title: Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets.
abstract: Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.
authors.affiliation: Ordway Research Institute, Albany, New York 12208, USA. gdrusano@ordwayresearch.org
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
authors.forename: T P
authors.initials: TP
authors.lastname: Lodise
authors.forename: D
authors.initials: D
authors.lastname: Melnick
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Oliver
authors.forename: A
authors.initials: A
authors.lastname: Mena
authors.forename: B
authors.initials: B
authors.lastname: VanScoy
authors.forename: A
authors.initials: A
authors.lastname: Louie
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D005260:Female; D006801:Humans; D000077731:Meropenem; D051379:Mice; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D009010:Monte Carlo Method; D011552:Pseudomonas Infections / Q000188:drug therapy; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D013845:Thienamycins; D000077731:Meropenem