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Mycobacterium tuberculosis (MTB) is capable of invading not only macrophages (Mφs) but also type II pneumocytes. In this study, we compared the antimicrobial activities of fluoroquinolones, including gatifloxacin, sitafloxacin and levofloxacin, against the MTB replication in the Mono Mac 6 human Mφ cell line (MM6-Mφs) and the A-549 human type II alveolar epithelial cell line (A-549 cells). When test quinolones were added at the MIC (0.125, 0.06 and 0.25 mg/L for gatifloxacin, sitafloxacin and levofloxacin, respectively) to the culture media of MTB-infected cells, these drugs exerted growth-inhibitory activity against intracellular organisms in the order of sitafloxacin > gatifloxacin > levofloxacin. On the other hand, when test quinolones were added at Cmax in the blood (1.7, 1.0 and 2.0 mg/L for gatifloxacin, sitafloxacin and levofloxacin, respectively), these drugs exhibited bactericidal activity against intracellular MTB in the order of gatifloxacin > sitafloxacin ≥ levofloxacin. In addition, when test drugs were added at 1/8Cmax to 1/2Cmax, the efficacy was in the order of sitafloxacin > gatifloxacin > levofloxacin. Thus, it appears that the MIC values of fluoroquinolones are not always predictive of their antimicrobial activity against intracellular MTB. In this context, it was also found that intracellular uptake of these quinolones by MM6-Mφs and A-549 cells was in the order of sitafloxacin > gatifloxacin > levofloxacin. This implies that the cellular permeability of these quinolones is an important factor that determines their efficacy to eliminate intracellular MTB organisms.