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Pharmacotherapeutic Group: Sensory Organs, Ophthalmologicals, Antiinfectives, Antibiotics. ATC Code: S01AE05.
Pharmacology: Pharmacodynamics: Levofloxacin
hydrate, is the L-isomer of the racemate ofloxacin, has almost two
times more potent antibiotic activity than ofloxacin.
Mechanism of Action: Main mechanism of action of levofloxacin hydrate is to inhibit bacterial DNA synthesis by inhibiting DNA gyrase (topoisomerase II) and topoisomerase IV activities. It depends on the bacteria strain as to how much potency is exerted: against DNA gyrase (topoisomerase II) or topoisomerase IV.
Antibacterial Activity: Antibacterial activity: Levofloxacin hydrate exerts a broad-spectrum potent antibacterial activity in vitro against organisms causing ophthalmological infections, including gram-positive bacteria (Staphylococcus sp., Streptococcus sp. [including S. pneumoniae], Micrococcus sp., Enterococcus sp., Corynebacterium sp., etc.), gram-negative bacteria (Pseudomonas sp. [including P. aeruginosa], Haemophilus influenzae, Moraxella sp., Serratia sp., Klebsiella sp., Proteus sp., Acinetobacter sp., Enterobacter sp. etc.), and anaerobic bacteria (Propionibacterium acnes, etc.).
Impact of dosage on emergence of levofloxacin resistance: In studies using in vitro ocular tissue concentration simulation model, this product, instilled 3 times daily was more effective than 0.5% product, in preventing the emergence of the levofloxacin-resistant methicillin-susceptible Staphylococcus aureus strain (HSA201-00027, levofloxacin MIC: 0.5 μg/mL) and the levofloxacin-resistant P. aeruginonosa strain (HSA201-00094, levofloxacin MIC: 1 μg/mL). Both of this product and 0.5% product, prevented the emergence of levofloxacin-resistant methicillin-susceptible coagulase-negative Staphylococci strain (HSA201-00039, levofloxacin MIC: 0.25 μg/mL).
Pharmacokinetics: Plasma concentration: Levofloxacin concentration in plasma was measured in 8 healthy adult volunteers during 8-day course of treatment with this product, bilateral instillation at one drop/eye/time, once daily for Day 1 and 8 times daily for 7 days (from Day 2-8). On Day 8, the mean maximum levofloxacin concentration of 24.1 ng/mL was measured after 26 minutes of the last instillation.
Ocular distribution in animals (white rabbit): Fifty μL of this product were ocular instilled once in the right eyes of rabbits. The mean maximum levofloxacin concentration of 32.5 μg/g in cornea was measured after 15 minutes of the instillation, and then levofloxacin concentration in cornea gradually decreased with half-life of 86 minutes. The mean maximum levofloxacin concentration of 14.7 μg/g in bulbar conjunctiva and palpebral conjunctiva was measured after 15 minutes of the instillation, and then levofloxacin concentration in bulbar conjunctiva and palpebral conjunctiva slightly rapidly decreased by 1 hour. The mean maximum levofloxacin concentration of 3.1 μg/mL in aqueous humor was measured after 30 minutes of the instillation, and then levofloxacin concentration in aqueous humor gradually decreased with half-life of 71 minutes.
Toxicology: Preclinical safety data: Ocular toxicity of levofloxacin (LVFX) ophthalmic solutions was evaluated in various regimens using albino or pigmented rabbits.
Ocular irritation of LVFX ophthalmic solutions was assessed at concentrations up to 25% after 10 repeated instillations in a single day at 30-minute intervals using albino rabbits. Ocular irritation was noted at 10% or higher, but not at 3.0% or lower.
Ocular toxicity of LVFX ophthalmic solutions was evaluated after 2 weeks instillations to the eyes of albino rabbits at concentrations up to 1.0%, and 4 and 26 weeks instillations to the eyes of pigmented rabbits at concentrations up to 3.0%. No evidences of ocular toxicity were observed in these studies.
Skin sensitization and skin photosensitization studies indicate that LVFX topically applied to the skin of guinea pigs is not immunogenic and photosensitizing.
Ocular safety of light-exposed and light-degraded LVFX ophthalmic solutions was assessed by 1 day ocular irritation study, since the reduction in LVFX content and production of degraded substance were recognized when LVFX ophthalmic solution was exposed to light in stressed condition. The light-induced degraded substances produced no abnormalities in the eyes.
