{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:49:28Z","timestamp":1790189368547,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82550115"],"award-info":[{"award-number":["82550115"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82550115"],"award-info":[{"award-number":["82550115"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Horizontal Research Project of China\u2013Japan Friendship Hospital","award":["2024-HX-JC-22"],"award-info":[{"award-number":["2024-HX-JC-22"]}]},{"name":"Horizontal Research Project of China\u2013Japan Friendship Hospital","award":["2025-HX-211"],"award-info":[{"award-number":["2025-HX-211"]}]},{"award":["2024-HX-JC-22"],"award-info":[{"award-number":["2024-HX-JC-22"]}],"id":[{"id":"https:\/\/ror.org\/037cjxp13","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2025-HX-211"],"award-info":[{"award-number":["2025-HX-211"]}],"id":[{"id":"https:\/\/ror.org\/037cjxp13","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Shionogi China Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: \u03b2-lactam\/\u03b2-lactamase inhibitor combinations (BL\/BLIs) and siderophore cephalosporin serve as critical polymyxin alternatives for carbapenem-resistant Pseudomonas aeruginosa (CRPA). However, systematic multicenter clinical data from China and the resistance mechanisms underlying non-susceptibility to these agents remain poorly defined. Methods: We collected 442 CRPA isolates from 10 hospitals across eight Chinese provinces (2017\u20132025), determined minimum inhibitory concentrations (MICs) for cefiderocol (FDC), ceftazidime\u2013avibactam (CZA), imipenem\u2013relebactam (IMR), and ceftolozane\u2013tazobactam (CT) through broth microdilution, and performed whole-genome sequencing. Resistance genes, virulence factors, and sequence types (STs) were identified. A chromosomal co-selection score (eight non-mobile resistance genes) was constructed. Multivariable regression and receiver operating characteristic (ROC) analysis identified predictors of non-susceptibility. Results: Carbapenemase genes were detected in only 33 isolates (7.5%): metallo \u03b2 lactamase (MBL) genes in 28, blaKPC-2 in 2, and blaGES 5\/14 in 3; the ST463 clone was absent. MBL producers were resistant to CZA, IMR, and CT (0\u20134% susceptible) but 100% susceptible to FDC. KPC 2 and GES producers were CZA-susceptible (100%) but IMR- and CT-resistant. Among 127 CZA non-susceptible isolates, 99 (78%) lacked carbapenemase genes; ST270 (from a single center) accounted for 64.6% of these. The chromosomal score independently predicted MIC (\u03c1: CT 0.64, FDC 0.59, IMR 0.50, CZA 0.25\u2014largely attributable to ST270; all p &lt; 0.001). ExoU positive isolates had lower MICs (FDC median 0.12 vs. 0.25 mg\/L, p &lt; 0.001). FDC remained active against 97.3% of all isolates and 100% of carbapenemase-positive ones. Genotype-based prediction yielded area under the ROC curve (AUC) values of 0.86 (CT) and 0.80 (CZA). Conclusions: Mechanisms other than acquired carbapenemases\u2014consistent with chromosomal determinants\u2014accounted for most non-susceptibility in this predominantly northern Chinese respiratory tract CRPA collection. Carbapenemase types determine distinct drug susceptibility patterns. Routine carbapenemase detection fails to identify most CZA-resistant strains. FDC retained the broadest in vitro activity and is a reliable therapeutic option pending clinical outcome data, and ST270-associated resistance deserves continuous surveillance.<\/jats:p>","DOI":"10.3390\/antibiotics15090835","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Beyond Carbapenemases: Chromosomal Resistance Mechanisms and Carbapenemase Type Determine Susceptibility to Novel \u03b2-Lactam\/\u03b2-Lactamase Inhibitor Combinations and Cefiderocol in Carbapenem-Resistant Pseudomonas aeruginosa from China"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-2034","authenticated-orcid":false,"given":"Jiankang","family":"Zhao","sequence":"first","affiliation":[{"name":"National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, New Cornerstone Science Laboratory, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Fan","sequence":"additional","affiliation":[{"name":"National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, New Cornerstone Science Laboratory, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Cao","sequence":"additional","affiliation":[{"name":"National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, New Cornerstone Science Laboratory, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China"},{"name":"Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S1473-3099(25)00118-5","article-title":"The WHO Bacterial Priority Pathogens List 2024: A prioritisation study to guide research, development, and public health strategies against antimicrobial resistance","volume":"25","author":"Sati","year":"2025","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e159","DOI":"10.1016\/S2666-5247(22)00329-9","article-title":"Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): A prospective cohort study","volume":"4","author":"Reyes","year":"2023","journal-title":"Lancet Microbe"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Xiao, S., Liang, X., Han, L., and Zhao, S. (2023). Incidence, antimicrobial resistance and mortality of Pseudomonas aeruginosa bloodstream infections among hospitalized patients in China: A retrospective observational multicenter cohort study from 2017 to 2021. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.1294141"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.cmi.2023.12.026","article-title":"Pseudomonas aeruginosa antimicrobial susceptibility profiles, resistance mechanisms and international clonal lineages: Update from ESGARS-ESCMID\/ISARPAE Group","volume":"30","author":"Oliver","year":"2024","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1016\/j.cmi.2025.03.013","article-title":"Emerging resistance mechanisms to newer \u03b2-lactams in Pseudomonas aeruginosa","volume":"31","author":"Oliver","year":"2025","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1093\/jac\/dkae263","article-title":"Impact of chromosomally encoded resistance mechanisms and transferable \u03b2-lactamases on the activity of cefiderocol and innovative \u03b2-lactam\/\u03b2-lactamase inhibitor combinations against Pseudomonas aeruginosa","volume":"79","author":"Maceiras","year":"2024","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1097\/QCO.0000000000001044","article-title":"Not all carbapenem-resistant Pseudomonas aeruginosa strains are alike: Tailoring antibiotic therapy based on resistance mechanisms","volume":"37","author":"Falcone","year":"2024","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e0207925","DOI":"10.1128\/spectrum.02079-25","article-title":"Activity of cefiderocol against Pseudomonas aeruginosa from the USA and Europe (2020\u20132023) with difficult-to-treat resistance phenotype, including those nonsusceptible to recently developed \u03b2-lactam\/\u03b2-lactamase inhibitor combinations: Results from the SENTRY antimicrobial surveillance program","volume":"13","author":"Kimbrough","year":"2025","journal-title":"Microbiol. Spectr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"ciae403","DOI":"10.1093\/cid\/ciae403","article-title":"Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections","volume":"81","author":"Tamma","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e0093223","DOI":"10.1128\/spectrum.00932-23","article-title":"Comparison of In Vitro Activity of Ceftazidime-Avibactam and Imipenem-Relebactam against Clinical Isolates of Pseudomonas aeruginosa","volume":"11","author":"Wang","year":"2023","journal-title":"Microbiol. Spectr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e0067523","DOI":"10.1128\/aac.00675-23","article-title":"Bla (KPC-2) overexpression and bla (GES-5) carriage as major imipenem\/relebactam resistance mechanisms in Pseudomonas aeruginosa high-risk clones ST463 and ST235, respectively, in China","volume":"67","author":"Li","year":"2023","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2497901","DOI":"10.1080\/21505594.2025.2497901","article-title":"Genomic insights into the rapid rise of Pseudomonas aeruginosa ST463: A high-risk lineage\u2019s adaptive strategy in China","volume":"16","author":"Dong","year":"2025","journal-title":"Virulence"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0218725","DOI":"10.1128\/spectrum.02187-25","article-title":"Novel KPC-2 variants and epidemic ST463 clones underlie ceftazidime\/avibactam resistance in carbapenem-resistant Pseudomonas aeruginosa","volume":"14","author":"Hu","year":"2026","journal-title":"Microbiol. Spectr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zhao, L., Pu, J., Liu, Y., Cai, H., Han, M., Yu, Y., and Tang, J. (2025). High prevalence of carbapenem-resistant Pseudomonas aeruginosa and identification of a novel VIM-type metallo-\u03b2-lactamase, VIM-92, in clinical isolates from northern China. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1543509"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lu, H., Zhang, C., Zhao, B., Li, Y., and Qin, S. (2025). Genomic insights into bla (AFM)-positive carbapenem-resistant Pseudomonas aeruginosa in China. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1546662"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e665","DOI":"10.1016\/S2666-5247(23)00113-1","article-title":"The epidemiology and virulence of carbapenem-resistant Pseudomonas aeruginosa in China","volume":"4","author":"Zhu","year":"2023","journal-title":"Lancet Microbe"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e0319624","DOI":"10.1128\/spectrum.03196-24","article-title":"Diagnostic algorithm for the detection of carbapenemases and extended-spectrum \u03b2-lactamases in carbapenem-resistant Pseudomonas aeruginosa","volume":"13","author":"Mancini","year":"2025","journal-title":"Microbiol. Spectr."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Xie, X., Liu, Z., Huang, J., Wang, X., Tian, Y., Xu, P., and Zheng, G. (2024). Molecular epidemiology and carbapenem resistance mechanisms of Pseudomonas aeruginosa isolated from a hospital in Fujian, China. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1431154"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.33073\/pjm-2025-022","article-title":"Antimicrobial Resistance Mechanisms in Carbapenem-Resistant Pseudomonas aeruginosa Clinical Strains Isolated in Shanghai, China","volume":"74","author":"Zhu","year":"2025","journal-title":"Pol. J. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12941-025-00800-z","article-title":"Diverse modes of ceftazidime\/avibactam resistance acquisition in carbapenem-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa from a Chinese intensive care unit","volume":"24","author":"Zhou","year":"2025","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e0140922","DOI":"10.1128\/aac.01409-22","article-title":"Biochemical Insights into Imipenem Collateral Susceptibility Driven by ampC Mutations Conferring Ceftolozane\/Tazobactam Resistance in Pseudomonas aeruginosa","volume":"67","author":"Cabot","year":"2023","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"108279","DOI":"10.1016\/j.ijid.2025.108279","article-title":"Susceptibilities of cefiderocol, meropenem-xeruborbactam, cefepime-taniborbactam, aztreonam-avibactam, and sulbactam-durlobactam against imipenem-non-susceptible Gram-negative bacilli in Taiwan","volume":"163","author":"Wang","year":"2026","journal-title":"Int. J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e0012724","DOI":"10.1128\/aac.00127-24","article-title":"Cefiderocol heteroresistance associated with mutations in TonB-dependent receptor genes in Pseudomonas aeruginosa of clinical origin","volume":"68","author":"Egge","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e0100923","DOI":"10.1128\/aac.01009-23","article-title":"The emergence of cefiderocol resistance in Pseudomonas aeruginosa from a heteroresistant isolate during prolonged therapy","volume":"68","author":"Teran","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e0141025","DOI":"10.1128\/aac.01410-25","article-title":"Loss of the ferripyochelin receptor FptA drives reduced cefiderocol susceptibility and impairs fitness in Pseudomonas aeruginosa PA14","volume":"70","author":"Kang","year":"2026","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e323","DOI":"10.1016\/S1473-3099(26)00317-8","article-title":"Cefiderocol heteroresistance in NDM Enterobacterales","volume":"26","author":"Ozturk","year":"2026","journal-title":"Lancet Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e0222423","DOI":"10.1128\/spectrum.02224-23","article-title":"The type III secretion system facilitates systemic infections of Pseudomonas aeruginosa in the clinic","volume":"12","author":"Wu","year":"2024","journal-title":"Microbiol. Spectr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/S1473-3099(24)00648-0","article-title":"Effectiveness of ceftazidime-avibactam versus ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the USA (CACTUS): A multicentre, retrospective, observational study","volume":"25","author":"Shields","year":"2025","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S1473-3099(25)00469-4","article-title":"Cefiderocol versus standard therapy for hospital-acquired and health-care-associated Gram-negative bacterial bloodstream infection (the GAME CHANGER trial): An open-label, parallel-group, randomised trial","volume":"26","author":"Paterson","year":"2026","journal-title":"Lancet Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1002\/cpbi.102","article-title":"Using SPAdes De Novo Assembler","volume":"70","author":"Prjibelski","year":"2020","journal-title":"Curr. Protoc. Bioinform."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/9\/835\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:39:07Z","timestamp":1787978347000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/9\/835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["antibiotics15090835"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics15090835","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]}}}