title: Combination treatment with meropenem plus levofloxacin is synergistic against Pseudomonas aeruginosa infection in a murine model of pneumonia.
abstract: BACKGROUND
  Meropenem plus levofloxacin treatment was shown to be a promising combination in our in vitro hollow fiber infection model. We strove to validate this finding in a murine Pseudomonas pneumonia model.
  
  
  METHODS
  A dose-ranging study with meropenem and levofloxacin alone and in combination against Pseudomonas aeruginosa was performed in a granulocytopenic murine pneumonia model. Meropenem and levofloxacin were administered to partially humanize their pharmacokinetic profiles in mouse serum. Total and resistant bacterial populations were estimated after 24 hours of therapy. Pharmacokinetic profiling of both drugs was performed in plasma and epithelial lining fluid, using a population model.
  
  
  RESULTS
  Meropenem and levofloxacin penetrations into epithelial lining fluid were 39.3% and 64.3%, respectively. Both monotherapies demonstrated good exposure responses. An innovative combination-therapy analytic approach demonstrated that the combination was statistically significantly synergistic (α = 2.475), as was shown in the hollow fiber infection model. Bacterial resistant to levofloxacin and meropenem was seen in the control arm. Levofloxacin monotherapy selected for resistance to itself. No resistant subpopulations were observed in any combination therapy arm.
  
  
  CONCLUSIONS
  The combination of meropenem plus levofloxacin was synergistic, producing good bacterial kill and resistance suppression. Given the track record of safety of each agent, this combination may be worthy of clinical trial.
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.affiliation: Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles.
authors.forename: Michael
authors.initials: M
authors.lastname: VanGuilder
authors.affiliation: Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Neely
authors.affiliation: Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles.
authors.forename: Alan
authors.initials: A
authors.lastname: Schumitzky
authors.affiliation: Laboratory of Applied Pharmacokinetics, University of Southern California, Los Angeles.
authors.forename: Roger
authors.initials: R
authors.lastname: Jelliffe
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: Steven
authors.initials: S
authors.lastname: Fikes
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kurhanewicz
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: Nichole
authors.initials: N
authors.lastname: Robbins
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: Dodge
authors.initials: D
authors.lastname: Baluya
authors.affiliation: Institute for Therapeutic Innovation, University of Florida, Lake Nona.
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D064704:Levofloxacin / Q000494:pharmacology*; D000077731:Meropenem; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D011014:Pneumonia / Q000188:drug therapy* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013845:Thienamycins / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D064704:Levofloxacin; D000077731:Meropenem
keywords: Mathematical Modeling; Pseudomonas aeruginosa; levofloxacin; meropenem; synergy