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 24h in immunocompetent and immunocompromised ICR mice. Two of the isolates were also evaluated over 72h 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≤16mg/L (statistically greater for one isolate; P<0.05). Whilst not statistically different at 24h in neutropenic mice, combination therapy demonstrated significantly greater efficacy over doripenem alone for one of two isolates at 72h (P<0.05). Use of ertapenem 2g did not enhance efficacy over ertapenem 1g (P>0.05). The beneficial effects of dual carbapenem therapy and potential difference in efficacy based on doripenem MICs are evident at 24h 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.