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



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



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.



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.
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK.|Floor 2, Bob Champion Research & Educational Building, James Watson Road, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.
David M
DM
Livermore
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK.
Shazad
S
Mushtaq
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK.
Marina
M
Warner
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK.
Anna
A
Vickers
Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK.
Neil
N
Woodford
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D000077723:Cefepime; D002511:Cephalosporins / Q000494:pharmacology*; D002954:Citrobacter / Q000187:drug effects; D034242:Cyclooctanes / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D004926:Escherichia coli / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D007709:Klebsiella / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002511:Cephalosporins; D034242:Cyclooctanes; D010880:Piperidines; D065093:beta-Lactamase Inhibitors; C000624484:zidebactam; D000077723:Cefepime