Comparison of the in vivo efficacy and resistance development potential between cefiderocol and ceftolozane/tazobactam human simulated exposures against Pseudomonas aeruginosa in 72-hour murine thigh infection model.

Abstract

Background: Pseudomonas aeruginosa with difficult-to-treat resistance is a clinical burden. Ceftolozane/tazobactam is recommended for difficult-to-treat P. aeruginosa although cefiderocol represents an option due to its in vitro potency against isolates with ceftolozane/tazobactam-resistance. Head-to-head data assessing these compounds against difficult-to-treat P. aeruginosa are lacking.

Objectives: To assess the efficacy and resistance development of cefiderocol and ceftolozane/tazobactam in a 72-h murine thigh infection model against five clinical difficult-to-treat P. aeruginosa isolates susceptible for both agents and previously developed resistance to ceftolozane/tazobactam in patients.

Methods: Human-simulating regimens of ceftolozane/tazobactam (2/1 g IV q8h) and cefiderocol (2 g IV q8h) were utilized. Efficacy was assessed as the change in bacterial density from starting inoculum and compared to translational endpoints of 1- and 2-log₁₀-kill. Development of resistance was defined as a post-exposure MIC increase greater than 4-fold dilutions.

Results: Cefiderocol reached the 24h 1-log₁₀-kill endpoint in all isolates; however, ceftolozane/tazobactam reached same endpoint in 3/5 isolates. Cefiderocol reached 2-log₁₀-kill in all isolates by 48 h. Conversely, ceftolozane/tazobactam achieved same endpoint in four isolates by 72 h. In the cefiderocol and ceftolozane/tazobactam-treated groups 17% and 8% of the cultures displayed bacterial eradication after exposure to the human-simulating regimens which hinder MIC testing for those samples. Resistance was not detected for either antibiotic postexposure.

Conclusion: Despite susceptibility to both cefiderocol and ceftolozane/tazobactam, cefiderocol provided a more rapid kill profile and achieved a greater magnitude of bactericidal activity relative to ceftolozane/tazobactam. While frank resistance did not develop to either compound, differences in the rate and extent of kill were observed.