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Effects of intravitreal injection of levofloxacin (LVFX) on the electroretinogram (ERG), visual evoked potential (VEP), and retinal histology were studied in 23 albino and 23 pigmented rabbits to establish the non-toxic intravitreal dosage of LVFX. Doses of 200, 500, 1,000 or 2,000 micrograms of LVFX were injected intravitreally. The ERG and VEP were recorded before injection, and 3 hours, 2 days, 1 week, 2 weeks and 4 weeks after injection. The oscillatory potential transiently deteriorated with 1,000 and 2,000 micrograms doses of LVFX in albino and pigmented rabbits. No ERG changes were observed with 200 and 500 micrograms doses. No abnormal changes were observed in the VEP or retinal histology with any doses of LVFX. These results indicate that intravitreal injections of 200 and 500 micrograms of LVFX are nontoxic to the rabbit retina.

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BACKGROUND: Fluoroquinolones have a strong affinity with melanin, and their ocular effects have been reevaluated. Norfloxacin, one of the fluoroquinolones, has broad-spectrum activity against aerobic gram-positive and gram-negative bacteria. We examined the retinal toxicity and intraocular pharmacokinetics of intravitreal norfloxacin in rabbits. METHODS: Twenty-three albino and 23 pigmented rabbits were divided into three groups to evaluate retinal toxicity and two groups to investigate the intraocular pharmacokinetics. Each of these five groups was further divided into two subgroups (albino rabbits and pigmented rabbits). RESULTS: With 500 micrograms norfloxacin, the oscillatory potential of the electroretinogram was transiently and selectively deteriorated in albino and pigmented rabbits, whereas the electroretinogram remained unchanged with 50 micrograms in pigmented rabbits. No changes were observed in the visual evoked potential or on histology of the retina 7 days after an intravitreal injection of 50 or 500 micrograms norfloxacin. The electroretinogram and the retinal histology became abnormal 7 days after four intravitreal injections of 500 micrograms norfloxacin at 7-day intervals. As regards the intraocular pharmacokinetics after an intravitreal injection, the norfloxacin concentration in the chorioretina was as high as that in the vitreous 3 h after injection and was much higher than that in the vitreous 7 days after injection. Similar results were obtained after multiple injections. CONCLUSIONS: These results indicate a high concentration of norfloxacin in the melanin-containing ocular tissues.

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The intraocular penetration of levofloxacin was studied in albino and pigmented rabbits after oral administration of 14C-levofloxacin at a dose of 20 mg/kg. The radioactivity of the eyeball of albino rabbits in the autoradiogram was much higher at 1 hr than at 2 or 6 hr after administration. On the other hand, the distribution of radioactivity in pigmented rabbits was similar at 1, 2, and 6 hr after administration. The radioactivity levels in melanin-containing tissues such as the iris-ciliary body and the choroid-retina were significantly higher in pigmented rabbits than in albino rabbits 2 hr after oral administration. The radioactivity levels in the ocular tissues without melanin except for the cornea were similar in albino and pigmented rabbits. These results indicate that the intraocular pharmacokinetics of levofloxacin are markedly affected by its affinity for melanin.

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The intraocular penetration of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), a new antiviral drug, after oral administration, the effects of non-toxic intravitreal doses of BV-araU, and the intraocular kinetics of BV-araU after intraocular injection were studied in rabbits. The intravitreal penetration of BV-araU after oral administration was very poor: 0.11 +/- 0.13 micrograms/ml and 0.20 +/- 0.02 microgram/ml respectively in albino and pigmented rabbits 2 h after 30 mg/kg. An intravitreal injection of 200 micrograms BV-araU caused transient electroretinographic (ERG) changes, whereas a 100-micrograms injection and intravitreal irrigation with 20 micrograms/ml BV-araU caused no ERG and histologic changes over the 4-week follow-up period. The half-life of the intravitreal concentration of BV-araU after an intravitreal injection was short (2.4 h). The results suggest that an intravitreal injection of 100 micrograms BV-araU or an intravitreal irrigating solution containing 20 micrograms/ml BV-araU is non-toxic to the retina and may be used for treatment of retinitis caused by varicella-zoster virus or herpes simplex virus type 1.

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A case of fungal endophthalmitis caused by Paecilomyces lilacinus after cataract surgery is reported. An 84-year-old woman had been suffering from diabetes mellitus and hypertension. She underwent an uncomplicated extracapsular cataract extraction with implantation of a posterior chamber intraocular lens in the right eye. Approximately one month after the surgery iritis was noted, and treated systemically and topically with corticosteroids and antibiotics. The inflammation was improved by these therapies at first, but worsened when the dose of oral corticosteroid was reduced. White fluffy exudates were present on the iris near the chamber angle with the hypopyon. Removal of the intraocular lens, vitrectomy and medicinal therapy were undertaken. The eye was salvaged but the final visual acuity was counting fingers. Paecilomyces lilacinus was identified from the intraocular specimen taken at the time of surgery. The clinical effects and the results of in-vitro sensitivity test showed that fluconazole and amphotericin B were ineffective, and that econazole, thimerosal and miconazole were effective.

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We studied the nontoxic intravitreal concentration of ofloxacin, a new quinolone antibacterial agent, by evaluating its effects on in vitro and in vivo electroretinograms (ERGs) in albino and pigmented rabbits. After perfusion with a 36 micrograms/ml solution of ofloxacin, the in vitro ERG remained unchanged. The in vivo ERG and the visually evoked potential remained unchanged 4 weeks after vitrectomy with 50 micrograms/ml ofloxacin, and the retina was within normal limits both ophthalmoscopically and histologically. Therefore, the retinal toxicity of ofloxacin is low and within safe limits at clinical dosage.

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The effects of lomefloxacin on the in-vitro ERG were studied in the rabbit. The ERG was unchanged during perfusion with 100 microM lomefloxacin. The oscillatory potential was selectively diminished with 300 microM lomefloxacin. The suppressive effect of 300 microM lomefloxacin on the oscillatory potential was antagonized by 0.2 microM bicuculline or 0.2 microM picrotoxin. Bicuculline (0.2 microM) or picrotoxin (0.2 microM) antagonized the suppressive effect of GABA (50 microM) on the oscillatory potential. Bicuculline (1.0 microM) alone, picrotoxin (1.0 microM) alone or GABA (50 microM) alone did not augment the oscillatory potential. The findings of the present study suggested that lomefloxacin, a new quinolone agent, inhibits GABA receptor binding in the rabbit retina.

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We studied the intraocular concentration of flomoxef sodium in nonvitrectomized and vitrectomized eyes of albino rabbits after intravenous administration of 100 mg/kg flomoxef sodium. The concentration of flomoxef sodium in the vitreous body was undetectable (< 0.1 micrograms/ml) in nonvitrectomized eyes. Retinal toxicity of flomoxef sodium was investigated with ophthalmoscopy, electroretinography (ERG) and light microscopy after intravitreal injection of 200, 500, 1,000 and 2,000 micrograms flomoxef sodium in albino and pigmented rabbits. No ERG changes were induced with 200 micrograms. Other higher doses caused transient ERG changes. After the 200-micrograms injection, the intravitreal concentration decreased exponentially, the half-life being 4.4 h. The antibacterial activity, broad coverage and low intravitreal toxicity of flomoxef sodium suggest that this compound may be used to treat bacterial endophthalmitis.

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The concentration of ceftazidime was determined in the aqueous humor and the vitreous body of normal, vitrectomized and aphakic/vitrectomized eyes and in the serum of albino rabbits 1 h after intravenous injection of 100 mg/kg ceftazidime. The intravitreal ceftazidime concentration was low (0.1-0.2 microgram/ml) in normal eyes 1 h after intravenous injection, and high (8.7 +/- 8.5 micrograms/ml) in vitrectomized and aphakic/vitrectomized eyes when injected immediately after surgery. The ceftazidime concentration was also determined in the aqueous humor and the vitreous body of normal eyes and in the serum of albino rabbits 3, 6, 12, 24 and 48 h after intravitreal injection of 200 micrograms. The intravitreal ceftazidime concentration after intravitreal injection decreased exponentially for 12 h (half-life about 7.4 h). It decreased more slowly thereafter and remained at 13.0 micrograms/ml (mean) even 48 h after injection. This concentration exceeded the minimum inhibitory concentrations against common gram-positive and gram-negative organisms causing endophthalmitis.

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The effect of an intravitreal injection of norfloxacin on the retina was evaluated by in-vivo electroretinogram (ERG) and histological examination in pigmented rabbits. The intraocular pharmacokinetics after an intravitreal injection of norfloxacin were also investigated. An intravitreal injection of 50 micrograms norfloxacin produced no significant change in the ERG. An injection of 500 micrograms norfloxacin decreased the amplitude of the oscillatory potentials, and delayed their peak latencies 3 hours after the injection, but these changes recovered within 7 days. A marked suppression of the c-wave was noted in one pigmented rabbit. Neither 50 micrograms nor 500 micrograms norfloxacin caused any apparent changes in the visual evoked potential and in the retinal histology 7 days after the injection. The intraocular pharmacokinetic study showed that the concentration of norfloxacin in the choroid-retina was almost the same level as that in the vitreous body 3 hours after the injection. However, the former was higher than the latter 7 days after the injection, suggesting the persistency of norfloxacin in the choroid-retina. An intravitreal injection of 50 micrograms norfloxacin could be used without retinal toxicity. A high dose-intravitreal use of norfloxacin needs careful attention with respects to its persistency in the pigmented ocular tissues.

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The retinal toxicity of vancomycin and ofloxacin was studied by electroretinogram (ERG) recorded before and after intravitreal injection in rabbits. A dose of 1.0 mg vancomycin caused no change in the ERG for at least 8 weeks after the injection. The ERG was nonrecordable during one to four weeks after an intravitreal injection of 10 mg vancomycin, with recovery of only the c-wave. A dose of 200 micrograms ofloxacin did not cause deterioration of the b-wave, the c-wave or the oscillatory potentials throughout the follow-up period of 8 weeks. Considering the individual susceptibility of the ERG components to these antimicrobial agents and taking into account the difference in vitreous volume between the rabbit and man, the results of this study indicate the recommended intravitreal doses of these antimicrobial agents for clinical use are as follows: vancomycin 1.0 mg/0.1 ml, and ofloxacin 200 micrograms/0.1 ml.

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We evaluated the retinal toxicity of antimicrobials (sulbenicillin, cefazolin, flomoxef, gentamicin, sisomicin, netilmicin, tobramycin, amikacin, vancomycin, ofloxacin, lomefloxacin, and miconazole) by the electroretinogram, before and after a single-shot intravitreal injection in rabbits. The clinical dosage for single-shot intravitreal injections which we recommend are 2 mg for sulbenicillin, 0.25 mg for cefazolin, 0.2 to 0.4 mg for flomoxef, 0.1 mg for gentamicin, 0.1 to 0.2 mg for netilmicin, 0.2 to 0.4 mg for amikacin, 0.2 mg for tobramycin, 1 mg for vancomycin, 0.2 mg for ofloxacin, 0.2 mg for lomefloxacin, and 0.05 mg for miconazole.

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The retinal toxicity of vancomycin and ofloxacin was studied by electroretinogram (ERG) before and after intravitreal injection in rabbits. Vancomycin is known to be effective on methicillin-resistant Staphylococcus aureus. A dose of 1mg vancomycin caused no ERG change for at least eight weeks after injection. The feature that ERG became non-recordable during one to four weeks after an intravitreal injection of 10mg vancomycin, with recovery of only the c-wave was conspicuous. A dose of 200 micrograms ofloxacin did not cause deterioration of the b-wave, the c-wave or the oscillatory potentials throughout the follow-up period up to eight weeks. Judging from the susceptibility of each ERG component to antimicrobials and taking into account the difference of vitreous volume between rabbits and humans, clinical doses of intravitreal single-shot injection should be less than 1mg for vancomycin and 200 micrograms for ofloxacin.

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We evaluated the retinal toxicity of aminoglycosides (gentamicin, sisomicin, netilmicin, tobramycin and amikacin) by ERG, before and after a single-shot intravitreal injection in rabbits. Gentamicin 200 micrograms abolished the c-wave one week after injection, only slightly diminishing the b-wave and the oscillatory potentials (OPs). Gentamicin 80 micrograms did not alter the ERG up to at least 8 weeks after injection. All the ERG components examined were abolished by 200 micrograms and were irreversibly suppressed by 80 micrograms of sisomicin for the entire period of follow-up. Netilmicin (200 micrograms) or tobramycin (200 micrograms) transiently suppressed the b-wave, c-wave and the OPs. Amikacin (200 micrograms) caused no ERG changes for at least 8 weeks after injection. The clinical doses for single-shot intravitreal injections that we recommend are 100 micrograms for gentamicin, 200 micrograms for netilmicin, 200 micrograms for tobramycin and 200-400 micrograms for amikacin.

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Toxicity of an intravitreal injection of gentamicin sulfate, disodium sulbenicillin and cefazolin sodium on the retina was investigated by electroretinogram in albino and pigmented rabbits. Recordings were made before injection and 2 hours and 3, 7, 14, and 21 days after injection. Significant differences were found in the susceptibility of the electroretinogram components to various antibiotics as follows. Gentamicin 0.24 mg/0.1 ml irreversibly abolished all the components examined. Sulbenicillin 4.0, 8.0, or 12 mg/0.1 ml transiently suppressed the b-wave and the oscillatory potentials incrementally with increasing dose. Cefazolin 0.5, 2.0, or 5.0 mg/0.1 ml selectively reduced the oscillatory potentials, leaving the a- and b-waves almost unattenuated. The cefazolin-suppressed oscillatory potentials recovered within 14 days after injection. Judging from the most susceptible electroretinogram components to each antibiotic, we recommend intravitreal doses of these antibiotics for clinical use as follows: gentamicin 0.1 mg/0.1 ml, sulbenicillin 2 mg/0.1 ml, and cefazolin 0.25 mg/0.1 ml.

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