Comparative In Vivo Antibacterial Activity of Human-Simulated Exposures of Cefiderocol and Ceftazidime against Stenotrophomonas maltophilia in the Murine Thigh Model.

ABSTRACT

Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of ß-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.