WCK 4234, a novel diazabicyclooctane potentiating carbapenems against Enterobacteriaceae, Pseudomonas and Acinetobacter with class A, C and D β-lactamases.
Several diazabicyclooctanes (DBOs) are under development as inhibitors of class A and C β-lactamases. Inhibition of OXA (class D) carbapenemases is variable, with those of Acinetobacter spp. remaining notably resistant. We describe a novel DBO, WCK 4234 (Wockhardt), with distinctive activity against OXA carbapenemases.



MICs of imipenem and meropenem were determined by CLSI agar dilution with WCK 4234 added at 4 or 8 mg/L. Test organisms were clinical Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa with carbapenemases or carbapenem resistance via porin loss plus AmpC or ESBL activity. AmpC mutants were also tested.



WCK 4234, which lacked direct antibacterial activity, strongly potentiated imipenem and meropenem against Enterobacteriaceae with OXA-48/OXA-181 or KPC enzymes, or with combinations of impermeability and AmpC or ESBL activity, with MICs reduced to ≤2 mg/L in almost all cases. Carbapenems likewise were potentiated against P. aeruginosa ( n  =   2) with OXA-181 enzyme, with MICs reduced from 64-128 to 2-8 mg/L and against A. baumannii with OXA carbapenemases, particularly OXA-23 or hyperproduced OXA-51, with MICs reduced to ≤2 mg/L for 9/10 acinetobacters with OXA-23 enzyme. Carbapenems were not potentiated against Enterobacteriaceae or non-fermenters with metallo-β-lactamases.



WCK 4234 distinctively overcame resistance mediated by OXA-type carbapenemases, including those of A. baumannii . It behaved similarly to other DBOs against strains with KPC carbapenemases or combinations of impermeability and ESBL or AmpC activity.
Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.
Shazad
S
Mushtaq
Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.
Anna
A
Vickers
Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.
Neil
N
Woodford
Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, 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, Norfolk NR4 7UQ, UK.
David M
DM
Livermore
D000151:Acinetobacter Infections / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000201:enzymology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D015780:Carbapenems / Q000494:pharmacology*; D034242:Cyclooctanes / Q000494:pharmacology*; D055808:Drug Discovery; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D006801:Humans; D015378:Imipenem / Q000494:pharmacology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D013845:Thienamycins / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001618:beta-Lactamases / Q000096:biosynthesis / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D015780:Carbapenems; D034242:Cyclooctanes; D013845:Thienamycins; C000624486:WCK 4234; D065093:beta-Lactamase Inhibitors; D015378:Imipenem; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem