Shazad Mushtaq1, Anna Vickers1, Neil Woodford1, David M Livermore1,2. 1. Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK. 2. Floor 2, Bob Champion Research & Educational Building, James Watson Road, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7UQ, UK.
Abstract
Background: 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. 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/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. Conclusions: 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.
Background: 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. 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/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. Conclusions: 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.
Authors: Krisztina M Papp-Wallace; Nhu Q Nguyen; Michael R Jacobs; Christopher R Bethel; Melissa D Barnes; Vijay Kumar; Saralee Bajaksouzian; Susan D Rudin; Philip N Rather; Satish Bhavsar; Tadiparthi Ravikumar; Prasad K Deshpande; Vijay Patil; Ravindra Yeole; Sachin S Bhagwat; Mahesh V Patel; Focco van den Akker; Robert A Bonomo Journal: J Med Chem Date: 2018-04-20 Impact factor: 7.446
Authors: Thomas F Durand-Réville; Satenig Guler; Janelle Comita-Prevoir; Brendan Chen; Neil Bifulco; Hoan Huynh; Sushmita Lahiri; Adam B Shapiro; Sarah M McLeod; Nicole M Carter; Samir H Moussa; Camilo Velez-Vega; Nelson B Olivier; Robert McLaughlin; Ning Gao; Jason Thresher; Tiffany Palmer; Beth Andrews; Robert A Giacobbe; Joseph V Newman; David E Ehmann; Boudewijn de Jonge; John O'Donnell; John P Mueller; Rubén A Tommasi; Alita A Miller Journal: Nat Microbiol Date: 2017-06-30 Impact factor: 17.745