Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens

Heteroresistance is a form of antibiotic resistance in which a bacterial isolate harbours a minority resistant subpopulation of cells that coexists with a majority susceptible population, and it is often undetected by standard antimicrobial susceptibility testing (AST; appendix pp 1–2).2 In the presence of the relevant antibiotic, the resistant subpopulation is selected for and predominates; however, after antibiotic removal, the resistant subpopulation returns to baseline (appendix p 3). In the CREDIBLE-CR study, the minimum inhibitory concentration of some isolates exposed to cefiderocol increased after treatment, which might be consistent with heteroresistance.1 CREDIBLE-CR involved isolates from 16 countries and SIDERO-CR involved those from 52 countries, with similar frequencies of detected cefiderocol resistance (by standard AST) as observed in our research, suggesting that the GA, USA, isolates are representative. [...]the widespread and undetected cefiderocol heteroresistance among carbapenem-resistant pathogens observed here might explain the discordance between this drug's excellent susceptibility profile in vitro and its association with increased patient mortality. The Georgia Emerging Infections Program and the Multi-Site Gram-negative Surveillance Initiative are funded by the Centers for Disease Control and Prevention.