Levofloxacin-Imipenem combination prevents the emergence of resistance among clinical isolates of Pseudomonas aeruginosa

A. 2-compartment in vitro pharmacokinetic model (IVPM) was used to assess the potential of a levofloxacin-imipenem combination to prevent the emergence of resistance during treatment of Pseudomonas aeruginosa infection. Log-phase cultures (10(8) cfu/mL) of 3 clinical isolates were inoculated into the peripheral compartment of the IVPMs and were treated with simulated human doses of levofloxacin (750 mg) and imipenem (250 mg). Pharmacodynamics and the emergence of resistance were evaluated over the course of 24 h. Resistant mutants were evaluated for transcriptional expression of specific efflux pumps. Initially, rapid killing was observed in association with each regimen. However, with levofloxacin and imipenem alone, rapid regrowth was observed as a result of the selection of resistant subpopulations. Analysis of mutants selected by levofloxacin demonstrated that mexEF-oprN-overexpressing subpopulations resistant to both levofloxacin and imipenem were selected from cultures of all 3 strains. Nevertheless, the levofloxacin-imipenem combination rapidly eradicated all 3 P. aeruginosa strains. These data suggest that levofloxacin-imipenem may be an effective combination for preventing the emergence of resistance among P. aeruginosa strains, even when subpopulations resistant to both drugs are present. Further studies are warranted to evaluate the use of this combination against strains with established resistance to either or both drugs.