Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens
Fig 8
An overview of the hybrid agent–based model that simulates granuloma formation and function, GranSim, and how pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics are incorporated in GranSim.
A) Our simulations begin with GranSim generating a large library of granulomas to be used for regimen testing. B) Antibiotic concentrations in plasma are simulated by a compartmental, ordinary differential equation model (ka, CL and Q are rate constants between compartments) with one (Z, E and M) or two transit compartments (H and R) representing oral absorption (one transit compartment shown in the figure). (C) Antibiotics in the plasma permeate through vascular sources into the lung tissue, i.e., onto the spatial grid of GranSim, where antibiotics can: diffuse, bind to caseum, be taken up by macrophages and penetrate into a granuloma. (D) We determine a killing rate for each Mtb phenotype (k1, k2 and k3) based on the local antibiotic concentration in their environment (grid compartment) (C1, C2 and C3) using a Hill equation calibrated to each Mtb type (nonreplicating, intracellular and extracellular). Emax_N, Emax_I and Emax_E are maximum–killing rate constants, respectively, C50N, C50I and C50E are the concentration at half maximal killing, respectively and hN, hI and hE are Hill curve constants for nonreplicating, intracellular and extracellular Mtb, respectively.