Synergism between ceftriaxone and amikacin against a intermediately resistant Klebsiella pneumoniae strain tested by an in vitro pharmacokinetic model

Background: A checkerboard titration method, E-test, or time-kill curve method usually tests synergism between two antibiotics. These methods have the limitation that the synergism is determined at the fixed concentration of the antibiotics. In this study, we investigated the possible synergism between ceftriaxone and amikacin against an isolate of Klebsiella pneumoniae with intermediate resistance to both antibiotics by an in vitro pharmacokinetic model. Methods: Logarithmic-phase culture was exposed to the peak serum concentrations of ceftriaxone and amikacin alone or in combination. Then human elimination pharmacokinetics was simulated. Bactericidal activities were analyzed by viable counts and compared with the results of the E-test and the time-kill curve study. Results: The results of E-test were discordant with those of time-kill curve method. Time-kill and pharmacokinetic studies revealed that antibiotic combinations were synergistic. In in vitro pharmacokinetic study, each antibiotic alone failed to reduce bacterial counts, but the significant decrease in bacterial counts and a marked delay up to 19.9 h in the combination assay were present. Conclusion: There was a synergism between ceftriaxone and amikacin at dynamically declining antibiotic concentrations, resulting in a significant killing of an intermediate resistant K. pneumoniae. Infections by K. pneumoniae showing the low degree of synergism in E-test could possibly be treated by a combination of theses drugs.