Establishment and validation of downsized hollow-fibre infection model and pharmacokinetics/pharmacodynamics analysis of VAN on Enterococcus faecium.

Objectives: This study clarified the target values of VAN against Enterococcus faecium using pharmacokinetics/pharmacodynamics (PK/PD) analysis and compared a downsized hollow fibre infection model (HFIM) with a conventional HFIM.

Methods: VAN was administered subcutaneously and blood concentrations were measured to calculate the PK parameters. PD studies were performed in an infected mouse model by administering VAN at doses ranging from 25 to 400 mg/kg based on PK parameters. PK/PD parameters correlated with antimicrobial efficacy were determined, and a target value of 2 log10 kills was calculated. The efficacy of VAN against E. faecium was evaluated by reproducing the VAN PK in the plasma at doses that achieved the target value using conventional and novel downsized HFIMs.

Results: PK/PD analysis showed that fAUC/minimum inhibitory concentration (MIC) demonstrated the most relevant index, with a target value of 249 to achieve a 2 log10 kill. Blood concentrations of 750 mg VAN every 12 h (equivalent to 260 fAUC/MIC) were simulated well with both HFIMs. Changes in E. faecium caused by continuous exposure to VAN resulted in a reduction in bacterial counts by ∼6.0 log10 kill 168 h after the start of treatment in both models. Downsizing reduced the extracapillary space volume, circulating medium, amount of drugs used and infectious waste. The total cost of the downsized cartridge system was approximately half that of the conventional model system.

Conclusions: We established a downsized HFIM and demonstrated its viability as a cost-effective and environmentally sustainable in vitro PK/PD. The findings highlighted its potential as a future PK/PD analysis standard.