Relationship of TonB-dependent receptors with susceptibility to cefiderocol in clinical isolates of Pseudomonas aeruginosa

Cefiderocol maintains activity against most MDR Gram-negative pathogens including Pseudomonas aeruginosa. In laboratory-derived isolates, down-regulation of TonB-dependent siderophore receptors have been implicated in resistance to cefiderocol.In this report, the expression of seven TonB-dependent siderophore receptors was examined in 10 clinical isolates with cefiderocol MICs ranging from ≤0.03-8 mg/L. In addition, genetic sequences of the siderophore receptors were analysed to identify potentially disruptive mutations.There was no clear association between expression of the receptors with cefiderocol susceptibility, including the receptors piuA/piuD and pirA previously implicated in cefiderocol uptake. In addition, there were no disabling mutations identified in the receptors. Acquired β-lactamase activity also could not explain the range in cefiderocol susceptibility.The aetiology of reduced susceptibility to cefiderocol in clinical isolates of P. aeruginosa remains an enigma and worthy of further investigation.