title: Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae.
abstract: OBJECTIVE
  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 potentiation 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 imipenem or, especially, ertapenem.
  
  
  CONCLUSIONS
  Biapenem/RPX7009 (Carbavance) overcame most resistance due to KPC and other class A carbapenemases. Class B and D carbapenemases were not inhibited but conferred less consistent resistance to biapenem than to other carbapenems.
authors.affiliation: Antimicrobial Resistance and Healthcare-Associated Infections Unit, Health Protection Agency Colindale, 61 Colindale Avenue, London NW9 5EQ, UK. d.livermore@uea.ac.uk
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000302:isolation & purification; D004756:Enterobacteriaceae Infections / Q000382:microbiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013845:Thienamycins / Q000494:pharmacology*; D018440:beta-Lactam Resistance / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D013845:Thienamycins; C065257:biapenem
keywords: KPC β-lactamase; Klebsiella pneumoniae; OXA-48 β-lactamase; carbapenemases; metallo-β-lactamase