Levofloxacin 1.5% shows significant aqueous penetration at three of four time points

June 1, 2009

An active comparator, parallel group study comparing levofloxacin 1.5% and moxifloxacin 0.5% in patients undergoing cataract surgery showed significantly greater aqueous penetration of levofloxacin, measured as area under the curve over a 6-hour interval. Levofloxacin also had a significantly higher Cmax and significantly higher maximum concentration at the end of the dose interval. These findings indicate a possible role for levofloxacin in the prophylaxis of endophthalmitis at the time of cataract surgery.

Key Points

These results suggest that levofloxacin could be beneficial in the prophylaxis of endophthalmitis at the time of cataract surgery, said Frank A. Bucci Jr., MD, a cataract and refractive surgery specialist in Wilkes-Barre, PA, who performed the single-center, single-masked study. The FDA indication for levofloxacin is treatment of bacterial corneal ulcers; the drug has not been studied or approved for pre- or post-surgical prophylaxis.

In evaluating fluoroquinolone antibiotics for an application such as prophylaxis before cataract surgery, the two most important considerations are the surface kill and the degree of corneal penetration, he said. In his study, Dr. Bucci focused on the latter attribute, comparing two widely used fluoroquinolones. He explained that moxifloxacin was considered to have the highest level of corneal penetration of the fluoroquinolones, although the 0.5% concentration of levofloxacin (Quixin, Vistakon Pharmaceuticals) also had a high level of penetration, similar or perhaps equal to that of moxifloxacin. No direct comparison studies ever had been performed, however, and estimates of the relative penetration levels were based on several papers.

It was assumed that the newer, more concentrated formulation of levofloxacin would have a higher penetration level, and testing that hypothesis was one reason for Dr. Bucci's study. He also decided to approach the study in a novel way: rather than capturing the concentration at one point in time and designating it as the maximum concentration level, he designed the study to examine the concentration level over the 6-hour dosing period on the day of surgery.

The study included 97 patients aged 18 or more years undergoing elective cataract surgery. After 1:1 randomization (levofloxacin, n = 49; moxifloxacin, n = 48), patients were instructed to take 1 drop of their study medication four times a day for 3 days prior to surgery. On the day of surgery, they were to use their study drop at one of four prearranged times. Aqueous samples were then taken at 1, 2, 4, or 6 hours (± 5 minutes) following the last drop, a statistical technique known as sparse sampling. The samples of the eight subgroups were collected through peripheral clear cornea with a 30-gauge needle.

"This was the first study in which the penetration was examined over the whole course of the treatment interval in patients with normal corneas," Dr. Bucci said.

He added that one previous study had looked at two time points in patients with diseased corneas, a factor that would affect penetration times.

"We found that there was never less than 50% more levofloxacin at each time period compared with the moxifloxacin. It was statistically significant at 1 hour, 2 hours, and 6 hours, and it trended toward significance at 4 hours," he said. "The reason it only trended at 4 hours was due to the small sample size. We performed a statistical analysis showing that at a sample size of 24, it would have shown significance."

Aqueous penetration levels

At 1 hour after the last study drop was given, the mean aqueous penetration levels were levofloxacin 1.34/moxifloxacin 0.83 µg/ml (p = 0.036, levofloxacin 61% > moxifloxacin). At 2 hours, the mean penetration levels were levofloxacin 1.43/moxifloxacin 0.87 µg/ml (p = 0.008, levofloxacin 65% > moxifloxacin). The 4-hour levels were levofloxacin 0.82/moxifloxacin 0.54 µg/ml (p = 0.10, levofloxacin 52% > moxifloxacin). At the final time point, 6 hours following instillation of the last drop of medication, the levels were levofloxacin 0.70/moxifloxacin 0.40 µg/ml (p = 0.13, levofloxacin 75% > moxifloxacin).

The mean area under the curve over the 6-hour dosing period was significantly higher for levofloxacin than for moxifloxacin (p < 0.001). The highest median concentration of levofloxacin (1.60 µg/ml) was almost twice as much (p < 0.001) compared with moxifloxacin (0.83 µg/ml).

The results indicate that levofloxacin will deliver very high levels of drug to both the cornea and aqueous, Dr. Bucci concluded.

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