The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of fluoroquinolones have been well-described, and susceptibility classifications are the main determinant of their use in clinical practice. Expert guidelines contain susceptibility breakpoints to aid clinicians with the interpretation of in vitro data. These breakpoints are based on the MIC distribution for a large number of microorganisms, the observed clinical response in patients treated with usual doses, and the PK-PD properties of the drug (8, 16, 16a, 22, 24, 25). The breakpoints are often used, in conjunction with susceptibility results, to predict clinical outcome. However, emerging data highlight the lack of association between in vitro susceptibility breakpoints and outcomes (3,30).Fluoroquinolones are considered to be concentration dependent, with both the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ) divided by the MIC (the AUC 0-24 /MIC ratio) and the maximum serum drug concentration (C max ) divided by the MIC (the C max /MIC ratio) as predictors of clinical outcome (13,24). Numerous studies have attempted to discern the parameter best associated with clinical outcome. Studies favoring the C max /MIC ratio have shown that maximum serum fluoroquinolone concentrations reaching 8 to 12 times the MIC are associated with favorable outcomes (4, 13, 26). However, evidence for the AUC 0-24 /MIC ratio is convincing if the colinearity of the C max /MIC and AUC 0-24 / MIC ratios is removed (27). Evaluations have shown previously that AUC 0-24 /MIC ratios greater than 125 are associated with optimal outcomes for infections with gram-negative organisms (13,17,23).The aforementioned studies were completed largely in vivo and did not account for protein binding (with the exception of one trial [4]). One can anticipate that slightly lower concentrations are needed when free drug is considered. As predicted, lower AUC 0-24 /MIC ratios are required when only free-drug values are used in calculations, and extrapolating free-drug concentrations from the data in the aforementioned clinical studies results in an optimal free-drug AUC 0-24 /MIC ratio between 61 and 105 (2,5,14).As currently defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing, the MIC breakpoint of levofloxacin for aerobic and facultative gram-negative organisms is 2 mg/liter (8, 16a; Levaquin package insert [http://www.levaquin.com]). The