In vitro activity of cefepime/zidebactam (WCK 5222) against Gram-negative bacteria.

Abstract

Objectives:

Diazabicyclooctanes (DBOs) inhibit class A, class C and some class D β-lactamases. A few also bind PBP2, conferring direct antibacterial activity and a β-lactamase-independent 'enhancer' effect, potentiating β-lactams targeting PBP3. We tested a novel DBO, zidebactam, combined with cefepime.

Methods:

CLSI agar dilution MICs were determined with cefepime/zidebactam in a chequerboard format. Bactericidal activity was also measured.

Results:

Zidebactam MICs were ≤2 mg/L (mostly 0.12-0.5 mg/L) for most Escherichia coli , Klebsiella , Citrobacter and Enterobacter spp., but were >32 mg/L for Proteeae, most Serratia and a few E. coli , Klebsiella and Enterobacter/Citrobacter . The antibacterial activity of zidebactam dominated chequerboard studies for Enterobacteriaceae, but potentiation of cefepime was apparent for zidebactam-resistant isolates with class A and C enzymes, illustrating β-lactamase inhibition. Overall, cefepime/zidebactam inhibited almost all Enterobacteriaceae with AmpC, ESBL, K1, KPC and OXA-48-like β-lactamases at 1 + 1 mg/L and also 29 of 35 isolates with metallo-carbapenemases, including several resistant to zidebactam alone. Zidebactam MICs for 36 of 50 Pseudomonas aeruginosa were 4-16 mg/L, and the majority of AmpC, metallo-β-lactamase-producing and cystic fibrosis isolates were susceptible to cefepime/zidebactam at 8 + 8 mg/L. Zidebactam MICs for Acinetobacter baumannii and Stenotrophomonas maltophilia were >32 mg/L; potentiation of cefepime was frequent for S. maltophilia , but minimal for A. baumannii . Kill curve results largely supported MICs.

Conclusions:

Zidebactam represents a second triple-action DBO following RG6080, with lower MICs for Enterobacteriaceae and P. aeruginosa . Clinical evaluation of cefepime/zidebactam must critically evaluate the reliance that can be placed on this direct antibacterial activity and on the enhancer effect as well as β-lactamase inhibition.

• Authors: David M Livermore, Shazad Mushtaq, Marina Warner, Anna Vickers, Neil Woodford
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 72 Issue 5 Pg. 1373-1385 (05 01 2017) ISSN: 1460-2091 [Electronic] England
• PMID: 28158732 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Anti-Bacterial Agents
• Azabicyclo Compounds
• Cephalosporins
• Cyclooctanes
• Piperidines
• beta-Lactamase Inhibitors
• zidebactam
• Cefepime

Topics

• Anti-Bacterial Agents (pharmacology)
• Azabicyclo Compounds (pharmacology)
• Cefepime
• Cephalosporins (pharmacology)
• Citrobacter (drug effects)
• Cyclooctanes (pharmacology)
• Enterobacteriaceae (drug effects)
• Enterobacteriaceae Infections (microbiology)
• Escherichia coli (drug effects)
• Gram-Negative Bacteria (drug effects)
• Humans
• Klebsiella (drug effects)
• Microbial Sensitivity Tests
• Piperidines (pharmacology)
• beta-Lactamase Inhibitors (pharmacology)