title: Levofloxacin/imipenem prevents the emergence of high-level resistance among Pseudomonas aeruginosa strains already lacking susceptibility to one or both drugs.
abstract: OBJECTIVE
  Previous studies have demonstrated that a combination of levofloxacin with imipenem could prevent the emergence of resistance during the treatment of susceptible Pseudomonas aeruginosa isolates in a two-compartment pharmacodynamic model of infection. In this study, the efficacy of levofloxacin/imipenem was further evaluated against a panel of characterized P. aeruginosa strains that lacked susceptibility to one or both drugs in the combination.
  
  
  METHODS
  Five P. aeruginosa strains with characterized resistance mechanisms were evaluated. Log-phase cultures were inoculated into the peripheral compartment of the in vitro pharmacokinetic model and treated using simulated doses of 750 mg levofloxacin (dosed every 24 h) and 250 mg or 1 g doses of imipenem (dosed every 12 h). Peak levels were adjusted for protein binding. Pharmacodynamic interactions were evaluated by measuring the changes in viable counts over 30 h. To evaluate the emergence of resistance, samples removed at 30 h were plated onto agar containing the drug at 4x MIC, and potential mutants were evaluated for changes in susceptibility.
  
  
  RESULTS
  Against strains overexpressing MexAB-OprM, MexCD-OprJ and MexEF-OprN efflux pumps, levofloxacin/imipenem prevented the emergence of resistance and achieved a 5 log total kill of one strain and eradication of two strains. Levofloxacin/imipenem also eradicated an imipenem-resistant strain lacking OprD. Although the combination initially killed 6-7 logs of a dual-resistant strain lacking OprD and overexpressing MexXY, it could not prevent the emergence of resistance when the 250 mg dose of imipenem was simulated in the combination. However, when the 1 g dose of imipenem was simulated with the combination, resistance was suppressed.
  
  
  CONCLUSIONS
  These data suggest that levofloxacin/imipenem may be an effective combination for preventing the emergence of resistance among P. aeruginosa, even with strains already lacking susceptibility to one or both drugs in the combination. Clinical evaluation of this combination is warranted.
authors.affiliation: Center for Research in Anti-Infectives and Biotechnology, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA. pdlister@creighton.edu
authors.forename: Philip D
authors.initials: PD
authors.lastname: Lister
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wolter
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wickman
authors.forename: Mark D
authors.initials: MD
authors.lastname: Reisbig
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D015378:Imipenem / Q000494:pharmacology*; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D064704:Levofloxacin; D015378:Imipenem; D015242:Ofloxacin