Pharmacodynamics of inhaled amikacin (BAY 41-6551) studied in an in vitro pharmacokinetic model of infection

Background: The pharmacodynamics of inhaled antimicrobials are poorly studied. Amikacin is being developed for inhalational therapy as BAY 41-6551. Objectives: We employed an in vitro pharmacokinetic model to study the pharmacokinetics/pharmacodynamics of amikacin. Methods: A dose-ranging design was used to establish fAUC/MIC and fC(max)/MIC targets for static, -1 log drop and -2 log drop effects for strains of Escherichia coil, Klebsiella pneumoniae and Pseudomonas aeruginosa. We then modelled epithelial lining fluid (ELF) concentration associated with inhaled amikacin (400 mg every 12 h), over 5 days using mean human concentrations. Results: The 24 h static effect fAUC/MIC targets and -1 log drop targets were 51.0 +/- 26.7 and 71.6 +/- 27.6 for all species of aerobic Gram-negative bacilli. fAUC/MIC targets for static effect, -1 log drop or -2 log drop were smaller than the 24 h values at 12 h and larger at 48 h. Emergence of resistance occurred maximally with E. coli in the fAUC/MIC range 12-60; K. pneumoniae 0-60 (48 h) and P. aeruginosa 12-80. When human ELF concentrations were modelled for strains with MIC <= 8 mg/L, there was rapid clearance and no regrowth. For strains with MIC >= 32 mg/L, there was initial clearance followed by regrowth. If MIC values were related to bacterial clearance then at least a static effect or -1 log drop in count would be expected for bacterial strains with MICs of <= 180 mg/L (static effect) or 148 mg/L (-1 log drop effect). Conclusions: An fAUC/MIC amikacin target of 50-80 is appropriate for aerobic Gram-negative bacilli and mean ELF concentrations of BAY 41-6551 would produce a static to -1 log clearance with strains up to 128 mg/L.