FIG 3.

The structure of the mechanism-based model of bacterial growth and killing by imipenem (IPM) and tobramycin (TOB) in monotherapies and optimized combination regimens. The first population, i.e., IPM^s/TOB^r, was susceptible to imipenem and resistant to tobramycin. The second population, i.e., IPMⁱ/TOB^r (imipenem intermediate and tobramycin resistant), is not shown. A life cycle growth model (63, 64) was utilized to describe the underlying biology of bacterial replication via two states for each of the two populations. The maximum killing rate constants (K_max) and the associated antibiotic concentrations (KC₅₀s) causing 50% of K_max are explained in Table 1. The permeabilizing effect of tobramycin on the bacterial outer membrane (i.e., tobramycin enhancing the target site penetration of imipenem) was applied to both populations. The parameters describing the outer membrane effect (I_max,OM,TOB and IC_50,OM,TOB) are explained in Table 1.