Outbreak-driven dissemination of KPC variant–producing Klebsiella pneumoniae: the emerging challenge of ceftazidime/avibactam and cefiderocol co-resistance

Ceftazidime/avibactam (CZA) resistance in KPC-producing Klebsiella pneumoniae is a critical public health threat, traditionally associated with in vivo selection. In this three-year study conducted in an Intensive Care Unit (ICU), we aimed to investigate the emergence of CZA-resistant (CZA-R) K. pneumoniae in patients treated with CZA, assessing the possible role of hospital outbreaks in dissemination. We analysed a three-year dataset of antibiotic consumption and K. pneumoniae isolates collected from ICU patients receiving CZA therapy. Whole-genome sequencing (Illumina/Oxford Nanopore) and epidemiological reconstruction were used to investigate resistance mechanisms, KPC variants, and transmission dynamics, including outbreak detection. Among 871 ICU patients, 17.9% received CZA therapy, and 9% of these tested positive for CZA-resistant strains. We identified eight distinct KPC variants, including the novel KPC-295. While in vivo evolution remained the primary driver (71.4%), epidemiological reconstruction revealed that 28.6% of resistant isolates resulted from horizontal transmission, forming three distinct outbreaks of KPC-31, KPC-62, and KPC-66 producers. Alarmingly, 76.2% of CZA-R isolates exhibited co-resistance to FDC, a phenomenon linked to the presence of KPC variants conferring CZA resistance and likely enhanced by the fec operon. These clones persisted in the hospital environment and gut reservoirs of CZA-naive patients. Our findings suggest that CZA-R outbreaks may be underreported due to difficulties in KPC variant diagnostics and outbreak reconstruction. The emergence of co-resistance to CZA and FDC severely limits treatment options and poses major challenges for patient care and antimicrobial stewardship. These findings underscore the need for strengthened infection prevention and control measures, including early microbiological detection, active surveillance, and prompt containment strategies in ICU settings.