Human serum proteins and susceptibility of Acinetobacter baumannii to cefiderocol: role of iron transport

LE, CASIN; PIMENTEL, CAMILA; PASTERAN, FERNANDO; TUTTOBENE, MARISEL ROMINA; SUBILS, TOMAS; ESCALANTE, JENNY; NISHIMURA, BRENT; VILA, ALEJANDRO J.; CORSO, ALEJANDRA; ACTIS, LUIS A.; TOLMASKY, MARCELO E.; BONOMO, ROBERT A.; RAMÍREZ, MARÍA SOLEDAD

Lisboa

Congreso; 32nd ECCMID; 2022

Background: Cefiderocol (CFDC) is a recently introduced antibiotic with a cephalosporin component that targets cell wall synthesis and a chlorocatechol siderophore moiety that facilitates cell penetration by active iron (Fe) transporters. Observations in recent clinical trials revealed that patients with pulmonary or bloodstream A. baumannii infections do not respond as well as expected to treatment with cefiderocol. Materials: The model multidrug-resistant A. baumannii strains AB5075, AMA16 and AB0057 were used. RNA Extraction and qRT-PCR were carried out from A. baumannii strains grown in 100% human serum (HS), 3.5% human serum albumin (HSA), or 4% human pleural fluid (HPF). CFDC susceptibility assays using E-test strips were performed using HS, HSA, and HPF. Results: The expression of genes related to the Fe uptake systems are down-regulated, while genes contributing to -lactam resistance are up-regulated in A. baumannii cells grown in the presence of HS, HSA, or HPF. Furthermore, minimum inhibitory concentration (MIC) values of CFDC were raised in the presence of the mentioned fluids. Conclusions: The reduced expression of the Fe-uptake systems and the concomitant increased expression of genes modulating β-lactam resistance may be contributing to the lower clinical response in patients with pulmonary or bloodstream A. baumannii infections due to the lower transport capabilities of CFDC and modification of genes associated with resistance to -lactams.