Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae

Abstract

The limited treatment options available for carbapenemase-producing Klebsiella pneumoniae (KPC) have made it a formidable pathogen. Previously we have shown the enhanced activity of pharmacodynamically optimized doripenem against KPC. Capitalizing on KPC's increased affinity for ertapenem, we evaluated the efficacy of a combination of ertapenem and doripenem in both an in vitro chemostat and an in vivo murine thigh infection model. Overall, the combination of doripenem plus ertapenem demonstrated enhanced efficacy over either agent alone.

Fig. 1.

Bacterial densities of KPC 354 over 24 h in the in vitro chemostat model (doripenem MIC, 4 μg/ml). The heavy black solid line represents the control group, the dashed line with squares represents the ertapenem control model (ertapenem alone), the dotted line with circles represents the doripenem control model (doripenem alone), and the dashed lines with either triangles or diamonds represent the doripenem-plus-ertapenem treatment model. The lower limit of detection is set at 10¹ CFU/ml.

Fig. 2.

Comparative efficacies of various dosing regimens of doripenem with or without ertapenem against KPC 354 in the in vivo murine thigh infection model (doripenem MIC, 4 μg/ml). The statistical significance of the difference between doripenem alone and doripenem at 2 g plus ertapenem at 1 g is indicated with an asterisk (*), while the statistical significance of the difference between the combination therapies is indicated with a number symbol (#).