ISSN 2706-6282 e-ISSN 2706-6290 Тернопільський національний медичний університет імені І. Я. Горбачевського Науково-практичний журнал Том 17, № 3 Заснований у 2019 році Періодичність випуску: щоквартально Тернопіль – 2023 Вісник медичних і біологічних досліджень Засновник: Тернопільський національний медичний університет імені І. Я. Горбачевського Рік заснування: 2019 Рекомендовано до друку та поширення через мережу Інтернет Вченою радою Тернопільський національний медичний університет імені І. Я. Горбачевського (протокол № 9 від 31 серпня 2023 р.) Свідоцтво про державну реєстрацію друкованого засобу масової інформації серії КВ № 23992-13832P Журнал входить до переліку наукових фахових видань України Категорія «Б». Спеціальності: 222 – «Медицина», 223 – «Медсестринство», 091 – «Біологія та біохімія» Журнал представлено у міжнародних наукометричних базах даних, репозитаріях та пошукових системах: Національна бібліотека України імені В. І. Вернадського, Фахові видання України, BASE, Index Copernicus Вісник медичних і біологічних досліджень / [редкол.: Л. Я. Федонюк (голов. ред.) та ін.]. – Тернопіль : Тернопільський національний медичний університет імені І. Я. Горбачевського, 2023. – Т. 17, № 3. – 59 с. Адреса редакції: Тернопільський національний медичний університет імені І. Я. Горбачевського 46001, майдан Волі, 1, м. Тернопіль, Україна E-mail: info@bmbr.com.ua www: https://bmbr.com.ua/uk © Тернопільський національний медичний університет імені І. Я. Горбачевського, 2023 ISSN 2706-6282 e-ISSN 2706-6290 М. С. Гнатюк, С. О. Нестерук, Л. В. Татарчук, Н. Я. Монастирська Морфометрична оцінка вікових структурних змін гемомікроциркуляторного русла передміхурової залози в умовах етанолової інтоксикації ......................................8 M. Hnatjuk, S. Nesteruk, L. Tatarchuk, N. Monastyrska Morphometric assessment of age-related structural changes in the vessels of the microcirculatory bed of the prostate gland under conditions of ethanol intoxication .........................8 Д. І. Заболотний, О. М. Кваша Біофізична оцінка ефективності застосування високочастотного біполярного електрозварювання для закриття дефектів твердої мозкової оболонки при пухлинах лобних пазух з інтракраніальним поширенням .................................................................................................................................. 16 D. Zabolotnyi, O. Kvasha Biophysical evaluation of the effectiveness of high-frequency bipolar electric welding for closing defects in the dura mater in frontal sinus tumours with intracranial spread ................................................................................. 16 Л. Я. Федонюк, Н. Б. Гливка, Я. С. Стравський Організаційні та методичні засади викладання вибіркової дисципліни «Сучасні аспекти медичної паразитології» для студентів навчально-наукового інституту медсестринства .......... 25 L. Fedoniuk, N. Hlyvka, Ya. Stravskyy Organizational and methodological principles of teaching the elective discipline “Modern Aspects of Medical Parasitology” for students of the Educational and Research Institute of Nursing ............... 25 Т. А. Ковальчук Сучасні методи дослідження вегетативних функцій у дітей із синкопе: огляд літератури ....................................... 33 T. Kovalchuk Modern methods of researching autonomic functions in children with syncope: A literature review .............................. 33 О. В. Кочнєва, О. В. Коцар Роль мікробних біоплівок при розвитоку ускладнень дихальної системи у пацієнтів З СOVID-19: огляд літератури ..................................................................................... 40 O. Kochnieva, O. Kotsar The role of microbial biofilms in the development of respiratory system complications in patients with COVID-19: A literature review ....................................................... 40 Т. І. П’ятковський Застосування газоподібного озону та його водного розчину для інактивації патогенних мікроорганізмів: огляд літератури ................................................................................. 47 T. Pyatkovskyy Application of gaseous ozone and its aqueous solution for inactivation of pathogenic microorganisms: A literature review ................................................................................. 47 ЗМІСТ / CONTENTS e INTRODUCTION Secondary bacterial infections play a crucial role in the morbidity and mortality of patients with COVID-19. One of the complications of coronavirus infection is the devel- opment of acute respiratory failure, which requires arti- ficial lung ventilation (ALV) using an endotracheal tube to correct hypoxaemia. Most microorganisms in natural and artificially designed environments exist as structured forms attached to biotic or abiotic surfaces, forming com- Suggested Citation: Kochnieva O, Kotsar O. The role of microbial biofilms in the development of respiratory system complications in patients with COVID-19: A literature review. Bull Med Biol Res. 2023;17(3):40–46 . DOI: 10.11603/bmbr.2706-6290.2023.3.40 *Corresponding author UDC579.61:[616.98:578.834.1COVID-19:616.24-002]-022.15-022.7:579.262 The role of microbial biofilms in the development of respiratory system complications in patients with COVID-19: A literature review Olena Kochnieva* PhD in Medical Sciences, Senior Lecturer Kharkiv National Medical University 61022, 4 Nauky Ave., Kharkiv, Ukraine https://orcid.org/0000-0002-1039-9313 Olena Kotsar PhD in Medical Sciences, Assistant Professor Kharkiv National Medical University 61022, 4 Nauky Ave., Kharkiv, Ukraine https://orcid.org/0000-0002-3797-1068 Abstract. One of the complications of COVID-19 is the development of acute respiratory failure, which may require artificial ventilation using an endotracheal tube to correct hypoxaemia. However, the establishment of biofilms during intubation of patients can pose a risk of microbial growth that can cause severe complications. Therefore, the research on the microbial composition of biofilms that causes such diseases becomes an urgent issue. The purpose of the research was to analyse and summarise the data from current studies on the role of microbial biofilms and their impact on the development of respiratory system complications in patients with COVID-19. After reviewing the literature, it was determined that Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans accounted for the majority of biofilms isolated from endotracheal tubes in patients with COVID-19. The level of antimicrobial resistance among the isolated strains was almost 70%. The examination of samples from endotracheal tubes identified representatives of the lung microbiome, Prevotella spp. and some species of Streptococcus, Veillonella. However, in the research on the microbial composition of biofilms isolated from endotracheal tubes, pathogenic representatives dominated, such as Pseudomonas spp., Staphylococcus spp., Streptococcus spp., Stenotrophomonas spp., Enterobacterales, Haemophilus spp. and Actinomyces spp. Changes in the composition of the lung microbiome in patients with COVID-19 can lead to the development of severe complications accompanied by the establishment of biofilms. Microorganisms in biofilms can be a reservoir for secondary pulmonary infections, which affects the duration of mechanical ventilation and the admission of patients with COVID-19 to intensive care units. The development and implementation of effective measures for the prevention and treatment of biofilm-related infections is an important task for modern medical practice Keywords: microbial biofilms; espiratory failure; pneumonia; secondary infection Copyright © The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/) Journal homepage: https://bmbr.com.ua/enDOI: 10.11603/bmbr.2706-6290.2023.3.40 Article’s History: Received: 18.05.2023; Revised: 28.07.2023; Accepted: 31.08.2023 Bulletin of Medical Bulletin of Medical and Biological Researchand Biological Research Vol. 17, No. 3 Vol. 17, No. 3 20232023 plex microbial communities surrounded by an exopoly- saccharide matrix called biofilms  [1]. The establishment of biofilms during the intubation of patients poses a risk of the growth of microorganisms that can cause pneumo- nia and other complications of the respiratory system. Such undesirable consequences can affect the treatment of patients and prolong their hospital stay. Despite on- going research in this area, the impact of biofilms on the https://orcid.org/0000-0002-1039-9313 https://orcid.org/0000-0002-3797-1068 O. Kochnieva and O. Kotsar 4141 Bulletin of Medical and Biological Research. 2023. Vol.17, No. 3 the composition of the lung microbiome and isolates iso- lated from endotracheal tubes. The main complications of the respiratory system in patients with COVID-19 and their connection with the development of biofilms were explored. The issues of treatment and prevention of com- plications in patients with COVID-19 associated with the development of biofilms are considered. e FEATURES OF THE MICROBIAL COMPOSITION OF BIOFILMS ISOLATED FROM PATIENTS WITH COVID-19 The composition of the lung microbiome can vary signifi- cantly depending on the influence of many factors. Among the representatives of normal biocinosis are microorgan- isms of the genus Prevotella, Streptococcus, and Veillonella. In addition, pathogenic representatives, such as Haemophi- lus spp., Neisseria spp. and Pseudomonas spp. can be isolat- ed from the respiratory tract, but they account for a smaller proportion of the microbiome [14, 15]. S.  Alhumaid et al.  [16] found that against the back- ground of COVID-19, the lung microbiome is usually dis- turbed and is characterised by an increase in commensals such as Prevotella spp. Thus, when examining samples from endotracheal tubes, representatives of the lung mi- crobiome, Prevotella spp. and some species of Streptococ- cus, Veillonella were identified. However, in the examina- tion of the microbial composition of biofilms isolated from endotracheal tubes, pathogenic representatives, such as Pseudomonas spp., Staphylococcus spp., Streptococcus spp., Stenotrophomonas spp., Enterobacterales, Haemophilus spp. and Actinomyces spp. dominated [17, 18]. Notably, out-of-hospital bacterial infections associat- ed with COVID-19 are quite rare, while hospital-acquired infections are more common and account for about 47% of cases [19]. Research conducted by G. Giacomo et al. [20] demonstrated that the percentage of clinically significant bacterial infections in hospitalised patients ranged from 4 to 14%, with these diseases often being recorded in pa- tients in intensive care units. In COVID-19 infection, hos- pital-acquired pathogens such as Mycoplasma pneumoniae, Pseudomonas aeruginosa and Haemophilus influenzae are spreading. In addition, other pathogens have been identi- fied, including Enterobacter cloacae, Acinetobacter bauman- nii and Klebsiella pneumoniae [21]. The literature review identified that isolated microor- ganisms from biofilms established on endotracheal tubes included both commensal and pathogenic agents. Staph- ylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans accounted for the majority of biofilms. Pathogens such as Paracoccus yeei were unusu- al, but they were detected in several patients. In addition, the isolated strains were tested for antibiotic susceptibility using the disc diffusion method. Thus, the level of antimi- crobial resistance among the isolated strains was almost 70%. Among the tested strains were isolates with resist- ance to meropenem and gentamicin. In addition, differ- ences in antibiotic susceptibility between various isolates of the same species isolated from the same endotracheal biofilm have been reported [22]. Studies have demonstrated a significant role of Acine- tobacter baumannii in the development of ventilator-asso- ciated pneumonia in patients with COVID-19 undergoing mortality rate of patients with coronavirus infection re- mains unexplored. Lung damage in COVID-19 and impaired immune re- sponse can promote the growth and persistence of micro- organisms in hospitalised patients and increase the risk of biofilm development. Studies by F.M. Carvalho et al [2] demonstrate that secondary bacterial pneumonia is a po- tential risk factor for severity and complications in patients with COVID-19. L. Meng et al. [3] and F. Zhou et al. [4] be- lieve that mechanical ventilation is necessary to treat pa- tients with acute respiratory symptoms and hypoxia, can increase the risk of pneumonia and promote the establish- ment of biofilms. Changes in oxygen levels, alveolar ven- tilation, and the density of affected cells affect microbial growth conditions in the lungs. According to a study by T.M. Rawson et al. [5], the over- use of broad-spectrum antibiotics creates an ideal envi- ronment for opportunistic bacterial colonisation, second- ary bacterial infections and increased levels of multidrug resistance, which leads to microflora disruption, the spread of resistant strains among COVID-19 patients and contrib- utes to the ability of pathogens to form biofilms. Studies demonstrate that bacteria spend most of their life cycle in the biofilm matrix. J. Yan & B.L. Bassler [6] found that the planktonic stage can only be considered as a way of moving a microbial cell from one surface to another, a short-term state in the life of bacteria that are free in the environment. Microorganisms in biofilms increase their resistance to dis- infectants, antibacterial drugs, bacteriophages, antibodies and phagocytes by 50-500 times [7, 8]. The extracellular matrix accounts for 85% of the biofilm mass, consisting of exopolysaccharides, proteins and nucle- ic acids. It is synthesised by the extracellular components of attached microorganisms and has important functions in the biofilm’s life. The extracellular matrix is a powerful bio- logical glue that allows the biofilm to be firmly fixed to any surface [9, 10]. The synthesis of virulence factors and the development of biofilms occurs only when there is a suffi- cient population density (Quorum sensing (QS)) [11]. QS is implemented by several means of perception and transmis- sion of information: physical contact between cells; gener- ation of physical fields; and synthesis of chemicals diffus- ing into the environment, which are called autoinducers. The concentration of extracellular autoinducers correlates with the density of cells in the population, and when cer- tain thresholds are reached, autoinducers enter the cell in- terior or activate receptors on their surface, which leads to changes in the expression of various genes [12, 13]. Thus, bacteria can “sense” the density of the cell population, and this mechanism allows bacteria to function as a mul- ticellular organism. Studies have demonstrated that the establishment of biofilms in coronavirus infection can af- fect the development of respiratory system complications and determine the severity and outcome of the disease. The purpose of the research was to explore the micro- bial composition of biofilms and their role in the develop- ment of respiratory system complications in patients with COVID-19. The research reviewed modern works of scien- tists from different countries, including scientific research- es, clinical data, using Internet resources, publications of professional journals, and the Medscape/PubMed medical database. A comparative analysis was conducted between The role of microbial biofilms... 4242 Bulletin of Medical and Biological Research. 2023. Vol.17, No. 3 mechanical ventilation. The pathogen is characterised by a significant level of resistance to many clinically relevant antibiotics, including meropenem, imipenem, gentamicin, tobramycin and levofloxacin. Antibiotic resistance has in- creased through using empirical broad-spectrum antibiot- ic therapy to treat COVID-19 bacterial superinfections. In addition, these pathogens have been identified as having a high ability to form biofilms [23]. The development of tracheobronchitis in patients with COVID-19 on mechanical ventilation is not uncommon, with an incidence of almost 15%. Microbiological studies have demonstrated that potentially resistant gram-nega- tive bacteria such as P. aeruginosa and carbapenem-resist- ant strains of Klebsiella pneumoniae are isolated from the pathological material of such patients [24]. Other entero- bacteria are isolated: Alcaligenes xylosoxidans, Acinetobac- ter spp. and Stenotrophomonas. Depending on the type and virulence of the bacteria and their interaction with the im- mune system, colonisation and biofilm development sub- sequently occur. Thus, normal biocinosis of the respiratory system plays an important role in maintaining homeostasis. Changes in the microbiome and the development of biofilms during using endotracheal tubes during coronavirus infection can affect the course of the disease and lead to the develop- ment of severe complications. e MAIN COMPLICATIONS OF THE RESPIRATORY SYSTEM IN PATIENTS WITH COVID-19 Both innate and acquired immunity are involved in the re- sponse to the infectious process. The development of com- plications in coronavirus infection is associated with sig- nificant dysfunction of the immune system. I.  Sulaiman et al. [25] established that patients with COVID-19 had a de- crease in the number of CD4+ and CD8+ T lymphocytes, an increase in neutrophils, and a decrease in the concen- tration of gamma interferon in the serum. Further studies confirmed these findings and identified the presence of such processes as a cytokine storm, characterised by an excess of proinflammatory molecules, inhibition of natural killer cells and cytotoxic lymphocytes, and morphological and phenotypic changes in monocytes [26]. Such immune response disorders can contribute to increased adhesion, growth, and spread of bacteria that can form biofilms. In addition, bacterial infection leads to an increased proba- bility of virus survival and replication, and tissue damage promotes the further spread of pathogens, which increases the risk of bloodstream infections. Thus, the presence of secondary infection in COVID-19 leads to further compli- cations, including the development of septic shock. Acute respiratory distress syndrome (ARDS), which often develops in patients with COVID-19, is a life-threat- ening form of respiratory failure. According to statistics, ARDS develops in about 1/3 (33%) of hospitalised pa- tients and almost 3/4 (75%) of patients in intensive care units  [27]. The known mechanisms of ARDS are associat- ed with the development of severe pulmonary infiltration, oedema and inflammation, which leads to a violation of alveolar homeostasis, changes in lung physiology, pulmo- nary fibrosis, endothelial inflammation and thrombosis. ARDS can occur both as a result of direct exposure to the virus and due to the action of substances synthesised by host cells. Activated cells of the immune system secrete specific enzymes and pro-inflammatory cytokines, in- cluding interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), which leads to the induction of a cytokine storm. Patients with ARDS require ALV and have a high mortality rate due to shock, septicaemia and multiple organ dysfunc- tion syndrome. Invasive ventilation in patients with ARDS can directly lead to lung damage, and prolonged use of me- chanical ventilation causes the development of biofilms by microorganisms, which significantly worsens the prognosis for recovery [27]. The most common bacterial complication of COV- ID-19 is ventilator-associated lower respiratory tract infec- tion, which includes ventilator-associated pneumonia and ventilator-associated tracheobronchitis. The mechanism underlying bacterial secondary infection in viral pneumo- nia is damage to ciliated cells, which leads to impaired mu- cociliary clearance and increased bacterial adhesion and colonisation of the airways [28]. During complications of coronavirus infection, me- chanical ventilation using an endotracheal tube can support pulmonary gas exchange disorders in critically ill patients. The development of biofilms inside the endotracheal tube and their subsequent movement to the distal airways dur- ing mechanical ventilation cycles is considered a possible pathogenic pathway for the development of ventilator-as- sociated pneumonia. Previous studies have demonstrated that biofilm formation on endotracheal tubes affects the in- cidence of bacterial infections in intubated patients and is a factor in the development of ventilator-associated pneu- monia, which occurs in 20-40% of cases [29]. T. Sakano et al. [30] established that a biofilm can be established on the surface of the tube within 24 hours after intubation and can be a reservoir for microorganisms that subsequently cause infection in the lungs. In addition, biofilm cells are inherently more resistant to antibiotics for a variety of rea- sons, including the lower metabolic rate of bacteria in the biofilm and poor penetration of antimicrobial drugs. The hypothesis that biofilms on endotracheal tubes play a role in the development of ventilator-associated pneumonia is supported by the fact that in many cases the same bacteria are identified in tube biofilms and other airway specimens [31]. Such pathogenetic features can complicate the treat- ment of biofilm-related infections. Ventilator-associated tracheobronchitis is a frequent and clinically significant infectious complication in pa- tients on mechanical ventilation for more than 48 hours, with a frequency similar to ventilator-associated pneumo- nia. Studies conducted by D. Koulenti et al. [32] demonstrat- ed that tracheobronchitis can be considered as an interme- diate process leading to ventilator-associated pneumonia. In addition, ventilator-associated tracheobronchitis has a limited impact on overall mortality but demonstrates a significant association with increased patient costs, length of hospital stay, antibiotic use, and duration of mechanical ventilation. Thus, patients affected by the coronavirus can devel- op various complications, the most common of which are pneumonia and ARDS. One of the important factors lead- ing to such complications is using endotracheal tubes and the development of biofilms, which worsen the patient’s O. Kochnieva and O. Kotsar 4343 Bulletin of Medical and Biological Research. 2023. Vol.17, No. 3 condition and increase mortality. The impact on microbi- al biofilms and the treatment of associated infections is a complex and unresolved problem. e STRATEGIES FOR THE TREATMENT AND PREVENTION OF MICROBIAL BIOFILM FORMATION IN PATIENTS WITH COVID-19 Since antibiotic therapy is ineffective in the treatment of biofilm infections, maximum efforts should be devoted to preventing the formation of biofilms. The main measures are designed to prevent the adhesion of microorganisms when using endotracheal tubes in patients with severe coronavirus infection. For this purpose, modified endotra- cheal tubes coated with antimicrobial compounds can be used, which has a high clinical effect. Using antimicrobi- al-coated endotracheal intubation tubes for prolonged mechanical ventilation allows delaying contamination of the respiratory tract tissues with microflora and reduces the microbial load on the lung parenchyma. Animal stud- ies have demonstrated that endotracheal tubes coated with silver ions lead to reduced adhesion of P. aeruginosa and a lower prevalence of ventilator-associated pneumonia com- pared to uncoated tubes [33]. Other modifications are used, including silicone or noble metal coating. Such modified endotracheal tubes can be used in combination with devic- es for drainage of bronchial secretions, which prevents the development of respiratory system complications. In addition, it is necessary to constantly monitor en- dotracheal aspirate in patients with COVID-19 on me- chanical ventilation. Such monitoring allows identifying pathogens that colonise the lower respiratory tract and de- termining their quantitative content. M.L. Blasco et al. [34] note that timely detection of pathogens will allow for early targeted antibiotic therapy and prevent the development of ventilator-associated pneumonia. Prevention of biofilm development in patients with COVID-19 on mechanical ventilation consists of meas- ures designed to reduce mucus viscosity and activate its evacuation. Mucus viscosity can be reduced with mucol- ytic agents. Special attention should be devoted to using N-acetylcysteine, which can prevent the establishment and destruction of bacterial biofilms, which is becoming espe- cially important in the era of antibiotic resistance. There is a growing body of evidence confirming the antimicrobial and antibiofilm activity of N-acetylcysteine against many respiratory pathogens, including pathogens of the follow- ing genera and species: Escherichia, Pseudomonas, Staph- ylococcus, Acinetobacter, Haemophilus influenze, Strepto- coccus pneumoniae, Moraxella catarrhalis and Klebsiella. F.L. Poe & J. Corn [35] proved that this mucolytic inhibits the establishment of biofilms by bacteria and fungi, and destroys mature biofilms. The destruction of the biofilm matrix facilitates the penetration of antibacterial drugs into the deeper layers of biofilms and significantly increas- es the effectiveness of treatment of bacterial infections. Clear criteria for prescribing antimicrobial therapy should be followed to prevent the development of antibi- otic resistance. Antibiotic therapy in patients with a diag- nosed coronavirus infection is justified if there are con- vincing signs of bacterial infection. These signs include: a change from a dry cough to a productive cough (especially with purulent sputum) in a patient with confirmed SARS- CoV-2 infection, a significant increase in blood procal- citonin levels, an increase in white blood cell count > 10- 12-109/L and/or a stain shift > 10%, signs of consolidation (alveolar infiltration) of the lung parenchyma according to computed tomography [36]. In addition, inappropriate treatment with broad-spec- trum antibiotics may increase the level of mycobacteri- al resistance and mortality of patients with COVID-19. C.  Rhee  et al.  [37] believe that early antibiotic treatment should be avoided in more than 75% of cases if the aetiolo- gy of superinfection is not proven using standard microbi- ological diagnostic methods. Recently, using monoclonal antibodies that can affect the proteins of the SARS-CoV-2 spike-like envelope pro- teins has become widely used to prevent and treat com- plications in patients with COVID-19. Their mechanism of action is to block the attachment of the virus to the cell membrane, which prevents SARS-CoV-2 from entering human cells, neutralises the virus’s effect and helps pre- vent the development of the disease, reducing the nature and duration of its clinical manifestations. M.P. O’Brien et al. [38] found that using a combination of drugs containing monoclonal antibodies in outpatients with coronavirus re- duces the incidence of hospitalisation or death by 70% due to a rapid reduction in viral load. Such measures to prevent complications can help reduce the frequency of ventilator use and reduce the risk of biofilm development. An important task of modern medicine is to develop new approaches to the identification and research of bio- films, including the immune response to these infections, changing the tactics of antibiotics, and searching for and introducing new antimicrobial agents. Scientists from different countries are researching the design of preven- tive measures and treatment of infections associated with the development of biofilms, but no general recommen- dations have been established, which requires further re- search on this issue. e CONCLUSIONS The literature review demonstrated that patients with COVID-19 may develop severe respiratory complications associated with the development of biofilms. The composi- tion of biofilms is diverse and contains many microorgan- isms that are clinically important and highly resistant to antibiotics. Among the microorganisms that are part of bi- ofilms, the most common are representatives of the genera Pseudomonas spp., Staphylococcus spp., Streptococcus spp., Stenotrophomonas spp., Enterobacterales, Haemophilus spp. and Actinomyces spp. These pathogens can cause severe complications associated with the development of venti- lator-associated pneumonia, ventilator-associated trache- obronchitis, ARDS and septic shock. The main measures for the treatment and prevention of complications associated with biofilm formation in patients with COVID-19 should include the prevention of microbial adhesion and the prin- ciples of rational antibiotic therapy. The correlation between the microbial composition of biofilms isolated from patients with respiratory system complications and clinical outcomes remains unexplored. However, microorganisms in biofilms can probably be a reservoir for secondary pulmonary infections. These pro- cesses can affect the duration of mechanical ventilation The role of microbial biofilms... 4444 Bulletin of Medical and Biological Research. 2023. Vol.17, No. 3 and the admission of patients with COVID-19 to intensive care units. The prospect of this research is to establish the impact of the microbial composition of biofilms on the de- velopment of complications, which will reduce the number of bed days spent in hospital and the cost of treatment. e ACKNOWLEDGEMENTS None. e CONFLICT OF INTEREST The authors declare no conflict of interest. e REFERENCES [1] Arciola CR, Campoccia D, Montanaro L. Implant infections: Adhesion, biofilm formation and immune evasion. Nat Rev Microbiol. 2018;16:397–9. DOI: 10.1038/s41579-018-0019-y [2] Carvalho FM, Lemos LN, Ciapina LP, Moreira RG, Gerber A, Guimarães APC, et al. Prevalence of bacterial pathogens and potential role in COVID-19 severity in patients admitted to intensive care units in Brazil. medRxiv. 2020. DOI: 10.1101/2020.12.22.20248501 [3] Meng L, Qiu H, Wan L, Ai Y, Xue Z, Guo Q, et al. Intubation and ventilation amid the COVID-19 outbreak: Wuhan’s experience. Anesthesiology. 2020;132(6):1317–32. DOI: 10.1097/ALN.0000000000003296 [4] Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020;395(10229):1054–62. DOI: 10.1016/S0140- 6736(20)30566-3 [5] Rawson TM, Moore LS, Zhu N, Ranganathan N, Skolimowska K, Gilchrist M, et al. Bacterial and fungal coinfection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing. Clin Infect Dis. 2020;71(9):2459–68. DOI: 10.1093/cid/ciaa530 [6] Yan J, Bassler BL. Surviving as a community: Antibiotic tolerance and persistence in bacterial biofilms. Cell Host Microbe. 2019;26(1):15–21. DOI: 10.1016/j.chom.2019.06.002 [7] Ciofu O, Moser C, Jensen PØ, Høiby N. Tolerance and resistance of microbial biofilms. Nat Rev Microbiol. 2022;20(10):621–35. DOI: 10.1038/s41579-022-00682-4 [8] Moser C, Jensen PØ, Thomsen K, Kolpen M, Rybtke M, Lauland AS, et al. Immune Responses to Pseudomonas aeruginosa Biofilm Infections. Front Immunol. 2021;12:625597. DOI: 10.3389/fimmu.2021.625597 [9] Rybtke M, Jensen PØ, Nielsen CH, Tolker-Nielsen T. The extracellular polysaccharide matrix of Pseudomonas aeruginosa biofilms is a determinant of polymorphonuclear leukocyte responses. Infect Immun. 2021;89(1). DOI:  10.1128/ iai.00631-20 [10] Palmer AG, Senechal AC, Haire TC, Mehta NP, Valiquette SD, Blackwell HE. Selection of appropriate autoinducer analogues for the modulation of quorum sensing at the host-bacterium interface. ACS Chem Biol. 2018;13(11):3115– 22. DOI: 10.1021/acschembio.8b00676 [11] Kranjec C, Morales Angeles D, Torrissen Mårli M, Fernández L, García P, Kjos M, Diep DB. Staphylococcal biofilms: Challenges and novel therapeutic perspectives. Antibiotics. 2021;10(2):131. DOI: 10.3390/antibiotics10020131 [12] Crabbé A, Jensen PO, Bjarnsholt T, Coenye T. Antimicrobial tolerance and metabolic adaptations in microbial biofilms. Trends Microbiol. 2019;27(10):850–63. DOI: 10.1016/j.tim.2019.05.003 [13] Dhesi Z, Enne VI, Brealey D, Livermore DM, High J, Russell C, et al. Organisms causing secondary pneumonias in COVID-19 patients at 5 UK ICUs as detected with the FilmArray test. medRxiv. 2020. DOI: 10.1101/2020.06.22.20131573 [14] Mirzaei R, Goodarzi P, Asadi M, Soltani A, Aljanabi HAA, Salimi Jeda A, et al. Bacterial co-infections with SARS-CoV-2. IUBMB Life. 2020;72(10):2097–11. DOI: 10.1002/iub.2356 [15] Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: A systematic review and meta- analysis. J Infect. 2020;81(2):266–75. DOI: 10.1016/j.jinf.2020.05.046 [16] Alhumaid S, Al Mutair A, Al Alawi Z, Alshawi AM, Alomran SA, Almuhanna MS, et al. Coinfections with bacteria, fungi, and respiratory viruses in patients with SARS-CoV-2: A systematic review and meta-analysis. Pathogens. 2021;10(7):809. DOI: 10.3390/pathogens10070809 [17] Cifuentes EA, Sierra MA, Yepes AF, Baldión AM, Rojas JA, Álvarez-Moreno CA, et al. Endotracheal tube microbiome in hospitalized patients defined largely by hospital environment. Respir Res. 2022;23:168. DOI: 10.1186/s12931-022- 02086-7 [18] He S, Liu W, Jiang M, Huang P, Xiang Z, Deng D, Chen P, Xie L. Clinical characteristics of COVID-19 patients with clinically diagnosed bacterial co-infection: A multi-center study. PloS One. 2021;16:e0249668. DOI: 10.1371/journal. pone.0249668 [19] Russell CD, Fairfield CJ, Drake TM, Turtle L, Seaton RA, Wootton DG, et al. Co-infections, secondary infections, and antimicrobial use in patients hospitalized with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: A multicentre, prospective cohort study. Lancet Microbe. 2021;2(8):e354–e365. DOI: 10.1016/S2666- 5247(21)00090-2 [20] Giacomo G, Scaravilli V, Mangioni D, Scudeller L, Alagna L, Bartoletti M, et al. Hospital-acquired infections in critically Ill patients with COVID-19. Chest. 2021;160(2):454–65. DOI: 10.1016/j.chest.2021.04.002 [21] Moreno-García E, Puerta-Alcalde P, Letona L, Meira F, Dueñas G, Chumbita M, et al. Bacterial co-infection at hospital admission in patients with COVID-19. Int J Infect Dis. 2022;118:197–2. DOI: 10.1016/j.ijid.2022.03.00 [22] Maldiney T, Pineau V, Neuwirth C, Ouzen L, Eberl I, Jeudy G, et al. Endotracheal tube biofilm in critically ill patients during the COVID-19 pandemic: Description of an underestimated microbiological compartment. Scientific Reports. 2022;12:22389. DOI: 10.1038/s41598-022-26560-w https://www.nature.com/articles/s41579-018-0019-y https://www.medrxiv.org/content/10.1101/2020.12.22.20248501v2 https://pubmed.ncbi.nlm.nih.gov/32195705/ https://pubmed.ncbi.nlm.nih.gov/32171076/ https://pubmed.ncbi.nlm.nih.gov/32171076/ https://pubmed.ncbi.nlm.nih.gov/32358954/ https://pubmed.ncbi.nlm.nih.gov/31295420/ https://pubmed.ncbi.nlm.nih.gov/35115704/ https://www.frontiersin.org/articles/10.3389/fimmu.2021.625597/full https://journals.asm.org/doi/10.1128/iai.00631-20 https://journals.asm.org/doi/10.1128/iai.00631-20 https://pubs.acs.org/doi/10.1021/acschembio.8b00676 https://www.mdpi.com/2079-6382/10/2/131 https://pubmed.ncbi.nlm.nih.gov/31178124/ https://www.medrxiv.org/content/10.1101/2020.06.22.20131573v1 https://pubmed.ncbi.nlm.nih.gov/32770825/ https://pubmed.ncbi.nlm.nih.gov/32473235/ https://www.mdpi.com/2076-0817/10/7/809 https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02086-7 https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-022-02086-7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249668 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249668 https://pubmed.ncbi.nlm.nih.gov/34100002/ https://pubmed.ncbi.nlm.nih.gov/34100002/ https://pubmed.ncbi.nlm.nih.gov/33857475/ https://pubmed.ncbi.nlm.nih.gov/35257905/ https://www.nature.com/articles/s41598-022-26560-w O. Kochnieva and O. Kotsar 4545 Bulletin of Medical and Biological Research. 2023. Vol.17, No. 3 [23] Novović K, Kuzmanović Nedeljković S, Poledica M, Nikolić G, Grujić B, Jovčić B, et al. Virulence potential of multidrug- resistant Acinetobacter baumannii isolates from COVID-19 patients on mechanical ventilation: The first report from Serbia. Front. Microbiol. 2023;14:1094184. DOI: 10.3389/fmicb.2023.1094184 [24] Salluh JIF, Souza-Dantas VC, Martin-Loeches I, Lisboa TC, Rabello LSCF, Nseir S, Póvoa P. Ventilator-associated tracheobronchitis: An update. Rev Bras Ter Intensiva. 2019;31(4):541–47. DOI: 10.5935/0103-507X.20190079 [25] Sulaiman I, Chung M, Angel L, Tsay JCJ, Wu BG, Yeung ST, et al. Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome. Nat Microbiol. 2021;6:1245–58. DOI: 10.1038/s41564-021-00961-5 [26] Søgaard KK, Baettig V, Osthoff M, Marsch S, Leuzinger K, Schweitzer M, et al. Community-acquired and hospital- acquired respiratory tract infection and bloodstream infection in patients hospitalized with COVID-19 pneumonia. J Intensive Care. 2021;9:10. DOI: 10.1186/s40560-021-00526-y [27] Aslan A, Aslan C, Zolbanin NM, Jafari R. Acute respiratory distress syndrome in COVID-19: Possible mechanisms and therapeutic management. Pneumonia (Nathan). 2021;13(1):14. DOI: 10.1186/s41479-021-00092-9 [28] Martin-Loeches I, Povoa P, Nseir S. Ventilator associated tracheobronchitis and pneumonia: One infection with two faces. Intensive Care Med. 2023. DOI: 10.1007/s00134-023-07086-9 [29] Vandecandelaere I, Matthijs N, Nelis HJ, Depuydt P, Coenye T. The presence of antibiotic-resistant nosocomial pathogens in endotracheal tube biofilms and corresponding surveillance cultures. Pathog Dis. 2013;69(2):142–48. DOI: 10.1111/2049-632X.12100 [30] Sakano T, Bittner EA, Chang MG, Berra L. Above and beyond: Biofilm and the ongoing search for strategies to reduce ventilator-associated pneumonia (VAP). Crit Care. 2020;24:510. DOI: 10.1186/s13054-020-03234-5 [31] Rouzé A, Martin-Loeches I, Povoa P, Makris D, Artigas A, Bouchereau M, et al. Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: A European multicenter cohort study. Intensive Care Med. 2021;47(2):188–98. DOI: 10.1007/s00134-020-06323-9 [32] Koulenti D, Arvaniti K, Judd M, Lalos N, Tjoeng I, Xu E, et al. Ventilator-associated tracheobronchitis: To treat or not to treat? Antibiotics (Basel). 2020;9(2):51. DOI: 10.3390/antibiotics9020051 [33] Lethongkam S, Sunghan J, Wangdee C, Durongphongtorn S, Siri R, Wunnoo S, et al. Biogenic nanosilver-fabricated endotracheal tube to prevent microbial colonization in a veterinary hospital. Appl Microbiol Biotechnol. 2023;107(2- 3):623–38. DOI: 10.1007/s00253-022-12327-w [34] Blasco ML, Buesa J, Colomina J, Forner MJ, Galindo MJ, Navarro J, et al. Co-detection of respiratory pathogens in patients hospitalized with Coronavirus viral disease-2019 pneumonia. Med Virol. 2020;92(10):1799–1. DOI: 10.1002/ jmv.25922 [35] Poe FL, Corn J. N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Med Hypotheses. 2020;143:e109862. DOI: 10.1016/j.mehy.2020.109862 [36] van Berkel M, Kox M, Frenzel T, Pickkers P, Schouten J; RCI-COVID-19 study group. Biomarkers for antimicrobial stewardship: A reappraisal in COVID-19 times? Crit Care. 2020;24(1):600. DOI: 10.1186/s13054-020-03291-w [37] Rhee C, Kadri SS, Dekker JP, Danner RL, Chen HC, Fram D, et al. Prevalence of antibiotic-resistant pathogens in culture-proven sepsis and outcomes associated with inadequate and broad-spectrum empiric antibiotic use. JAMA Netw Open. 2020;3(4):e202899. DOI: 10.1001/jamanetworkopen.2020.2899 [38] O’Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, et al. Subcutaneous REGEN-COV antibody combination to prevent COVID-19. N Engl J Med. 2021;385(13):1184–95. DOI: 10.1056/NEJMoa2109682 https://www.frontiersin.org/articles/10.3389/fmicb.2023.1094184/full https://pubmed.ncbi.nlm.nih.gov/31967230/ https://www.nature.com/articles/s41564-021-00961-5 https://jintensivecare.biomedcentral.com/articles/10.1186/s40560-021-00526-y https://pubmed.ncbi.nlm.nih.gov/34872623/ https://pubmed.ncbi.nlm.nih.gov/37160828/ https://pubmed.ncbi.nlm.nih.gov/24115610/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432533/ https://pubmed.ncbi.nlm.nih.gov/33388794/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168312/ https://pubmed.ncbi.nlm.nih.gov/36562803/ https://pubmed.ncbi.nlm.nih.gov/32320082/ https://pubmed.ncbi.nlm.nih.gov/32320082/ https://pubmed.ncbi.nlm.nih.gov/32504923/ https://pubmed.ncbi.nlm.nih.gov/33023606/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163409/ https://pubmed.ncbi.nlm.nih.gov/34347950/ The role of microbial biofilms... 4646 Bulletin of Medical and Biological Research. 2023. Vol.17, No. 3 Роль мікробних біоплівок при розвитоку ускладнень дихальної системи у пацієнтів З СOVID-19: огляд літератури Олена Володимирівна Кочнєва Кандидат медичних наук, старший викладач Харківський національний медичний університет 61022, просп. Науки, 4, м. Харків, Україна https://orcid.org/0000-0002-1039-9313 Олена Василівна Коцар Кандидат медичних наук, доцент Харківський національний медичний університет 61022, просп. Науки, 4, м. Харків, Україна https://orcid.org/0000-0002-3797-1068 Анотація. Одним із ускладнень СOVID-19 є розвиток гострої дихальної недостатності, що може потребувати штучної вентиляції легень із використанням ендотрахіальної трубки для корекції стану гіпоксемії. Однак утворення біоплівок в процесі інтубації хворих може стати ризиком розмноження мікроорганізмів, здатних викликати важкі ускладнення. Тому, актуальним питанням стає дослідження мікробного складу біоплівок, який викликає такі захворювання. Мета дослідження полягала в аналізі та узагальненні даних сучасних досліджень, які стосуються вивчення ролі мікробних біоплівок та їх впливу на розвиток ускладнень дихальної системи у пацієнтів з СOVID-19. Після проведеного аналізу літератури встановлено, що в структурі біоплівок, виділених з ендотрахеальних трубок у пацієнтів із COVID-19 більшу частку складали Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa і Candida albicans. При цьому рівень резистентності до антимікробних препаратів серед виділених штамів складав майже 70 %. При дослідженні зразків з ендотрахеальних трубок були виявлені представники мікробіому легень, Prevotella spp., деякі види Streptococcus, Veillonella. Однак при дослідженні мікробного складу біоплівок, виділених з ендотрахеальних трубок, домінували саме патогенні представники, такі як, Pseudomonas spp., Staphylococcus spp., Streptococcus spp., Stenotrophomonas spp., Enterobacterales, Haemophilus spp. та Actinomyces spp. Зміни складу мікробіому легень у хворих з СOVID-19 можуть призводити до розвитку важких ускладнень, які супроводжуються утворенням біоплівок. Мікроорганізми у біоплівках можуть бути резервуаром для вторинних легеневих інфекцій, що впливає на тривалість використання штучної вентиляції легень та прибування пацієнтів з COVID-19 у відділеннях інтенсивної терапії. Розробка та впровадження ефективних заходів для профілактики та лікування інфекцій, пов’язаних з утворенням біоплівок є важливим завданням для сучасної медичної практики Ключові слова: мікробні біоплівки; дихальна недостатність; пневмонія; вторинна інфекція https://orcid.org/0000-0002-1039-9313 https://orcid.org/0000-0002-3797-1068