title: In vitro activity of the {beta}-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases.
abstract: BACKGROUND
  NXL104 is a novel-structure beta-lactamase inhibitor with potent activity against both class A and class C enzymes. Among the class A carbapenemases, KPC-type enzymes are now spreading rapidly and KPC-related carbapenemase resistance is an emerging phenomenon of great clinical importance. The activity of NXL104 against KPC beta-lactamases was examined.
  
  
  METHODS
  Enzymatic activity of purified recombinant KPC-2 was measured with nitrocefin as reporter substrate and inhibition by NXL104 was measured by determination of IC(50) values. Antimicrobial susceptibility testing of various beta-lactams combined with a fixed concentration of NXL104 at 4 mg/L against strains producing KPC enzymes was performed by the broth microdilution method.
  
  
  RESULTS
  NXL104 was a potent inhibitor of KPC-2 with an IC(50) of 38 nM. NXL104 restored the antimicrobial activity of ceftazidime, ceftriaxone, imipenem and piperacillin against Enterobacteriaceae strains producing KPC-2 or KPC-3. MIC values of ceftazidime against KPC producers were reduced by up to 1000-fold by combination with NXL104.
  
  
  CONCLUSIONS
  NXL104 inhibitory activity is unique in terms of spectrum, encompassing class A extended-spectrum beta-lactamases, class C enzymes and class A carbapenemases. Given the limited therapeutic options available for infections caused by multiresistant Enterobacteriaceae isolates, NXL104 beta-lactamase inhibitor is a promising agent to be used in combination with a beta-lactam to protect its antibacterial activity.
authors.affiliation: Novexel SA, Parc Biocitech, 102 avenue Gaston Roussel, 93230 Romainville, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Stachyra
authors.forename: Premavathy
authors.initials: P
authors.lastname: Levasseur
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Péchereau
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Girard
authors.forename: Monique
authors.initials: M
authors.lastname: Claudon
authors.forename: Christine
authors.initials: C
authors.lastname: Miossec
authors.forename: Michael T
authors.initials: MT
authors.lastname: Black
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002511:Cephalosporins / Q000378:metabolism; D004755:Enterobacteriaceae / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D002511:Cephalosporins; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C543519:avibactam; C491478:beta-lactamase KPC-2; D001618:beta-Lactamases; C021720:nitrocefin