Antibiotic effects of WP-0405, a thermo-setting ofloxacin gel, on methicillin-resistant Staphylococcus aureus keratitis in rabbits.
OBJECTIVE
The chemotherapeutic effects and pharmacokinetics properties of WP-0405 (a thermo-setting in situ 0.3% ofloxacin-containing ophthalmic gel) and ofloxacin (a conventional 0.3% ofloxacin solution) on methicillin-resistant Staphylococcus aureus (MRSA) keratitis were compared in a rabbit model.


METHODS
The single-instillation pharmacokinetics of WP-0405 and ofloxacin in the cornea, aqueous humor, conjunctiva, and iris-ciliary body were determined in normal rabbit eyes. To compare the duration of antimicrobial action, WP-0405 or ofloxacin was instilled oncedaily in an early-treatment model of keratitis, and corneas were either removed immediately or 4 or 8 h postinstillation. In another experiment, WP-0405 was instilled two or three times daily to compare its antibiotic efficacy with three-times daily instillation of ofloxacin in the same early-treatment model of keratitis; corneas were then removed after determining the extent of the abscess area. In another experiment, WP-0405 was instilled four or eight times daily to compare its effects with eight-times daily instillation of ofloxacin in a late-treatment model of keratitis, and corneas were removed. The number of viable bacteria in the corneas was determined in all experiments.


RESULTS
Cmax and AUC0- in tissues treated with WP-0405 were 1.5-3.4-fold and 1.8-2.9-fold greater than those treated with ofloxacin, respectively. WP-0405 significantly reduced the number of viable bacteria for up to 8 h after a single instillation. WP-0405 not only significantly reduced the number of viable bacteria, but also the size of the abscess area at the same frequency of instillation. When compared to ofloxacin, WP-0405 exhibited an approximately equivalent antibiotic effect, with fewer administrations.


CONCLUSIONS
As a result of its pharmacokinetics, WP-0405 had a more potent, longer-acting antibiotic effect than did ofloxacin. Furthermore, because of its lower required instillation frequency, which would improve patient compliance, WP-0405 has great potential therapeutic benefits.
Fukaya
Yasuhiro
Y
Research and Development Division, Wakamoto Pharmaceutical Co., Ltd., Kanagawa, Japan. fukaya@wakamoto-pharm.co.jp
Kurita
Ai
A
Tsuruga
Hidekazu
H
Naito
Akira
A
Nakaya
Seigo
S
Sato
Masami
M
Kamata
Yoshie
Y
Hirata
Haruhisa
H
Kambara
Yumiko
Y
Kurasawa
Noriko
N
Wada
Takahiro
T
Toyoda
Yoshihiro
Y
Shirasawa
Eiichi
E
Ohashi
Yuichi
Y
D000287:Administration, Topical; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D002924:Ciliary Body / Q000378:metabolism; D015169:Colony Count, Microbial; D003228:Conjunctiva / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D004195:Disease Models, Animal; D015818:Eye Infections, Bacterial / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D005782:Gels; D007634:Keratitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008712:Methicillin / Q000494:pharmacology; D016106:Methicillin Resistance / Q000187:drug effects*; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification*; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D005782:Gels; D015242:Ofloxacin; D008712:Methicillin