for H.pylori infection and form-
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2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023
■ peptic ulcer disease ■ chronic pancreatitis
■ chronic cholecystitis ■ gastroesophageal reflux disease
Fig. 2. Detection rates of H.pylori DNA in the main nosological forms in dynamics, %
ing groups of patients who require individual selection of drugs, resistance to macrolides was studied in 2 groups of patients:
- patients with helicobacteriosis, identified for the first time, who have no history of indications for taking macrolides during the last year;
- patients with H. pylori infection who have undergone a first-line eradication course with clarithromycin in the last 1-3 years.
The dynamics of primary and secondary H.pylori genetic resistance to macrolides are characterized by a continuous increase in the of detection rate of resistant isolates from 2011 to
2014 and stabilization with slight fluctuations in subsequent years (Fig. 3).
Primary resistance was detected in 20112013 in 5.3-7.6% of patients. From 2014 to 2022, the proportion of H. pylori infected patients containing the ermB gene increased 1.5 times and amounted to 11.8% in 2016 and 17.0% in 2018. In 2023, primary Hpylori resistance to macrolides was found in 16.8% of patients. In patients who had previously received a standard course of eradication therapy, the minimum detection rate of ermB gene was found in 2011, amounting to 16.2%. Already in 2012, the twenty percent resistance threshold
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0,0 -
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023
> Primary resistance, % 9 resistance threshold,%
> Secondary resistance, %
Fig. 3. Monitoring of primary and secondary H.pylori resistance to macrolides in patients with gastroduo-denal pathology
was exceeded and amounted to 22.2%. From 2014 to 2020 secondary resistance was found in more than 30% of patients with fluctuations from 30.5% in 2017 to 35.4% in 2022.
Discussion
According to international and domestic recommendations, the choice of an anti-Helico-bacter therapy regimen should be based on information about the effectiveness of the course of treatment in a given population, which is largely determined by H.pylori sensitivity to antibiotics (Malfertheiner, 2018; Ivashkin et al., 2018; Malfertheiner et al., 2022; Park et al., 2023; Nyssen, 2024). According to the results of most regional studies, figures of H.pylori strain resistance to clarithromycin in Russia are
no higher than 15.0%. Data on the absence of high H. pylori resistance to metronidazole and a low level of double resistance to clarithromycin and metronidazole were obtained (Kalugin et al., 2016; Zaharova et al., 2016; Lazebnik et al., 2017; Serebrova et al., 2018; Maev et al., 2020).
The study of genetic H.pylori resistance to macrolides is relevant for patients with repeated H.pylori infection who need individual selection of drugs. Resistance to antibacterial drugs significantly reduces the effectiveness of treatment regimens, especially those that include macrolides (Georgopoulos et al., 2024). The World Health Organization has classified clarithromycin resistant H.pylori as a risk factor for the progression of H. pylori infection. A cor-
rectly selected H.pylori eradication regimen can cure gastric and duodenal ulcers, reduce the risk of developing gastric cancer, and, consequently, improve the quality of life of patients with H.pylori gastroduodenal pathology.
Conclusions
During the observation period, a progressive reduction in the proportion of patients with gastric and duodenal ulcers among patients with gastroenterological diseases was revealed.
The study of primary and secondary H.pylori resistance to macrolides showed an increase in the detection rate of resistant isolates in Nizhny Novgorod.
The study of genetic H.pylori resistance to macrolides is necessary when re-identifying in patients who previously received a course of eradication and in patients who took clarithromycin for other reasons, for the optimal selection of drugs included in the re-treatment regimen of infection.
Conflict of interest: none declared.
Financing: the study was conducted without sponsorship.
Acknowledgments
The authors want to thank Flekhner T.V., medical information officer, for help in preparing an article.
References
AKHMETOVA D.G., BALTABEKOVA A.ZH. & SHUSTOV A.V. (2018): Antibiotic resistance of Helicobacter pylori: an overview of epidemiological trends and problems of breast cancer therapy. Medical Review 2(7), 13-18.
AMIEVA M. & PEEK R.M. (2016): Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology 150(1), 64-78. https://doi.org/10.1053/j.gastro.2015.09.004.
BINMAEIL H., HANAFIAH A., MOHAMED ROSE I. & RAJA ALI R A. (2021): Development and validation of multiplex quantitative PCR assay for detection of Helicobacter pylori and mutations conferring resistance to clarithromycin and levofloxacin in gastric biopsy. Infect. Drug. Resist. 14, 4129-4145.
BORDIN D.S. & LIWZAN M.A. (2022): The Maastricht VI Consensus Published: What's New? Effective pharmacotherapy 18(22), 72-84.
BUJANDA L., NYSSEN O.P., VAIRA D., SARACINO IM., FIORINI G., LERANG F., GEORGOPOU-LOS S., TEPES B., HELUWAERT F., GASBARRINI A., ROKKAS TH., BORDIN D., SMITH S, LAMY V., CALDAS M., RESINA E., MUNOZ R., COSME A., PUIG I., MEGRAUD F., O'MO-RAIN C. & GISBERT J.C. (2021): Antibiotic resistance prevalence and trends in patients infected with Helicobacter pylori in the period 2013-2020: results of the European Registry on H. pylori Management (Hp-EuReg). Antibiotics (Basel) 10(9), 1058. DOI: 10.3390/antibiotics10091058
BUSHUEVA T V., KARPOVA E.P., ROSLAYA N.A., GURVICH V.B., LABZOVA A.K., & GRI-BOVA YU.V. (2023): State of immune response and formation of Streptococcus pneumoniae carriage as risk factors for health of workers of coke-chemical and converter production. Health risk analysis 4, 116-123. DOI: 10.21668/health.risk/2023.4.11.
CHO S.H., PARK M.S., PARK S.Y., KIM D.H., YOU H S. & KIM H.S. (2023): Effectiveness of 7-day triple therapy with half-dose clarithromycin for the eradication of Helicobacter pylori without the A2143G and A2142G point mutations of the 23S rRNA gene in a high clarithromycin resistance area. Front Med (Lausanne) 10, 1150396. DOI: 10.3389/fmed.2023.1150396.
DEKHNICH N.N., E.A. KOSTYAKOVA E.A., PUNIN A.A., ALIMOV A.V., IVANCHIK N.V. & KO-ZLOV R.S. (2011): Antibiotic-resistance of H. pylori: results of microbiologic regional investigation. Rus J Gastroenterol Hepatol Coloproctol. 21(2), 37-42. (in Russ.).
ISAEVA G.SH. (2010): Antimicrobial resistance of H.pylori and susceptibility determination metods. Clinical Microbiology and Antimicrobial Chemotherapy 12(1), 57-66. (in Russ.).
IVANOV M.E., FURSOVA N.K. & POTAPOV V.D. (2022): Pseudomonas aeruginosa efflux pump super-family (review of literature). Klinichescheskaya Laboratornaya Diagnostika (Russian Clinical Laboratory Diagnostics) 67(1), 53-58. DOI: https://dx.doi.org/10.51620/0869-2084-2022-67-1-53-58 (In Russ.).
IVASHKIN V.T., MAYEV I.V., LAPINA TL., SHEPTULIN A.A., TRUKHMANOV A.S. & BARANSKAYA YE.K. (2018): Diagnostics and treatment of Helicobacter pylori infection in adults: Clinical guidelines of the Russian gastroenterological association. Rus J Gastroenterol Hepatol Coloproctol. 28(1), 55-70. https://doi.org/ 10.22416/1382-4376-2018-28-1-55-70 (In Russ.).
GEORGOPOULOS S.D., XIROUCHAKIS E., LIATSOS C., APOSTOLOPOULOS P., KASAPIDIS P., MARTINEZ-GONZALEZ B., LAOUDI F., STOUPAKI M., AXIARIS G., SGOURAS D., MENTIS A. & MICHOPOULOS S. (2024): Equivalence Trial of the Non-Bismuth 10-Day Concomitant and 14-Day Hybrid Therapies for Helicobacter pylori Eradication in High Clarithromycin Resistance Areas. Antibiotics (Basel) 13(3), 280. DOI: 10.3390/antibiotics13030280.
GOSPODARYK A.V., ULAKHANOVA L A., ESIEV S.S., POLYAKOVA E.V., SHANSKY Y D. & BE-SPYATYKH J.A. (2022): The role of mef and ermB drug resistance genetic markers in the selection of fecal microbiota donors. Vestnik RGMU.RU 6, 5-12. DOI: 10.24075/vrgmu.2022.059.
GRAHAM D.Y. & FISCHBACH L. (2010): Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 59, 1143-1153. https://doi.org/10.1136/gut.2009.192757.
HASANUZZAMAN M., BANG C S. & GONG E.J. (2024): Antibiotic Resistance of Helicobacter pylori: Mechanisms and Clinical Implications. J Korean Med Sci. 39(4), e44. DOI: 10.3346/jkms.2024.39.e44.
HO J.J., NAVARRO M., SAWYER K., ELFANAGELY. Y. & MOSS S.F. (2022): Helicobacter pylori antibiotic resistance in the United States between 2011 and 2021: a systematic review and meta-analysis. Am. J. Gastroenterol. 117(8), 1221-1230.
KAKIUCHI T., OKUDA M., MATSUO M. & FUJIMOTO K. (2022): Smart Gene™ as an effective non-invasive point-of-care test to detect Helicobacter pylori clarithromycin-resistant mutation. J. Gastroen-terol. Hepatol. 37(9), 1719-1725. DOI: 10.1111/jgh.15887
KALUGIN A.A., STEPCHENKO A.A., VOROPAEV E.V., OSIPKINA O.V. & ZYATKOV A.A. (2016): Frequency of detection of polymorphism of Helicobacter pylori genes associated with resistance to clarithromycin. Kursk scientific and practical bulletin "Man and his health" 3, 17-21. (in Russ.).
KIM I., MAENG L S., KIM J.S., KIM B.W., CHEUNG D.Y., KIM J.I. & PARK S.H. (2023): Quantitative multiplex real-time polymerase chain reaction assay for the detection of Helicobacter pylori and clarithromycin resistance. BMC Microbiol. 23(1), 155. DOI: 10.1186/s12866-023-02868-z.
LAZEBNIK L B., TKACHENKO E.I., ABDULGANIYEVA D.I., ABDULKHAKOV R A., ABDULKHA-KOV S R., AVALUYEVA E.B. (2017): VI national guidelines for the diagnosis and treatment of acid-related and Helicobacter pylori-associated diseases (VI Moscow agreement). Experimental and Clinical Gastroenterology 2(138), 3-21. (In Russ.).
LEE J.W., KIM N., CHOI S.I., JANG J.Y., SONG C.H., NAM R H., et al. (2023): Prevalence and trends of multiple antimicrobial resistance of Helicobacter pylori in one tertiary hospital for 20 years in Korea. Helicobacter 28(1), e12939. DOI: 10.1111/hel.12939.
LEE Y.C., CHIANG T.H. & CHOU C.K. (2016): Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: a Systematic Review and Meta-analysis. Gastroenterology 150(5), 113-1124. https://doi.org/10.1053Zj.gastro.2016.01.028.
LI Y., CHOI H., LEUNG K., JIANG F., GRAHAM D.Y. & LEUNG W.K. (2023): Global prevalence of Helicobacter pylori infection between 1980 and 2022: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 8(6), 553-564. DOI: 10.1016/S2468-1253(23)00070-5
LIN Y., SHAO Y., YAN J., YE G. (2023): Antibiotic resistance in Helicobacter pylori: From potential bio-molecular mechanisms to clinical practice. J. Clin. Lab. Anal. 37(7), e24885. DOI: 10.1002/jcla.24885.
MAYEV I.V., ANDREYEV D.N., BORDIN D.S., KUCHERYAVYI YU.A., KUDRYAVTSEVA L.V. & VYUCHNOVA YE. S. (2020): Helicobacter pylori Resistance to Clarithromycin in the Russian Federation. Effective pharmacotherapy 16(30), 16-22. https://doi.org/ 10.33978/2307-3586-2020-16-30-16-22 (In Russ.).
MAEV I.V., ANDREEV D.N., DICHEVA D.T., KUCHERYAVY YU.A., ZABOROVSKIY A.V. & PARTSVANIA-VINOGRADOVA E.V. (2017): Diagnosis and treatment of Helicobacter pylori infection: main statements of the Maastricht V/Florence consensus report (2015). Archive of internal medicine 7(2), 85-94. https://doi.org/10.20514/2226-6704-2017-7-2-85-94 (in Russ.).
MAEV I.V., KHUCHERIAVYI YU.A., ANDREEV D.N. & BARKALOVA E.V. (2014): Eradication therapy for Helicobacter pylori infection: Review of word trends. Terapevticheskii Arkhiv 86(3), 94-99. (in Russ).
MAEV I.V., SAMSONOV A.A. & ANDREEV D.N. (2016): Infektiya Helicobacter pylori [Helicobacter pylori infection]. M.: GEOTAR-Media, 256 pp. (in Russ.)
MALFERTHEINER P. (2018): Helicobacter pylori treatment for gastric cancer prevention. N Engl J Med. 378(12), 1154-1156. https://doi.org/10.1056 / NEJMe1800147 URL: https://www.researchgate.net/pub-lication/323 94453 6
MALFERTHEINER P., MEGRAUD F., O'MORAIN CA., GISBERT J.P., KUIPERS E.J., AXON AT., ET AL. (2017): Management of Helicobacter pylori infection - the Maastricht V/Florence Consensus Report. Gut 66, 6-30. https://doi.org/10.1136/gutjnl-2016-312288
MALFERTHEINER P., MEGRAUD F., ROKKAS T., GISBERT J.P., LIOU J.-M., SCHULZ CH., ET AL. (2022): Management of Helicobacter pylori infection: the Maastricht VI - Florence consensus report. Gut 71, 1724-1762. https://doi.org/10.1136/gutjnl-2022-327745..
MALFERTHEINER P., VENERITO M. & SCHULZ C. (2018): Helicobacter pylori infection: new facts in clinical management. Current Treatment Options in Gastroenterology 16(4), 605-615. https://doi.org/10.1007/s11938-018-0209-8
MEGRAUD F., BRUYNDONCKX R., COENEN S., WITTKOP L., HUANG TD., HOEBEKE M., BÉ-NÉJAT L., LEHOURS PH., GOOSSENS H. & GLUPCZYNSKI Y. (2021): Helicobacter pylori resistance to antibiotics in Europe in 2018 and its relationship to antibiotic consumption in the community. Gut 70(10), 1815-1822. DOI: 10.1136/gutjnl-2021-324032
NEUMOINA M.V., PERFILOVA K.M., NEUMOINA N.V., SHUTOVA I.V., TROSHINA TA., SHMA-KOVA T V. & DENISENKO T.L. (2020): The problem of resistance of Helicobacter Pylori to antibacterial drugs as a risk factor for the progression of infection. Health risk analysis 2, 175-184. DOI: 10.21668/health.risk/2020.2.19. (In Russ.).
NG H.Y., LEUNG W.K., CHEUNG K.S. (2023): Antibiotic Resistance, Susceptibility Testing and Stewardship in Helicobacter pylori Infection. Int. J. Mol. Sci. 24(14), 11708. DOI: 10.3390/ijms241411708.
NYSSEN O.P., MARTÍNEZ B., MÉGRAUD F., SAVARINO V., FALLONE CA., BAZZOLI F. & GISBERT J.P. (2024): Sequential versus Standard Triple Therapy for First-Line Helicobacter pylori Eradication: An Update. Antibiotics (Basel) 13(2), 136. DOI: 10.3390/antibiotics13020136.
PARK S.Y., LEE E.H., KIM D., SONG Y.G. & JEONG S.J. (2023): Novel mutations conferring amoxicillin resistance in Helicobacter pylori in South Korea. Antibiotics (Basel) 12(4), 748. DOI: 10.3390/antibiot-ics12040748.
REBROVA O.YU. (2002): Statistical analysis of medical data. Application of the application software packages STATISTICA. M.: MediaSfera, 312 pp. (in Russ.)
REDONDO J.J., KELLER P.M., ZBINDEN R. & WAGNER K. (2018): A novel RT-PCR for the detection of Helicobacter pylori and identification of clarithromycin resistance mediated by mutations in the 23S rRNA gene. Diagn. Microbiol. Infect. Dis. 90(1), 1-6. DOI: 10.1016/j.diagmicrobio.2017. 09.014.
SEREBROVA S.YU., PROKOFIEV A.B., EREMENKO N.N., ZHURAVLEVA M.V. & ALEXAN-DROVA T.A. (2018): Clinical and Pharmacological Aspects of Resistance to Eradication Therapy of Helicobacter pylori Infection. Antibiotics and Chemotherapy 63(9-10), 31-38. (In Russ.).
SHIRANI M., PAKZAD R., HADDADI M.H., AKRAMI S., ASADI A., KAZEMIAN H., MORADI M., KAVIAR V.H., ZOMORODI AR., KHOSHNOOD S., SHAFIEIAN M., TAVASOLIAN R., HEI-DARY M. & SAKI M. (2023): The global prevalence of gastric cancer in Helicobacter pylori-infected individuals: a systematic review and meta-analysis. BMC Infect Dis. 23(1), 543. DOI: 10.1186/s12879-023-08504-5.
SRISUPHANUNT M., WILAIRATANA P., KOOLTHEAT N., DUANGCHAN T., KATZENMEIER G. & ROSE J.B. (2023): Molecular mechanisms of antibiotic resistance and novel treatment strategies for Helicobacter pylori infections. Trop. Med. Infect. Dis. 8, 163-179. https://doi.org/10.3390/tropi-calmed8030163.
SUGANO K., TACK J. & KUIPERS J.E. (2015): Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64(9), 1353-1367. https://doi.org/10.1136/gutjnl-2015-309252.
SUZUKI S., KUSANO C., HORII T., ICHIJIMA R. & IKEHARA H. (2022): The ideal Helicobacter pylori treatment for the present and the future. Digestion 103(1), 62-68. DOI: 10.1159/000519413.
SIDORENKO S.V. (2007) Mechanisms of resistance of microorganisms. In: Practical guide to anti-infectious chemotherapy (edited by STRACHUNSKY L. S., BELOUSOV YU. B., KOZLOV S. N.), p. 1221. Smolensk: Interregional Association. in clinical microbiology and antimicrobial chemotherapy. (In Russ.).
TSAPKOVA L A., POLYAKOVA V.V., BODUNOVA N.A., BARATOVA I.V., VOYNOVAN IN., DEKHNICH NN., IVANCHIK N.V., SABELNIKOVA E.A. & BORDIN D.S. (2022): Possibilities of the Molecular Genetic Method for Detecting Resistance to Clarithromycin and Levofloxacin in Helico-bacter pylori. Effective pharmacotherapy 18(42), 16-21. DOI 10.33978/2307-3586-2022-18-42-16-21 (In Russ.).
TSUKANOV V.V., KASPAROV E.V., VASYUTIN A.V. & TONKIKH Y.L. (2015): Eradication of Helicobacter pylori. Meditsinskiy sovet = Medical Council 13, 26-29. https://doi.org/10.21518/2079-701X-2015-13-26-29 (In Russ.)
ZAHAROVA N.V., SIMANENKOV V I., SAVILOVA I.V. & SVARVAL A.V. (2016): Helicobacter pylori - isotopic diagnosis of infection and testing of resistance. Pharmateca 2, 23-27 (In Russ.).
