Impact of various conditions on the efficacy of dual carbapenem therapy against KPC-producing Klebsiella pneumoniae

Abstract

The efficacy of dual carbapenem therapy under various conditions, including increased MIC, different immune status and treatment duration and use of a higher ertapenem dose, was evaluated in a murine thigh model. Three KPC-producing Klebsiella pneumoniae isolates with different phenotypic profiles were used. Human-simulated doripenem and ertapenem doses were given alone or in combination. Three isolates were tested over 24 h in immunocompetent and immunocompromised ICR mice. Two of the isolates were also evaluated over 72 h in neutropenic mice. High-dose ertapenem regimens were also evaluated. The efficacy of combination therapy was enhanced in the immunocompetent model over the neutropenic model (P<0.05 for all three isolates). In the immunocompetent model, bacterial density was further reduced with use of combination therapy over doripenem monotherapy for two isolates with doripenem MICs≤16 mg/L (statistically greater for one isolate; P<0.05). Whilst not statistically different at 24 h in neutropenic mice, combination therapy demonstrated significantly greater efficacy over doripenem alone for one of two isolates at 72 h (P<0.05). Use of ertapenem 2g did not enhance efficacy over ertapenem 1 g (P>0.05). The beneficial effects of dual carbapenem therapy and potential difference in efficacy based on doripenem MICs are evident at 24 h in an immunocompetent setting. Within a neutropenic setting, enhanced efficacy with combination therapy may only be evident with continued therapy. Dual carbapenem regimens may represent a promising option for infections caused by KPC-producing isolates, particularly when the MIC is low.