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Purpose <p>Novel β-lactam/β-lactamase inhibitor combinations (BL/BLICs) such as ceftazidime/avibactam (CAZ/AVI), meropenem/vaborbactam (MEM/VAB), imipenem/relebactam (IMP/REL) and aztreonam/avibactam (ATM/AVI) have expanded therapeutic choices against KPC-producing <i>K. pneumoniae</i>. However, emerging resistance threatens their long-term efficacy. We investigated the prevalence, genomic mechanisms, and clinical correlates of resistance to these agents among KPC-producing <i>K. pneumoniae</i> bloodstream isolates.</p> Methods <p>Consecutive KPC-producing <i>K. pneumoniae</i> bloodstream isolates collected between 2021 and 2024 at a tertiary university hospital were tested for susceptibility to novel BL/BLICs and comparators. Whole-genome sequencing (WGS) was performed on isolates resistant to any BL/BLIC to characterise genetic backgrounds. Clinical data from corresponding patients were analysed to explore risk factors and outcomes.</p> Results <p>Among 178&#xa0;K<i>. pneumoniae</i> isolates, ATM/AVI, IMP/REL and MEM/VAB retained excellent in vitro activity (≥ 96% susceptible), while 11% were resistant to CAZ/AVI. One hundred fifty-four (86.5%) were susceptible to all BL/BLICs, whereas 24 (13.5%) displayed resistance to at least one agent, most commonly CAZ/AVI. WGS revealed a genetically diverse population mainly comprising high-risk clones ST512 and ST101. Resistance was driven by KPC variants (KPC-31, KPC-167, KPC-93, KPC-49, KPC-14, KPC-121, KPC-33) and porin disruptions (OmpK36 insertions, OmpK35 loss). Most patients (91%) had prior colonisation and recent β-lactam exposure; median time to resistance emergence was 47&#xa0;days. The 28-day mortality among patients with BL/BLIC-resistant infections was 21.7%.</p> Conclusion <p>Resistance to novel BL/BLICs among KPC-producing <i>K. pneumoniae</i> is emerging in Italian hospitals, largely mediated by <i>bla</i><sub>KPC</sub> variants and porin defects under selective antibiotic pressure. While ATM/AVI, MEM/VAB and IMP/REL remain highly active, resistance to CAZ/AVI is increasingly frequent. Continuous genomic surveillance and optimised antimicrobial stewardship are essential to preserve the efficacy of these last-line agents.</p>

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Emergence of resistance to novel β-lactam/β-lactamase inhibitor combinations in KPC-producing Klebsiella pneumoniae: clinical and genomic insights from consecutive bloodstream infections

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Matteo Boattini,
  • Sara Comini,
  • Guido Ricciardelli,
  • Lisa Pastrone,
  • Roberto Casale,
  • Luisa Guarrasi,
  • Rossana Cavallo,
  • Cristina Costa,
  • Paolo Gaibani,
  • Gabriele Bianco

摘要

Purpose

Novel β-lactam/β-lactamase inhibitor combinations (BL/BLICs) such as ceftazidime/avibactam (CAZ/AVI), meropenem/vaborbactam (MEM/VAB), imipenem/relebactam (IMP/REL) and aztreonam/avibactam (ATM/AVI) have expanded therapeutic choices against KPC-producing K. pneumoniae. However, emerging resistance threatens their long-term efficacy. We investigated the prevalence, genomic mechanisms, and clinical correlates of resistance to these agents among KPC-producing K. pneumoniae bloodstream isolates.

Methods

Consecutive KPC-producing K. pneumoniae bloodstream isolates collected between 2021 and 2024 at a tertiary university hospital were tested for susceptibility to novel BL/BLICs and comparators. Whole-genome sequencing (WGS) was performed on isolates resistant to any BL/BLIC to characterise genetic backgrounds. Clinical data from corresponding patients were analysed to explore risk factors and outcomes.

Results

Among 178 K. pneumoniae isolates, ATM/AVI, IMP/REL and MEM/VAB retained excellent in vitro activity (≥ 96% susceptible), while 11% were resistant to CAZ/AVI. One hundred fifty-four (86.5%) were susceptible to all BL/BLICs, whereas 24 (13.5%) displayed resistance to at least one agent, most commonly CAZ/AVI. WGS revealed a genetically diverse population mainly comprising high-risk clones ST512 and ST101. Resistance was driven by KPC variants (KPC-31, KPC-167, KPC-93, KPC-49, KPC-14, KPC-121, KPC-33) and porin disruptions (OmpK36 insertions, OmpK35 loss). Most patients (91%) had prior colonisation and recent β-lactam exposure; median time to resistance emergence was 47 days. The 28-day mortality among patients with BL/BLIC-resistant infections was 21.7%.

Conclusion

Resistance to novel BL/BLICs among KPC-producing K. pneumoniae is emerging in Italian hospitals, largely mediated by blaKPC variants and porin defects under selective antibiotic pressure. While ATM/AVI, MEM/VAB and IMP/REL remain highly active, resistance to CAZ/AVI is increasingly frequent. Continuous genomic surveillance and optimised antimicrobial stewardship are essential to preserve the efficacy of these last-line agents.