A Novel {beta}-lactam Enhancer Zidebactam Augments the In vivo Pharmacodynamic Activity of Cefepime in Neutropenic Mouse Lung A. baumannii Infection Model [Mechanisms of Action]

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

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