In Vitro Activity of Colistin Alone and in Combination with Doripenem against KPC-producing K. pneumoniae Isolates

Purpose: 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 and colistin alone and in combination against KPC- producing K. pneumoniae.

Methods: MICs were determined for doripenem (DOR) and colistin (COL) against 4 non-duplicate KPC-K. pneumoniae isolates. All isolates carried bla_KPC-3 and genes encoding TEM-1 and SHV-11/36 as previously described in the clinical outcomes evaluation (J Clin Microbiol 2010;48:623-5). Time-kill curves were performed with the following antibiotic concentration (mcg/mL) alone and in combination with DOR (6) and COL (2x MIC). Bacterial densities were determined at 0, 4, 8, 12, 24 and 48 hrs. 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:

MICs for COL ranged from 0.0625 to 0.5 µg/mL and all isolates were resistant to DOR (MICs ranged 16 - 32 mcg/mL). Monotherapy with COL displayed killing activity within 12 hours; however, significant re-growth occurred by 24 hours for COL monotherapy in all isolates. Monotherapy with DOR did not show bactericidal activity in any isolate.  Synergy occurred in combination of COL with DOR against all isolates and was sustained at 48 hours. Combination of COL and DOR demonstrated rapid bactericidal activity by 4 hours in all isolates and was sustained for 24 hours.

Conclusion: Colistin in combination with doripenem may be an important treatment modality despite colistin susceptibility to reduce potential resistance when treating KPC-producing organisms.