Antimicrobial activity of high-dose cefepime-tazobactam (WCK 4282) against a large collection of gram-negative organisms collected worldwide in 2018 and 2019.

Background: High-dose cefepime-tazobactam (WCK 4282) is currently under clinical development at a dosage of 2 grams/2 grams every 8 hours with prolonged infusion (90 minutes).

Objective: To evaluate the in vitro activity of high-dose cefepime-tazobactam.

Methods: A total of 23, 246 gram-negative organisms were collected from 133 medical centers (34 countries) in 2018-2019 and susceptibility was tested by broth microdilution method against cefepime-tazobactam (tazobactam at fixed 8 mg/L) and comparator agents.

Results: Cefepime-tazobactam and cefepime inhibited 97.6% and 85.4% of Enterobacterales isolates (n = 18,143) at ≤8 mg/L, respectively. Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem (97.0% susceptible) and greater than ertapenem (95.2% susceptible) or piperacillin-tazobactam (88.0% susceptible). Moreover, cefepime-tazobactam retained potent activity against meropenem-susceptible Enterobacterales isolates that were nonsusceptible to ceftazidime, ceftriaxone, and piperacillin-tazobactam (96.3% inhibited at ≤8 mg/L) or ceftolozane-tazobactam (96.2% inhibited at ≤8 mg/L). Against P. aeruginosa (n = 4,553), the percentage of isolates inhibited at ≤8 mg/L of cefepime-tazobactam (82.7%) was higher than meropenem (76.0%) or piperacillin-tazobactam (76.4%), and the percentage inhibited at the proposed pharmacokinetic/pharmacodynamic breakpoint of ≤16 mg/L (92.2%) was comparable with ceftolozane-tazobactam (93.5%).

Conclusions: The results of this in vitro study support the clinical development of cefepime-tazobactam as a carbapenem-sparing option to treat infections caused by Enterobacterales and P. aeruginosa, including multidrug-resistant isolates.