Vol 12, No 1 (2022)

Cover Page

Full Issue


CRISPR/Cas-based diagnostic platforms

Volkov A.A., Dolgova A.S., Dedkov V.G.


Over the last few years, CRISPR/Cas systems have been extensively studied and used for a wide range of applied purposes. The variety of their applications is accounted for by the ability of Cas-type nucleases to targetly cleave specified nucleic acid sequences. In this case, the researcher might set the necessary sequence of the guiding elements in the CRISPR/Cas system, played by so-called single guide RNAs allowing it to act on select targets. This potential underlies one of the reasons for exerting interest in CRISPR/Cas systems. One of the first areas for applying these systems was its use for genomic editing. Later, the list of potential opportunities has been expanded: e.g., they can be used in gene therapy and epigenetic research. It is possible to create sgRNA libraries which might be used to create a pool of viral vectors applied for bacterial cell transformation with subsequent cas-protein transduction that cause target gene knockout. This approach allows finding genes responsible for resistance or sensibility to diverse substances. Using such systems in molecular diagnostics of infectious diseases is considered as one of the most promising directions allowing to detect even extremely low concentrations of pathogenic organisms in samples due to their specific nucleotide sequences. Simultaneously, such assays turn out to be accurate, rapid and easy to utilize. In addition, some platforms may work without using expensive equipment, because methods for fast and simple sample preparation have already been developed, whereas modern preamplification approaches allow to avoid applying thermocycling devices. Interestingly, a great amount of diverse types of natural CRISPR/Cas systems have been already discovered. Such abundance promotes development of multiple artificial systems, each of which exerting own unique characteristics. Therefore, a variety of diagnostic platforms with different properties are created on their basis that allows researchers and physicians to choose an optimal approach for performing specific tasks. For this reason, insights into structure and operation of CRISPR/Cas systems are necessary for selecting a suitable platform. The current classification of systems is based on such principles serving as the basis, in turn, for convenient evaluation of the very variety of molecular diagnostics platforms and presentation of the typical technical characteristics and nuances for each method. Thus, this review, which is mainly devoted to the platforms for molecular diagnostics of infectious diseases, also touches upon the issues of functioning, devices, and classification of CRISPR/Cas systems.

Russian Journal of Infection and Immunity. 2022;12(1):9-20
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The role of Helicobacter pylori in complex human comorbidity

Sergeeva A.V., Shkarin V.V., Kovalishena O.V.


One of the main features of modern medicine is the fact that the majority of somatic diseases lose their mononosological nature and acquire the status of comorbidity. Examining complex comorbidity is a priority for specialists in various medical disciplines. Accomplishing scientific research and obtaining nessesary data as well as their further comprehension allowed to formulate major directions for investigating a comorbidity issue. Primarily, it concerns studying rate and general patterns for combination of pathologies, determining features of clinical course and strategy for using drug therapy. Comorbidity issue is rarely considered among infectious diseases. It should be understood that a term “comorbidity” refers to the state of the concomitant detection of several diseases. This terminology may and should be applied to combined somatic and infectious pathology envisioned as a complex pathological condition, but with some additions. The term “complex comorbidity”, in our opinion, is also valid both in case of either simultaneous or sequential presence of psychosomatic pathology and monoetiological infection, as well as somatic pathology and polyetiological infection. After H. pylori was discovered, over the past decades a significant number of studies have emerged regarding a role of helicobacter in etiology and pathogenesis of a large number of somatic diseases. The accumulated knowledge has determined that Helicobacteriosis is the most common bacterial infection in human, and H. pylori is considered as the cause for developing pathology of the gastrointestinal tract as well as other host organs and systems. At the current stage in the development of medicine, H. pylori is not only associated with occurrence of gastric and duodenal ulcers, because the microbe-linked pathogenic effect is not limited only to diseases of the gastroduodenal area. Helicobacter pylori infection can be considered as a trigger in emerging somatic pathology such as chronic gastritis, gastric and duodenal ulcer, MALT lymphoma, and gastric adenocarcinoma. These conditions may be referred to the status of complex comorbidity. To date, association links between Helicobacter pylori and idiopathic iron deficiency anemia, as well as idiopathic thrombocytopenic purpura, have been reliably determined. Thus, various clinical aspects of H. pylori infection are heterogeneous and have a wide range of pathological conditions, which evidence base is replenished with data both in terms of pathogenesis and clinical components.

Russian Journal of Infection and Immunity. 2022;12(1):21-32
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Major pathogenicity factors of Streptococcus pyogenes

Burova L.A., Totolian A.A.


Streptococcal diseases and their complications are among the global problems of international health. S. pyogenes (group A streptococci — GAS) is a pathogen that causes significant morbidity in different countries and different age groups of the population, occurring both sporadically and epidemically. Due to ineffective antibacterial therapy or its absence, 3–5% of people who have had streptococcal infection may develop complications such as acute rheumatic fever, rheumatic heart disease, acute post-streptococcal glomerulonephritis and invasive complications: necrotizing fasciitis and myositis, septicemia and toxic shock syndrome, highly lethal due to the rapid development of the process and systemic organ damage. According to recent estimates, at least 517 000 deaths occur annually in the world due to diseases caused by GAS. The diverse arsenal of pathogenic factors of this pathogen is manifested in a combination of joint or sequential reactions in the process of microbial colonization of tissue, formation of the focus of infection and overcoming the host's defense mechanisms. It is an important point in the process of studying the pathogenesis of diseases caused by these microbes. The pathogenic factors of GAS can be divided into extracellular and associated with the microbial cell, predominantly with its cell wall. The spectrum activity of pathogenicity factors can be quite wide (M proteins, pyrogenic exotoxins, superantigens) or limited (serine and cysteine proteinases, streptokinase). Information about the specificity of pathogenicity factors, their properties, relationships, regulation and specific function in pathology is the task of scientific, as well as complex researches, leading to understanding the pathogen-host interaction. An integrated approach to the investigation of GAS pathogenicity factors is needed to study the pathogenicity of streptococci, since pathogenicity factors do not manifest themselves in isolation and are not always independently regulated. In many cases, regulators control the expression of more than one of them. S. pyogenes has been studied for about 150 years, but a number of issues related to their pathogenicity remain unknown to this day. Some factors need more in-depth study: for example, endo-β-N-acetylglucosaminidase, arginine deiminase. Immunoglobulin-degrading enzymes require special attention due to their possible participation in the genesis of immunopathological processes of streptococcal etiology. This review summarizes the literature data about most of the pathogenicity factors of S. pyogenes and their role in the infectious process.

Russian Journal of Infection and Immunity. 2022;12(1):33-50
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Clinical significance of Streptococcus members in developing periodontitis

Bazhutova I.V., Ismatullin D.D., Lyamin A.V., Trunin D.A., Zhestkov A.V., Razumnyj V.A.


Bacteria of the genus Streptococcus are one of the most numerous and diverse representatives in the normal biocenosis of human organs and systems particularly being abundant as obligatory inhabitants of the oral cavity. All streptococci are divided into six groups: S. mitis, S. anginosus, S. salivarius, S. mutans, S. bovis and S. pyogenes, among which their certain number may potentially participate in the infectious process of developing periodontitis. Owing to the presence of a wide range of adhesion, invasion and colonization factors, they are capable of performing a protective function such as colonization resistance, but they may also cause formation of a pathological process in the tooth tissues and dento-facial system. The most prominent adhesion factors are antigens I/II (Ag I/II), fibronectin, collagen, laminin, fibrinogen binding proteins, serine-rich glycoproteins, pili, protein M, proteases, C5a peptidases, and the presence of a tooth capsule. Among the complex of proteolytic enzymes, it is important to note that streptococci contain enzymes hyaluronidase and lyase, which cleave the β1,4 bond between N-acetylglucosamine and d-glucuronic acid as the components of hyaluronic acid being a part of the connective tissues. The members of the S. anginosus group are able to release chondroitin sulfatase, which destroys chondroitin sulfates as specific components in cartilage, ligaments and other connective tissue structures. The enzymes noted contribute to a deeper spread of microorganisms in host tissues. Pathological processes associated with the development of periodontitis comprise a complex problem, wherein several important elements take part, including an infectious agent, a macroorganismal response in the form of nonspecific and adaptive immunity, as well as involvement of anti-inflammatory components. A great number of studies in research literature are dedicated to describe to participation of the members within the “red”, “orange” and “green” complexes as the principal components in developing periodontitis. Whereas the “yellow” and the “purple” complex play a more protective role by acting as antagonists while interacting with periodontopathogens, but it should not be ruled out a potential participation for some representatives, particularly S. intermedius, S. gordonii, A. odontolyticus, A. naeslundii in developing periodontal disease. Altogether, it poses a problem, which may be solved solely based on a multidisciplinary approach by inviting not only dentists and bacteriologists but also researchers of other specialties. Here we review the studies found in international and national data bases such as Scopus, Web of Science, Springer, RSCI.

Russian Journal of Infection and Immunity. 2022;12(1):51-58
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Genotyping clinical cytomegalovirus isolates in solid-organs-transplant recipients

Vankova O.E., Brusnigina N.F.


Cytomegalovirus infection remains one of the leading problems in contemporary healthcare. It belongs to socially and economically significant infections with a high incidence both in children and adults, characterized by polymorphic clinical manifestations and a variety of routes and factors for infection transmission. CMV infection of blood and organ recipients is a serious problem. It should be noted that, despite the great medical and social significance, in the Russian Federation there is no system of CMV epidemiological surveillance and control as it was traditionally developed for other topical infections. The aim of this study is to search for optimal method of cytomegalovirus (CMV) genotyping and estimate genotypic diversity of CMV isolates in Russia for patients underwent solid organ transplantation. The research presents the data after examining blood samples, leukocytes, saliva, urine and lacrimal discharge collected from 160 patients at the Transplantation Department of the Privolzhsky District Medical Center of the FMBA, aged 22 to 64 years, after liver and kidney transplantation. Molecular biological and serological methods were used for testing. Genotyping was carried out by the NGS sequencing of CMV DNA fragments. A high prevalence of CMV was found in patients undergoing solid organ transplantation. For 41.8±3.8% patients, cytomegalovirus DNA was detected in saliva and urine samples, and for 18.1±3.04% of them — in blood samples. In 98.8±3.2% of patients, the diagnosis of Cytomegalovirus infection (CMVI) was confirmed serologically. Based on a summary of reported data, estimation of various methodological approaches for genotyping of clinical CMV isolates was carried out. As a result, a typing option based on genotype determining for two variable genes UL55 (gB) and UL73 (gN) was selected. The spectra and proportional distribution of gB and gN CMV genotypes circulating among adults were determined. It was found that genotype prevalence in the group of patients who underwent solid organ transplantation was as follows: gB2, gN4c, gN4a, gN1. In some cases, a mixed infection was found due to the association of two and three CMV genotypes. The performed phylogenetic analysis of UL55 and UL73 gene nucleotide sequences indicates the genetic heterogeneity found for Russia-wide CMV isolates from in adult patients in the risk group.

Russian Journal of Infection and Immunity. 2022;12(1):59-68
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Pathomorphology of experimental infection caused by dormant Yersinia pseudotuberculosis strains

Somova L.M., Andryukov B.G., Lyapun I.N., Drobot E.I., Ryazanova O.S., Matosova E.V., Bynina M.P., Timchenko N.F.


In the 2000s, with the development of scientific research on the uncultivated (dormant) state of pathogenic bacteria, the ideas about persistent, chronically recurrent infections, difficult to respond to antibiotic therapy have begun to shape. However, regarding human pseudotuberculosis (Far Eastern scarlet-like fever, FESLF), this question remains open. While analyzing the pathology of pseudotuberculosis, its clinical and epidemic manifestation as FESLF, we identified the etiopathogenetic prerequisites for the disease recurrence and development of persistent infection. In this study it was found that the strains of Yersinia pseudotuberculosis which were in a dormant state caused the development of a peculiar granulomatous inflammation in target organs with pronounced delayed-type hypersensitivity reactions in vivo. To reproduce the experimental infection, sexually mature white mice were inoculated with the strain 512 Y. pseudotuberculosis, serotype I stored for 10 years at the Museum of Somov Research Institute of Epidemiology and Microbiology and transformed into a dormant state. For comparative studies, a dormant form from vegetative bacteria of the strain 512 Y. pseudotuberculosis was obtained by exposure to a large dose of kanamycin (the minimum antibiotic dose was exceeded 25 times). The infecting dose of both forms of bacteria was 108 μ/mouse. Samples of target organs (lung, liver, spleen) were collected for histological examination on days 3, 7, 10, 14, 21 and 32 after infection. Histological sections with 3–5 μm thickness were stained with hematoxylin and eosin according to standard techniques. It was established that strains of Y. pseudotuberculosis in dormant state caused in vivo development of a peculiar granulomatous inflammation due to delayed-type hypersensitivity reactions (DHR), which characterizes the protective reaction in infected host and reflects formation of local, tissue immunity in target organs. The peculiarities of granulomatous inflammation were revealed, in comparison with that of found during infection with vegetative (“wild”) Y. pseudotuberculosis bacteria, namely: the granulomas were predominantly small in size, clearly delimited from the surrounding tissue, without destruction of central zone cells and formation of the so-called “granulomas with central karyorrhexis” (terminology proposed by A.P. Avtsyn); perivascular infiltrates and vasculitis consisted mainly of lymphocytes and often had a follicle-like appearance, resembling the follicles in lymphoid organs; in the lungs, a well-marked reaction of the bronchial-associated lymphoid tissue was observed, and in the spleen, a follicular hyperplasia, indicating a T-cell defense reaction, was observed. Thus, the causative agent of Y. pseudotuberculosis infection/FESLF, being in a dormant state, initiates the development of immunomorphological changes of protective nature such as productive granulomatous inflammation with reactions of local tissue immunity in target organs and can contribute to the formation of persistent infection.

Russian Journal of Infection and Immunity. 2022;12(1):69-77
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Performance of GeneXpert MTB/RIF in the diagnosis of extrapulmonary tuberculosis in Morocco

Aainouss A., Momen G., Belghiti A., Bennani K., Lamaammal A., Chetioui F., Messaoudi M., Blaghen M., Mouslim J., Khyatti M., El Messaoudi M.D.


Tuberculosis (TB), a chronic bacterial disease caused by Mycobacterium tuberculosis, commonly affects the lung but can also affect other parts of the body (extrapulmonary tuberculosis, EPT). A rapid diagnosis is essential to initiate a specific and effective treatment. Although mycobacterial culture remains the gold standard for EPT diagnosis, molecular tools are attracting increasing interest. GeneXpert MTB/RIF, a rapid automated diagnostic test, allows the detection of Mycobacterium tuberculosis as well as mutations in the hot-spot region of the rpoB gene associated with Rifampicin resistance. The present study was performed to evaluate the performance of the GeneXpert MTB/RIF test for the diagnosis of EPT compared to the standard method. This prospective study was conducted on 304 clinical samples collected from 192 patients attending the Laboratory of Mycobacteria and Tuberculosis of Pasteur Institute of Morocco, between 2016 and 2017. Out of the 304 samples, 113 were pleural f luids decontaminated using the Petroff method and 191 were biopsies (78 lymph nodes and 113 pleural biopsies) decontaminated using the Löwenstein method. Mycobacterium tuberculosis detection and identification were performed on all samples using smear microscopy, Löwenstein–Jensen medium culture and the GeneXpert MTB/RIF test. Our results showed that 54.5 (103/189) were men and 45.5% (86/189) were women. The age of patients ranged from 2–78 years and the majority of patients was in the age group 25–45 years. Extrapulmonary samples were derived from lymph nodes, pleural f luids and pleural tissues, with a percentage of 25.66, 37.17 and 37.17%, respectively. Interestingly, the sensitivity of the GeneXpert was 51.4 for all samples and 83.3% for lymph nodes. In conclusion, the present study revealed that the performance of the GeneXpert test depends highly on the type of sample, with a high sensitivity observed for lymph nodes. Additionally, we clearly showed that the GeneXpert MTB/RIF test presents limitations in the diagnosis of pleural TB. Thus, we recommend the coupled use of the GeneXpert MTB/RIF and the conventional techniques for EPT diagnosis.

Russian Journal of Infection and Immunity. 2022;12(1):78-84
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Assessing the 2019 rubella elimination status in the Russian Federation

Chekhlyaeva T.S., Tsvirkun O.V., Turaeva N.V., Erokhov D.V., Barkinkhoeva L.A., Tikhonova N.T.


In 2002, the WHO Regional Office for Europe developed the Strategic Program for the Prevention of Measles and Congenital Rubella Infections in the European Region, which was revised in 2004. As a result of the revision, an additional target was set to eliminate endemic rubella in the region by 2010. Rubella is a disease well controlled by vaccination that accounts for a theoretical potential to interrupt its global transmission. Since 2013, the Russian Federation has been implementing the National Rubella Elimination Program. Elimination criteria have been revised as the Program proceeds. Currently, the main criterion for rubella elimination is the absence of endemic (local) virus transmission for at least 36 months, which should be confirmed by molecular genetic research methods. In addition, in the Russian Federation, an incidence rate of less than 1 case per 1 million population is also used as one of the elimination criteria. Since 2013, due to a high (over 95%) coverage of preventive vaccinations a decrease in incidence rates and their stabilization at a level of less than 1 per 1 million population since 2014 state in favor of successfully implemented Program. Genetic monitoring of rubella virus strains circulating in human population noted the termination of endemic virus transmission. While implementing the Elimination Program, the prevailing virus genotypes that circulate in Russia were found to be genotypes 1E and 2B showing a global distribution. The data obtained after molecular genetic monitoring allowed to find that the strains isolated during this period belonged to different clusters accounting for in favor of being imported. Considering the above factors such as high vaccination coverage, low incidence rate and lack of endemic virus transmission, the 2017 WHO Committee on verification of measles and rubella elimination assigned the Russian Federation the status of a country that has achieved rubella elimination. The continuation of the phase of infection elimination is confirmed annually. This article presents the results on comprehensive assessment of rubella elimination status in the Russian Federation by specialists from the National Scientific and Methodological Center for Measles and Rubella and WHO EURO Moscow regional reference laboratory for measles and rubella based on 2019 epidemiological data and molecular genetic studies.

Russian Journal of Infection and Immunity. 2022;12(1):85-94
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Etiological pattern of community-acquired pneumonia related to the new coronavirus infection COVID-19 pandemic in the Saratov Region

Portenko S.A., Kazakova E.S., Naidenova E.V., Osina N.A., Proskuriakova M.V., Katyshev A.D., Sharkova E.A., Kedrova O.V., Chumachkova E.A., Shamyunov M.R., Kharitonova V.F., Gureva L.A., Popova N.Y., Maksimova L.V., Bugorkova S.A., Scherbakova S.A., Kutyrev V.V.


Community-acquired pneumonia is a polyetiological infectious disease of bacterial or viral nature. In most cases, it is caused by pathogens such as Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Chlamydophila pneumoniae, Staphylococcus aureus, Legionella spp. However, despite that a wide range of modern diagnostic methods have been introduced into laboratory practice, the etiology of the disease can be determined only in 40–60% of cases. Here, we analyzed the causative agents of community-acquired pneumonia and relevant markers samples of clinical material collected from patients undergoing treatment in the medical facilities of the city of Saratov and the Saratov Region during the period from July to August, 2020, coupled to increase number of cases of new coronavirus infection COVID-19. Clinical material (oropharyngeal swabs, saliva, sputum, blood and blood serum) was obtained from 129 patients and investigated by using microbiological, immunoserological and molecular genetic methods. For this, there were used transport and nutrient media, diagnostic drugs, reagents, discs with antibacterial domestic and foreign drugs registered in the Russian Federation. As a result, 82 (63.6%) patients were found to have markers of the pathogen COVID-19 (viral RNA or specific antibodies of IgM and/or IgG classes), whereas 42% of cases had overlapped RT-PCR and ELISA data. There was a predominance of severe clinical forms of the disease in the group of patients with pneumonia caused by SARS-CoV-2 virus (17.1%), compared with pneumonia of another etiology (12.8%). No marked differences in specific pattern of the accompanying microflora and its sensitivity to antibacterial agents were observed in persons with/without markers of COVID-19. While being examined by bacteriological methods, S. aureus, K. pneumoniae, S. pneumoniae, M. pneumoniae, Acinetobacter spp., both in monoculture and in associations, were isolated from samples of clinical material collected from the majority of patients. In 49.6% of cases, pathogenic microflora, including pathogens causing community-acquired pneumonia, has not been identified, which may be due to the use of antibacterial drugs before the collection of clinical material and treatment applied due to comorbid chronic diseases.

Russian Journal of Infection and Immunity. 2022;12(1):95-104
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Revealing measles cases in Vietnam during the spread of a new coronavirus infection

Lavrentieva I.N., Hoang M., Antipova A.Y., Bichurina M.A., Totolyan A.A.


Introduction. According to the WHO Strategic Plan, five out of six geographical regions were expected to achieve measles elimination by 2020, among which is the Western Pacific Region (WPR), which includes the Socialist Republic of Vietnam (VNM). In 2019, 14 156 measles cases were detected in Vietnam, which significantly exceeds the level required to achieve its elimination (less than 1 case per 1 million population). Analyzing the causes of the ongoing measles virus circulation in diverse global regions is very important. It is also important to assess a potential impact on the measles incidence due to anti-epidemic measures aimed at combating the COVID-19 pandemic. This research is devoted to revealation measles cases in South Vietnam within the period covering January 2020 to March 2021. Materials and methods. 799 samples of blood sera obtained from different territories of South Vietnam in 2020–2021 were examined for IgM antibodies against measles virus using the Anti-Measles Virus ELISA (IgM) test system (Euroimmun, Germany). The presence of IgM measles virus antibodies in the blood serum was assessed as an acute measles infection. Results. The measles virus was actively circulating in South Vietnam in the first months of 2020. Residents of large cities and industrial centers were mainly involved in the epidemic process. Measles spread mainly among unvaccinated (71.58%) subjects, or who was unaware of vaccinations (25.48%), but also among those who were vaccinated (2.12%) and revaccinated (0.64%). The absolute majority of cases (71%) affected children under the age of three, with a predominance of those at the first year of life. Among the latter, 48% were children aged 7-9 months old. In March- April 2020, there was a sharp decrease in the number of measles cases in South Vietnam, down to a sporadic level (from May 2020 to March 2021). This is probably due to the anti-epidemic measures that were carried out in the VNM in order to limit the spread of COVID-19. Consequently, after the restrictions are lifted, we can expect an increase in the measles incidence in VNM.

Russian Journal of Infection and Immunity. 2022;12(1):105-112
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A complex diagnostics of early gastric cancer associated with Helicobacter pylori infection in the adult population of the Krasnoyarsk Territory

Smirnova O.V., Tsukanov V.V., Sinyakov A.A., Moskalenko O.L., Elmanova N.G., Ovcharenko E.S.


The aim of our study was to evaluate the clinical-anamnestic, serological, immunological and biochemical tests used for early diagnostics of gastric cancer associated with Helicobacter pylori infection in the adult population of the Krasnoyarsk Territory. Materials and methods. The control group consisted of 104 apparently healthy blood donors, the comparison group – 97 patients with chronic atrophic gastritis as well as a group of patients with early gastric cancer comprising 98 subjects. Assessment of monocyte and neutrophil spontaneous and induced chemiluminescence (CL) was carried out on a 36-channel biochemiluminometer BLM-3607. Phagocytosis was measured by using a Beckman Coulter FC 500 flow cytometer. A Varian Cary Eclipse spectrofluorometer was used to study lipid peroxidation and factors of the antioxidant defense system. Results and discussion. While studying the phagocytic arm of immunity, it was found that all patients with early gastric cancer were reported to have parameters of the maximum intensity for neutrophil spontaneous CL from 17 831 c.u. and lower, whereas induced CL reached at least 30 000 c.u. Phagocytic activity of neutrophilic granulocytes in patients with early gastric cancer was 36% or less. While studying the indicators of monocytes, it was found that spontaneous and induced CL decreased from 454 c.u. and 1186 c.u., respectively, in the patients with early gastric cancer. Monocytic activity in early gastric cancer was 34% or less. In the study of lipid peroxidation, an antioxidant defense in patients with chronic atrophic gastritis and gastric cancer had increased malondialdehyde (MDA) level. Patients with gastric cancer had decreased activity of the enzyme catalase (CAT), whereas subjects with chronic atrophic gastritis had reduced glutathione peroxidase (GPO) level. In contrast, patients with early gastric cancer were featured with increased GPO activity. We have proposed coefficients for assessing the factors of the antioxydant defence system in patients: the ratio for superoxide dismutase to catalase activity (SOD/CAT) as well as the ratio for superoxide dismutase to glutathione peroxidase activity (SOD/GPO). Conclusion. During the study, threshold values of parameters were obtained for assigning groups at high risk of developing early gastric cancer, which can be used for screening in adult population.

Russian Journal of Infection and Immunity. 2022;12(1):113-119
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A differential and diagnostic significance of monocytosis in treatment of moderate COVID-19 forms

Shperling M.I., Shperling E.A., Kovalev A.V., Vlasov A.A., Polyakov A.S., Noskov Y.A., Morozov A.D., Merzlyakov V.S., Zvyagintsev D.P., Tishko V.V.


Despite the relatively rare comorbidity with bacterial infections, in most cases treatment of COVID-19-associated pneumonia is accompanied by empirical antibiotic therapy. In addition, the occurrence of leukocytosis in response to glucocorticosteroid (GCS) therapy is often perceived as comorbid bacterial flora and is a reason for initiating antibiotic therapy. Therefore, an urgent task is to properly interpret leukocytosis in response to GCS therapy in COVID-19. The aim of the study was to examine dynamic changes in count of venous blood leukocytes, neutrophils and monocytes in patients with moderate COVID-19 after systemic GCS. We analyzed parameters of complete blood count in 154 patients with verified moderate COVID-19, at the Temporary Infectious Diseases Hospital, the “Patriot” Park of the Moscow Region. The comparison group (I) consisted of 128 patients without clinical signs of bacterial infection and leukocytosis observed on admission, who were prescribed GCS therapy. The control group (II) consisted of 26 subjects showing on admission signs of bacterial infection — a cough with purulent sputum combined with neutrophilic leukocytosis. The dynamics in venous blood cell count was assessed in group I of patients before the onset, 3 and 6 days after beginning GCS therapy. We also compared count of leukocytes, neutrophils and monocytes between patients with developed leukocytosis in group I vs. group II. As a result, an increased count of leukocytes, neutrophils and monocytes was revealed according to assessing complete blood count test in patients from group I on days 3 and 6 of ongoing GCS therapy. All patients with developed leukocytosis after GCS admission (103 subjects) had no clinical signs of bacterial infection. Patients with developed leukocytosis from group I had increased count of monocytes (0.90 (0.84; 1.02) on day 3 after GCS onset and 0.94 (0.87; 1.26) on day 6 of GCS) compared with group II (0.61 [0.50; 0.71]), p < 0.001. The inter-group count of leukocytes and neutrophils did not differ. Monocytosis after GCS therapy may serve as a differential diagnostic criterion to distinguish between glucocorticoid-induced leukocytosis and comorbid bacterial infection. This may be one of the factors influencing a decision to prescribe antibiotic therapy.

Russian Journal of Infection and Immunity. 2022;12(1):120-126
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Influenza vaccination influencing level of specific humoral immunity in healthy individuals

Krivitskaya V.Z., Kuznecova E.V., Maiorova V.G., Petrova E.R., Sominina A.A., Danilenko D.M.


To assess an effect of vaccination on the level of humoral anti-influenza herd immunity, 2955 sera were collected and analyzed by HIT in the 2019–2020 and 2020–2021 epidemiological seasons. All sera were obtained from healthy adult donors residing in various cities of the Russian Federation. Among them, 1057 volunteers were vaccinated with seasonal influenza trivalent inactivated vaccine. Characteristics of humoral anti-influenza immunity (average geometric antibody titers and the proportion of individuals seropositive for the vaccine viruses) obtained in autumn 2019 and 2020 (1–2 months after vaccination) in vaccinated individuals vs. unvaccinated subjects were found to be markedly higher evidencing about a positive vaccination-related contribution to developing herd immunity against influenza in the preepidemic periods. After the 2019–2020 influenza epidemic, in spring 2020 (6–7 months after vaccination), the levels of antibodies to all vaccine components decreased by 2.6–3.5-fold in vaccinated donors compared to the pre-epidemic period in 2019 autumn. Antibody titers became substantially lower than the protective level (titer by HIT < 1/40). At the same time, no significant differences between the groups of vaccinated vs. unvaccinated individuals were observed afterwards. This indicates instability of post-vaccination anti-influenza humoral immunity. As a result, it may decrease an influenza-resistant population cohort of working age on the eve of new epidemic season. The immunogenicity of the inactivated trivalent seasonal influenza vaccine was estimated by HIT while analyzing paired sera obtained from 295 and 112 healthy individuals of various ages vaccinated in autumn 2019 and 2020, respectively. The response to the vaccine was found to be age-related. Children aged 3–14 years vs. older subjects showed a more efficient response. Insufficient immunogenicity of influenza B virus vaccine components was shown. In all age groups, average geometric titers for influenza B virus antibodies were lower (2–8-fold) than for current A(H1N1)pdm09-like strains and influenza A(H3N2) viruses 1–1.5 months post-vaccination. Analyzing vaccine immunogenicity showed a significant inverse relationship between the level of preexisting strain-specific serum antibodies before vaccination and formation of antibodies to the corresponding vaccine virus 1–1.5 months after vaccination. Seroconversion to each vaccine component was remarkably more frequent in individuals with a low preexisting level of antibodies specific to the corresponding virus.

Russian Journal of Infection and Immunity. 2022;12(1):127-141
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In vitro antiviral activity of VIFERON® rectal suppositories against SARS-CoV-2

Isakova-Sivak I.N., Stepanova E.A., Rudenko L.G., Bartov M.S., Vyzhlova E.N., Malinovskaya V.V.


In 2020–2021, the world was engulfed by the pandemic of a new coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus. The low population coverage with vaccination against COVID-19 and the lack of herd immunity result in the need to find an effective and safe etiotropic treatment. Medicinal agents for treatment of COVID-19, approved while preparing this publication, have several limitations related to the conditions of their use and/or population category. In this situation, interferon-containing drugs widely used in Russia and the CIS for prevention and treatment of viral infectious diseases, i.e. ARVI and influenza, may hold promise. This study aims to confirm in vitro antiviral activity against SARS-CoV-2 for the preparation VIFERON® containing recombinant human interferon alpha-2b (IFNα-2b). Materials and methods. Vero CCL-81 cells were infected with hCoV-19/StPetersburg-RII3524VR4/2020 strain of SARS-CoV-2 at doses of 10 TCID50 or 100 TCID50 per well. The suppressive effect of IFN-2b, extracted from VIFERON® in dosage form of rectal suppositories, was evaluated by qRT-PCR at 24 h and 48 h after the infection of cells in two schemes, simulating preventive (24 h before infection) and therapeutic (2 h after infection) use of drugs. Results. IFNα-2b at concentrations of 800, 400, 200, 100 and 50 IU/ml, extracted from rectal suppositories of VIFERON®, showed high biological activity, displayed as inhibition of SARS-CoV-2 strain replication in both infectious doses evaluated either at 24 h or at 48 h after cell infection. The “preventive” vs. “therapeutic” scheme was found to be more effective. In the “preventive” scheme the virus titre decreased by more than 3 lg TCID50 at 24 hours post-infection and by 5–6 lg TCID50 at 48 hours post-infection after administration of 800 IU/ml IFNα-2b. Conclusion. The study results evidence that VIFERON® in dosage form of rectal suppositories may be promising for prevention and treatment of new coronavirus infection in clinical practice.

Russian Journal of Infection and Immunity. 2022;12(1):142-148
pages 142-148 views

Fungal allergies in patients with atopic dermatitis and psoriasis

Barilo A.A., Smirnova S.V.


Examining a role of fungal allergy in the development of atopic dermatitis (AD) and psoriasis (PS) is of particular interest and determines the relevance of the current study. The purpose of the study is to analyze and carry out a comparative analysis for multiple sensitizations to fungal allergens in patients with AD and PS. Materials and methods. The study involved patients with atopic dermatitis (group 1, n = 53, mean age 33.0±1.3 years) and psoriasis (group 2, n = 53, mean age 40.0±1.8 years) aged from 18 to 66 years old. Sensitization to fungal allergens was assessed by skin prick testing with standardized fungal allergens: Candida albicans, Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum, Penicillium notatum (Allergopharma, Germany) and nutritional yeast (Microgen, Russia). The concentration of allergen-specific IgE to a mixture of fungal allergens: Penicillium notatum, Cladosporium herbarum, Aspergillus fumigatus, Mucor racemosus, Alternaria alternata (Alkor Bio, Russia) was determined by the method of indirect immunofluorescence analysis on a semiautomatic analyzer Multiskan FC (ThermoFisher Scientific, Finland). The test was considered positive at an IgE level of ≥ 0.35 kE/L. Statistica 8.0 software package was used for statistical analysis. Results and discussion. When studying the features of sensitization to fungal allergens, it was determined that in the group of patients with AD was the highest frequency of sensitization to nutritional yeast, as well as fungi of the genus Alternaria alternata and Cladosporium herbarum. In the group of PS patients, the highest frequency of sensitization to fungi of the genus Cladosporium herbarum, Aspergillus fumigatus and Alternaria alternata was found. When studying intergroup differences, it was determined that the rate of sensitization to fungi was insignificantly higher in the group of patients with PS in comparison with AD. Sensitization to a mixture of fungal allergens based on the concentration of allergen-specific IgE was more often observed in the group of AD patients vs. patients with PS: 15% versus 5,3%. Most likely, reagins of a different class (IgG4) can participate in the development of AD and PS, or other immunopathological mechanisms of allergy triggering (according to the Gell and Coombs classification) can be involved. Thus, fungal allergy may play an important role in the etiopathogenesis of atopic dermatitis and psoriasis. Our research can guide clinicians in terms of personalized approaches to the diagnosis and treatment of these pathologies, including specific allergological examination, not only for patients with AD, but also for those with PS.

Russian Journal of Infection and Immunity. 2022;12(1):149-157
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Immunograph-based analysis of the influenza a(H1N1)pdm09 vaccine strain immunogenicity in the pandemic and post-pandemic period (2009–2014)

Vakin V.S., Amosova I.V., Vojcekhovskaya E.M., Timoshicheva T.A., Vasileva A.A., Pozdnyakova M.G., Lyalina L.V., Marchenko V.A., Nikonorov I.Y., Grudinin M.P.


Currently, the assessment of the immunogenic properties of influenza viruses as a part of influenza vaccines is carried out by using seroprotection, seroconversion as well as the rate of increases in post-vaccination antibodies.    At the same time, significant differences in the immunogenicity of vaccines related to dynamic formation of high antibody titers responsible for long-term protection of the vaccinated, are neglected. Influenza viruses such as A(H1N1)pdm09 that caused 2009–2010 pandemic continue to circulate in the population, therefore, the assessment of the immunogenic activity of vaccine viruses prepared during the pandemic period is interesting in for the methodology to prepare pandemic vaccines to be used in various groups (adults, children, elderly people). Analyzing immunogenicity of influenza vaccines used during the 2009–2010 swine influenza pandemic and the post-pandemic period up to the year 2014 was carried out by applying the graphical method for assessing immunogenicity (immunographs) measured as follows: for each group of vaccinated subjects (depending on the vaccine used), an increased rate in antibody level was calculated and the graphs of immunogenicity were plotted. An increased rate of serum antibodies magnitude from vaccinated subjects and the number of sera (in %) with a given fold increase rate in antibody level from 1 to the maximum magnitude were plotted on the x- and y-axis, respectively. The proposed method for assessing immunogenicity allows to plot immunogenicity graphs regardless of the serum antibodies level found in volunteers. The assessment described above revealed a several features for developing immune response to the pandemic virus A(H1N1)pdm09 such as the lack of immune response in a substantial number of adult volunteers (25–27%) and young children (60–70%) after monovaccine administration. The reason for such immune response can be both an insufficient dose of vaccine-containing viral antigen and suppressed immune response caused by the influenza A(H1N1)pdm09. A study on the immunogenic properties for seasonal influenza vaccines containing the influenza A(H1N1)pdm09 virus antigen in the years 2010–2014 revealed a variety in emerging humoral immunity ranging from a short-term, low-frequency increase in antibodies from vaccinated children to the formation   of high antibody titers in elderly. Practically, immunographic analysis of influenza vaccines particularly those derived from the influenza A(H1N1)pdm09 virus, may result in proposing recommendations to increase an antigenic load at  the beginning of a pandemic cycle and/or block the suppressive properties of vaccine-contained viruses in pediatric vaccines, because escalating virus dose in the vaccine may not always be achievable in this case.

Russian Journal of Infection and Immunity. 2022;12(1):158-164
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Changes in vascular endothelial growth factor level in Helicobacter pylori-associated gastroduodenal diseases

Matveeva L.V., Kapkaeva R.H., Chudaikin A.N., Soldatova A.A., Mosina L.M., Kostina Y.A., Solodovnikova G.A.


A populational infection with Helicobacter (H.) pylori poses a global problem. Mucosal colonization of H. pylori in the gastroduodenal area can initiate development multiple diseases with hyper- or hypoplasia of mucosal epithelial cells secreting vascular endothelial growth factor (VEGF). The aim of the study was to assess VEGF serum level, its diagnostic and prognostic value in diseases affecting the gastroduodenal area. Materials and methods. 180 patients with exacerbated chronic gastritis, gastric ulcer, duodenal ulcer as well as 30 healthy volunteers were examined after providing an informed consent. Patients were divided into groups depending on the degree of mucous contamination with H. pylori. In the subjects examined during esophagogastroduodenoscopy, a biological material was collected during targeted biopsy for microscopic and histological studies. Blood samples for immunological examination were obtained in the morning on an empty stomach from the ulnar vein in the volume of 5 ml, and the serum was isolated by centrifugation. The level of VEGF, pepsinogens, and titer of total antibodies against the H. pylori cytotoxin-associated protein were determined in the blood serum from the subjects by using the enzyme immunoassay method. The long-term prognosis was analyzed for up to 2 years. The data obtained were processed statistically. Results. Patients were found to have excessive serum VEGF levels in healthy volunteers. For gastric ulcer associated with H. pylori, 80% of cases had increased discriminatory VEGF level. In patients, direct relationships between the serum VEGF level and degree, stage of gastritis, the degree of contamination with H. pylori, the serum pepsinogens level were uncovered. Regression analysis found that patients with diseases targeting gastroduodenal area had serum VEGF level equal to or greater than 231 pg/ml in 60% of cases that correctly predicted an increase in mucosal atrophy. If the amount of VEGF ≥ 373 pg/ml in 91.5% of cases, then ulceration of gastric epithelium developed, whereas for ≥ 396 pg/ml level it was observed in 89% cases with ulceration of the intestinal epithelium. The probability of gastroduodenal bleeding at a serum VEGF level of 408 pg/ml or higher was predicted correctly in 96% of cases. Conclusion. More than 54% of patients with H. pylori-associated chronic gastritis, peptic ulcer disease had level of VEGF significantly exceeding magnitude found in healthy volunteers and the discriminatory level reflects the morphofunctional state of the stomach and duodenum. Assessing serum VEGF level in gastroduodenal diseases can be recommended for predicting development of atrophy, ulceration of the gastric and intestinal epithelium, and gastroduodenal bleeding.

Russian Journal of Infection and Immunity. 2022;12(1):165-171
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Imbalanced immunobiological reactivity, infection and mutagenesis factors in the hepatobiliary system affected by a natural focal habitat factor — a trematode invasion by Opisthorchis felineus

Rybka A.G.


An interaction between decreasing host anti-infective defense due to long-term invasion with Opisthorchis felineus in the hepatobiliary system, duct bile colonization by microflora and revealing the endogenous mutagenesis (carcinogenesis) factor in bile — secondary bile acids — is considered in the article. The role of organism genotype in pathogen-related immune response to Opisthorchis felineus trematode and helminth development in the hepatobiliary system has been shown. The role of dysregulated mechanisms of tissue homeostasis in induction of compensatory chronic homeostatic proliferation and somatic cell oncogenesis is discussed. The study results evidence that disturbed functioning of regulatory T cells, inhibition of the NK cell effector function and very high functional activity of memory B cells are of great importance in imbalanced host immunobiological reactivity, caused by chronic opistorchis invasion. Decreased host anti-infective protection causes intrahepatic bile duct infection with different bacterial species. Presence of secondary bile acids in hepatobiliary system was associated with biliary bacterial strains inhabiting intestinal tract: Proteus vulgaris, Proteus mirabilis, Citrobacter freundii, Bacteroides alcaligues faecalis, Clostridium, Streptococcus faecalis, Еscherichia coli — gut microflora agents. Participation of microbiota in bile acid biotransformation immediately in the duct bile has been confirmed in experiments in vitro. Experimental methods on Drosophila melanogaster and Salmonella typhimurium strains: TA100, TA98 allowed to find out that bile from chronic opistorchiasis patients exerts higher mutagenic activity compared to control groups. Mutational events in somatic and bacterial cells depend on the presence of secondary bile acids (deoxycholic, lithocholic) in duct bile, as well as the level of total bile acid concentration. The study data confirm the concept by Professor A.A. Shain about the presence of endogenous risk factor for developing primary cholangiocellular liver cancer such as secondary bile acids in the bile of chronic opistorchiasis patients. A concept of cholangiocarcinogenesis, based on mutational events, is added up with disturbance of generative cycle in tissue cells and their differentiation due to decreased chalone factor activity, as well as sensitivity threshold to it. Level of investigation and understanding of mechanisms underlying cholangiocarcinogenesis during chronic opisthorchis invasion will allow to develop pathogenetic approaches to correct homeostasis regulation and prevention of cholangiocarcinomas.

Russian Journal of Infection and Immunity. 2022;12(1):172-178
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Human cytopenia variants at diverse HIV infection stages

Baryshnikova D.V., Mordyk A.V., Puzyreva L.V.


Over decades, HIV infection and its complications have been one of the most debated problems in the world. The human immunodeficiency virus not only weaken the immune system, but also disrupts normal hematopoiesis manifested as cytopenia (anemia, thrombocytopenia and neutropenia). Materials and methods. A retrospective analysis of cases of combined HIV infection and inhibited hematopoiesis was carried out according to hemogram data of patients admitted for treatment at the Infectious Clinical Hospital No. 1 named after D. Dalmatov, Omsk. The inclusion criteria were cytopenia during hospitalization detected in detailed blood test (by calculating hemoglobin level, counts of erythrocytes, leukocytes, platelets). The age of the patients included in the study differed: from 20 to 29 years — 27 patients (24.6%), from 30 to 39 years — 69 patients (62.7%), from 40 to 49 years — 13 patients (11.8%), over 50 years old 1 patient (0.9%). All patients had suppression of at least one hematopoietic cell lineage. Anemia was considered as decreased hemoglobin level below than 130 g/l in men and 120 g/l in women. Erythrocytopenia was considered as decreased erythrocyte count below 4.76 × 1012/L. Leukopenia was defined as decreased total count of leukocytes below 4.0 × 109/L, while a decrease in the absolute count of neutrophils below 1000 cells/μL was considered as neutropenia. Thrombocytopenia was determined as decreased platelet count below 150 × 109/L. Results. All patients had suppression of at least one hematopoietic cell lineage. 6 patients with stage 2 had one-cell lineage cytopenias, 7 — two-cell lineages. While analyzing the data obtained, it can be concluded that in patients with stage 2 HIV, inhibition of erythroid and platelet cell lineage predominates, whereas thrombocytopenia reached grade IV. At stage 3 HIV, all 7 patients had inhibition of only one cell lineage. In this group, the inhibition of hematopoiesis had a lighter degree in all hematopoietic cell lineages. In 46 patients with stage 4, there were various oppression of one of the hematopoietic cell lineages, in 44 patients there were two-cell lineage cytopenias. For patients with a more advanced stage of HIV, a decrease in the number of all cellular elements of the blood in the hemogram is characteristic; these disorders are more severe and persistent.

Russian Journal of Infection and Immunity. 2022;12(1):179-184
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Antimicrobial resistance monitoring of potential pathogens causing bloodstream infections

Zakhvatova A.S., Daryina M.G., Svetlichnaya Y.S., Zueva L.P., Aslanov B.I., Chervyakova M.A.


Microbiological monitoring, being an integral component of epidemiological surveillance of healthcare associated infection (HAI), is one of the most important components in hospital patient safety. The purpose of monitoring is the etiological interpretation of pathogens, the identification of microbial hospital strains and development of strategies as well as tactics for combating them. In modern conditions development of healthcare and humanity as a whole, the most important problem is the steady increase in the number of HAI caused by antimicrobial drug-insensitive pathogens and decreased drug effectiveness used in therapy. The structure of infectious conditions in the hospital is specific and is determined by the profile and nature of the treatment, nosology and age of patients. The main pathogens in the etiological structure of HAI are Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Enterococcus faecalis and Enterococcus faecium. The study estimated the prevalence of bloodstream infections pathogens resistant to antimicrobial agents in healthcare facilities in St. Petersburg. We retrospectively analyzed data on the antimicrobial resistance for the six clinically significant HAI pathogens that were detected in the blood samples at the 50 hospitals of St. Petersburg during the years 2016–2019. It was found that the use of β-lactam antibiotics is not effective in the treatment of patients with bloodstream infections (BSI) caused by S. aureus (in 21.9% of BSI cases), E. coli (2.1%), Klebsiella spp. (39.6%), P. aeruginosa (40.5%), Acinetobacter spp. (66.7%), Enterococcus spp. (4.4%). This article shows that targeted microbiological monitoring of HAI caused by resistant pathogens should be considered as an effective organizational mechanism for timely detection and prevention of complications that are observed in medical care to patients at high risk for bloodstream infections. Identification of the features of the epidemic process for purulentseptic infections in medical organizations contributes to the improved preventive measures in order to improve the quality of medical care. Microbiological monitoring data are necessary for the development and implementation of measures to curb the further growth of antimicrobial resistance of infectious disease pathogens.

Russian Journal of Infection and Immunity. 2022;12(1):185-192
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Antimicrobial activity of polyhexamethylene guanidine hydrochloride derivatives against multiresistant microbial strains

Ochirov O.S., Burasova E.G., Stelmakh S.A., Grigor'eva M.N., Okladnikova V.O., Mognonov D.M.


The resistance of bacteria to the disinfectants used is one of the pressing health problems requiring to be addressed in order to prevent formation and spread of resistant strains. Bacterial resistance leads to a sharply decreased effectiveness of anti-epidemic measures and contributes to maintaining a high morbidity level. In the context of the growing HAI incidence rate and related polyetiology, the large adaptive potential of opportunistic microorganisms, and the growing resistance to antimicrobial drugs, it is necessary to search for new or modify the corresponding substances of plant or synthetic origin exerting antimicrobial action used as antimicrobial agents. One of the representatives of this class of compounds are polyguanidines, characterized by high antimicrobial activity and low toxicity. Due to the high reactivity of the guanidine group, as well as ease of synthesis and relative availability of raw materials, N-phenyl- and N-octyl-substituted derivatives of polyhexamethylene guanidine hydrochloride were able to be obtained by melt polycondensation, their molecular weight characteristics were measured as well as the structure investigated by IR spectroscopy. An earlier study on the acute toxicity for polyhexamethylene guanidine hydrochloride derivatives after a single oral drug intake in laboratory animals (white mice) allowed to establish the following LD50 values: polyhexamethylene guanidine hydrochloride — 850.0±112.02 mg/ kg; N-phenyl-substituted polyhexamethylene guanidine hydrochloride — 1399.9±120.51 mg/kg; N-octyl-substituted polyhexamethylene guanidine hydrochloride — 1150.0±137.40 mg/kg. Such values, according to the tabulation of hazard classes, allow the synthesized derivatives to be classified into the fourth hazard class and open up an opportunity for using disinfectants as active components. The evaluation of the antibacterial sample properties was carried out by using serial dilutions in agar on hospital bacterial and fungal strains isolated from the biomaterial of patients at the Republican Clinical Hospital named after V.I. Semashko, according to the clinical guidelines “Laboratory diagnosis of community-acquired pneumonia” 2014, “Bacteriological analysis of urine” 2014, “Determination of the susceptibility of microorganisms to antimicrobial drugs” 2015. It was found that N-substituted derivatives exhibit a greater antimicrobial effect compared with unsubstituted polymer. The most sensitive to all the drugs presented was the yeast-like fungi Candida albicans (No. 2495) (complete suppression), as well as methicillin-resistant S. aureus (no. 2544), and the substituted samples almost completely suppress its growth. The most resistant strains are P. aeruginosa (No. 2281), A. baumannii (No. 2806) and K. pneumoniae (No. 3023), the percentage of reduction of these bacteria under the action of substituted samples does not exceed 41%, which is accounted for by their multi-resistance.

Russian Journal of Infection and Immunity. 2022;12(1):193-196
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