Cravit Ophthalmic Solution/Cravit 1.5% Ophthalmic Solution Mechanism of Action

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.
Clinical Studies: Efficacy by diagnosis: The effectiveness rates of Cravit 1.5% ophthalmic solution by diagnosis in open label Phase III study conducted on 176 patients with bacterial conjunctivitis and bacterial keratitis are summarized as follows. (See Table 1.)

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Efficacy by organism susceptible to levofloxacin: The effectiveness rates in the above 176 patients classified by the causative organisms are listed as follows. (See Table 2.)

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Efficacy on aseptic treatment during a perioperative period for ocular surgery: (data on Cravit 0.5%, for reference): As the result of evaluation of preoperative aseptic effect of Cravit 0.5% ophthalmic solution on patients before ophthalmic operation, the aseptic ratio was 70% (35/55).
Pharmacokinetics: Plasma concentrations: 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 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 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 maximum levofloxacin concentration of 14.7 μg/g in bulbar conjunctiva and palpebral conjunctiva slightly rapidly decreased by 1 hour. The 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.
Microbiology: 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. aeruginosa 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.