Cefiderocol - a promising new antibiotic for the antibiotic-resistant pathogens of the highest epidemiological priority

Lorenc Karol, Kozioł Magdalena, Sobek Alicja, Pawlicki Mateusz, Łopuszyńska Anna, Misztal Zofia, Lewicki Marcin, Smoleń Agata. Cefiderocol - a promising new antibiotic for the antibiotic-resistant pathogens of the highest epidemiological priority. Journal of Education, Health and Sport. 2019;9(5):81-88. eISSN 2391-8306. DOI http://dx.doi.org/10.5281/zenodo.2667284 http://ojs.ukw.edu.pl/index.php/johs/article/view/6881 https://pbn.nauka.gov.pl/sedno-webapp/works/912614 The journal has had 7 points in Ministry of Science and Higher Education parametric evaluation. Part B item 1223 (26/01/2017). 1223 Journal of Education, Health and Sport eISSN 2391-8306 7 © The Authors 2019; This article is published with open access at Licensee Open Journal Systems of Kazimierz Wielki University in Bydgoszcz, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 12.04.2019. Revised: 25.04.2019. Accepted: 04.05.2019. Cefiderocol - a promising new antibiotic for the antibiotic-resistant pathogens of the highest epidemiological priority Karol Lorenca, Magdalena Kozioła, Alicja Sobeka, Mateusz Pawlickia, Anna Łopuszyńskaa, Zofia Misztalb, Marcin Lewickic, Agata Smoleńc aStudent Scientific Association at Department of Epidemiology and Clinical Research Methodology, Medical University of Lublin, ul. Radziwiłłowska 11, Lublin 20-080, Poland; [email protected]; 0000-0002-6414-5984; [email protected]; 0000-0002-8671-5968; [email protected]; 0000-0001-5563-9344; [email protected]; 0000-0001-8318-6573; [email protected]; 0000-0001-5133-4180; bStudent Scientific Association at Department of Family Medicine, Medical University of Lodz, ul. Narutowicza 60, Lodz 90-136, Poland; [email protected]; 0000-0003-2317-9667 cDepartment of Epidemiology and Clinical Research Methodology of the Medical University of Lublin, ul. Radziwiłłowska 11, Lublin 20-080, Poland; [email protected]; 0000-0003-1906-9326; [email protected]; 0000-0003-0764-6667; ABSTRACT: Increase in the incidence of multidrug-resistant Gram-negative bacterial strains pose a significant threat to healthcare system worldwide. New antibiotics are necessary to combat particularly resitant pathogens. WHO’s global priority pathogens list was published in 2017 to promote research and development of new antibiotics, as part of WHO’s efforts to address growing global resistance to antimicrobial agents. Acinetobacter baumannii, Pseudomonas aeruginosa and carbapenem-resistant, third-generation cephalosporin-resistant Enterobacteriaceae were classified as highest priority pathogens requiring a new antibiotic treatment options. Cefiderocol is a novel parenteral siderophore cephalosporin that shows efficacy against listed Gram-negative bacteria. The results of the presented studies showed that cefiderocol has a strong antimicrobial effect against problematic strains that produce carbapenemases, such as KPC (K. pneumoniae carbapenemase) and B-class metallo-β-lactamases, including NDM-1 (New Delhi metallo-β-lactamase), as well as the ESBL-producing strains. In addition, it does not require the use of the β-lactamase inhibitor. The new agent demonstrates a favorable side effect profile. There is an urgent need to develop new antibiotics. Cefiderocol is a new antibiotic that has a potential to effectively combat particularly resistant bacteries such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, as well as carbapenem and 3rd generation cephalosporin-resistant Enterobacteriaceae. Key words: Cefiderocol; cephalosporin; antibiotic resistanc

Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells

Intercellular communication within the bone marrow niche significantly promotes leukemogenesis and provides protection of leukemic cells from therapy. Secreted factors, intercellular transfer of mitochondria and the receptor–ligand interactions have been shown as mediators of this protection. Here we report that tunneling nanotubes (TNTs)—long, thin membranous structures, which have been identified as a novel mode of intercellular cross-talk—are formed in the presence of stroma and mediate transfer of cellular vesicles from stroma to leukemic cells. Importantly, transmission of vesicles via TNTs from stromal cells increases resistance of leukemic cells to the tyrosine kinase inhibitor, imatinib. Using correlative light-electron microscopy and electron tomography we show that stromal TNTs contain vesicles, provide membrane continuity with the cell bodies and can be open-ended. Moreover, trans-SILAC studies to reveal the non-autonomous proteome showed that specific sets of proteins are transferred together with cellular vesicles from stromal to leukemic cells, with a potential role in survival and adaptation. Altogether, our findings provide evidence for the biological role of the TNT-mediated vesicle exchange between stromal and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells

Risk factors for reoperation after surgical treatment for degenerative spinal disease in Poland: a nationwide retrospective study of 38,953 hospitalisations

Introduction. Degenerative spinal disease (DSD) is one of the most common musculoskeletal conditions and a leading cause of sickness absence. It also contributes significantly to the global burden of disease. The aim of this study was to assess the frequency of reoperation after surgical treatment of DSDs in Poland, and to identify risk factors for reoperation.Material and methods. A retrospective analysis of hospitalisations for DSD in 2018 that were reported to Poland’s National Health Fund (NHF) was performed. Reoperations reported within 365 days of hospital discharge were identified. Demographic factors and multimorbidities were included in the analysis. A logistic regression model was then performed to assess risk factors for reoperations.Results. In 2018, 38,953 surgical hospitalszations for DSD were reported. A total of 3,942 hospitalised patients (10.12%) required reoperation within 365 days. Patients requiring reoperation were predominantly female (female-to-male ratio 1.34:1) and elderly (mean age of reoperated patients 56.66 years, mean age of other patients 53.24). The percentage reoperated upon correlated with multiple diseases (from 8.81% in the group of patients without comorbidities to 15.31% in the group of patients with three or more comorbidities). The risk of reoperation was most increased by comorbid depression, neurological diseases, obesity, and older age. The risk of reoperation was reduced by instrumented spinal surgery, surgery in a neurosurgical unit, and hospitalisations other than same-day surgery.Conclusions. Reoperations within a year after DSD surgical treatment are common. Identifying risk factors for reoperation, including those related to the presence of comorbidities and the phenomenon of multimorbidity, can be an important tool in reducing reoperation rates

Cefiderocol - a promising new antibiotic for the antibiotic-resistant pathogens of the highest epidemiological priority

Increase in the incidence of multidrug-resistant Gram-negative bacterial strains pose a significant threat to healthcare system worldwide. New antibiotics are necessary to combat particularly resitant pathogens. WHO’s global priority pathogens list was published in 2017 to promote research and development of new antibiotics, as part of WHO’s efforts to address growing global resistance to antimicrobial agents. Acinetobacter baumannii, Pseudomonas aeruginosa and carbapenem-resistant, third-generation cephalosporin-resistant Enterobacteriaceae were classified as highest priority pathogens requiring a new antibiotic treatment options. Cefiderocol is a novel parenteral siderophore cephalosporin that shows efficacy against listed Gram-negative bacteria. The results of the presented studies showed that cefiderocol has a strong antimicrobial effect against problematic strains that produce carbapenemases, such as KPC (K. pneumoniae carbapenemase) and B-class metallo-β-lactamases, including NDM-1 (New Delhi metallo-β-lactamase), as well as the ESBL-producing strains. In addition, it does not require the use of the β-lactamase inhibitor. The new agent demonstrates a favorable side effect profile. There is an urgent need to develop new antibiotics. Cefiderocol is a new antibiotic that has a potential to effectively combat particularly resistant bacteries such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, as well as carbapenem and 3rd generation cephalosporin-resistant Enterobacteriaceae

Design and synthesis of new quinazolin-4-one derivatives with negative mGlu7mGlu_7 receptor modulation activity and antipsychotic-like properties

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment

Delineating the legis rei sitae and legis contractus in determining the law applicable to retention of title

Retention of title as a security on tangible assets is well known in many legal systems. It enables to strengthen the position of the seller in such a contract of sale in which the payment of the price is agreed to be done later than the handing over the good. This instrument disturbs the traditional model of sale in two ways. Firstly, the conclusion of the contract is not directly followed — which takes usually place — by the performance of the obligation to transfer the property. Secondly, the right of property receives in that way a new role to play — it becomes a security right, guarantying the pecuniary claim of the seller and ceases the function of the principal right. In order to find the law applicable to the retention of title, its different aspects — contractual and real — should be qualified according to their nature. These aspects should be treated separately and be assessed according to the proper legal system. For example, the law applicable to contractual assets of retention of title defines if such belated transfer of ownership affects any general rights and obligations of parties, such as the right to receive benefits from the asset or to bear costs of its maintenance. On the other hand, the law of actual location of the asset as a law applicable to real aspects of the retention of title defines the nature of the element disturbing the transfer of ownership and the scope of rights of the seller towards charged good as its owner

Structural Determination of Pectins by Spectroscopy Methods

Plant polysaccharides include pectins, which are responsible for an important role in plant physiology and are part of the plant cell wall. These compounds are known as gelling and stabilizing agents, which are widely used in the food industry. The scientific literature lacks precise information on the spectroscopy of apple pectin and citrus pectin. Therefore, the aim of this work was to test and compare the physicochemical properties of these compounds. The curves of FT-IR, NMR, ESI-MS, and thermogravimetric analysis (TGA) of pectin samples were measured and discussed. The analysis of the spectroscopic results confirms that the isolated pectins using various enzymes (xylanase and cellulase) have a structure similar to the commercially available pectin (PectaSol-C), with a noticeable change in morphology. These characteristics are helpful for further basic research and application