Bacteraemia with an MBL-producing Klebsiella pneumoniae: treatment and the potential role of cefiderocol heteroresistance

Infections with carbapenem-resistant Enterobacterales (CRE) are associated with mortality rates of up to 50% in the USA.1 Optimal empirical treatment remains challenging and requires collaboration between microbiologists, clinicians and sometimes translational researchers as traditional susceptibility testing methods may fail to detect clinically meaningful resistance. Here we describe a patient with Klebsiella pneumoniae bloodstream infection where heteroresistance to cefiderocol may have contributed to clinical failure despite seemingly appropriate antimicrobial therapy. Heteroresistance is a phenomenon whereby an established minority subpopulation of resistant bacteria within the larger community proliferates under specific antibiotic pressure. These subpopulations are often infrequent enough that they are not detected using standard antimicrobial susceptibility testing. After prolonged exposure to the specific antibiotic, the resistant subpopulation expands, and clinically meaningful resistance can occur. Transient and unstable gene amplification or mutations that revert if antibiotic pressure is withdrawn may drive the resistant subpopulation.2 Recently, cefiderocol heteroresistance has been reported in CRE, but the clinical implications are unresolved.3 Our findings raise concern that the increased mortality observed with cefiderocol use in trials such as CREDIBLE-CR might be attributed to undetected heteroresistance despite reported susceptibility using conventional testing.3