Antibiotic susceptibility to new antibiotics and genetic characterisation of carbapenemase-producing Enterobacterales: low activity of cefiderocol against NDM-producing isolates

Carbapenemase-producing Enterobacterales (CPEs) pose a serious medical threat. In recent years several new antibiotics targeting carbapenem-resistant Gram-negative bacteria have been introduced, including cefiderocol, ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam. However, no systematic monitoring of susceptibility levels is routinely performed, which challenges rational use and the effectiveness of the new antibiotics due to the risk of rapid emergence of resistance. To assess the susceptibility of new antibiotics targeting carbapenem-resistant Gram-negative bacteria against CPEs in Sweden. All CPE isolates collected through Sweden's national microbial surveillance programme in 2022 were included. Susceptibility testing for the new antibiotics and other agents relevant to CPEs was performed with broth microdilution for all drugs except for cefiderocol and fosfomycin, for which EUCAST disk diffusion was applied. Whole-genome sequencing was performed for genetic characterisation. In total, 286 CPEs were included in the study. Susceptibility rates were high for ceftazidime-avibactam in OXA-48-like producing isolates (n=116, >95%) and for ceftazidime-avibactam and meropenem-vaborbactam against KPC/IMI-producing isolates (n=22, ≥90%). In contrast, susceptibility to cefiderocol was low in MBL-producing Enterobacterales according to disk diffusion: 0% (0/76) of Escherichia coli and 6% (3/54) of Klebsiella pneumoniae were classified susceptible, and 93% (71/76) and 39% (21/54), respectively, were resistant. The presence of blaNDM-5 was associated with the highest level of resistance. Considerable variability was observed in the susceptibility rates of the newly introduced antibiotics against CPEs collected in Sweden. Continued surveillance is warranted to guide rational use of these new last-resort antibiotics.