title: Polymyxins and Doripenem Combination Against KPC-Producing Klebsiella pneumoniae.
abstract: BACKGROUND
  Most KPC-producing organisms have maintained susceptibility to polymyxins; however, development of resistance to polymyxins has been increasingly reported. One potential treatment modality is to optimize the use of combination therapy. Therefore, we evaluated the in vitro activity of doripenem, colistin sulfate, polymyxin B alone and in combination against KPC- producing K. pneumoniae.
  
  
  METHODS
  In-vitro time-kill assays were performed for four non-duplicate KPC-3 producing K. pneumoniae isolates with the following antibiotics: doripenem, polymyxin B and colistin sulfate alone and in combination. Bacterial densities were determined at 0, 4, 8, 12, 24 and 48 hours. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the starting inoculum. Synergism was defined as ≥ 2-log10 reduction with the combination when compared to the most active single agent at 24 hours.
  
  
  RESULTS
  Minimum inhibitory concentrations (MICs) for polymyxin B and colistin sulfate ranged from 0.0625 to 0.25 µg/mL, and all isolates were resistant to doripenem (MICs ranged 16 - 32 µg/mL). Monotherapy with colistin sulfate and polymyxin B displayed bacterialcidal activity within 12 hours; however, significant re-growth occurred by 24 hours in all isolates. Monotherapy with doripenem did not show bactericidal activity in any isolate. Synergy occurred with combinations of both colistin sulfate and polymyxin B with doripenem against all isolates and was sustained at 48 hours. Combinations of colistin sulfate or polymyxin B with doripenem demonstrated rapid bactericidal activity by 4 hours in all isolates and was sustained for 24 hours.
  
  
  CONCLUSIONS
  Polymyxin B and colistin sulfate in combination with doripenem may be an important treatment modality in treating KPC-producing organisms.
authors.affiliation: University of Texas Health Science Center at San Antonio, Pharmacotherapy Education and Research Center, 7703 Floyd Curl Drive - MC 6220, San Antonio, TX, U.S ; College of Pharmacy, University of Texas at Austin, 1 University Station, Austin, TX U.S.
authors.forename: Grace C
authors.initials: GC
authors.lastname: Lee
authors.forename: David S
authors.initials: DS
authors.lastname: Burgess
keywords: Carbapenem; Carbapenemase; Colistin; Doripenem; KPC; Klebsiella pneumoniae; Polymyxin B; Synergy; Time-kill