Scholarlink

<p><i>Klebsiella pneumoniae</i> carbapenemase (KPC) is a frequent and widespread carbapenemase, with over 260 variants identified. While KPC often evolves resistance to ceftazidime-avibactam, cefiderocol remains a key treatment option. Some variants, such as KPC-33 (D179Y), reduce cefiderocol susceptibility, but typically with only modest MIC increases. However, KPC’s genetic adaptability raises concern that further mutations could lead to high-level resistance, compromising cefiderocol’s efficacy. To anticipate this risk, we explored the mutational potential of <i>bla</i><sub>KPC-2</sub>, <i>bla</i><sub>KPC-3</sub>, and <i>bla</i><sub>KPC-33</sub> using random mutagenesis followed by 10-day selection under increasing cefiderocol pressure and whole genome sequencing. Libraries of 10<sup>5</sup>, 10<sup>4</sup>, and 10<sup>5</sup> mutants, respectively, yielded isolates with significantly elevated MICs, some exceeding 32&#xa0;mg/L. All resistant clones shared a phenotype marked by cross-resistance to cefiderocol, ceftazidime, ceftazidime-avibactam, cefixime, and piperacillin, but restored susceptibility to carbapenems and most other β-lactams. Our findings highlight that no single mutation enables KPC to efficiently hydrolyze cefiderocol. Instead, high-level resistance requires a combination of enzymatic mutations and chromosomal alterations—such as disruptions in <i>cirA</i> and <i>ybiX</i>—suggesting a multifactorial and stepwise evolutionary pathway. Notably, <i>ybiX</i> has not previously been associated with cefiderocol resistance. These results underscore the importance of ongoing surveillance to detect emerging cefiderocol resistance in KPC-producing <i>Enterobacterales</i>.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Exploring mutational possibilities of KPC variants to reach high level resistance to cefiderocol

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月25日

查看全文
  • Sidonie Hanna,
  • Kevin La,
  • Yutaka Yoshii,
  • Maud Gits-Muselli,
  • Imane El Meouche,
  • Yasmine Benhadid-brahmi,
  • Stéphane Bonacorsi,
  • André Birgy

摘要

Klebsiella pneumoniae carbapenemase (KPC) is a frequent and widespread carbapenemase, with over 260 variants identified. While KPC often evolves resistance to ceftazidime-avibactam, cefiderocol remains a key treatment option. Some variants, such as KPC-33 (D179Y), reduce cefiderocol susceptibility, but typically with only modest MIC increases. However, KPC’s genetic adaptability raises concern that further mutations could lead to high-level resistance, compromising cefiderocol’s efficacy. To anticipate this risk, we explored the mutational potential of blaKPC-2, blaKPC-3, and blaKPC-33 using random mutagenesis followed by 10-day selection under increasing cefiderocol pressure and whole genome sequencing. Libraries of 105, 104, and 105 mutants, respectively, yielded isolates with significantly elevated MICs, some exceeding 32 mg/L. All resistant clones shared a phenotype marked by cross-resistance to cefiderocol, ceftazidime, ceftazidime-avibactam, cefixime, and piperacillin, but restored susceptibility to carbapenems and most other β-lactams. Our findings highlight that no single mutation enables KPC to efficiently hydrolyze cefiderocol. Instead, high-level resistance requires a combination of enzymatic mutations and chromosomal alterations—such as disruptions in cirA and ybiX—suggesting a multifactorial and stepwise evolutionary pathway. Notably, ybiX has not previously been associated with cefiderocol resistance. These results underscore the importance of ongoing surveillance to detect emerging cefiderocol resistance in KPC-producing Enterobacterales.