Гентамицин является одним из компонентов комбинированной терапии инфекционных эндокардитов, вызванных Staphylococcus aureus, включая метициллинорезистентные штаммы (methicillin-resistant S.aureus, MRSA). Цель исследования — анализ влияния десяти 6-часовых циклов воздействия высоких концентраций (16 мкг/мл) гентамицина in vitro на изменение фенотипа и генотипа аминогликозидочувствительных штаммов S.aureus, относящихся к четырём сиквенс-типам: ST5 (ATCC 29213), ST8, ST97 и ST22 (MRSA). Для всех штаммов, кроме ATCC 29213, после селекции отмечалось увеличение МПК гентамицина до 8–64 мкг/мл. Один штамм (SA0937) диссоциировал на три морфотипа, включая мелкоколониевый вариант (small colony variant, SCV). Вариант производного штамма SA0937 с колониями нормального размера характеризовался ассоциированной устойчивостью к даптомицину за счёт мутации P314L в MprF. Формирование устойчивости не сопровождалось изменением скорости роста, кроме морфотипа SCV. Для штамма ATCC 29213 после селекции отмечалось появление толерантности, проявляющейся в увеличении эффективного киллинга до 14 ч в 24-часовом time-killing эксперименте с концентрацией антибиотика 16 мкг/мл. У штамма ATCC 29213 выявлены мутации в пептидил т-РНК гидролазе (Pth). У трёх штаммов были обнаружены делеции в гене atpG, входящим в состав АТФ-синтазного комплекса. У остальных производных штаммов были выявлены делеции и мутации в генах метаболизма менахинона hepS, menA и трансляционном факторе элонгации G (fusA). Таким образом, использование гентамицина сопряжено с возможным быстрым формированием устойчивости и толерантности, не связанными с приобретением генов аминогликозид-модифицирующих ферментов. Выявление SCV ассоциировано с неблагоприятными клиническими исходами. При использовании комбинированной терапии необходимо учитывать, что существует возможность формирования устойчивости к даптомицину на фоне селекции гентамицином.
The created cell line of human proximal renal tubules RPTEC/TERT1 showed maximum compliance with primary human RPTEC, which makes it optimal for use in studies of the nephrotoxic properties of xenobiotics. Transepithelial resistance measurement (TEER) is a valuable non-invasive method that can be used to quantify the integrity of the cell barrier at various stages of cell growth and differentiation, as well as to predict the toxicity and permeability of drugs. The aim of the study was to examine the dynamics of changes in transepithelial resistance in the model of the RPTEC/TERT1 cell line during incubation with drugs with nephrotoxic effects. Material and methods. The human proximal renal tubule cell line RPTEC/TERT was obtained from the ATCC cell culture bank. Cells at passage 14 were used in the experiment. The following drugs were studied: cisplatin: 2.5 mcg/ml; vancomycin: 50 mcg/ml; doripenem — 20mcg/ml; cefepim — 150mcg/ml. 4–5 repetitions were performed for each concentration of the drug in the experiment. THEER measurements were carried out 4–5 times for each well. Results. Cisplatin, vancomycin, doripenem, and cefepim in the concentrations used do not show a cytotoxic effect on the RPTEC cell line according to TEER dynamics.
Background. The modern healthcare system is constantly improving and introducing new measures to protect the population from viral diseases, but the experience of the COVID-19 pandemic has shown that infections cannot always be controlled on global scale. In this regard, the development of new broad-spectrum antiviral drugs is more relevant than ever.The aim of the study was to investigate the antiviral activity and cytotoxicity of copolymers of sodium styrene sulfonate and vinyl monomers of various chemical structures, as well as to identify promising polymers for the development of new antiviral agents.Materials and methods. 14 copolymers of sodium styrene sulfonate (NaSS) with various functional comonomers were synthesized. Three viruses with different reproduction strategies and transmission methods — respiratory syncytial virus, influenza virus, and herpes virus — were selected for the assessment of antiviral activity.Results. The screening identified copolymers that showed high activity against all three viruses. It was found that the introduction of various functional groups into the structure of NaSS did not decrease antiviral activity, but significantly reduced cytotoxicity. The molecular weight has also shown a noticeable effect on the activity. Different sensitivity of viruses and cells to the studied polymers was revealed, likely due to the structural features of the virus shell and cell wall.Conclusions. The results demonstrate the potential of sodium styrene sulfonate copolymers as a model for developing a broad-spectrum antiviral drug.
A significant increase in sales of antibacterial drugs in pharmacies and their purchases by medical institutions of the Russian Healthcare System was observed against the background of the past pandemic of a novel coronavirus infection in Russia. Microbiological monitoring that was carried out at City Clinical Hospital No. 67 named after. L. A. Vorokhobov (Moscow) in 2020–2021, revealed a pressing problem — primarily gram-negative bacteria, with a predominance of multidrug-resistant (MDR) strains, were isolated from patients with healthcare-associated infections (HAIs). As shown by pharmacoeconomic studies conducted by the authors, the cost of one course of targeted antibacterial therapy for HAI in this case could increase by 6–12 times compared to a similar course of therapy in the absence of both MDR strains and XDR strains of hospital pathogens. In order to achieve a reduction in the cost of antibacterial therapy developed and used by the authors, in addition to the development of effective antibacterial therapy regimens for HAIs caused by MDR/XDR pathogens, another study was carried out as a continuation of the work on creating and improving biotherapy regimens for HAIs, namely the development of personalized phage therapy regimens for patients with hospital-acquired pneumonia caused by MDR bacterial strains. Based on the data obtained, the concept of a personalized approach to phage therapy of various nosological forms of HAIs caused by hospital-acquired MDR pathogens in patients of a multidisciplinary hospital was proposed and tested. As a result of this approach, the effectiveness of phage therapy for various nosological forms of HAIs caused by MDR and XDR strains of hospital pathogens in City Clinical Hospital No. 67 named after. L. A. Vorokhobov increased by 30%, and the effectiveness of the initial antibiotic regimen was 70%. The economic effect of the combination of antibiotic therapy and phage therapy («booster therapy») amounted to 3,000,000 rubles, compared with the use of antibiotics alone in the treatment of patients with HAIs caused by MDR/XDR strains of hospital pathogens.
Aim. To study the efficacy and safety of Riamilovir in patients diagnosed with acute respiratory viral infection using several dosage regimens of the drug.Material and Methods. The clinical efficacy and safety of Riamilovir were evaluated based on the results of a study, that included 150 patients in three comparative groups, 50 patients each. The research groups received etiotropic antiviral therapy with 1 capsule (250 mg) of Riamilovir 3 times per day for 5 days in the first group; in the second group, patients received Riamilovir off-label — 1 capsule (250 mg) 5 times per day for 5 days; and the third group included 50 patients who received only pathogenetic treatment.Results. As a result of the study, Riamilovir demonstrated a high safety profile regardless of the dosage regimen; no adverse events were registered. It was shown that Riamilovir use, regardless of the dosage regimen, led to a statistically significant reduction in the duration of inpatient treatment. It should be noted that the shortest periods of hospitalization were observed in patients who received the studied drug at increased daily dosages. Riamilovir was found to reduce the duration and severity of general infectious signs of the disease, while complete elimination of ARVI pathogens occurred by the 6th day of hospitalization; the shortest total duration of fever and a number of respiratory tract syndromes was registered among patients receiving Riamilovir at a daily dose of 1250 mg for 5 days.Conclusion. The etiotropic antiviral drug Riamilovir has shown clinical efficacy when used in both treatment regimens in patients with acute respiratory viral infections, as well as a good safety profile.
The review article discusses current trends in antibiotic resistance in bacterial and protozoal sexually transmitted infections (STIs). Antimicrobial resistance in STIs has increased significantly in recent decades due to the overuse and misuse of antibiotics, fueled by population migration and the high incidence of STIs worldwide. While emerging cephalosporin-resistant strains of Neisseria gonorrhoeae are one of the most pressing problems in the world, other pathogenic STIs that are resistant to antibiotics, such as Mycoplasma genitalium and Chlamydia trachomatis, are increasingly being reported. The emergence of multidrugresistant strains of bacterial STIs is of particular concern for researchers. The emerging global crisis in STI treatment is the result of neglect and inattention to repeated warnings from researchers about the emergence of STI strains resistant to the existing antibiotics, as well as shifting priorities in the pharmaceutical industry, which limited the development of new antibiotics. The current antimicrobial portfolio does not provide cause for optimism, as it contains few new antibiotics, and most developments are in the early stages of clinical trials. Experts have suggested that the failure of existing STI treatment regimens is largely inevitable and have called for the creation of entirely new classes of antimicrobial drugs that would take decades to develop. Currently, there are several promising alternative strategies for the treatment of antibiotic-resistant STIs. The use of phage therapy, antimicrobial peptides, and hydrolytic enzymes are particularly promising directions.
Background. To date, virologists have identified more than 25,000 influenza virus А serotypes, and their number will increase in the future. Therefore, the development of new antiviral drugs will always be relevant.The aim of the study is to obtain and test the chemical composition and antiviral activity of the lichen Cetraria islandica extracts against the influenza A virus.Material and methods. Samples of lichen Cetraria islandica (aqueous and ethanol extracts) were tested for toxic properties and antiviral activity against influenza A virus in MDCK cell culture.Results. Samples of aqueous and ethanol extracts of Cetraria islandica were obtained; their chemical composition was described. In MDCK cell culture, the extracts exhibited antiviral activity against human influenza virus А/H3N2 and avian influenza virus А/H5N1. When studying the mechanism of action of Cetraria islandica extracts, it was noted that Cetraria islandica samples possess pronounced antiviral properties against avian influenza A/chicken/Kurgan/05/2005 (H5N1) and human influenza A/Aichi/2/68 (H3N2) at the stage of their adsorption and reproduction.Conclusions. Samples of Cetraria islandica have antiviral activity at the stage of adsorption and reproduction of influenza A virus in MDCK cell culture. The ethanol extract shows a higher antiviral efficacy compared to the aqueous extract.
Background. The study of new antimicrobial substances isolated from the living organism tissues is of particular importance for medicine and the biopharmaceutical industry. Leukocyte peptides can act as an alternative to traditional antibiotics to overcome the bacterial antibiotic resistance problem.Aim. Evaluation of molecular weight and biological activity of ultrasound-derived leukocyte peptides.Methods. Separation of leukocyte peptide complexes into particular fractions by reverse phase chromatography and evaluation of their antibacterial activity by serial dilution and diffusion methods.Results. Studies have shown that one peptide fraction with a molecular weight of 440–570 Da has pronounced antibacterial activity.Conclusion. The obtained experimental data testify to the high therapeutic potential of the leukocyte protein-peptide complex, which has a wide spectrum of antibacterial activity.
The aim of the study was to investigate the effect on the psycho-emotional state and adherence to treatment in patients with pulmonary tuberculosis of remaxol inclusion in the accompanying therapy regimens.Material and methods. The data from 326 patients (252 men and 74 women) with various forms of pulmonary tuberculosis treated at the Regional Clinical Tuberculosis Dispensary were analyzed; the average age of patients was 41.3±1.6 years. A low level of adherence to treatment, as well as clinical and laboratory signs of grade I hepatotoxicity were revealed in patients receiving a course of etiotropic therapy in the main group (N=72). In this regard, in addition to the psychological support for the main course of treatment, accompanying therapy was prescribed: remaxol 400 ml intravenous drip every other day (course No. 5), after-wards — 1 time a week (course No. 4). Patients in the comparison group (N=254) received standard treatment. In addition to the standard examination, the cytokine profile (the level of IL-1β, 4, 6), TNF-α and IFN-γ) was determined in dynamics according to the indications in patients. The level of adherence to the treatment was also determined in dynamics through testing according to the original methodology.Results. The study revealed that the inclusion of remaxol in the treatment regimens facilitated more pronounced positive dynamics in clinical and laboratory data compared with the standard regimen: a decrease in signs of hepatotoxicosis and a tendency towards improvement in cytokine profile parameters. This contributed to maintaining the etiotropic therapy regimen and improving the well-being of patients, which, in turn, increased the level of adherence and therefore the effectiveness of treatment in patients.Conclusions. The combination of positive effects of remaxol use in patients with pulmonary tuberculosis contributes to an increase in their psycho-emotional state and thereby increases adherence to treatment and its effectiveness.
Introduction. Due to the ability of the influenza virus to mutate, it is necessary to constantly search for new drugs with preventive and direct antiviral effects. The aim of the study is to investigate the protective antiviral properties of the drug Thymogen ® , a dosed nasal spray, on a model of lethal influenza pneumonia in laboratory animals. Material and methods. White mature mice were selected for the experiment on the antiviral activity of the tested drug samples against H1N1 influenza virus; the mice were divided into the following groups (30 animals each): two negative control groups; two groups receiving Thymogen ® , a dosed nasal spray (before and after infection); one group of animals received Tamiflu ® , and one received Hexoral ® . The mortality of animals with influenza pneumonia was assessed; histological and morphometric analyses were also carried out. Results and discussion. The morphological picture of the lungs of animals correlated with their protective activity when analyzing the survival of animals. The normalization of tissue structure was pronounced the most in the group of animals infected with the virus, pre-incubated with Thymogen ® , a dosed nasal spray, and in the group receiving Tamiflu ® . Moreover, the viral load in the lungs was lower by 1.5 and 1.2 orders of magnitude in the group receiving Thymogen ® , dosed nasal spray, compared to the negative control group (the 3 rd and the 6 th days of the experiment, respectively), which corresponds to a decrease in the intensity of viral reproduction by 31.6 and 15.8 times
Background. The COVID-19 pandemic is caused by the SARS-CoV-2 virus. Insufficient attention is paid to the cardiotoxic potential of the drugs used in the treatment of COVID-19.Aim. A brief report on the effect of the drugs commonly used in the treatment of COVID-19 on the cardiovascular system.Discussion. Various medications have been used to treat COVID-19. Some of the most common drugs include hydroxychloroquine, remdesvir, favipiravir, fluoroquinolones, interferon-α2b, glucocorticoids, molnupiravir, and ritonavir/nirmatrelvir. Most medications can cause changes in the cardiovascular system, especially in the QT interval.Conclusions. Physicians should take into account the cardiotoxic potential of all medications used in the treatment of COVID-19. Therapists and general practitioners should be aware of cardiovascular risks in the management of patients with COVID-19, as well as the prophylactic medical examinations of the population.
The purpose of this study was to investigate the antimicrobial activity of staphylococcal bacteriophage on a model of a skin wound infected with Staphylococcus aureus. The study of antimicrobial activity was carried out in vivo by experimental modeling of a skin wound infected with S.aureus in the interscapular region in nonlinear male rats. All manipulations with animals were performed in accordance with the requirements of regulatory documentation overseeing the management of laboratory animals and work with them. The results obtained indicate the pronounced antimicrobial activity of staphylococcal bacteriophage in conditions of wound infection when applied externally, which is confirmed by a decrease in the degree of bacterial contamination of wound discharge, as well as a decrease in inflammatory phenomena, both at the local level in the form of a decrease in hyperemia, and generalized in the form of a decrease in C-reactive protein levels, total leukocyte count, as well as a decrease in the leukocyte inflammatory index. The identified antimicrobial effect is comparable to the external use of an antiseptic drug — a solution of chlorhexidine digluconate 0.05%, however, when assessing microbial contamination, it was found that the bacteriophage exhibits more pronounced antibacterial activity. Thus, the staphylococcal bacteriophage showed pronounced antimicrobial activity in a model of a skin wound infected with S.aureus, confirmed by a decrease in the number of colonies of the microorganism in the wound discharge, as well as a decrease in the severity of inflammation.
Biofilms play a significant role in the existence of bacteria under adverse conditions and the pathogenesis of infections. They contribute to the creation of reservoirs of antibiotic-resistant pathogens. This determines the relevance of the search for biologically active substances that inhibit the formation of biofilms. In recent years, the objects of intensive study are fucoidans — sulfated polysaccharides from marine brown algae, which have a wide polyfunctional spectrum of action. Their influence on the formation of Yersinia pseudotuberculosis biofilm in a dynamic model simulating the natural conditions of ecosystems of fucoidans belonging to different structural groups was investigated in this study. They are synthesized by brown algae: Fucus evanescens, Saccharina cichorioides, and Saccharina japonica. The fucoidan isolated from F.evanescens have showed the most pronounced antibiotic activity. The authors developed a new approach that allows obtaining stable results of multidirectional action of sulfated polysaccharides on the biofilm formation of Y.pseudotuberculosis.
Background. One of the main problems of antibiotic therapy is the development of resistance in microorganisms. In this regard, the search for new natural antibiotics, including those of plant origin, is relevant. The aim of the study was the determination of antibacterial action mechanisms of aqueous and alcoholic extracts of medicinal plants collected on the territory of the Republic of Bashkortostan. Methods. The bark, roots, stems, leaves, and inflorescences of medicinal plants were selected as objects of the study. The mechanisms of antibacterial action of plant preparations were determined via high throughput screening using the Dualrep2 double reporter system. Results. The mechanisms of the antibacterial action of certain plant extracts obtained from fresh and dried raw materials were established. It has been shown that the products of alcohol extraction of yarrow inflorescences inhibit protein synthesis, while the products of celandine roots and stems cause the activation of the SOS DNA repair system in Escherichia coli bacteria. Conclusion. The results obtained allow us to consider the studied extracts of medicinal plants as a basis for obtaining new antibacterial agents with a specific mechanism of action.
Background. Previously, genetic markers rs11385942 G>GA and rs657152 C>A of disease severity were identified for COVID-19. The study of the prevalence of clinically significant genetic markers may be useful for the development of region-specific approaches to disease control, considering, among other things, the ethnic composition of the territory, which is especially relevant for Russia. Based on the ethnic heterogeneity of the population of the Republic of Dagestan, this region was chosen as an example to study the distribution of COVID-19 severity markers of interest. Objective. Investigation of the prevalence of rs11385942 G>GA and rs657152 C>A markers among five ethnic groups residing in Dagestan. Methods. The study included 605 healthy volunteers (158 men and 447 women) from five different autochthonous ethnic groups living in the Republic of Dagestan: 118 Avars, 121 Dargins, 116 Laks, 127 Kumyks, and 123 Lezgins. Blood served as a material for determining polymorphisms. Carriage of polymorphic markers was determined by real-time polymerase chain reaction method. Results. The prevalence of rs11385942 G>GA marker ranges from 10.17% among Avars to 15.04% among Lezgins; significant differences were found in comparison with Russian ethnic group from literature sources. The second marker – rs657152 A>C — is distributed relatively homogeneously in the studied groups, without significant differences, and correlates with the data on the frequency of marker detection among Russians, as well as among European populations and worldwide — 50–60%. Conclusion. No differences were found within the ethnic groups of Dagestan in the carriage of both studied COVID-19 severity markers. At the same time, the rs11385942 G>GA marker detection frequency in the analyzed groups was on average higher in comparison with Russians and the average values for European populations.
Currently, a decrease is seen in the effectiveness of treatment in patients with tuberculosis due to the appearance of adverse reactions to anti-tuberculosis drugs. Hepatotoxic reactions play an especially important role in anti-tuberculosis therapy, and phthisiologists often have to deal with the cancellation of a number of anti-tuberculosis drugs. The aim of the study was to investigate the relationship of polymorphic gene variants of xenobiotic biotransformation metabolizing enzymes (NAT2 (590G>A (rs1799930), CYP2E1 (9896C>G (rs2070676), ABCB1 (3435T>C (rs1045642), GSTM1 (E/D), GSTT1 (E/D) with the risk of hepatotoxic reactions in patients with pulmonary tuberculosis. Material and methods. The logistic regression analysis method was used to predict the probability of hepatoxic reactions during specific anti-tuberculosis therapy. Results: 1 statistically significant model was obtained, which reflects the association with hepatotoxic reactions to anti-tuberculosis drugs of the TS genotypes or the TS gene (T allele) ABSV1 (rs1045642). Conclusion. Pharmacogenetic testing used in the study allows us to identify risk groups of patients with pulmonary tuberculosis according to the likelihood of hepatotoxic reactions, which may provide an individualized approach to the treatment of these patients in the future.
The article presents an overview of specialized medical information systems that perform ABC/VEN analysis. It provides a comparison of specific examples, describes their advantages and disadvantages, as well as the possibility of automating the processes of searching for information on the proven effectiveness of drugs, selecting alternative drugs within one ATC group, selecting alternative drugs within the framework of the current clinical recommendations of the Ministry of Health of the Russian Federation, assessing drug-drug interactions, as well as the reference information from the instructions for use of the drugs.
Liberal oxygen therapy for COVID-19 causes hyperoxemia in most patients and reduces their survival rate. Even moderate hyperoxemia reduces oxygen delivery, and high levels of oxygen in central venous blood increase mortality in COVID-19 patients. These facts occur due to the manifestation of toxic effects of oxygen (vasoconstriction, bronchoconstriction) requiring the use of medications that reduce toxic effects. The aim of the study was to assess the ability of succinate preparations to eliminate the toxic effects of oxygen affecting central hemodynamics and blood oxygenation in patients with COVID-19. Material and methods. The effect of medicines containing succinates (Cytoflavin and Reamberin) in stopping the manifestations of hyperoxia in 51 surviving patients with the novel coronavirus infection who received high-flow oxygen therapy (HFOT) was analyzed in a retrospective study. Results. Monitoring of heart rate, respiratory rate, SpO₂, PaO₂ and PaO₂/FiO₂ during HFOT within 12 hours from the start of oxygen therapy showed an indirect, but statistically significant effect of stopping the toxic effects of oxygen. This was expressed in a decrease in tachycardia and tachypnea [to 86.7–115.0 (at P<0.001) and 22–24 (P<0.001), respectively] against the background of concomitantly administered succinate preparations, that provided effective oxygen absorption and contributed to the effective elimination of hypoxia and hypoxemia (an increase in PaO₂/FiO₂ to 196.0 [(184.2–249.0) at P<0.001], which was confirmed by a dynamic decrease in the level of lactate (to 2.6±0.8 mmol/l at P<0.001). Conclusion. The results obtained indirectly confirm the protective effect of succinates, which are more pronounced in Citoflavin, but require additional confirmation of the hypothesis of succinate effectiveness in stopping the toxic effects of oxygen in further studies.
Spiramycin is a natural 16-membered macrolide antibiotic that has been used in clinical practice for about 70 years. Despite long-term use, spiramycin retains its position in clinical practice; the resistance of the main respiratory and urogenital pathogens is lower to spiramycin than to 14- and 15-membered macrolides. The interest in spiramycin is due to the fact that its physico-chemical and pharmacokinetic properties are similar to the last semi-synthetic macrolides, and it lacks the disadvantages of erythromycin. Special biological properties of spiramycin explain its consistently high clinical efficacy that has lasted for 70 years of clinical use in various infections. It is necessary to emphasize the uniqueness of spiramycin as an antibiotic with not only the direct effect on microbes, but also non-antibiotic properties. This allowed the experts at the time to declare the «paradox» of spiramycin — the presence of a higher real clinical efficacy than expected according to in vitro studies. Such properties of spiramycin include pro-antibiotic and post-antibiotic effects, immunomodulatory effect, as well as high intracellular and extracellular concentrations of the antibiotic. The review discusses antimicrobial, pharmacokinetic, and pharmacodynamic characteristics of spiramycin and its place in the treatment of various infections — respiratory, ENT, urogenital, gynecological, and dental.
The article presents an analysis of studies assessing the effectiveness of new nonspecific medications against hemorrhagic fevers caused by arenaviruses. The possible targets for nonspecific medications, classes of researched antiviral preparations, methods of preclinical investigation of antiviral preparations in vitro and on laboratory animals, as well as prospects for their use in healthcare at present are considered. It has been shown that the level of development of nonspecific medications against hemorrhagic fevers caused by arenaviruses is significantly inferior to those against filovirus infections. Favipiravir should currently be considered as the most effective nonspecific medication against hemorrhagic fevers caused by arenaviruses.
