Contribution of Iron-Transport Systems and β-Lactamases to Cefiderocol Resistance in Clinical Isolates of Acinetobacter baumannii Endemic to New York City

The development of resistance to cefiderocol among multidrug resistant Acinetobacter baumannii has been attributed to downregulation in iron transport systems and a variety of beta-lactamases. However, the precise contribution of each in clinical isolates remains to be determined. The development of resistance to cefiderocol among multidrug resistant Acinetobacter baumannii has been attributed to downregulation in iron transport systems and a variety of beta-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 bla(ADC) and bla(OXA-51-type) were analyzed by real time RT-PCR. The acquisition of a variety of beta-lactamases was also determined. In 2 isolates the impact of silencing the bla(ADC) 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 mu g/mL) lowered most cefiderocol MICs to 2 to 4 mu g/mL. Most isolates possessed ADC-25 or ADC-33. Cefiderocol resistance correlated with over-expression of bla(ADC); silencing of this beta-lactamase resulted in a >= 8-fold decrease in cefiderocol MICs. Over-expression of specific bla(ADC) subtypes, in a background of generalized repression of ferric uptake systems, were consistent features in clinical isolates of cefiderocol-resistant A. baumannii.

Automated summary

The development of resistance to cefiderocol among multidrug resistant Acinetobacter baumannii has been attributed to downregulation in iron transport systems and a variety of beta-lactamases. However, the precise contribution of each in clinical isolates remains to be determined. This study investigated 16 clinical isolates with varying degrees of cefiderocol resistance, analyzing the expression of iron transport systems and beta-lactamases, as well as determining the impact of silencing the bla(ADC) gene and the addition of avibactam. The results showed that resistance to cefiderocol in Acinetobacter baumannii is associated with over-expression of specific bla(ADC) subtypes, along with repression of ferric uptake systems.