Deciphering variable resistance to novel carbapenem-based β-lactamase inhibitor combinations in a multi-clonal outbreak caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae resistant to ceftazidime/avibactam.

Carbapenemase-producing Enterobacterales represent a major cause of difficult-to-treat infections world-wide. Novel β-lactam/β-lactamase inhibitor combinations, including ceftazidime/avibactam (CZA), meropenem/vaborbactam (MVB), and imipenem/relebactam (IMR), represented a break-through in the treatment of some carbapenemase-producing Enterobacterales infections. However, acquired resistance to these agents has been reported in Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Herein, we reported an outbreak caused by CZA-resistant, KPC-producing Klebsiella pneumoniae (KPC-Kp), which was also variably resistant to carbapenem-based β-lactam/β-lactamase inhibitor combinations. Bacterial isolates were subjected to antimicrobial susceptibility testing, whole-genome sequencing, determination of bla Overall, 15 KPC-Kp, nine CZA-resistant (CZA In this multi-clonal outbreak of KPC-Kp, the overproduction of KPC-3 was the leading mechanism of cross-resistance to CZA and MVB, whereas resistance to IMR appeared less affected. The emergence and dissemination of similar resistance mechanisms may have relevant clinical and diagnostic implications, and their surveillance is warranted.

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