Abstract
The development of resistance to cefiderocol among multidrug resistant Acinetobacter baumannii has been attributed to downregulation in iron transport systems and a variety of β-lactamases. However, the precise contribution of each in clinical isolates remains to be determined. Sixteen clinical isolates with varying degrees of cefiderocol resistance were investigated. Susceptibility testing was performed with and without the presence of iron and avibactam. Expression of 10 iron transport systems and blaADC and blaOXA-51-type were analyzed by real time RT-PCR. The acquisition of a variety of β-lactamases was also determined. In 2 isolates the impact of silencing the blaADC gene was achieved using a target specific group II intron. For most resistant isolates, MICS for cefiderocol were similar with or without the presence of iron, and there was an overall decrease in expression of receptors (including pirA and piuA) involved in ferric uptake. However, expression of the ferrous uptake system (faoA) persisted. The addition of avibactam (4 μg/mL) lowered most cefiderocol MICs to 2 to 4 μg/mL. Most isolates possessed ADC-25 or ADC-33. Cefiderocol resistance correlated with over-expression of blaADC; silencing of this β-lactamase resulted in a ≥ 8-fold decrease in cefiderocol MICs. Over-expression of specific blaADC subtypes, in a background of generalized repression of ferric uptake systems, were consistent features in clinical isolates of cefiderocol-resistant A. baumannii.