FIG 2.

P. aeruginosa dose response. Normal mice were inoculated with about 10⁷ (a) or 10⁸ (b) bacteria per thigh. The levofloxacin MIC and minimal bacterial concentration (MBC) were 0.8 mg/liter and 1.6 mg/liter, respectively. The x axis displays the dose exposures in milligrams per kilograms. The model allowed calculation of the dose necessary to achieve stasis (i.e., to return the colony counts at sacrifice to that used for the challenge), as well as 1, 2, and 3 log₁₀ (CFU/g) reductions in bacterial counts from the stasis point. These data are displayed in the insets as AUC/MIC ratio values for each of these degrees of drug effect. Comparison of microbiological outcome endpoints shows that levofloxacin treatment of P. aeruginosa infections is inoculum dependent. At the higher infection inoculum, the microbial population burden significantly exceeded the inverse of the mutation frequency with respect to resistance. At exposures that killed the sensitive population, the resistant population was able to survive, allowing this subpopulation to be amplified by the drug pressure. Only with sufficient exposure to inhibit and kill the resistant subpopulation do we attain a larger overall reduction of bacterial load.