title: Susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin.
abstract: OBJECTIVE
  To determine the susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampicin and clarithromycin. NAB739 and NAB7061 are novel polymyxin derivatives that lack the cationic charges in the linear peptide portion of polymyxin B and have pharmacokinetic properties different from those of polymyxin B.
  
  
  METHODS
  MIC determinations were performed by the agar dilution method using CLSI guidelines. Polymyxin B was used as a comparison. Synergism studies measured fractional inhibitory concentration indices (FICIs) by using increasing concentrations of the compounds in Mueller-Hinton agar and Etests.
  
  
  RESULTS
  The MICs of NAB739 for all nine polymyxin-susceptible, carbapenemase-producing strains were identical or very close to those determined for E. coli ATCC 25922, for K. pneumoniae ATCC 13883, as well as for 18 clinical carbapenem-susceptible isolates. At a concentration of 4 mg/L, NAB7061 decreased the MIC of rifampicin and clarithromycin for all carbapenemase strains by factors ranging from 6 to 500. The polymyxin-resistant strain K. pneumoniae CL5762B was sensitized by a factor of 24 to rifampicin (FICI, 0.167) and by a factor of 12 to clarithromycin (FICI, 0.208).
  
  
  CONCLUSIONS
  Polymyxin-susceptible, carbapenemase-producing strains are as susceptible to NAB739 as are the carbapenem-susceptible clinical isolates. In addition, NAB7061 has notable synergism with rifampicin and clarithromycin against all the carbapenemase-producing strains tested, including the polymyxin-resistant K. pneumoniae strain.
authors.affiliation: Northern Antibiotics Ltd, FI-00720 Helsinki, Finland. martti.vaara@northernantibiotics.com
authors.forename: Martti
authors.initials: M
authors.lastname: Vaara
authors.forename: Osmo
authors.initials: O
authors.lastname: Siikanen
authors.forename: Juha
authors.initials: J
authors.lastname: Apajalahti
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
authors.forename: Timo
authors.initials: T
authors.lastname: Vaara
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000096:biosynthesis*; D017291:Clarithromycin / Q000494:pharmacology*; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D011113:Polymyxins / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology*; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; C546018:NAB 7061 peptide; C546019:NAB 739 peptide; D011113:Polymyxins; D001618:beta-Lactamases; C063912:carbapenemase; D017291:Clarithromycin; D012293:Rifampin