WCK 5222 is a combination of
cefepime and the high-affinity PBP2-binding β-
lactam enhancer
zidebactam. The
cefepime-zidebactam combination is active against multidrug-resistant Gram-negative bacteria, including
carbapenemase-expressing Acinetobacter baumannii The mechanism of action of the combination involves concurrent multiple
penicillin binding protein inhibition, leading to the enhanced bactericidal action of
cefepime. The aim of the present study was to assess the impact of the
zidebactam-mediated enhanced in vitro bactericidal action in modulating the percentage of the time that the free drug concentration remains above the MIC (percent fT>MIC) for
cefepime required for the in vivo killing of A. baumannii
Cefepime and
cefepime-zidebactam MICs were comparable and ranged from 2 to 16 mg/liter for the A. baumannii strains (n = 5) employed in the study. Time-kill studies revealed the improved killing of these strains by the
cefepime-zidebactam combination compared to that by the constituents alone. Employing a neutropenic mouse lung
infection model, exposure-response analyses for all the A. baumannii strains showed that the
cefepime fT>MIC required for 1-log10 kill was 38.9%. In the presence of a noneffective dose of
zidebactam, the
cefepime fT>MIC requirement dropped significantly to 15.5%, but it still rendered a 1-log10 kill effect. Thus,
zidebactam mediated the improvement in
cefepime's bactericidal effect observed in time-kill studies, manifested in vivo through the lowering of
cefepime's pharmacodynamic requirement. This is a first-ever study demonstrating a β-
lactam enhancer role of
zidebactam that helps augment the in vivo activity of
cefepime by reducing the magnitude of its pharmacodynamically relevant exposures against A. baumannii.