{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:24:31Z","timestamp":1793363071160,"version":"4.5.0"},"reference-count":112,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007052","name":"University of Verona to Paolo Gaibani","doi-asserted-by":"publisher","award":["FUR2024"],"award-info":[{"award-number":["FUR2024"]}],"id":[{"id":"10.13039\/501100007052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Carbapenemase-producing Enterobacterales (CPE) represent an important threat to global health, resulting in an urgent issue in clinical settings. CPE often exhibit a multidrug-resistant (MDR) phenotype, thus reducing the antimicrobial armamentarium, with few antibiotics retaining residual antimicrobial activity against these pathogens. Carbapenemases are divided into three classes (A, B, and D) according to the Ambler classification system. Among these, KPC (class A), NDM, VIM, IMP (class B), and OXA-48-like (class D) represent the most important carbapenemases in terms of diffusion and clinical impact. CPE diffusion has been observed worldwide, with current endemicity in multiple territories around the world. In this context, the clonal spread and plasmid-mediated transmission of carbapenemases have contributed to the global spread of CPE worldwide and to the diffusion of carbapenemases among different Enterobacterales species. In recent years, novel molecules showing excellent in vitro and in vivo activity have been developed against CPE. However, the recent emergence of novel traits of resistance to these molecules has already been reported in several cases, mitigating the initial promising results. This review aims to provide an updated description of the major classes of carbapenemases, their global distribution, and future perspectives to limit the diffusion of CPEs.<\/jats:p>","DOI":"10.3390\/antibiotics14020141","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T04:36:51Z","timestamp":1738557411000},"page":"141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Epidemiology and Genetic Traits of Carbapenemase-Producing Enterobacterales: A Global Threat to Human Health"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8177-3616","authenticated-orcid":false,"given":"Gualtiero","family":"Alvisi","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, University of Padua, 35135 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8101-4196","authenticated-orcid":false,"given":"Antonio","family":"Curtoni","sequence":"additional","affiliation":[{"name":"Department of Public Health and Paediatrics, University of Turin, 10100 Turin, Italy"},{"name":"Microbiology and Virology Unit, University Hospital Citt\u00e0 della Salute e della Scienza di Torino, 10100 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1916-6878","authenticated-orcid":false,"given":"Rossella","family":"Fonnesu","sequence":"additional","affiliation":[{"name":"Microbiology and Virology Unit, Azienda Ospedaliera Universitaria Integrata Di Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0535-2542","authenticated-orcid":false,"given":"Aurora","family":"Piazza","sequence":"additional","affiliation":[{"name":"Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Unit of Microbiology and Clinical Microbiology, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Signoretto","sequence":"additional","affiliation":[{"name":"Microbiology and Virology Unit, Azienda Ospedaliera Universitaria Integrata Di Verona, 37134 Verona, Italy"},{"name":"Department of Diagnostics and Public Health, Microbiology Section, Verona University, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6800-5522","authenticated-orcid":false,"given":"Giorgia","family":"Piccinini","sequence":"additional","affiliation":[{"name":"Department of Public Health and Paediatrics, University of Turin, 10100 Turin, Italy"},{"name":"PhD National Programme in One Health Approaches to Infectious Diseases and Life Science Research, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Sassera","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy"},{"name":"Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3791-8635","authenticated-orcid":false,"given":"Paolo","family":"Gaibani","sequence":"additional","affiliation":[{"name":"Unit of Microbiology and Clinical Microbiology, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy"},{"name":"Department of Diagnostics and Public Health, Microbiology Section, Verona University, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"dlad099","DOI":"10.1093\/jacamr\/dlad099","article-title":"Clonal Dissemination of Klebsiella Pneumoniae Resistant to Cefiderocol, Ceftazidime\/Avibactam, Meropenem\/Vaborbactam and Imipenem\/Relebactam Co-Producing KPC and OXA-181 Carbapenemase","volume":"5","author":"Bovo","year":"2023","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e0021622","DOI":"10.1128\/aac.00216-22","article-title":"OXA-48-Like \u03b2-Lactamases: Global Epidemiology, Treatment Options, and Development Pipeline","volume":"66","author":"Boyd","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S1473-3099(16)30257-2","article-title":"Occurrence of Carbapenemase-Producing Klebsiella Pneumoniae and Escherichia Coli in the European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE): A Prospective, Multinational Study","volume":"17","author":"Grundmann","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1080\/22221751.2022.2048972","article-title":"Carbapenemase-Producing Pseudomonas Aeruginosa -an Emerging Challenge","volume":"11","author":"Tenover","year":"2022","journal-title":"Emerg. Microbes Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S1473-3099(10)70143-2","article-title":"Emergence of a New Antibiotic Resistance Mechanism in India, Pakistan, and the UK: A Molecular, Biological, and Epidemiological Study","volume":"10","author":"Kumarasamy","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/CMR.00102-19","article-title":"The Global Ascendency of OXA-48-Type Carbapenemases","volume":"33","author":"Pitout","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1097\/QCO.0000000000000608","article-title":"Epidemiology of Carbapenem-Resistant Gram-Negative Infections Globally","volume":"32","author":"Brink","year":"2019","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, Research, and Development of New Antibiotics: The WHO Priority List of Antibiotic-Resistant Bacteria and Tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e714","DOI":"10.1016\/j.ijid.2013.02.007","article-title":"Outbreak of Citrobacter Freundii Carrying VIM-1 in an Italian Hospital, Identified during the Carbapenemases Screening Actions, June 2012","volume":"17","author":"Gaibani","year":"2013","journal-title":"Int. J. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s40265-017-0851-9","article-title":"Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-\u03b2-Lactamase Inhibitor Combinations","volume":"78","author":"Zhanel","year":"2018","journal-title":"Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.3201\/eid2911.230830","article-title":"Ceftazidime\/Avibactam Resistance in Carbapenemase-Producing Klebsiella Pneumoniae","volume":"29","author":"Cui","year":"2023","journal-title":"Emerg. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gaibani, P., Lombardo, D., Bussini, L., Bovo, F., Munari, B., Giannella, M., Bartoletti, M., Viale, P., Lazzarotto, T., and Ambretti, S. (2021). Epidemiology of Meropenem\/Vaborbactam Resistance in KPC-Producing Klebsiella Pneumoniae Causing Bloodstream Infections in Northern Italy, 2018. Antibiotics, 10.","DOI":"10.21203\/rs.3.rs-237255\/v1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13756-017-0259-z","article-title":"Infection Prevention and Control Measures and Tools for the Prevention of Entry of Carbapenem-Resistant Enterobacteriaceae into Healthcare Settings: Guidance from the European Centre for Disease Prevention and Control","volume":"6","author":"Magiorakos","year":"2017","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1097\/MCC.0000000000000967","article-title":"Antimicrobial Stewardship","volume":"28","author":"Lanckohr","year":"2022","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1089\/fpd.2014.1865","article-title":"Multidrug-Resistant Pathogens in the Food Supply","volume":"12","author":"Doyle","year":"2015","journal-title":"Foodborne Pathog. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1098\/rstb.1980.0049","article-title":"The Structure of \u03b2-Lactamases","volume":"289","author":"Ambler","year":"1980","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1042\/bj2760269","article-title":"A Standard Numbering Scheme for the Class A Beta-Lactamases","volume":"276","author":"Ambler","year":"1991","journal-title":"Biochem. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1128\/AAC.39.6.1211","article-title":"A Functional Classification Scheme for Beta-Lactamases and Its Correlation with Molecular Structure","volume":"39","author":"Bush","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1080\/14787210.2023.2194633","article-title":"Classification for \u03b2-Lactamases: Historical Perspectives","volume":"21","author":"Bush","year":"2023","journal-title":"Expert. Rev. Anti Infect. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1128\/AAC.01009-09","article-title":"Updated Functional Classification of Beta-Lactamases","volume":"54","author":"Bush","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1128\/CMR.00001-07","article-title":"Carbapenemases: The Versatile \u03b2-Lactamases","volume":"20","author":"Queenan","year":"2007","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1128\/AAC.37.5.939","article-title":"Biochemical Properties of a Carbapenem-Hydrolyzing Beta-Lactamase from Enterobacter Cloacae and Cloning of the Gene into Escherichia Coli","volume":"37","author":"Nordmann","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1128\/AAC.38.6.1262","article-title":"Cloning and Sequence Analysis of the Gene for a Carbapenem-Hydrolyzing Class A Beta-Lactamase, Sme-1, from Serratia Marcescens S6","volume":"38","author":"Naas","year":"1994","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1128\/AAC.48.6.2321-2324.2004","article-title":"Molecular Characterization of a Carbapenem-Hydrolyzing Class A Beta-Lactamase, SFC-1, from Serratia Fonticola UTAD54","volume":"48","author":"Henriques","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1128\/AAC.47.2.755-758.2003","article-title":"Emergence in Klebsiella Pneumoniae of a Chromosome-Encoded SHV Beta-Lactamase That Compromises the Efficacy of Imipenem","volume":"47","author":"Poirel","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.2174\/1389450117666160310144501","article-title":"Structural and Functional Aspects of Class A Carbapenemases","volume":"17","author":"Naas","year":"2016","journal-title":"Curr. Drug Targets"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1128\/AAC.00223-12","article-title":"Class A Carbapenemase FPH-1 from Francisella Philomiragia","volume":"56","author":"Toth","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/AAC.01076-18","article-title":"Past and Present Perspectives on \u03b2-Lactamases","volume":"62","author":"Bush","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ding, L., Shen, S., Chen, J., Tian, Z., Shi, Q., Han, R., Guo, Y., and Hu, F. (2023). Klebsiella Pneumoniae Carbapenemase Variants: The New Threat to Global Public Health. Clin. Microbiol. Rev., 36.","DOI":"10.1128\/cmr.00008-23"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hammoudi Halat, D., and Ayoub Moubareck, C. (2020). The Current Burden of Carbapenemases: Review of Significant Properties and Dissemination among Gram-Negative Bacteria. Antibiotics, 9.","DOI":"10.3390\/antibiotics9040186"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e0044722","DOI":"10.1128\/aac.00447-22","article-title":"Klebsiella Pneumoniae Carbapenemase Variants Resistant to Ceftazidime-Avibactam: An Evolutionary Overview","volume":"66","author":"Hobson","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Galdadas, I., Lovera, S., P\u00e9rez-Hern\u00e1ndez, G., Barnes, M.D., Healy, J., Afsharikho, H., Woodford, N., Bonomo, R.A., Gervasio, F.L., and Haider, S. (2018). Defining the Architecture of KPC-2 Carbapenemase: Identifying Allosteric Networks to Fight Antibiotics Resistance. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-31176-0"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.2147\/IDR.S207993","article-title":"Molecular and Phenotypical Characterization of Two Cases of Antibiotic-Driven Ceftazidime-Avibactam Resistance in BlaKPC-3 Harboring Klebsiella Pneumoniae","volume":"12","author":"Venditti","year":"2019","journal-title":"Infect. Drug Resist."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Palombo, M., Secci, B., Bovo, F., Gatti, M., Ambretti, S., and Gaibani, P. (2023). In Vitro Evaluation of Increasing Avibactam Concentrations on Ceftazidime Activity against Ceftazidime\/Avibactam-Susceptible and Resistant KPC-Producing Klebsiella Pneumoniae Clinical Isolates. Antibiotics, 12.","DOI":"10.3390\/antibiotics12121707"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gaibani, P., Giani, T., Bovo, F., Lombardo, D., Amadesi, S., Lazzarotto, T., Coppi, M., Rossolini, G.M., and Ambretti, S. (2022). Resistance to Ceftazidime\/Avibactam, Meropenem\/Vaborbactam and Imipenem\/Relebactam in Gram-Negative MDR Bacilli: Molecular Mechanisms and Susceptibility Testing. Antibiotics, 11.","DOI":"10.3390\/antibiotics11050628"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/jac\/dkz508","article-title":"Different Phenotypic Expression of KPC \u03b2-Lactamase Variants and Challenges in Their Detection","volume":"75","author":"Oueslati","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Oelschlaeger, P., Kaadan, H., and Dhungana, R. (2023). Strategies to Name Metallo-\u03b2-Lactamases and Number Their Amino Acid Residues. Antibiotics, 12.","DOI":"10.3390\/antibiotics12121746"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1749-6632.2012.06796.x","article-title":"Metallo-\u03b2-Lactamase Structure and Function","volume":"1277","author":"Palzkill","year":"2013","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113667","DOI":"10.1016\/j.ejmech.2021.113667","article-title":"Recent Research and Development of NDM-1 Inhibitors","volume":"223","author":"Wang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1093\/jac\/dki130","article-title":"Revised Ambler Classification of \u03b2-Lactamases","volume":"55","author":"Hall","year":"2005","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5046","DOI":"10.1128\/AAC.00774-09","article-title":"Characterization of a New Metallo-\u03b2-Lactamase Gene, BlaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella Pneumoniae Sequence Type 14 from India","volume":"53","author":"Yong","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/CMR.00115-18","article-title":"NDM Metallo-\u03b2-Lactamases and Their Bacterial Producers in Health Care Settings","volume":"32","author":"Wu","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2337678","DOI":"10.1080\/22221751.2024.2337678","article-title":"Transmission of BlaNDM in Enterobacteriaceae among Animals, Food and Human","volume":"13","author":"Fu","year":"2024","journal-title":"Emerg. Microbes Infect."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Li, X., Zhao, D., Li, W., Sun, J., and Zhang, X. (2021). Enzyme Inhibitors: The Best Strategy to Tackle Superbug NDM-1 and Its Variants. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010197"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/nchembio.2083","article-title":"Membrane Anchoring Stabilizes and Favors Secretion of New Delhi Metallo-\u03b2-Lactamase","volume":"12","author":"Bahr","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/AAC.01856-17","article-title":"Antimicrobial Activities of Aztreonam-Avibactam and Comparator Agents against Contemporary (2016) Clinical Enterobacteriaceae Isolates","volume":"62","author":"Sader","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1128\/AAC.43.7.1584","article-title":"Cloning and Characterization of BlaVIM, a New Integron-Borne Metallo-\u03b2-Lactamase Gene from a Pseudomonas Aeruginosa Clinical Isolate","volume":"43","author":"Lauretti","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/febs.14695","article-title":"Crystal Structures of VIM-1 Complexes Explain Active Site Heterogeneity in VIM-class Metallo-\u03b2-lactamases","volume":"286","author":"Salimraj","year":"2019","journal-title":"FEBS J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1128\/AAC.35.1.147","article-title":"Transferable Imipenem Resistance in Pseudomonas Aeruginosa","volume":"35","author":"Watanabe","year":"1991","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Pongchaikul, P., and Mongkolsuk, P. (2022). Comprehensive Analysis of Imipenemase (IMP)-Type Metallo-\u03b2-Lactamase: A Global Distribution Threatening Asia. Antibiotics, 11.","DOI":"10.20944\/preprints202201.0156.v1"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4288","DOI":"10.1021\/bi992569m","article-title":"Crystal Structure of the IMP-1 Metallo \u03b2-Lactamase from Pseudomonas Aeruginosa and Its Complex with a Mercaptocarboxylate Inhibitor: Binding Determinants of a Potent, Broad-Spectrum Inhibitor","volume":"39","author":"Concha","year":"2000","journal-title":"Biochemistry"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Li, W., Guo, H., Gao, Y., Yang, X., Li, R., Li, S., Sun, C., Du, W., Chen, S., and Xu, P. (2022). Comparative Genomic Analysis of Plasmids Harboring BlaOXA-48-like Genes in Klebsiella Pneumoniae. Front. Cell Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1082813"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1128\/AAC.48.1.15-22.2004","article-title":"Emergence of Oxacillinase-Mediated Resistance to Imipenem in Klebsiella Pneumoniae","volume":"48","author":"Poirel","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jgar.2024.03.020","article-title":"Global Trends in Carbapenem- and Difficult-to-Treat-Resistance among World Health Organization Priority Bacterial Pathogens: ATLAS Surveillance Program 2018\u20132022","volume":"37","author":"Wise","year":"2024","journal-title":"J Glob Antimicrob Resist"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/CMR.00047-19","article-title":"Epidemiology of \u03b2-Lactamase-Producing Pathogens","volume":"33","author":"Bush","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Bonnin, R.A., Jousset, A.B., Emeraud, C., Oueslati, S., Dortet, L., and Naas, T. (2021). Genetic Diversity, Biochemical Properties, and Detection Methods of Minor Carbapenemases in Enterobacterales. Front. Med., 7.","DOI":"10.3389\/fmed.2020.616490"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ma, J., Song, X., Li, M., Yu, Z., Cheng, W., Yu, Z., Zhang, W., Zhang, Y., Shen, A., and Sun, H. (2023). Global Spread of Carbapenem-Resistant Enterobacteriaceae: Epidemiological Features, Resistance Mechanisms, Detection and Therapy. Microbiol. Res., 266.","DOI":"10.1016\/j.micres.2022.127249"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13756-022-01061-7","article-title":"Phenotype-Genotype Correlations among Carbapenem-Resistant Enterobacterales Recovered from Four Egyptian Hospitals with the Report of SPM Carbapenemase","volume":"11","author":"Abdelaziz","year":"2022","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.3201\/eid3005.231558","article-title":"Detection of OXA-181 Carbapenemase in Shigella Flexneri","volume":"30","author":"Dhabaan","year":"2024","journal-title":"Emerg. Infect. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e01406-22","DOI":"10.1128\/aac.01406-22","article-title":"Epidemiology of Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Study, 2018 to 2019","volume":"67","author":"Estabrook","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"dlae052","DOI":"10.1093\/jacamr\/dlae052","article-title":"Antimicrobial Resistance of Clinical Bacterial Isolates in China: Current Status and Trends","volume":"6","author":"Qin","year":"2024","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.jgar.2023.10.008","article-title":"Epidemiology, Risk Factors, and Clinical Outcomes of Carbapenem-Resistant Enterobacterales in Africa: A Systematic Review","volume":"35","author":"Phumuzile","year":"2023","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Takei, K., Ogawa, M., Sakata, R., and Kanamori, H. (2023). Epidemiological Characteristics of Carbapenem-Resistant Enterobacterales in Japan: A Nationwide Analysis of Data from a Clinical Laboratory Center (2016\u20132022). Pathogens, 12.","DOI":"10.3390\/pathogens12101246"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Brkic, S., and Cirkovic, I. (2024). Carbapenem-Resistant Enterobacterales in the Western Balkans: Addressing Gaps in European AMR Surveillance Map. Antibiotics, 13.","DOI":"10.3390\/antibiotics13090895"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2200774","DOI":"10.2807\/1560-7917.ES.2023.28.27.2200774","article-title":"Nationwide, Population-Based Observational Study of the Molecular Epidemiology and Temporal Trend of Carbapenemase-Producing Enterobacterales in Norway, 2015 to 2021","volume":"28","author":"Ljungquist","year":"2023","journal-title":"Eurosurveillance"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Yao, Y., Falgenhauer, L., Falgenhauer, J., Hauri, A.M., Heinm\u00fcller, P., Domann, E., Chakraborty, T., and Imirzalioglu, C. (2021). Carbapenem-Resistant Citrobacter spp. as an Emerging Concern in the Hospital-Setting: Results From a Genome-Based Regional Surveillance Study. Front. Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.744431"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e0004","DOI":"10.5041\/RMMJ.10461","article-title":"The Changing Epidemiology of Carbapenemase-Producing Enterobacterales","volume":"13","author":"Hussein","year":"2022","journal-title":"Rambam Maimonides Med. J."},{"key":"ref_68","unstructured":"(2025, January 01). European Centre for Disease Prevention and Control Antimicrobial Resistance in the EU\/EEA (EARS-Net). Available online: https:\/\/www.ecdc.europa.eu\/en\/about-us\/networks\/disease-networks-and-laboratory-networks\/ears-net-data."},{"key":"ref_69","unstructured":"(2025, January 01). UK Health Security Agency English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) Report 2022 to 2023, Available online: https:\/\/webarchive.nationalarchives.gov.uk\/ukgwa\/20240127185100mp_\/https:\/\/assets.publishing.service.gov.uk\/media\/6555026e544aea000dfb2e19\/ESPAUR-report-2022-to-2023.pdf."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2317915","DOI":"10.1080\/22221751.2024.2317915","article-title":"ESKAPE in China: Epidemiology and Characteristics of Antibiotic Resistance","volume":"13","author":"Luo","year":"2024","journal-title":"Emerg. Microbes Infect."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1128\/AAC.45.4.1151-1161.2001","article-title":"Novel Carbapenem-Hydrolyzing \u03b2-Lactamase, KPC-1, from a Carbapenem-Resistant Strain of Klebsiella Pneumoniae","volume":"45","author":"Yigit","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"ofad046","DOI":"10.1093\/ofid\/ofad046","article-title":"Changing Epidemiology of Carbapenemases Among Carbapenem-Resistant Enterobacterales From United States Hospitals and the Activity of Aztreonam-Avibactam Against Contemporary Enterobacterales (2019\u20132021)","volume":"10","author":"Sader","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"JJID.2023.213","DOI":"10.7883\/yoken.JJID.2023.213","article-title":"High Prevalence of Carbapenem-Resistant Enterobacterales; Producing OXA-48 among Carbapenem-Resistant Isolates in a Regional Hospital in Central Taiwan","volume":"77","author":"Wu","year":"2024","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Chiu, S.-K., Ma, L., Chan, M.-C., Lin, Y.-T., Fung, C.-P., Wu, T.-L., Chuang, Y.-C., Lu, P.-L., Wang, J.-T., and Lin, J.-C. (2018). Carbapenem Nonsusceptible Klebsiella Pneumoniae in Taiwan: Dissemination and Increasing Resistance of Carbapenemase Producers During 2012\u20132015. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-26691-z"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"101031","DOI":"10.1016\/j.drup.2023.101031","article-title":"Global Distribution and Genomic Characteristics of Carbapenemase-Producing Escherichia Coli among Humans, 2005\u20132023","volume":"72","author":"Li","year":"2024","journal-title":"Drug Resist. Updates"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jmii.2022.07.012","article-title":"The Molecular and Epidemiological Characteristics of Carbapenemase-Producing Enterobacteriaceae Isolated from Children in Shanghai, China, 2016\u20132021","volume":"56","author":"Fu","year":"2023","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"S300","DOI":"10.1093\/cid\/ciab767","article-title":"High-Resolution Genomic Profiling of Carbapenem-Resistant Klebsiella Pneumoniae Isolates: A Multicentric Retrospective Indian Study","volume":"73","author":"Nagaraj","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1007\/s10096-020-03845-4","article-title":"Carbapenem-Resistant Enterobacteriaceae in Patients with Bacteraemia at Tertiary Hospitals in South Africa, 2015 to 2018","volume":"39","author":"Perovic","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"542","DOI":"10.7196\/SAMJ.2022.v112i8.16351","article-title":"Carbapenem-Resistant Enterobacterales in Patients with Bacteraemia at Tertiary Academic Hospitals in South Africa, 2019\u20132020: An Update","volume":"112","author":"Lowe","year":"2022","journal-title":"S. Afr. Med. J."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kuzmenkov, A.Y., Trushin, I.V., Vinogradova, A.G., Avramenko, A.A., Sukhorukova, M.V., Malhotra-Kumar, S., Dekhnich, A.V., Edelstein, M.V., and Kozlov, R.S. (2021). AMRmap: An Interactive Web Platform for Analysis of Antimicrobial Resistance Surveillance Data in Russia. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.620002"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Lian, S., Liu, C., Cai, M., Cao, Y., and Xu, X. (2024). Risk Factors and Molecular Characterization of Carbapenem Resistant Escherichia Coli Recovered from a Tertiary Hospital in Fujian, China from 2021 to 2023. BMC Microbiol, 24.","DOI":"10.1186\/s12866-024-03525-9"},{"key":"ref_82","unstructured":"(2024, December 17). Beta-Lactamase DataBase\u2014Structure and Function. Available online: http:\/\/bldb.eu\/."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1093\/jac\/dkx148","article-title":"Genomic Epidemiology of Global VIM-Producing Enterobacteriaceae","volume":"72","author":"Matsumura","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"dlae135","DOI":"10.1093\/jacamr\/dlae135","article-title":"Prevalence of Carbapenem-Resistant Enterobacterales with Bla IMP-6 Predominance in Hospitals from 2018 to 2021 in Nara, Japan","volume":"6","author":"Kishi","year":"2024","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jgar.2022.04.004","article-title":"Clinical Characteristics and Treatment Outcomes of Carbapenem-Resistant Enterobacterales Infections in Japan","volume":"29","author":"Oka","year":"2022","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_86","first-page":"75","article-title":"An Outbreak of Infection Due to Metallo-\u00df-Lactamase-Producing Proteus Mirabilis in the Surgical Intensive Care Unit","volume":"42","year":"2011","journal-title":"Scr. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6062","DOI":"10.1128\/AAC.00838-12","article-title":"Isolation of Klebsiella Pneumoniae Producing NDM-1 Metallo-\u03b2-Lactamase from the Urine of an Outpatient Baby Boy Receiving Antibiotic Prophylaxis","volume":"56","author":"Mirovic","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1128\/AAC.00049-11","article-title":"Emergence of NDM-1-Producing Enterobacteriaceae in Belgium","volume":"55","author":"Bogaerts","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ijantimicag.2014.05.008","article-title":"Emergence of Klebsiella Pneumoniae Co-Producing NDM-1, OXA-48, CTX-M-15, CMY-16, QnrA and ArmA in Switzerland","volume":"44","author":"Seiffert","year":"2014","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Ranieri, S.C., Fabbrizi, V., D\u2019 Amario, A.M., Frascella, M.G., Di Biase, V., Di Francesco, C., Di Sante, S., De Berardis, L., De Martinis, M., and Partenza, M. (2024). First Report of a BlaNDM-Producing Extensively Drug Resistant Klebsiella Pneumoniae ST437 in Italy. Front. Cell Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1426817"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jgar.2024.02.015","article-title":"Coexistence of BlaNDM-5, BlaCTX-M-15, BlaOXA-232, BlaSHV-182 Genes in Multidrug-Resistant K. Pneumoniae ST437-Carrying OmpK36 and OmpK37 Porin Mutations: First Report in Italy","volume":"37","author":"Perilli","year":"2024","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.jgar.2024.04.008","article-title":"Multidrug-Resistant Klebsiella Pneumoniae Clinical Isolates Producing NDM- and OXA-Type Carbapenemase in Nepal","volume":"37","author":"Takei","year":"2024","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Pathak, A., Tejan, N., Dubey, A., Chauhan, R., Fatima, N., Singh, S., Bhayana, S., and Sahu, C. (2023). Outbreak of Colistin Resistant, Carbapenemase (BlaNDM, BlaOXA-232) Producing Klebsiella Pneumoniae Causing Blood Stream Infection among Neonates at a Tertiary Care Hospital in India. Front. Cell Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1051020"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Markovska, R., Stankova, P., Popivanov, G., Gergova, I., Mihova, K., Mutafchiyski, V., and Boyanova, L. (2024). Emergence of BlaNDM-5 and BlaOXA-232 Positive Colistin- and Carbapenem-Resistant Klebsiella Pneumoniae in a Bulgarian Hospital. Antibiotics, 13.","DOI":"10.3390\/antibiotics13070677"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Gonzalez, C., Oueslati, S., Rima, M., Nermont, R., Dortet, L., Hopkins, K.L., Iorga, B.I., Bonnin, R.A., and Naas, T. (2024). Molecular, Genetic, and Biochemical Characterization of OXA-484 Carbapenemase, a Difficult-to-Detect R214G Variant of OXA-181. Microorganisms, 12.","DOI":"10.3390\/microorganisms12071391"},{"key":"ref_96","unstructured":"(2025, January 01). European Centre for Disease Prevention and Contro Increase in OXA-244-Producing Escherichia Coli in the European Union\/European Economic Area and the UK since 2013\u2014First Update; Stockholm. Available online: https:\/\/www.ecdc.europa.eu\/sites\/default\/files\/documents\/OXA-244-producing-E-coli-in-EU-EEA-since-2013-first-update.pdf."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2200773","DOI":"10.2807\/1560-7917.ES.2023.28.27.2200773","article-title":"Intraregional Hospital Outbreak of OXA-244-Producing Escherichia Coli ST38 in Norway, 2020","volume":"28","author":"Lindemann","year":"2023","journal-title":"Eurosurveillance"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jhin.2023.12.020","article-title":"Emergence and Dissemination of Epidemic-Causing OXA-244 Carbapenemase-Producing Escherichia Coli ST38 through Hospital Sewage in Norway, 2020\u20132022","volume":"145","author":"Grevskott","year":"2024","journal-title":"J. Hosp. Infect."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1007\/s10096-024-04954-0","article-title":"Several Epidemic and Multiple Sporadic Genotypes of OXA-244-Producing Escherichia Coli in Poland; Predominance of the ST38 Clone","volume":"43","author":"Biedrzycka","year":"2024","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2300666","DOI":"10.2807\/1560-7917.ES.2024.29.22.2300666","article-title":"Large Hospital Outbreak Caused by OXA-244-Producing Escherichia Coli Sequence Type 38, Poland, 2023","volume":"29","author":"Izdebski","year":"2024","journal-title":"Eurosurveillance"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e00985-24","DOI":"10.1128\/aac.00985-24","article-title":"Colonization with Resistant Bacteria in Hospital Employees: An Epidemiological Surveillance and Typing Study","volume":"68","author":"Badinski","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s10096-023-04565-1","article-title":"A Rare Class A Carbapenemase FRI-11 in Enterobacter Clinical Strain","volume":"42","author":"Wu","year":"2023","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_103","first-page":"1535","article-title":"Serratia Marcescens Producing SME Carbapenemases: An Emerging Resistance Problem in the UK?","volume":"72","author":"Hopkins","year":"2017","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"dlad126","DOI":"10.1093\/jacamr\/dlad126","article-title":"Serratia Marcescens Enzyme SME-2 Isolated from Sputum in New Zealand","volume":"5","author":"Creighton","year":"2023","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"ref_106","unstructured":"(2025, January 01). World Health Organization Ten Threats to Global Health in 2019. Available online: https:\/\/www.who.int\/news-room\/spotlight\/ten-threats-to-global-health-in-2019."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Salam, M.A., Al-Amin, M.Y., Salam, M.T., Pawar, J.S., Akhter, N., Rabaan, A.A., and Alqumber, M.A.A. (2023). Antimicrobial Resistance: A Growing Serious Threat for Global Public Health. Healthcare, 11.","DOI":"10.20944\/preprints202305.0555.v1"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.2147\/IDR.S234610","article-title":"Antimicrobial Resistance: Implications and Costs","volume":"12","author":"Dadgostar","year":"2019","journal-title":"Infect. Drug Resist."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"S521","DOI":"10.1093\/cid\/ciz824","article-title":"Epidemiology and Diagnostics of Carbapenem Resistance in Gram-Negative Bacteria","volume":"69","author":"Nordmann","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Bucataru, A., Turcu-Stiolica, A., Calina, D., Balasoiu, A.T., Zlatian, O.M., Osman, A., Balasoiu, M., and Ghenea, A.E. (2024). Systematic Review and Meta-Analysis of Clinical Efficacy and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179574"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1093\/infdis\/jiw282","article-title":"The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace","volume":"215","author":"Logan","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13613-023-01153-6","article-title":"Rationale and Evidence for the Use of New Beta-Lactam\/Beta-Lactamase Inhibitor Combinations and Cefiderocol in Critically Ill Patients","volume":"13","author":"Barbier","year":"2023","journal-title":"Ann. Intensive Care"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/2\/141\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:25:31Z","timestamp":1760027131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/14\/2\/141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,1]]},"references-count":112,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["antibiotics14020141"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics14020141","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,1]]}}}