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

Infection. 2026 Apr;54(2):841-852. doi: 10.1007/s15010-025-02716-4. Epub 2025 Dec 23.

Abstract

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.

Keywords: Aztreonam/avibactam; Ceftazidime/avibactam; Imipenem/relebactam; KPC variant; Meropenem/vaborbactam; Novel β-lactam/β-lactamase inhibitor.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Bacterial Agents* / pharmacology
  • Anti-Bacterial Agents* / therapeutic use
  • Azabicyclo Compounds
  • Bacteremia* / drug therapy
  • Bacteremia* / microbiology
  • Ceftazidime
  • Drug Combinations
  • Drug Resistance, Multiple, Bacterial / genetics
  • Female
  • Humans
  • Klebsiella Infections* / drug therapy
  • Klebsiella Infections* / epidemiology
  • Klebsiella Infections* / microbiology
  • Klebsiella pneumoniae* / drug effects
  • Klebsiella pneumoniae* / enzymology
  • Klebsiella pneumoniae* / genetics
  • Klebsiella pneumoniae* / isolation & purification
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Whole Genome Sequencing
  • beta-Lactamase Inhibitors* / pharmacology
  • beta-Lactamase Inhibitors* / therapeutic use
  • beta-Lactamases* / genetics
  • beta-Lactamases* / metabolism
  • beta-Lactams* / pharmacology

Substances

  • beta-Lactamase Inhibitors
  • beta-Lactamases
  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • beta-Lactams
  • avibactam, ceftazidime drug combination
  • Drug Combinations
  • Ceftazidime