title: Activity of OP0595/β-lactam combinations against Gram-negative bacteria with extended-spectrum, AmpC and carbapenem-hydrolysing β-lactamases.
abstract: BACKGROUND
  OP0595 is a diazabicyclooctane that (i) acts as a PBP2-active antibacterial, (ii) inhibits Class A and C β-lactamases and (iii), like mecillinam, gives β-lactamase-independent potentiation of β-lactams targeting other PBPs. We tested its behaviour against β-lactam-resistant Enterobacteriaceae and non-fermenters.
  
  
  METHODS
  Organisms were UK clinical isolates; MICs were determined by CLSI agar dilution for OP0595 alone or combined at 1-4 mg/L with aztreonam, biapenem, cefepime or piperacillin.
  
  
  RESULTS
  MICs of OP0595 for Escherichia coli, Enterobacter, Citrobacter and Klebsiella spp. were mostly 1-4 mg/L but values >4 mg/L were seen for minorities of isolates irrespective of other resistances, and for 50%-60% of those with ertapenem resistance involving porin loss plus ESBL or AmpC activity. OP0595 MICs for Serratia, Proteeae and non-fermenters mostly were >4 mg/L. When its MIC was ≤4 mg/L, OP0595's antibacterial activity dominated combination activity. For 'OP0595-resistant' (MIC >4 mg/L) isolates with Class A or C β-lactamases OP0595 achieved strong potentiation of substrate β-lactams, contingent on β-lactamase inhibition. β-Lactamase-independent potentiation was evident with aztreonam, cefepime and piperacillin-less so for biapenem-for many OP0595-resistant Enterobacteriaceae with Class B carbapenemases, which are not inhibited by OP0595. OP0595 acted solely as a β-lactamase inhibitor for non-fermenters.
  
  
  CONCLUSIONS
  OP0595 inhibited Enterobacteriaceae, not non-fermenters; its combinations had broad activity versus Enterobacteriaceae, largely contingent on OP0595's antibacterial activity but also on inhibition of Class A and C β-lactamases and on the β-lactam-enhancer effect, which allowed activity against many OP0595-resistant metallo-β-lactamase-producing Enterobacteriaceae. For non-fermenters OP0595 acted only as a β-lactamase inhibitor.
authors: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK Norwich Medical School, University of East Anglia, Norwich, UK d.livermore@uea.ac.uk.
authors: David M
authors: DM
authors: Livermore
authors: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK.
authors: Shazad
authors: S
authors: Mushtaq
authors: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK.
authors: Marina
authors: M
authors: Warner
authors: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK.
authors: Neil
authors: N
authors: Woodford
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D004347:Drug Interactions; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology; D016905:Gram-Negative Bacterial Infections / Q000382:microbiology; D007769:Lactams / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D006113:United Kingdom; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D007769:Lactams; D047090:beta-Lactams; C000608518:nacubactam; D001618:beta-Lactamases