Fig. 2. Modeling framework and simulation workflow.
The developed modeling framework included four bacterial subpopulations (WT, RA, RB, RAB) and the pharmacokinetic-pharmacodynamic (PK-PD) relationships for two hypothetical antibacterial drugs (DA and DB). The framework includes infection- and pathogen-specific parameters and fixed drug PK parameters. The model input includes both drug- and pathogen-related factors, which vary between different scenarios. The framework was used to simulate different treatment schedules of two-week multi-drug treatments using DA and DB for n patients. In the example shown, a three-day cycling treatment regimen (PK panel) is simulated for six patients. The resulting patient-specific bacterial profiles are shown in the PD panel. Resistance was evaluated for each patient and each bacterial subpopulation at the end of treatment (EoT), for which the corresponding probability of resistance (PoR) was calculated.