Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic In Vitro Hollow-Fiber Infection Model

Given that aminoglycosides, such as amikacin, may be used for multi-drug resistant infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible to inform ventilator-associated pneumonia and sepsis treatment choices.A hollow-fibre infection model with two isolates (MIC 2 and 8 mg/L) with an initial inoculum ∼10 colony-forming unit/mL was used to test different amikacin dosing regimens. Three regimens (15, 25 and 50 mg/kg) simulating a blood exposure and a 30 mg/kg regimen simulating the epithelial lining fluid (ELF) for potential respiratory tract infection were tested. Data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Whole genome sequencing was used to identify mutations associated with resistance emergence.While bacterial density was reduced by >6-logs within the first 12 h in simulated blood exposures, following this initial bacterial kill, there was amplification of a resistant sub-population with ribosomal mutations that were likely mediating amikacin resistance. No appreciable bacterial killing occurred with subsequent doses. There was less (