ABSTRACTKlebsiella pneumoniaeAR 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 inompK35contributed to cefiderocol resistance. Heterologous expression ofblaSHV-5orblaSHV-12inEscherichia coliincreased 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 ofompK35.IMPORTANCEUnderstanding cefiderocol resistance mechanisms is essential for providing solutions to treat infections and to prevent resistance development. Cefiderocol resistance inKlebsiella pneumoniaeAR 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.