1544. Efficacy of Human-Simulated Cefiderocol Exposure Against Gram-Negative Bacteria in an Iron-Overloaded Murine Thigh Infection Model

Abstract

Abstract Background Cefiderocol (CFDC) is a siderophore-cephalosporin conjugate which exploits bacterial iron scavenging in reaction to the hypoferremic response of host immunity and achieves potent in vivo activity against various Gram-negative bacteria (GNB). In patients with hereditary or iatrogenic hemochromatosis, the hypoferremic response may be altered by iron overload, which could hypothetically suppress the bacterial iron scavenging that bolsters CFDC efficacy. We compared CFDC efficacy between iron-overloaded (Fe+) and normal iron (NFe) murine thigh infection models. Methods Female CD-1 mice received iron dextran 100 mg/kg/d for 14 d to induce iron overload (Fe+) (ASM Microbe 2019 abstract HMB-373); an equal number of same-age mice were not dosed (NFe). On day 15, both thighs of mice rendered neutropenic were inoculated with GNB suspensions of 107 CFU/mL. Twenty CFDC-susceptible isolates with previously determined CFDC MIC from 0.25 to 4 mg/L, including Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriales, were used. Two hours after inoculation, treatment mice were dosed with a CFDC regimen simulating the human plasma PK profile after doses of 2g q8h (3 h infusion), while control mice were sacrificed (0 h) or dosed with saline placebo on the same schedule as the CFDC regimen (24 h). All procedures were simultaneously performed in Fe+ and NFe mice. Efficacy was defined as a change in log10 CFU/thigh at 24 h vs. 0 h and was compared between Fe+ and NFe mice for individual isolates using Student’s t-test. Results Mean (SD) bacterial burdens at 0 h in Fe+ and NFe control mice were 5.77 (0.52) and 5.76 (0.52) and log10 CFU/thigh, respectively, and, at 24 h, increased by 3.49 (0.73) and 3.42 (0.96) log10 CFU/thigh, respectively. Mean (SD) efficacies of CFDC in Fe+ and NFe mice were -1.98 (0.83) and -1.98 (0.72) log10 CFU/thigh, respectively. For 17 of 20 individual isolates, no significant differences in efficacy between Fe+ and NFe mice were observed (P > 0.05); 2 of the 3 isolates with a difference had greater efficacy in Fe+ mice. Conclusion Human-simulated exposure of CFDC is equally efficacious in iron-overloaded and normal hosts against a variety of GNB susceptible to CFDC. The potential clinical use of CFDC to treat GNB infections in patients with iron overload is supported. Disclosures All authors: No reported disclosures.