Polymyxins and Doripenem Combination Against KPC-Producing Klebsiella pneumoniae

Abstract

Background: Most KPC-producing organisms have maintained susceptibility to polymyxins; however, development of resis-tance 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-pro-ducing K. pneumoniae. Methods: In-vitro time-kill assays were performed for four non-duplicate KPC-3 producing K. pneumoniae isolates with the fol-lowing 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-log 10 CFU/mL reduction from the starting inoculum. Synergism was defined as ≥ 2-log 10 reduction with the combination when com-pared to the most active single agent at 24 hours. Results: Minimum inhibitory concentrations (MICs) for polymyx-in 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 bac-terialcidal 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. Com-binations of colistin sulfate or polymyxin B with doripenem dem-onstrated rapid bactericidal activity by 4 hours in all isolates and was sustained for 24 hours. Conclusion: Polymyxin B and colistin sulfate in combination with doripenem may be an important treatment modality in treating KPC-producing organisms.