Rapid Development of cefiderocol resistance in a carbapenem-resistant Pseudomonas aeruginosa isolate associated with mutations in the pyoverdine biosynthesis pathway

Here we report the in vivo development of cefiderocol resistance within 11 days after therapy initiation in a critically ill patient with bloodstream infection, infection of anal fistula and pneumonia caused by carbapenem-resistant P. aeruginosa. Compared to a cefiderocol-naive P. aeruginosa blood culture isolate, agar diffusion susceptibility testing found a reduced cefiderocol inhibition zone diameter in a P. aeruginosa recovered from anal abscess tissue cultures after initiation of cefiderocol therapy. Subsequent whole genome sequencing suggested that both isolates were of clonal origin. Comparison of genomes found an accumulation of missense mutations within genes associated with biosynthesis of pyoverdine, the main siderophore produced by P. aeruginosa. Quantification of pyoverdine production under iron-depleted conditions showed a significantly higher pyoverdine production by the cefiderocol-resistant isolate. This case highlights the potentially rapid emergence of cefiderocol resistance in P. aeruginosa, and pinpoints towards a potential involvement of iron up-take systems in this process.