WCK 5222 (#Cefepime / #Zidebactam) Pharmacodynamic Target Analysis against Metallo-β-lactamase producing #Enterobacteriaceae in the #Neutropenic Mouse #Pneumonia Model (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

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

Alexander J. Lepak, Miao Zhao, David R. Andes

DOI: 10.1128/AAC.01648-19

 

ABSTRACT

WCK 5222 is a combination of cefepime and the novel β-lactam enhancer (BLE) zidebactam. Zidebactam has a dual mechanism of action involving high-affinity penicillin binding protein (PBP) 2 binding as well as inhibition of Ambler class A, and C, enzymes. In the current study, we evaluated the effect of zidebactam on the cefepime pharmacodynamic target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) secondary to MBL-production. Plasma and ELF pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered as protein binding is <10%. Both drugs exhibited similar PK exposures including terminal elimination half-life (cefepime ∼0.4 h, zidebactam 0.3-0.5 h). The penetration into ELF was concentration dependent for both drugs, reaching 50% and 70% for cefepime and zidebactam, respectively. Dose ranging studies were performed in lung-infected mice with one of eight MBL-producing clinical strains. WCK 5222 was administered in Q4- and Q8-hourly regimens to vary exposures from 0-100% T>MIC. The results were modelled to evaluate the relationship between cefepime T>MIC, when zidebactam was co-administered, and therapeutic effect. The results revealed a strong association between T>MIC and effect (R2 0.82). Net stasis in organism burden occurred at cefepime T>MIC exposures of only 18%. A 1-log kill endpoint was demonstrated for the group of organisms at approximately 31% T>MIC. These target exposures for stasis and 1-log kill are much lower than previously observed cephalosporin monotherapy PK/PD targets.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Cefepine; Zidebactam.

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Activity of #cefepime / #zidebactam (WCK 5222) against #Enterobacteriaceae, #Pseudomonas aeruginosa and #Acinetobacter baumannii endemic to #NYC #medical centres (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Activity of cefepime/zidebactam (WCK 5222) against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii endemic to New York City medical centres

Zeb Khan, Alejandro Iregui, David Landman, John Quale

Journal of Antimicrobial Chemotherapy, dkz294, https://doi.org/10.1093/jac/dkz294

Published: 11 July 2019

 

Abstract

Background

The combination of cefepime and zidebactam (WCK5222), a novel β-lactam enhancer, has demonstrated activity against a wide variety of Gram-negative pathogens and is currently under clinical evaluation.

Objectives

To examine the activity of cefepime/zidebactam against: (i) a contemporary collection of Gram-negative isolates from New York City; (ii) a collection of carbapenem-resistant clinical isolates; and (iii) a collection of isolates with characterized resistance mechanisms.

Methods

Susceptibility tests were performed using broth microdilution for cefepime, zidebactam and cefepime/zidebactam (1:1).

Results

More than 99% of a contemporary collection of Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. had cefepime/zidebactam MICs ≤2 mg/L, the susceptibility breakpoint for cefepime. For K. pneumoniae, the acquisition of blaKPC resulted in increased MICs, although MICs remained ≤2 mg/L for 90% of KPC-possessing isolates. Overall for Pseudomonas aeruginosa, 98% of isolates had MICs ≤8 mg/L and MICs were affected by increased expression of ampC. For carbapenem-resistant P. aeruginosa, 78% of isolates had cefepime/zidebactam MICs ≤8 mg/L. The activity of cefepime/zidebactam against Acinetobacter baumannii was lower, with 85% of all isolates and 34% of carbapenem-resistant isolates with MICs ≤8 mg/L (cefepime interpretative criteria).

Conclusions

Cefepime/zidebactam demonstrated excellent activity against Enterobacteriaceae and P. aeruginosa, although activity was reduced in carbapenem-non-susceptible isolates. The activity against A. baumannii was reduced and studies examining the therapeutic efficacy in strains with high cefepime/zidebactam MICs are warranted.

Topic:  pseudomonas aeruginosa – cefepime – enterobacter – enterobacteriaceae – new york city – acinetobacter baumannii – bacterial carbapenemase resistance blakpc gene – malnutrition-inflammation-cachexia syndrome – carbapenem resistance

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Enterobacteriaceae; Pseudomonas aeruginosa; Acinetobacter baumannii; Cefepine; Zidebactam; USA; NYC.

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