WCK 4234, a novel diazabicyclooctane potentiating carbapenems against Enterobacteriaceae, Pseudomonas and Acinetobacter with class A, C and D β-lactamases

Background: Several diazabicyclooctanes (DBOs) are under development as inhibitors of Class A and C -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. 
Methods: 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. 
Results: WCK 4234, which lacked direct antibacterial activity, strongly potentiated imipenem and meropenem against Enterobacteriaceae with OXA-48/181, 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 mg/L 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--lactamases. 
 Conclusion: WCK 4234 distinctively overcame resistance mediated by OXA-type carbapenemases, including in A. baumannii. It behaved similarly to other DBOs against strains with KPC carbapenemases or combinations of impermeability and ESBL or AmpC activity.