In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) against Multidrug-Resistant Pseudomonas aeruginosa in the Neutropenic Murine Thigh Infection Model

Abstract

We describe the in vivo efficacy of human-simulated WCK 5222 (cefepime-zidebactam) exposure against multidrug-resistant Pseudomonas aeruginosa (meropenem MICs 8 to >256 μg/ml) in a neutropenic murine thigh infection model. WCK 5222 MICs ranged from 4 to 32 μg/ml. Substantial in vivo WCK 5222 activity was observed against all isolates, further enhancing the efficacy of zidebactam alone in 11/16 isolates (WCK 5222 mean reduction, –1.62 ± 0.58 log10 CFU/thigh), and a lack of activity was observed with cefepime monotherapy.

Comparative Evaluation of the In Vitro Activities of WCK 5222 (Cefepime-Zidebactam) and Combination Antibiotic Therapies against Carbapenem-Resistant Pseudomonas aeruginosa

“…Coverage achieved with WCK 5222 alone was comparable to that achieved with C/T plus amikacin or fosfomycin. Taken together with the recently reported in vivo efficacy of WCK 5222 human-simulated exposures against MDR P. aeruginosa (5), our results suggest that WCK 5222, once approved as a single intravenous product, will be a future key player in empirical and definitive treatment of MDR and Carb r P. aeruginosa infections. Clinical and in vivo studies are needed to further characterize and assess the efficacy of WCK 5222 monotherapy compared to antibiotic combination therapies.…”

“…If these 30 strains are considered to be representative of CRP strains causing infections in regions burdened with increasing carbapenem resistance rates, an optimal empirical regimen would be represented by any combination that contained Ն1 antibiotic that inhibited growth at concentrations lower than an established susceptibility breakpoint (9), either when tested alone or in combination. This "best case scenario" among the 30 strains was C/T plus AMK (26/30, 87%), which was not as active as WCK 5222 alone, considering that 29/30 (97%) strains were inhibited at concentrations of 16 mg/liter, a potential breakpoint supported by in vivo data (5). Against clinical CRP, WCK 5222 demonstrated remarkable in vitro potency and greater activity than currently available broad spectrum ␤-lactams, including ceftolozane-tazobactam.…”

WCK 5222 (Cefepime-Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-Lactamase-Producing Enterobacteriaceae in the Neutropenic Mouse Pneumonia Model

“…However, BCHs, such as the afore- mentioned zidebactam, were developed because they not only exert ␤-lactamase inhibition but also have a direct antibacterial effect via high-affinity binding to PBP2 (16,17,20). The combination of agents that target PBP3 (cefepime) and PBP2 (zidebactam) has been shown to exhibit enhanced in vitro and in vivo activity compared to cefepime alone (15)(16)(17)(18)(19)(20)(28)(29)(30)(31). In fact, despite the fact that zidebactam possesses no direct inhibitory activity against MBL enzymes, potent activity against MBL-producing organisms has been demonstrated for cefepime with zidebactam, due to the complementary PBP binding activity (15,16,18,20).…”

The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

“…The discrepancy in the in vitro and in vivo observations was likely due to the β-lactam 'enhancer' properties of zidebactam that alter the PK/PD properties of cefepime [128]. A similar observation was obtained with P. aeruginosa [129]. The eventual cefepime-zidebactam MIC susceptibility breakpoints will likely need to take these disagreements into account [130].…”