Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases · 2025
In vitro activity and resistance mechanisms of sulbactam/durlobactam against Acinetobacter baumannii clinical isolates in China (2019-2020).
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Xu Qingye, Liu Xiaochen, Liu Haiyang, Yang Siyuan, Lei Tailong, Hua Xiaoting, Yu Yunsong
Аннотация
OBJECTIVES: Carbapenem-resistant Acinetobacter baumannii poses a critical threat, with carbapenem-resistance rate exceeding 70% and limited therapeutic options in China. This multicentre 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 1303 A. baumannii isolates collected nationwide (2019-2020) were investigated. Antimicrobial susceptibility was determined by broth microdilution following clinical and laboratory standards institute guidelines. SUL-DUR-nonsusceptible 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, single-nucleotide polymorphisms-based phylogenetic reconstruction, and pbp3 mutation mapping. Resistance mechanisms were investigated through quantitative reverse transcription PCR, site-directed mutagenesis, knockout and cloning experiments.
RESULTS: SUL-DUR demonstrated potent activity, with MIC50/90 values of 2/4 mg/L and 4/4 mg/L and 95.47% susceptibility. Carbapenem-resistant isolates showed a 32-fold median MIC reduction compared with sulbactam alone, attributed to durlobactam's inhibition of OXA-23 and other β-lactamases. Among 59 nonsusceptible 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 (New Delhi Metallo-β-lactamase) -producing isolates exhibited elevated MICs, among which one strain harboured 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 carbapenem-resistant A baumannii, 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.
METHODS: A total of 1303 A. baumannii isolates collected nationwide (2019-2020) were investigated. Antimicrobial susceptibility was determined by broth microdilution following clinical and laboratory standards institute guidelines. SUL-DUR-nonsusceptible 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, single-nucleotide polymorphisms-based phylogenetic reconstruction, and pbp3 mutation mapping. Resistance mechanisms were investigated through quantitative reverse transcription PCR, site-directed mutagenesis, knockout and cloning experiments.
RESULTS: SUL-DUR demonstrated potent activity, with MIC50/90 values of 2/4 mg/L and 4/4 mg/L and 95.47% susceptibility. Carbapenem-resistant isolates showed a 32-fold median MIC reduction compared with sulbactam alone, attributed to durlobactam's inhibition of OXA-23 and other β-lactamases. Among 59 nonsusceptible 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 (New Delhi Metallo-β-lactamase) -producing isolates exhibited elevated MICs, among which one strain harboured 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 carbapenem-resistant A baumannii, 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.