Acinetobacter baumannii and cefiderocol between cidality and adaptability

Among the bacterial species included in the ESKAPE group, Acinetobacter baumannii is of great interest due to its intrinsic and acquired resistance to many antibiotic classes and its ability to infect different body districts. Cefiderocol is a novel cephalosporin active against Gram-negative bacteria with promising efficacy on A. baumannii infections, but some studies have reported therapeutic failures even in the presence of susceptible A. baumannii strains. This study aims to investigate the interactions between cefiderocol and ten A. baumannii strains with different susceptibility profiles to this drug. We confirmed diverse susceptibility profiles in the strains, with resistance values close to the EUCAST-proposed breakpoints. MBC/MIC (minimal bactericidal concentration/minimal inhibitory concentration) ratios, demonstrated bactericidal activity of the drug; on the other hand, bacterial regrowth was evident after exposition to cefiderocol, as were changes in the shape of colonies and bacterial cells. A switch to a non-susceptible phenotype in the presence of high cefiderocol concentrations was found as adaptation mechanisms implemented by these A. baumannii strains to overcome the cidal activity of this antibiotic, also confirmed by the presence of heteroresistant, unstable subpopulations. As our isolates harbored numerous {beta}-lactamase genes, {beta}-lactamase inhibitors showed the ability to restore the antimicrobial activity of cefiderocol regardless of the different non-susceptibility levels of the tested strains. These in vitro results, can sustain the concept of using combination therapy to eliminate drug-adapted subpopulations and regain full cefiderocol activity in this difficult-to-treat species.