Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae

David M. Livermore*, Shazad Mushtaq

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

Objectives: The proliferation of carbapenemases in Enterobacteriaceae demands new therapies, with current interest centred on β-lactamase inhibitor combinations. RPX7009 is a new boron-based inhibitor of several class A and C β-lactamases and is being developed in combination with biapenem (RPX2003). We investigated the in vitro activity of the combination. Methods: Three hundred Enterobacteriaceae isolates, representing major carbapenemase types, were tested. MICs were determined by CLSI agar dilution with RPX7009 at 2, 4 and 8 mg/L or in a chequerboard format with RPX7009 in doubling dilutions from 0.25 to 32 mg/L. Results: RPX7009 lacked direct antibacterial activity but achieved a dose-dependent potentiation of biapenem against Enterobacteriaceae possessing KPC, SME or IMI/NMC-A carbapenemases: concentrations as low as 2 mg/L reduced the MICs of biapenem to =1 mg/L for over 90% of isolates. RPX7009 also gave a weak potenti-ation of biapenem against Enterobacteriaceae with combinations of AmpC or extended-spectrum β-lactamase activity and impermeability, although any practical gain against such strains will depend on the breakpoints assigned. RPX7009 had no effect on the MICs of biapenem for isolates with metallo- (IMP, NDM or VIM) or OXA-48 β-lactamases; however, most isolates with these enzymes were less resistant to biapenem than to imi-penem or, especially, ertapenem. Conclusions: Biapenem/RPX7009 (Carbavance) overcame most resistance due to KPC and other class A carba-penemases. Class B and D carbapenemases were not inhibited but conferred less consistent resistance to bia-penem than to other carbapenems.

Original languageEnglish
Article numberdkt118
Pages (from-to)1825-1831
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume68
Issue number8
DOIs
Publication statusPublished - Aug 2013

Bibliographical note

Funding Information:
This work was supported by Rempex Pharmaceuticals, to whom we are grateful.

Keywords

  • Carbapenemases
  • KPC β-lactamase
  • Klebsiella pneumoniae
  • Metallo-β-lactamase
  • OXA-48 β-lactamase

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