Cefiderocol Resistance in Pseudomonas aeruginosa ST175: A Case Report with Genomic Analysis

Background: Cefiderocol, a novel siderophore cephalosporin, has shown promising activity against multidrug-resistant (MDR) Gram-negative pathogens, including metallo-β-lactamase (MBL) producers. However, emerging reports suggest rapid resistance development under selective pressure, particularly in epidemic Pseudomonas aeruginosa lineages. Case presentation: We describe a 50-year-old man with a history of aortic dissection who developed ventilator-associated pneumonia due to P. aeruginosa ST175 carrying an IMP-type carbapenemase. Initial treatment with ceftazidime/avibactam plus aztreonam was followed by cefiderocol monotherapy. Although the patient showed early improvement, clinical relapse occurred within days, with subsequent isolation of cefiderocol-resistant P. aeruginosa. Whole-genome sequencing revealed high-impact mutations in iron acquisition systems (including fptA and pvdE) and multiple resistance determinants (oprD, efflux pump regulators, ampD/ampR), disrupting siderophore-mediated uptake and favoring multidrug resistance. Despite rescue therapy with ceftazidime/avibactam plus aztreonam and adjunctive agents, the patient ultimately died from septic shock and multiorgan failure. Discussion: This case highlights the ability of high-risk P. aeruginosa clones to rapidly adapt to cefiderocol, driven by combined alterations in iron metabolism and classical resistance pathways. The development of resistance within less than one week of exposure underscores the risk of using cefiderocol as monotherapy in infections caused by epidemic MDR clones. Conclusions: Cefiderocol resistance can emerge rapidly in vivo during treatment of infections caused by P. aeruginosa ST175. Continuous surveillance, molecular characterization of resistance mechanisms, and cautious use of cefiderocol—preferably in combination regimens—are warranted to preserve its clinical utility.