In vivo activity of WCK 4282 (high-dose cefepime/tazobactam) against serine β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa in the neutropenic murine thigh infection model

Objectives: WCK 4282, high-dose cefepime/tazobactam, possesses potent in vitro activity against Gram-negative organisms including ESBL- and cephalosporinase-harbouring strains. The purpose of this evaluation was to investigate the in vivo activity of human-simulated exposures of WCK 4282 against serine-β-lactamase-harbouring Enterobacterales and Pseudomonas aeruginosa.

Methods: Nineteen clinical isolates were evaluated (ESBL/cephalosporinase producers, n = 8 Escherichia coli, n = 4 P. aeruginosa; KPC producers, n = 3 Klebsiella pneumoniae, n = 1 Klebsiella aerogenes; OXA-48/181 producers, n = 2 K. pneumoniae, n = 1 E. coli). WCK 4282 MICs ranged from 4 to 32 mg/L compared with 16 to >128 mg/L for cefepime. Thigh-infected neutropenic mice received cefepime, WCK 4282 or sham control over 24 h prior to harvest. Cefepime and tazobactam dosing regimens produced plasma profiles of fAUC, fT>MIC and fCmax similar to human exposure after WCK 4282 2/2 g every 8 h (1.5 h infusion).

Results: Bacterial burdens (log10 cfu/thigh) were 5.81 ± 0.36 at 0 h and 9.29 ± 0.88 at 24 h in untreated controls. WCK 4282 produced potent activity against ESBL/cephalosporinase-producing strains with WCK 4282 MIC ≤16 mg/L; mean changes in log10 cfu/thigh from 0 h were -1.70 ± 0.77 and +1.86 ± 2.03 log10 cfu/thigh for WCK 4282 and cefepime human-simulated regimens, respectively. WCK 4282 produced variable activity against serine-carbapenemase-harbouring isolates. For the KPC-harbouring strains, WCK 4282 produced bacteriostasis with a mean -0.1 ± 0.61 log10 cfu/thigh. Against OXA-48/181-harbouring isolates, WCK 4282 produced a range of change in bacterial burden of -1.23 ± 0.33 to +1.04 ± 0.7 log10 cfu/thigh.

Conclusions: Human-simulated exposures of WCK 4282 produced in vivo efficacy against ESBL/cephalosporinase-producing, piperacillin/tazobactam- and ceftolozane/tazobactam-non-susceptible Enterobacterales and P. aeruginosa. These findings support further development of this combination as a carbapenem-sparing agent.