1336. Assessment of the In Vivo Efficacy of WCK 5222 (Cefepime-Zidebactam) Against Carbapenems-Resistant Acinetobacter baumannii (CR-ACBN) in the Neutropenic Murine Thigh Infection Model

Abstract

BackgroundZidebactam (ZID) is a novel β-lactam enhancer with high binding affinity to PBP2 and intrinsic activity against many Gram-negative pathogens, with the exception of ACBN. ZID also inhibits β-lactamases but not OXA carbapenemases associated with ACBN or metallo-β-lactamases. However, WCK 5222 (a combination of cefepime [FEP] and ZID) has shown in vitro activity against ACBN, including OXA producers. Moreover, we have previously shown that WCK 5222 human-simulated regimen (HSR) causes extensive (i.e., >2 log) eradication of ACBN from neutropenic mice lung. This study aimed to evaluate the in vivo efficacy of the HSR of WCK 5222 compared with FEP HSR or ZID HSR alone against ACBN in the neutropenic murine thigh infection model.MethodsSix CR-ACBN clinical isolates, including five isolates expressing OXA-23 or OXA-24, were studied. FEP and WCK 5222 MICs were 128 to >512 and 16 to 64 mg/L, respectively. The ZID MIC was >512 mg/L for all isolates. ICR mice were rendered transiently neutropenic via cyclophosphamide prior to thigh inoculation with bacterial suspensions of 107 CFU/mL. Treatment mice received either FEP HSR (equivalent to a clinical dose of 2 g IV q8h as a 1 hour infusion), ZID HSR (equivalent to a clinical dose of 1 g IV q8h as 1 hour infusion), or WCK 5222 HSR (FEP HSR + ZID HSR). Control mice were vehicle-dosed. Changes in log10 CFU/mL at 24 hours compared with 0 hours controls were measured to assess efficacy.ResultsThe average log10 CFU/thigh at 0 hours across all isolates was 5.85 ± 0.22. Compared with 0 hours control, the mean bacterial growth at 24 hours in the untreated control mice, FEP HSR, and ZID HSR were 2.34 ± 0.93, 1.36 ± 1.40, and 2.04 ± 0.80 log10CFU/thigh, respectively. The WCK 5222 HSR produced a decline in bacterial burden for all isolates [mean reduction of −2.09 ± 1.01 log10CFU/thigh]; 4/6 isolates achieved ≥ 2-log reduction while ≥1-log reduction was attained with the remaining two isolates.ConclusionHSR of WCK 5222 showed potent in vivo activity against CR-ACBN expressing OXA carbapenemases in the murine thigh model which is attributed to the β-lactam enhancing effect of ZID, driven by the complementary PBP binding of FEP and ZID. These results support the clinical evaluation of WCK 5222 for the management of infections due to CR-ACBN.Disclosures D. P. Nicolau, Wockhardt: Investigator, Research support.