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 bla(KPC) 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.