title: NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum beta-lactamases and carbapenemases.
abstract: BACKGROUND
  The beta-lactamase landscape is changing radically, with CTX-M types now the most prevalent extended-spectrum beta-lactamases (ESBLs) worldwide, except maybe in the USA. In addition, there are growing numbers of Enterobacteriaceae with KPC and metallo-carbapenemases. We examined whether combinations of oxyimino-cephalosporins with NXL104, a novel non-beta-lactam beta-lactamase inhibitor, overcame these resistances.
  
  
  METHODS
  NXL104 was tested at 4 mg/L in combination with cefotaxime and ceftazidime versus: (i) Escherichia coli transconjugants and wild-type Enterobacteriaceae with CTX-M ESBLs; (ii) Enterobacteriaceae with ertapenem resistance contingent on combinations of impermeability and ESBLs or AmpC; and (iii) Enterobacteriaceae with KPC, SME, metallo- or OXA-48 carbapenemases.
  
  
  RESULTS
  MICs of cefotaxime + NXL104 were < or = 1 mg/L for most Enterobacteriaceae with CTX-M, KPC or OXA-48 enzymes and were < or = 2 mg/L for those that also had ertapenem resistance contingent on combinations of beta-lactamase and impermeability. MICs of the ceftazidime + NXL104 combination were < or = 4 mg/L, except for a single Enterobacter aerogenes with KPC and AmpC enzymes together with porin loss, which required an MIC of 32 mg/L. The major gap was that NXL104 could not potentiate cephalosporins against Enterobacteriaceae with IMP or VIM metallo-enzymes.
  
  
  CONCLUSIONS
  Oxyimino-cephalosporin + NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.
authors.affiliation: Health Protection Agency Centre for Infections, London, UK. david.livermore@hpa.org.uk
authors.forename: David M
authors.initials: DM
authors.lastname: Livermore
authors.forename: Shazad
authors.initials: S
authors.lastname: Mushtaq
authors.forename: Marina
authors.initials: M
authors.lastname: Warner
authors.forename: Christine
authors.initials: C
authors.lastname: Miossec
authors.forename: Neil
authors.initials: N
authors.lastname: Woodford
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002439:Cefotaxime / Q000494:pharmacology; D002442:Ceftazidime / Q000494:pharmacology; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D001618:beta-Lactamases / Q000032:analysis* / Q000096:biosynthesis; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D047090:beta-Lactams; D002442:Ceftazidime; D001618:beta-Lactamases; D002439:Cefotaxime