Good Correlation of Cefiderocol Between In Vivo Efficacy Murine Thigh/Lung Infection Models and MIC Determined in Iron-Depleted Conditions

BACKGROUND: Cefiderocol (S-649266) is a novel siderophore cephalosporin active against a wide variety of carbapenem-resistant Gram-negative bacteria such as Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. This potent activity is mainly due to its efficient penetration through the outer membrane via active iron transporter systems and its high stability to both serine- and metallo-carbapenemases. The antibacterial activity is evaluated under iron-deficient conditions to mimic the infection sites in human. In this study, the efficacy in murine infection models was evaluated in order to show that the MIC under iron-deficient conditions is more predictive for the in vivo efficacy. METHODS: A total of 19 strains of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii were used for the in vivo efficacy studies using neutropenic murine thigh or lung infection models. The efficacy was evaluated by the bacterial reduction at 24 hours after treatment by subcutaneous q3h administration of cefiderocol which was initiated at 2 hours post-infection. MIC of cefiderocol was determined by broth microdilution methods according to CLSI instruction using both CAMHB and iron-depleted CAMHB (ID-CAMHB). The PK/PD analysis was conducted by calculating the percentage T>MIC value of free plasma concentrations (fT>MIC) in infected mice. RESULTS: The efficacy in murine thigh and lung infection models were evaluated by using 12 and 15 strains, respectively. The average fT>MIC value required for static effect and 1 log(10) reduction was shown to be 75% and 85%, respectively irrespective of Gram-negative bacterial species and the infection sites. The PK/PD analysis for 3 strains, which had large different MIC between two conditions (16, 2 and 2 mg/mL in ID-CAMHB and 128, 32 and 32 mg/mL in CAMHB, respectively) showed that the fT>MIC required for 1 log(10) reduction ranged from 71.7% to 89.0% using the MIC in ID-CAMHB. On the other hand, these values were significantly lower (ranging from 10 to 50%) using the MIC in CAMHB. CONCLUSION: The PK/PD analysis using murine thigh/lung infection models showed that ID-CAMHB is the appropriate media for MIC determination for the prediction of in vivo efficacy irrespective of infection sites and bacterial species. DISCLOSURES: Y. Yamano, SHIONOGI & CO., LTD.: Employee, Salary; R. Nakamura, SHIONOGI & CO., LTD.: Employee, Salary; T. Sato, SHIONOGI & CO., LTD.: Employee, Salary; M. Tsuji, Shionogi & Co.: Employee, Salary; R. Echols, Shionogi & CO., LTD: Consultant, Consulting fee