Cefiderocol (FDC) and ceftazidime-avibactam (CZA) are among the latest generation of commercialized antibiotics against carbapenem-resistant Gram negatives. However, emergence of CZA resistance is being increasingly reported, involving different KPC variants in Enterobacterales. By analyzing two CZA-resistant KPC-3 clinical variants, KPC-41 and KPC-50, we showed that KPC-41, and to a lesser extent KPC-50, may also have an impact on susceptibility to FDC leading to a cross-resistance. This feature highlights that a susceptibility testing to FDC is mandatory prior any clinical use of FDC for treating infections due to KPC producers.