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
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • IDWeek poster-WCK 5222 thigh 9-5-18.pdf (508.3 kB)
  • Background: Zidebactam (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.

    Methods: Six CR-ACBN clinical isolates, including 5 isolates expressing OXA-23 or OXA-24, were studied. FEP and WCK 5222 MICs were 128 - >512 and 16 - 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 1h infusion), ZID HSR (equivalent to a clinical dose of 1 g IV q8h as 1h infusion), or WCK 5222 HSR (FEP HSR + ZID HSR). Control mice were vehicle-dosed. Changes in log10 CFU/mL at 24h compared with 0h controls were measured to assess efficacy.

    Results: The average log10 CFU/thigh at 0h across all isolates was 5.85 ± 0.22. Compared with 0h control, the mean bacterial growth at 24h 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 2 isolates.

    Conclusion: HSR 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.

    Safa Almarzoky Abuhussain, PharmD, Department of Pharmacy, Um-alQura university, Makkah, Saudi Arabia, Lindsay Avery, PharmD, Center of Anti-Infective Researchand Development, Hartford Hospital, Hartford, CT, Kamilia Abdelraouf, Ph.D., Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT and David P. Nicolau, PharmD, FCCP, FIDSA, Division of Infectious Diseases, Hartford Hospital, Hartford, CT

    Disclosures:

    S. Almarzoky Abuhussain, None

    L. Avery, None

    K. Abdelraouf, None

    D. P. Nicolau, Wockhardt: Investigator , Research support .

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