FIG 6.

Killing rate constants for PAO1-RH at low bacterial densities for immediate killing and delayed killing (with or without adaptive resistance) for a range of extracellular tobramycin concentrations (i.e., tobramycin in broth). Adaptive resistance due to overexpression of the MexXY-OprM pump decreased the intracellular tobramycin concentration (C_intra) and therefore affected the delayed killing (due to the effect on protein synthesis) (Fig. 1) but not the immediate killing. In the absence of adaptive resistance, the intracellular tobramycin concentration (C_intra) was equal to the tobramycin concentration in broth (C_broth). The relationship between C_intra and C_broth at steady state is described in Materials and Methods. This figure illustrates the killing rate constants at low bacterial densities (i.e., Sig_Response = 0), and attenuated killing at high bacterial densities is not shown in this figure. Phenotypic tolerance at high bacterial densities attenuated both immediate and delayed killing. If the sum of the immediate and delayed killing rate constant equals the dotted, horizontal line, stasis of bacterial counts is achieved for the respective population. Stasis required approximately 0.7 mg/liter for the susceptible, 2 to 3.5 mg/liter for the intermediate, and 4 to 16 mg/liter for the resistant populations (ranges caused by adaptive resistance).