In Vivo Efficacy of Humanized Exposures of Cefiderocol Compared with Cefepime (FEP) and Meropenem (MEM) against Gram-negative Bacteria in a Murine Thigh Model

Abstract

BackgroundCefiderocol (S-649266) is a novel siderophore cephalosporin under development by Shionogi (Osaka, Japan). Previous studies have demonstrated cefiderocol efficacy against a diverse population of Gram-negative bacteria with MICs ≤ 4 μg/mL. Our aim was to further define the agent’s clinical role by comparing the efficacy of humanized regimens of cefiderocol, FEP, and MEM against a subset of these Gram-negative isolates.Methods15 Gram-negative isolates were studied. MICs were determined by broth microdilution in triplicate, using reference CLSI methods. Pharmacokinetic studies were conducted to reproduce the humanized exposures of cefiderocol 2g q8h (3h inf.), FEP 2g q8h (3h inf.), and MEM 2g q8h (3 hours inf.). Antibiotics were started 2h post thigh inoculation (0h) and continued for 24 hours in immunocompromised mice. Efficacy was determined as the change in log10CFU at 24h compared with 0 hour controls.Results8 Enterobacteriaceae, 4 A. baumannii, and 3 P. aeruginosa isolates were studied. Cefiderocol, FEP, and MEM MICs were in the range of 0.12 to 8 μg/mL, ≤0.03 to >64 μg/mL, and ≤0.06 to >64 μg/mL, respectively. Three of the 15 isolates were susceptible to both meropenem and cefepime. All remaining isolates demonstrated in vitro resistance to one or both comparator agents. Cefiderocol was efficacious against all 15 isolates, regardless of FEP or MEM resistance, producing bacterial reductions from 0 hour between 0.89 to 3.04 log10 CFU. Against FEP and MEM susceptible isolates, cefiderocol treatment resulted in bacterial kill of 2.6 ± 0.5 and 2.1 ± 0.9 log10 CFU, respectively, similar to that of FEP (2.6 ± 0.5) and MEM (2.2 ± 0.6). Against MEM and FEP resistant isolates, cefiderocol produced a mean (± SD) bacterial reduction of 1.5 ± 0.4 log10 CFU at 24 hours.ConclusionCefiderocol humanized exposures produced antibacterial efficacy similar to MEM and FEP for susceptible pathogens, while also displaying activity against Enterobacteriaceae, A. baumannii, and P. aeruginosa with phenotypic resistance to the comparator β-lactams. These studies support the potential clinical utility of cefiderocol against these difficult-to-treat multidrug-resistant pathogens.Disclosures M. Tsuji, Shionogi & Co.: Employee, Salary; Y. Yamano, Shionogi & Co.: Employee, Salary; R. Echols, Shionogi & Co.: Employee, Salary; D. P. Nicolau, Shionogi & Co.: Research Contractor, Research support