Cefiderocol Resistance in Klebsiella pneumoniae Is Linked to SHV Extended-Spectrum β-Lactamase Activities and Functional Loss of the Outer Membrane Porin OmpK35.

Abstract

Klebsiella pneumoniae AR 0047 from the CDC and FDA Antibiotic Resistance Isolate Bank is resistant to cefiderocol, a siderophore-conjugated cephalosporin. Genomics analysis and genetic complementation revealed that a frameshift mutation in ompK35 contributed to cefiderocol resistance. Heterologous expression of blaSHV-5 or blaSHV-12 in Escherichia coli increased the host resistance to cefiderocol. Moreover, avibactam, a β-lactamase inhibitor, enhanced cefiderocol activity against the resistant strain. Therefore, cefiderocol resistance is linked to SHV and the loss of ompK35. IMPORTANCE Understanding cefiderocol resistance mechanisms is essential for providing solutions to treat infections and to prevent resistance development. Cefiderocol resistance in Klebsiella pneumoniae AR 0047 is linked to SHV β-lactamase activities and functional loss of outer membrane porin. The cefiderocol-avibactam combination represents an opportunity to increase potency against cefiderocol-resistant pathogens.