title: Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model.
abstract: OBJECTIVE
  Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.
  
  
  METHODS
  In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem.
  
  
  RESULTS
  A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h.
  
  
  CONCLUSIONS
  The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance.
authors: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden Institute for Medical Research, Kuala Lumpur, Malaysia.
authors: Ami F
authors: AF
authors: Mohamed
authors: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden anders.kristoffersson@farmbio.uu.se.
authors: Anders N
authors: AN
authors: Kristoffersson
authors: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
authors: Matti
authors: M
authors: Karvanen
authors: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors: Elisabet I
authors: EI
authors: Nielsen
authors: Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
authors: Otto
authors: O
authors: Cars
authors: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors: Lena E
authors: LE
authors: Friberg
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D058491:Bacterial Load; D003091:Colistin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D024881:Drug Resistance, Bacterial; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem; D003091:Colistin