{"title":"In Vitro Activity and Resistance Mechanisms of Sulbactam/Durlobactam Against Acinetobacter baumannii Clinical Isolates in China (2019-2020).","authors":"Qingye Xu, Xiaochen Liu, Haiyang Liu, Siyuan Yang, Tailong Lei, Xiaoting Hua, Yunsong Yu","doi":"10.1016/j.cmi.2025.09.016","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a critical threat, with carbapenem-resistance rate exceeding 70% and limited therapeutic options in China. This multicenter study aimed to evaluate in vitro activity and resistance mechanisms of sulbactam/durlobactam (SUL-DUR), a newly approved β-lactam/β-lactamase inhibitor combination in China, against clinical A. baumannii isolates.</p><p><strong>Methods: </strong>A total of 1,303 A. baumannii isolates collected nationwide (2019-2020) were investigated. Antimicrobial susceptibility was determined by broth microdilution following CLSI guidelines. SUL-DUR-non-susceptible isolates underwent whole-genome sequencing through Illumina and/or Nanopore, and were assembled using shovill or unicycler. Genomic analyses included sequence typing, resistance gene annotation, SNP-based phylogenetic reconstruction, and pbp3 mutation mapping. Resistance mechanisms were investigated through qRT-PCR, site-directed mutagenesis, knockout and cloning experiments.</p><p><strong>Results: </strong>SUL-DUR demonstrated potent activity, with MIC<sub>50/90</sub> values of 2/4 and 4/4 mg/L and 95.47% susceptibility. Carbapenem-resistant isolates showed a 32-fold median MIC reduction compared to sulbactam alone, attributed to durlobactam's inhibition of OXA-23 and other β-lactamases. Among 59 non-susceptible isolates, PBP3 substitutions were the dominant resistance mechanism (48/59, 81.36%), confirmed by MIC reversions in mutagenesis experiments. Residual resistance in some strains implicated efflux pumps and unidentified factors. Six NDM-producing isolates exhibited elevated MICs, among which one strain harbored a novel NDM-87 with higher resistance to SUL-DUR. Genomic analyses highlighted the high-risk ST164 strains carrying chromosomal bla<sub>NDM-1</sub> and the regional dissemination ST2 clones with diverse PBP3 mutations.</p><p><strong>Conclusions: </strong>Despite SUL-DUR's strong efficacy against CRAB, the emergence of PBP3 mutations and NDM variants highlights the need for vigilant resistance monitoring. This study underscores the importance of integrated surveillance and mechanistic research to optimize SUL-DUR use in China and preserve its therapeutic effectiveness.</p>","PeriodicalId":10444,"journal":{"name":"Clinical Microbiology and Infection","volume":" ","pages":""},"PeriodicalIF":8.5000,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Microbiology and Infection","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.cmi.2025.09.016","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
引用次数: 0
Abstract
Objectives: Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a critical threat, with carbapenem-resistance rate exceeding 70% and limited therapeutic options in China. This multicenter study aimed to evaluate in vitro activity and resistance mechanisms of sulbactam/durlobactam (SUL-DUR), a newly approved β-lactam/β-lactamase inhibitor combination in China, against clinical A. baumannii isolates.
Methods: A total of 1,303 A. baumannii isolates collected nationwide (2019-2020) were investigated. Antimicrobial susceptibility was determined by broth microdilution following CLSI guidelines. SUL-DUR-non-susceptible isolates underwent whole-genome sequencing through Illumina and/or Nanopore, and were assembled using shovill or unicycler. Genomic analyses included sequence typing, resistance gene annotation, SNP-based phylogenetic reconstruction, and pbp3 mutation mapping. Resistance mechanisms were investigated through qRT-PCR, site-directed mutagenesis, knockout and cloning experiments.
Results: SUL-DUR demonstrated potent activity, with MIC50/90 values of 2/4 and 4/4 mg/L and 95.47% susceptibility. Carbapenem-resistant isolates showed a 32-fold median MIC reduction compared to sulbactam alone, attributed to durlobactam's inhibition of OXA-23 and other β-lactamases. Among 59 non-susceptible isolates, PBP3 substitutions were the dominant resistance mechanism (48/59, 81.36%), confirmed by MIC reversions in mutagenesis experiments. Residual resistance in some strains implicated efflux pumps and unidentified factors. Six NDM-producing isolates exhibited elevated MICs, among which one strain harbored a novel NDM-87 with higher resistance to SUL-DUR. Genomic analyses highlighted the high-risk ST164 strains carrying chromosomal blaNDM-1 and the regional dissemination ST2 clones with diverse PBP3 mutations.
Conclusions: Despite SUL-DUR's strong efficacy against CRAB, the emergence of PBP3 mutations and NDM variants highlights the need for vigilant resistance monitoring. This study underscores the importance of integrated surveillance and mechanistic research to optimize SUL-DUR use in China and preserve its therapeutic effectiveness.
期刊介绍：
Clinical Microbiology and Infection (CMI) is a monthly journal published by the European Society of Clinical Microbiology and Infectious Diseases. It focuses on peer-reviewed papers covering basic and applied research in microbiology, infectious diseases, virology, parasitology, immunology, and epidemiology as they relate to therapy and diagnostics.
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