Novel PiuC, PirA, and PiuA mutations leading to cefiderocol resistance progression in IMP-16- and KPC-2-producing from a leukemic patient.

UNLABELLED

is an opportunistic pathogen capable of causing severe infections in immunocompromised individuals, who often require prolonged antibiotic therapy. The emergence of carbapenemase-producing has further complicated the management of nosocomial infections, limiting therapeutic options. Cefiderocol has recently emerged as a promising antipseudomonal agent, using the bacterial iron transport system to gain entry into the cell; however, there have been reports of resistant to cefiderocol. We describe the cefiderocol resistance progression of four consecutive isolates from one patient with T-cell acute lymphoblastic leukemia. Analysis of potential genes involved in cefiderocol transport resulted in three genes mutated in two resistant isolates. One isolate presented a S116F substitution in PiuC, and the other presented a deletion of 29 amino acids in the signal peptide of PiuA and a STOP substitution in PirA, resulting in the deletion of a piece of the channel. These mutations increased 24- and 64-folds the cefiderocol minimum inhibitory concentration, respectively. The mutations in the aforementioned genes may directly impact siderophore internalization, thereby contributing to an elevation in the MIC of the antibiotic.

IMPORTANCE

Carbapenem-resistant poses a significant challenge due to its broad antibiotic resistance. Cefiderocol is a novel antibiotic aimed at combating infections caused by such organisms. However, if these pathogens develop resistance to this new drug, it hinders treatment efficacy and options. Therefore, it is crucial to identify and describe mutations in the genes involved in the uptake of cefiderocol to find better treatment strategies for patients infected with multidrug-resistant .