Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model

Cefiderocol is a siderophore-cephalosporin conjugate with greater in vitro potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models. Female CD-1 mice rendered neutropenic received 2 weeks of iron dextran at 100 mg/kg of body weight/day intraperitoneally (iron-overloaded model) or no injections (standard model). Mice were inoculated (10⁷ CFU/ml) with Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa with previously determined cefiderocol MICs from 0.25 to 64 mg/liter. Human-simulated regimens of cefiderocol or meropenem (2 g every 8 h [q8h], 3-h infusion) were administered for 24 h (31 strains) or 72 h (15 strains; cefiderocol only). Procedures were simultaneously performed in standard and iron-overloaded models. Mean bacterial burdens (log₁₀ CFU/thigh) at baseline were 5.75 ± 0.47 versus 5.81 ± 0.51 in standard versus iron-overloaded models, respectively. At 24 h, mean burdens in standard versus iron-overloaded models decreased by -0.8 ± 1.9 versus -1.2 ± 2.0 (P = 0.25) in meropenem-treated mice and by -1.5 ± 1.4 versus -1.6 ± 1.5 (P = 0.54) in cefiderocol-treated mice. At 72 h, mean burdens in cefiderocol-treated mice decreased by -2.5 ± 1.5 versus -2.5 ± 1.4. No overall differences in efficacy between the models were observed for meropenem or cefiderocol. Human-simulated exposure of cefiderocol is equally efficacious in iron-overloaded and normal hosts. The potential clinical use of cefiderocol to treat Gram-negative infections in patients with iron overload is supported.