Analysis of the clinical pipeline of treatments for drug resistant bacterial infections: despite progress, more action is needed

There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

Comparative analysis of resistance of main etiological agents of chronic osteomyelitis isolated from association and in monoculture

Introduction. To date, a significant number of works have been published devoted to the analysis of the sensitivity of the leading causative agents of osteomyelitis to modern drugs, however, in the available literature there are no data on a comparative analysis of the antibiotic resistance of bacteria isolated from the osteomyelitis focus from the association and in monoculture. Purpose of the work: to compare the resistance profiles of the leading causative agents of osteomyelitis, depending on the bacterial composition of the focus of infection.Materials and methods. The study included 216 clinical isolates, of which 114 were isolated as part of two-component associations, 102 – in a monoculture from pathological material in patients with chronic osteomyelitis who were treated in the purulent department of National Medical Scientific Centre of Traumatology and Orthopedics n.a. academician G.E. Ilizarov (Kurgan, Russia) from 2018 to 2020. To analyze the resistance profiles, depending on the type of microorganism, modern drugs used in the clinic for the treatment of osteomyelitis were taken into account.Results and its discussion. Effective drugs against P. aeruginosa strains isolated from the association were polymyxin and meropenem, and in monoculture–polymyxin, piperacillin/tazobactam, tobramycin; in relation to strains of K. pneumoniae isolated from the association, it was imipenem, in monoculture – amikacin. S. aureus strains isolated both from the association and in monoculture were highly susceptible to antibacterial drugs.Conclusion. The analysis of the sensitivity of the leading causative agents of osteomyelitis, isolated in monoculture and from the association, to the antibacterial drugs used in the clinic, showed significant differences in the resistance profiles between the groups: for S. aureus strains, 4 antibiotics tested out of 13, for P. aeruginosa strains – 7 out of 13, for K. pneumoniae strains – 12 out of 16. The tested antibacterial drugs were less active against P. aeruginosa and S. aureus strains isolated from associations. In contrast, the percentage of resistant strains of K. pneumoniae was higher among monocultures.

Bacterial corneal ulcers in pediatric patients. Algorithms of pharmacotherapy. Part II

Part I of the article presents a review of publications highlighting current exogenous and endogenous risk factors contributing to the occurrence of bacterial corneal ulcers, laboratory diagnostic methods, clinical differential diagnostic features of bacterial corneal ulcers. A wide variety of objective symptoms characterizes the clinical picture of bacterial corneal ulcers. Still, objective differential diagnostic signs make it possible with a high degree of probability to assume the etiology of the disease during the first biomicroscopy and immediately begin etiotropic therapy, on the timing of which the outcome of the disease depends. Standard laboratory examination of patients with bacterial corneal ulcers includes the bacterioscopic and cultural examination of the contents of the conjunctival sac. However, the absence of etiotropic therapy while waiting for the results of microbiological research methods, which takes from 3 to 7 days, contributes to the rapid progression of the disease, the development of endophthalmitis, and corneal perforation, up to the loss of an eye in children. In this regard, treatment must be started immediately. Therefore, the choice of a drug is determined not only by the causative agent, proven laboratory but, first of all, based on clinical differential diagnostic signs of the disease. The traditional, undeniable approach to the conservative treatment of bacterial corneal ulcers is conventional etiotropic therapy using local and systemic antibacterial drugs. In addition, timely intensive specific drug therapy prevents the destruction of all layers of the cornea, and the use of metabolic drugs that improve regeneration and trophism promotes epithelialization of corneal ulcers. Attention should be given to the necessity and validity of the choice of antibacterial drugs for various etiological forms of bacterial corneal ulcers in children. An individual approach is a basis for effective antibiotic therapy in pediatric ophthalmology. The article presents an up-to-date review of publications and modern algorithms for treating bacterial corneal ulcers in children, the main causative agents of which are: Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Neisseria gonorrhoeae.

CONVALESCENT PLASMA TRANSFUSION FOR THE TREATMENT CRIMEAN-CONGO HEMORRHAGIC FEVER (REVIEW)

Проведен анализ литературных данных о применении плазменной терапии при лечении Конго-Крымской геморрагической лихорадки в мире. Данный обзор проведен для оценки эффективности плазменной терапии у пациентов с Конго-Крымской геморрагической лихорадкой на основе научных данных, опубликованных до настоящего времени. В последние годы отмечается определенный интерес к изучению плазменной терапии при лечении пациентов с Конго-Крымской геморрагической лихорадкой, хотя в литературе имеются лишь ограниченные данные по эффективности иммунотерапии и применения рибавирина при Конго-Крымской геморрагической лихорадке, при этом действенность рибавирина остается еще не доказанной. Однако можно предположить, что помимо противовирусных препаратов, применение плазменной терапии у больных с Конго-Крымской геморрагической лихорадкой может быть эффективным способом лечения, улучшающим клинические симптомы у пациентов, прогноз и снижающим смертность. The analysis of the literature data on the using of plasma therapy in the treatment of Congo-Crimean hemorrhagic fever was carried out. This review was conducted to evaluate the effectiveness of plasma therapy in patients with Congo-Crimean hemorrhagic fever on the basis of publications published so far. In recent years, there has been some interest in studying plasma therapy in the treatment of patients with Congo-Crimean hemorrhagic fever, although there are only limited data in the literature on the effectiveness of immunotherapy and the use of ribavirin in therapy, while the effectiveness of ribavirin remains not yet proven. However, it can be assumed that in addition to antiviral and antibacterial drugs, the use of plasma therapy in patients with Congo-Crimean hemorrhagic fever can be an effective treatment method that improves clinical symptoms in patients and reduces mortality.

Stimulation of Sulfonamides Antibacterial Drugs Activity as a Result of Complexation with Ru(III): Physicochemical and Biological Study

Antibiotic resistance is a global problem, and one promising solution to overcome this issue is using metallodrugs, which are drugs containing metal ions and ligands. These complexes are superior to free ligands in various characteristics including anticancer properties and mechanism of action. The pharmacological potential of metallodrugs can be modulated by the appropriate selection of ligands and metal ions. A good example of proper coordination is the combination of sulfonamides (sulfamerazine, sulfathiazole) with a ruthenium(III) ion. This work aimed to confirm that the activity of sulfonamides antibacterial drugs is initiated and/or stimulated by their coordination to an Ru(III) ion. The study determined the structure, electrochemical profile, CT-DNA affinity, and antimicrobial as well as anticancer properties of the synthesized complexes. The results proved that Ru(III) complexes exhibited better biological properties than the free ligands.

Suppressing Alpha-Hemolysin as Potential Target to Screen of Flavonoids to Combat Bacterial Coinfection

The rapid emergence of bacterial coinfection caused by cytosolic bacteria has become a huge threat to public health worldwide. Past efforts have been devoted to discover the broad-spectrum antibiotics, while the emergence of antibiotic resistance encourages the development of antibacterial agents. In essence, bacterial virulence is a factor in antibiotic tolerance. However, the discovery and development of new antibacterial drugs and special antitoxin drugs is much more difficult in the antibiotic resistance era. Herein, we hypothesize that antitoxin hemolytic activity can serve as a screening principle to select antibacterial drugs to combat coinfection from natural products. Being the most abundant natural drug of plant origins, flavonoids were selected to assess the ability of antibacterial coinfections in this paper. Firstly, we note that four flavonoids, namely, baicalin, catechin, kaempferol, and quercetin, have previously exhibited antibacterial abilities. Then, we found that baicalin, kaempferol, and quercetin have better inhibitions of hemolytic activity of Hla than catechin. In addition, kaempferol and quercetin, have therapeutic effectivity for the coinfections of Staphylococcus aureus and Pseudomonas aeruginosa in vitro and in vivo. Finally, our results indicated that kaempferol and quercetin therapied the bacterial coinfection by inhibiting S. aureus α-hemolysin (Hla) and reduced the host inflammatory response. These results suggest that antitoxins may play a promising role as a potential target for screening flavonoids to combat bacterial coinfection.

An in vitro approach to combat multidrug resistance in Salmonella typhi and human colon cancer with Excoecaria agallocha L. extract

Background The incidence of antibacterial resistance and colon cancer is increasing in India. Antibacterial resistance and chemoresistance demand the need of developing herbal or natural chemotherapeutic agents. Our study thus, aims to determine the antibacterial and anticancer activities of the leaf extracts of the mangrove Excoecaria agallocha. Results Liquid chromatography–mass spectroscopy analysis of the ethanolic E. agallocha extracts revealed the presence of Bergenin. The plant extract fraction containing Bergenin had potent antibacterial action against a resistant strain of Salmonella typhi with an MIC value of 15.7 ± 0.04 µg/mL. Treatment of the bacteria with the plant extract made it moderately susceptible to the antibacterial drugs ampicillin, aztreonam, cefotaxime, chloramphenicol and imipenem. The plant extract caused membrane damage and disrupted the expression of a 33 kDa outer membrane protein (OmpA) in S. typhi. It was plausibly due to this mechanism of the plant extract that made the bacteria susceptible to the antibacterial drugs to a certain extent. Further, fluorescence microscopy analysis revealed the anticancer property of the extract against a human colon cancer (DLD-1) cell line by activation of Caspase-3followed by subsequent apoptosis and exhibited cytotoxicity against the cancerous cell line with an IC50 value of 17.99 ± 1.12 µg/mL. Caspase-3 activity was observed to increase in a dose-dependent manner as determined by spectrophotometric assays. Moreover, the expression of the metalloproteinase-7 (MMP-7) was significantly reduced in plant extract treated DLD-1 colon cancer cells. Conclusion The results indicate that E. agallocha is a novel source of Bergenin, and the plant extract fraction under study may be used in combination therapy along with antibacterial drugs to combat antibacterial resistance of S. typhi and also to alleviate the risks of colon cancers in human. However, further investigations may be undertaken for its therapeutic application and to explore its potential bioactivity against other bacterial strains and human cancer cell lines.

Sensitivity of vaginal and mammary bacterial microflora of sows from patients with postpartum dysgalactic syndrome to antibacterial drugs

Purpose: Investigation of the sensitivity of conditionally pathogenic and pathogenic causative agents of postpartum disgalacting syndrome isolated from the pathological discharge of the vagina and the secretion of the mammary glands of patients with sorts to the most common antibacterial drugs.Materials and methods. The fence of the biological material was carried out within 2-3 days after supporting in sows of different ages and parity with the clinical manifestation of postpartum disgalacting syndrome from June to August 2021. In sows, the purse was taken in a mosper, milk, discharge from the vagina for the purpose of bacteriological research.Samples of vaginal wasches were sent in a special transportation environment of Ames. Samples of colostrum and milk (3-5 ml) were gained in sterile test tubes in compliance with the rules of antiseptics (the mammary glands were laid with warm water and 70% ethyl alcohol were treated). For the allocation and study of pure cultures of microorganisms from the above biomaterials produced crops on various nutrient media.The material brought to the laboratory was studied as follows: from the transport medium was carried out primary sowing on triptica-soybean agar, tryptichase-soybean broth, triptichase-soy agar with the addition of 5% of the defibrous blood of the ram; Samples were incubated in aerobic conditions at 37; The growth was taken into account after 24 hours. Then, pure cultures were isolated for the study of the cultural and morphological properties of the microorganisms obtained.The primary identification of the strains of microorganisms was carried out using the Microflex® LRF Bruker Maldi Biotyper system. The accuracy of the results obtained was confirmed by classical microbiological methods based on morphological, cultural and biochemical signs of microorganisms.The resistance of the isolated and identified pure crops to antibiotics was determined by diffusion in agar. In the study, the "advanced set of disks to estimate the antibiotic sensitivity of enterobacteria was used.Results. Inflammatory processes in the reproductive path of sows with postpartum diskalactic syndrome are caused by predominant gram-negative microorganisms, in lactic glands - associations of gram-positive and gram-negative microflora. The main conditionally pathogenic and pathogenic pathogens of endometritis and / or mastitis associated with postpartum diskalactic syndrome are the microorganisms of Escherichia, Enterobacter, Klebsiella, Actinobacillus, Rothia, Weisella, Pseudomonas, Proteus, Enterococcus, Streptococcus and Staphylococcus. It has been established that the overwhelming majority of microorganisms are sensitive to cephalosporine antibiotics: cefepim, zefisim, cefotaxim, ceftazidim, ceftriaxone, ceftinibuthen, cefuroxime.Conclusion. With respect to a large number of the most frequently used antibacterial drugs on this pig-breeding enterprise, high resistance is observed in microorganisms. Treatment of postpartum diskalactic syndrome sowers using antibacterial drugs is recommended to be carried out taking into account sensitivity to them allocated conditional and pathogenic microorganisms.

Clinical case of associative course of panleukopenia and intestinal yersiniosis in cats

The study of the course and manifestation of mixed infections is an important modern problem of both humane and veterinary medicine because their diagnosis is quite complex and time-consuming. The clinical manifestation of double and sometimes triple infection has its characteristics, which depend on various biotic and abiotic factors. To date, it has been proven that the associative course of several infectious diseases is registered more and more often, which confirms the case of simultaneous manifestation of panleukopenia and intestinal yersiniosis in domestic outbred cats. Diagnosis of mixed infection was comprehensive through general clinical and laboratory studies, the use of rapid test systems to confirm the diagnosis of panleukopenia and RNGA with specific yersinia antigens to determine the status of intestinal yersiniosis in cats. The latter was caused by serovar Y. enterocolitica O: 9 with a diagnostic titer of 1: 400. Thanks to microbiological studies, the causative agent of intestinal yersiniosis Y. enterocolitica was isolated. Its biological properties were determined, and antimicrobial sensitivity to enrofloxacin and doxycycline was established against the background of polyresistance to ceftriaxone and tetracycline. During treatment, it was found that the clinical case of intestinal yersiniosis was also due to the simultaneous infection of Y. enterocolitica with two types of serotypes O: 3 and O: 9. Which also have their own specific features. But in most cases, we have different sensitivity to antibacterial drugs, in contrast to the case we described. Clinical signs of the associated course of panleukopenia and intestinal yersiniosis in domestic outbred cats were characterized by prolonged diarrhea, streaks of blood and mucus, apathy, refusal to feed, general weakness. Therapeutic measures containing antibacterial drugs, energy sources, crystalloids, buffer infusions which were aimed at reducing dehydration and maintaining water-salt balance in the complex, were effective, clinical signs of the disease disappeared on the eighth day of treatment, and complete isolation of the pathogen in the environment ceased on the thirteenth day, which indicated the complete recovery of the animal. However, to prevent re-infection, it was recommended to treat disinfectants with care items and utensils. And also to avoid direct contact with animals that have pronounced clinical signs of disease. To prevent the occurrence of panleukopenia, scheduled mass vaccinations with mandatory observance of time limits.

INFLUENCE OF IRRATIONAL PRESCRIPTION OF ANTIBACTERIAL THERAPY ON THE PROGNOSIS OF TREATMENT AND SURVIVAL IN PATIENTS WITH COVID-19

IIntroduction. The COVID-19 pandemic became a major challenge for healthcare systems around the world. The development and improvement of basic treatments for coronavirus patients is important to improve public health and improve quality of life after recovery. The aim of the study: to determine the frequency and structure of prescribing antibacterial drugs in the prehospital and hospital stages, used in patients with COVID-19. Assess the relationship between irrational use of antibacterial drugs with the length of hospital stay of patients with coronavirus disease, the risk of transfer to the intensive care unit (ICU) and mortality. Materials and methods: Statistical, retrospective analysis of 400 case histories of patients with COVID-19 who were treated at the Municipal Non-Profit Enterprise «Kyiv City Clinical Hospital №17» (KNP «KMKL#17») for the period from September 2020 to November 2021 with severe coronavirus disease. Results: 400 medical charts were selected for the study, which were divided into two groups according to the purpose of antibacterial therapy. Of the group of patients who received pre-hospital antibacterial therapy (200 people), indications for its appointment had only 7 % of patients. Among the group receiving antibacterial drugs there is a prolongation of the length of stay in the hospital, the risk of transfer to ICU increases. There is also higher risk of mortality in patients of group 1 (14,5 %), compared with group 2 (8 %), whose antibacterial drugs were not prescribed at the prehospital stage. Conclusion: as a result of the study it was found that patients who were unreasonably prescribed antibacterial therapy prolongs the period of general hospitalization by 2.3 ± 0.8 days, increasing the need for transfer of patients due to deterioration to ICU by an average of 13 %, increase in the incidence of antibiotic-associated diarrhea by 7-8 %, and there is a tendency to increase mortality from COVID-19. Antibacterial drugs should be used only on the basis of indications in the case of proven bacterial co-infection (superinfection) or reasonable suspicion of it in patients with respiratory disease caused by SARS-CoV-2 and in no case should be prophylactic.