Activity of Cefiderocol and Other New Antibiotics Against Extensively Drug-Resistant Klebsiella pneumoniae Strains

Abstract

Background. The spread of extensive drug-resistance among gram-negative bacteria calls for the search for antimicrobics with new mechanisms of actions.The aim was to assess susceptibility of extensively drug-resistant K. pneumoniae strains to cefiderocol and other new inhibitor-protected β-lactams, and to determine genetic mechanisms of antibiotic resistance.Methods. This study included 30 extensively drug-resistant K. pneumoniae strains collected in 2016–2021 from 4 regions of Belarus. Carbapenemase genes were detected by real-time PCR. Minimum inhibitory concentrations (MICs) for cefiderocol and other new antibiotics were assessed by microdilution method using the Sensititre system. Whole genome sequencing was performed for 2 resistant and 3 cefiderocol-susceptible strains. Genome assemblies and annotation were performed using UGENE v. 37.0 software. Nucleotide sequences were translated using CLC  Sequence Viewer v. 8.0 (QIAGEN) package. The PROVEAN software was used to assess amino asides substitutions and their influence on the functional activity of proteins.Results. KPC carbapenemase-producers were 4 strains, OXA-48 — 17, KPC+OXA-48 — 1, NDM — 7, OXA-48 + NDM — 1. All KPC-producers were susceptible to imipenem/relebactam and meropenem/vaborbactam. Resistance to ceftazidime-avibactam was noted in all NDM  producers and OXA-48+NDM  co-producer. The study has identified 9 cefiderocol-resistant strains. These were NDM and OXA-48-producers isolated from hospitalized patients with COVID-19 infection from 3 regions of Belarus. Resistant strains had functionally significant nonsynonymous  substitutions in the genes of TonB-dependent receptors for catecholate siderophores FepA (F472V, P64S) and Fiu (T92S).Conclusion. The study has shown high efficacy of new inhibitor-protected carbapenems and cephalosporins against certain types of carbapenemase-producers. Strains with mutational resistance to cefiderocol, an antibiotic not previously used in Belarus, have been identified.