P. aeruginosa dose response. Normal mice were inoculated with about 107 (a) or 108 (b) bacteria per thigh. The levofloxacin MIC and MBC were 0.8 μg/ml and 1.6 μg/ml, respectively. The x axis displays the exposures in mg/kg doses. 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 (CFUs/g) reductions in bacterial counts from the stasis point. These data are displayed in the inset 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. Isolation of drug-resistant P. aeruginosa mutants in vitro was common and occurred with a frequency of 0.1 × 10–6 to 2 × 10–6. At the higher infection inoculum, the microbial population burden significantly exceeded the mutation frequency. At exposures that killed the sensitive population, the resistant population was able to survive. This allowed this subpopulation to be selected and amplified by the drug pressure. Subsequently, a subpopulation of mutant organisms that behaved quite differently under antibiotic pressure emerged. Only with sufficient exposure to inhibit and kill the resistant subpopulation do we attain larger overall reduction of bacterial load.