In Vivo Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Murine Urinary Tract Infection Models

BACKGROUND: Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In the cefiderocol global surveillance study that focused on carbapenem-resistant Gram-negatives (SIDERO-CR-2014/2016), the most frequent bacterial species recovered from patients with urinary tract infection (UTI) were K. pneumoniae and P. aeruginosa. The purpose of this study was to evaluate the in vivo efficacy of cefiderocol againt carbapenem-resistant K. pneumoniae and P. aeruginosain murine UTI models. METHODS: Cefiderocol, ceftazidime/avibactam (CZA), ceftolozane/tazobactam (C/T), meropenem (MEM) and cefepime (FEP) were used as the test compounds. Four test strains of E. coli EC-14, K. pneumoniae VA-357 harboring KPC-2, P. aeruginosa SR10163 (FEP-resistant strain), and NUBL-1122 harboring IMP-1 were used. MIC was determined by broth microdilution method. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller Hinton broth. ICR female mice (n = 3–6) were infected by transurethral inoculation (ca. 2 × 10(5)CFU/mouse). Treatment was initiated 4, 10, 28, 34 hours post-infection. Viable cells in kidney tissue at 48 hours post-infection were counted. RESULTS: Against VA-357 (KPC-2), cefiderocol and CZA had the MICs of 1 and 2 μg/mL, respectively, and they showed ≥ 3-log(10)CFU from the initial therapy with 100 mg/kg treatment. These efficacy were superior to those of C/T, MEM and FEP at the same dose. Against NUBL-1122 (IMP-1), cefiderocol of 100 mg/kg significantly decreased the viable cells with ≥ 3-log(10)CFU (MIC, 1 μg/mL), while CZA, C/T, MEM and FEP did not show the bactericidal efficacy (MIC, ≥32 μg/mL). All the test compounds showed dose-dependent decrease in the viable cells in kidneys against ceftazidime-susceptible and -resistant strains of EC-14 and SR10163, respectively, in a reflection of their MICs. CONCLUSION: Cefiderocol exhibited in vivo bactericidal efficacy against carbapenem-resistant K. pneumoniae and P. aeruginosa in the UTI models, suggesting that cefiderocol is promising antibacterial agent for the treatment of cUTI infections caused by these resistant strains. DISCLOSURES: S. Matsumoto, SHIONOGI & CO., LTD.: Employee, Salary; S. Kanazawa, SHIONOGI & CO., LTD.: Employee, Salary; R. Nakamura, SHIONOGI & CO., LTD.: Employee, Salary; M. Tsuji, Shionogi & Co.: Employee, Salary; T. Sato, SHIONOGI & CO., LTD: Employee, Salary; Y. Yamano, SHIONOGI & CO., LTD.: Employee, Salary