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Notes: Background  Fluoroquinolone antibiotics (FQs) are associated with phototoxic skin reactions following exposure to sunlight.Objectives  We aimed to compare the phototoxic potential of sitafloxacin, a novel FQ with three others: sparfloxacin, enoxacin, levofloxacin and placebo in Caucasian volunteers. In a second study, two dosage regimens of sitafloxacin were compared with placebo in Oriental subjects.Methods  Randomized, placebo-controlled, assessor-blinded clinical trial. In 40 healthy Caucasians, sitafloxacin 100 mg twice a day (n = 8), sparfloxacin 200 mg day−1 (n = 8), enoxacin 200 mg three times a day (n = 8), levofloxacin 100 mg three times a day (n = 8) and placebo (n = 8) were given in oral doses for 6 days. In the second study, sitafloxacin 50 mg and 100 mg, both twice daily, were compared with placebo in 17 healthy Oriental subjects. Using an established monochromator technique, baseline threshold erythema levels were established pre-drug and on-drug. The phototoxic index (PI) baseline, minimal erythema dose (MED) divided by on-drug MED for each medication at each wavelength was determined and related to sitafloxacin peak plasma levels. The duration of susceptibility to phototoxicity was assessed by repeat phototesting daily after stopping medication.Results  In the Caucasian study, sitafloxacin 100 mg twice a day produced mild ultraviolet (UV) A-dependent phototoxicity (median PI = 1·45) at 365 ± 30 nm (half-maximum bandwidth), maximal at 24 h with normalization by 24 h postdrug cessation. The sparfloxacin group experienced severe phototoxicity maximal at 24 h and, unusually for an FQ, extended in the visible region (430 ± 30 nm), maximal at 400 ± 30 nm (median PI = 12·35) with abnormal pigmentation at on-drug phototest sites lasting, although fading, for up to 1 year. Enoxacin showed UVA-dependent phototoxicity (335–365 ± 30 nm) median PI 3·94 (at 365 ± 30 nm) returning to normal 48 h after stopping the drug. Fading pigmentation at phototoxic sites also lasted up to 1 year. Phototoxicity was not detected in the levofloxacin or placebo groups. In the Oriental study, no clinically relevant phototoxicity was seen with either sitafloxacin or placebo groups.Conclusions  We conclude that 100 mg twice a day sitafloxacin in Caucasians is associated with a mild degree of cutaneous phototoxicity. Enoxacin 200 mg three times a day and sparfloxacin 200 mg day−1 are much more photoactive. Sparfloxacin phototoxicity is induced by UVA and visible wavelengths. Levofloxacin and placebo failed to show a phototoxic effect. In the Oriental study, sitafloxacin 50 mg twice a day and 100 mg twice a day failed to demonstrate a clinically significant phototoxic effect.