Changes in ocular flora in eyes exposed to ophthalmic antibiotics.

PURPOSE: To determine changes in ocular flora in individuals repeatedly exposed to topical macrolide or fluoroquinolone antibiotics. DESIGN: Prospective, controlled, longitudinal study with 1-year follow-up. PARTICIPANTS: Forty-eight eyes of 24 patients undergoing serial unilateral intravitreal injection for choroidal neovascularization. METHODS: Patients received 4 consecutive monthly unilateral intravitreal injections and were then treated as needed. Each patient was randomized to 1 of 4 antibiotics (azithromycin 1%, gatifloxacin 0.3%, moxifloxacin 0.5%, ofloxacin 0.3%) and used only their assigned antibiotic for 4 days after each injection. Conjunctival cultures of the treated eye and untreated fellow eye (control) were taken at baseline and before each injection. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. MAIN OUTCOME MEASURES: Changes in bacteria composition of the conjunctiva over time. RESULTS: In azithromycin-treated eyes, Staphylococcus epidermidis and Staphylococcus aureus accounted for 54.5% and 18.2% of cultured isolates, respectively, at baseline and 90.9% (P<0.01) and 4.5% (P<0.01), respectively, after azithromycin exposure. In fluoroquinolone-treated eyes, 45.7% and 6.5% of cultured isolates at baseline were S epidermidis and S aureus, respectively, but these percentages increased to 63.4% (P<0.03) and 13% (P = 0.24), respectively, after fluoroquinolone exposure. In contrast, the percentage of gram-negative species decreased from 8.7% at baseline to 1.6% (P<0.05) in fluoroquinolone-treated eyes. The percentage of S epidermidis isolated from azithromycin-treated eyes was significantly greater when compared with fellow control eyes (P<0.01) or fluoroquinolone-treated eyes (P<0.01). CONCLUSIONS: The percentage of S epidermidis isolated from the conjunctival surface significantly increases after repeated exposure to azithromycin and to a lesser degree fluoroquinolone antibiotics at the expense of other commensal flora. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections.

PURPOSE: To determine whether repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics promotes antimicrobial resistance in patients undergoing intravitreal injections for choroidal neovascularization (CNV). DESIGN: Prospective, randomized, controlled, clinical trial. PARTICIPANTS: Forty-eight eyes of 24 patients undergoing unilateral intravitreal injections for CNV. METHODS: Patients were assigned randomly to 1 of 4 ophthalmic antibiotics (azithromycin 1%, ofloxacin 0.3%, gatifloxacin 0.3%, moxifloxacin 0.5%) to be used after each injection in the treatment eye only. Bilateral conjunctival and unilateral nasopharyngeal cultures on the treatment side were obtained at baseline and were repeated at each subsequent visit for 1 year. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. Genetic analysis of bacteria strains was performed using pulse-field gel electrophoresis. MAIN OUTCOME MEASURES: Changes in antibiotic susceptibility patterns of conjunctival and nasopharyngeal flora over time and emergence of resistant strains. RESULTS: Eight subjects (33%) grew Staphylococcus aureus from the nasopharynx and 1 subject (13%) showed emergence of a resistant strain. Coagulase-negative staphylococci (CNS) cultured from eyes repeatedly exposed to fluoroquinolone antibiotics demonstrated significantly increased rates of resistance to third- and fourth-generation fluoroquinolones compared with untreated eyes. Resistance to ofloxacin and levofloxacin was roughly 85% (P = 0.003), and resistance to gatifloxacin and moxifloxacin approached 67% (P = 0.009) and 77% (P<0.001), respectively. In contrast, CNS isolated from eyes repeatedly exposed to azithromycin demonstrated significantly increased resistance (94%) to erythromycin and azithromycin when compared with control eyes (P = 0.009) and decreased resistance to third-generation (P<0.03) and fourth-generation (P<0.001) fluoroquinolones when compared with eyes exposed to fluoroquinolones. CONCLUSIONS: Repeated exposure of ocular and nasopharyngeal flora to ophthalmic antibiotics selects for resistant strains.

Ophthalmic antibiotic use and multidrug-resistant staphylococcus epidermidis: a controlled, longitudinal study.

PURPOSE: To analyze the emergence of multidrug-resistant Staphylococcus epidermidis after repeated conjunctival exposure to topical macrolide or fluoroquinolone antibiotics. DESIGN: Prospective, controlled, longitudinal study with 1-year follow-up. PARTICIPANTS: Forty-eight eyes of 24 patients undergoing serial unilateral intravitreal (IVT) injections for choroidal neovascularization. METHODS: Subjects received 4 consecutive monthly unilateral IVT injections and then were treated as needed. Each subject was assigned randomly to 1 of 4 antibiotics (azithromycin 1%, gatifloxacin 0.3%, moxifloxacin 0.5%, ofloxacin 0.3%) and used only their assigned antibiotic after each injection. Conjunctival culture specimens of the treated and untreated fellow eye (control) were obtained at baseline and after each injection. All bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. MAIN OUTCOME MEASURES: Antibiotic susceptibility patterns and multidrug resistance of S. epidermidis. RESULTS: After 4 consecutive treatments, a total of 58 isolates of S. epidermidis each were isolated from control and treated eyes. Resistance to 3 or more antibiotics was present in 69% of S. epidermidis isolated from control eyes compared with 90% from treated eyes (P<0.02). A total of 46 and 38 isolates of S. epidermidis were cultured from control and treated eyes, respectively, from the fifth until the final injection. Resistance to 5 or more antibiotics was present in 48% of control eyes compared with 71% of treated eyes (P<0.05). In a significant number of fluoroquinolone-treated eyes, S. epidermidis developed resistance to third-generation (P<0.01) and fourth-generation (P<0.01) fluoroquinolones compared with control eyes. In addition, these organisms developed resistance to trimethoprim/sulfamethoxazole (P<0.01), gentamicin (P<0.03), and clindamycin (P<0.05). Similarly, a significant number of azithromycin-treated eyes developed S. epidermidis resistant to macrolides (P<0.01) compared with control eyes and also developed increased resistance to trimethoprim/sulfamethoxazole (P<0.02) and doxycycline (P<0.01). CONCLUSIONS: Conjunctival S. epidermidis repeatedly exposed to fluoroquinolone or azithromycin antibiotics rapidly develop resistance. Coresistance to other antibiotics also was observed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Antibiotic resistance of conjunctiva and nasopharynx evaluation study: a prospective study of patients undergoing intravitreal injections.

PURPOSE: To determine the baseline antibiotic susceptibility patterns of conjunctival and nasopharyngeal flora isolated from patients undergoing intravitreal (IVT) injections for choroidal neovascularization (CNV). DESIGN: Prospective, observational study. PARTICIPANTS: Forty-eight eyes of 24 patients undergoing unilateral IVT injections for CNV. METHODS: Bilateral conjunctival and unilateral nasopharyngeal cultures on the treatment side were taken before application of any topical medications. MAIN OUTCOME MEASURES: Bacterial isolates were identified and tested for antibiotic susceptibility to 16 different antibiotics using the Kirby-Bauer disc diffusion technique. RESULTS: A total of 57 bacterial isolates were obtained from the conjunctiva of 48 eyes. Coagulase-negative staphylococci (CNS) accounted for 37 of the 57 isolates (65%). The most common CNS organisms were Staphylococcus epidermidis and Staphylococcus lugdunensis accounting for 73% and 11% of CNS isolates, respectively. More than half of S. epidermidis isolates demonstrated some level of resistance to ofloxacin and levofloxacin, and 33% and 37% of isolates showed some level of resistance against gatifloxacin and moxifloxacin, respectively. Some 60% and 30% of CNS isolates were resistant to ≥ 3 and ≥ 5 antibiotics, respectively. Among the 24 nasopharyngeal cultures, 8 (33%) grew Staphylococcus aureus, and 1 of the 8 isolates (13%) was resistant to all penicillin, cephalosporin, macrolide, and fluoroquinolone antibiotics tested. CONCLUSIONS: Our results demonstrate subtantial levels of resistance to third- and fourth-generation fluoroquinolones and multiresistance among ocular CNS isolated from patients undergoing IVT injections for CNV.

Improved assessment of laser-induced choroidal neovascularization.

The primary objective of this study was to develop and evaluate new methods of analyzing laser-induced choroidal neovascularization (CNV), in order to make recommendations for improving the reporting of experimental CNV in the literature. Six laser burns of sufficient power to rupture Bruch's membrane were concentrically placed in each eye of 18 adult Norway rats. Eyes received intravitreal injections of either triamcinolone acetonide, ketorolac, or balanced salt solution (BSS). Fluorescein angiography (FA) was performed 2 and 3 weeks after injection, followed by choroidal flat mount preparation. Vascular leakage on FAs and vascular budding on choroidal mounts were quantified by measuring either the cross-sectional area of each CNV lesion contained within the best-fitting polygon using Adobe Photoshop (Lasso Technique or Quick Selection Technique), or the area of bright pixels within a lesion using Image-Pro Plus. On choroidal mounts, the Lasso Technique and Image-Pro Plus detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while the Quick Selection Technique did not (Lasso Technique, 0.78 and 0.64; Image-Pro Plus, 0.77 and 0.65). On FA, the Lasso Technique and Quick Selection Technique detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while Image-Pro Plus did not (Lasso Tool, 0.81 and 0.54; Quick Selection Tool, 0.76 and 0.57). Choroidal mounts and FA are both valuable for imaging experimental CNV. Adobe Photoshop and Image-Pro Plus are both able to detect subtle differences in CNV lesion size, when images are not manipulated. The combination of choroidal mounts and FA provides a more comprehensive assessment of CNV anatomy and physiology.

Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF.

We assessed the effect of topical ketorolac on laser-induced choroidal neovascularization (CNV), measured retinal PGE(2) and VEGF levels after laser treatment, and determined the effect of ketorolac on PGE(2) and VEGF production. Six laser burns were placed in eyes of rats which then received topical ketorolac 0.4% or artificial tears four times daily until sacrifice. Fluorescein angiography (FA) was performed at 2 and 3 weeks and retinal pigment epithelium-choroid-sclera flat mounts were prepared. The retina and vitreous were isolated at 1, 3, 5, 7, and 14 days after laser treatment and tested for VEGF and PGE(2). Additional animals were lasered and treated with topical ketorolac or artificial tears and tested at 3 and 7 days for retinal and vitreous VEGF and PGE(2.) Ketorolac reduced CNV on FA by 27% at 2 weeks (P<0.001) and 25% at 3 weeks (P<0.001). Baseline retina and vitreous PGE(2) levels were 29.4 µg/g and 16.5 µg/g respectively, and reached 51.2 µg/g and 26.9 µg/g respectively, 24h after laser treatment (P<0.05). Retinal VEGF level was 781pg/g 24h after laser treatment and reached 931pg/g by 7 days (P<0.01). Ketorolac reduced retinal PGE(2) by 35% at 3 days (P<0.05) and 29% at 7 days (P<0.001) and retinal VEGF by 31% at 3 days (P=0.10) and 19% at 7 days (P<0.001). Topical ketorolac inhibited CNV and suppressed retinal PGE(2) and VEGF production.

Ocular HSV-1 latency, reactivation and recurrent disease.

Ocular infection with HSV-1 continues to be a serious clinical problem despite the availability of effective antivirals. Primary infection with HSV-1 can involve ocular and adenaxial sites and can manifest as blepharitis, conjunctivitis, or corneal epithelial keratitis. After initial ocular infection, HSV-1 can establish latent infection in the trigeminal ganglia for the lifetime of the host. During latency, the viral genome is retained in the neuron without producing viral proteins. However, abundant transcription occurs at the region encoding the latency-associated transcript, which may play significant roles in the maintenance of latency as well as neuronal reactivation. Many host and viral factors are involved in HSV-1 reactivation from latency. HSV-1 DNA is shed into tears and saliva of most adults, but in most cases this does not result in lesions. Recurrent disease occurs as HSV-1 is carried by anterograde transport to the original site of infection, or any other site innervated by the latently infected ganglia, and can reinfect the ocular tissues. Recurrent corneal disease can lead to corneal scarring, thinning, stromal opacity and neovascularization and, eventually, blindness. In spite of intensive antiviral and anti-inflammatory therapy, a significant percentage of patients do not respond to chemotherapy for herpetic necrotizing stromal keratitis. Therefore, the development of therapies that would reduce asymptomatic viral shedding and lower the risks of recurrent disease and transmission of the virus is key to decreasing the morbidity of ocular herpetic disease. This review will highlight basic HSV-1 virology, and will compare the animal models of latency, reactivation, and recurrent ocular disease to the current clinical data.

Binasal visual field defects from simultaneous bilateral retinal infarctions in sickle cell disease.

PURPOSE: To report a case of retinal occlusive disease producing binasal visual field defects in a patient with sickle cell (SC) disease. DESIGN: Retrospective case report. METHODS: A 21-year-old man with SC disease presented with binasal field defects and 20/20 acuity in each eye. RESULTS: Initial ophthalmoscopy and fluorescein angiography revealed no abnormalities. Optical coherence tomography (OCT) demonstrated bilateral temporal inner retinal hyperreflectivity, and multifocal electroretinography (mfERG) confirmed retinal dysfunction. Several weeks later, ophthalmoscopy and angiography demonstrated macular arteriolar occlusive disease. CONCLUSIONS: Simultaneous bilateral macular occlusive events are uncommon in patients particularly with SC disease. Although the binasal field defects raised the suspicion of a process affecting the optic nerves, the OCT and mfERG proved essential in diagnosing retinal rather than optic nerve disease.

The retinal ciliopathies.

While the functions of many of the proteins located in or associated with the photoreceptor cilia are poorly understood, disruption of the function of these proteins may result in a wide variety of phenotypes ranging from isolated retinal degeneration to more pleiotropic phenotypes. Systemic findings include neurosensory hearing loss, developmental delay, situs-inversus, infertility, disorders of limb and digit development, obesity, kidney disease, liver disease, and respiratory disease. The concept of "retinal ciliopathies" brings to attention the importance of further molecular analysis of this organelle as well as provides a potential common target for therapies for these disorders. The retinal ciliopathies include retinitis pigmentosa, macular degeneration, cone-dystrophy, cone-rod dystrophy, Leber congenital amaurosis, as well as retinal degenerations associated with Usher syndrome, primary ciliary dyskinesia, Senior-Loken syndrome, Joubert syndrome, Bardet-Biedl syndrome, Laurence-Moon syndrome, McKusick-Kaufman syndrome, and Biemond syndrome. Mutations for these disorders have been found in retinitis pigmentosa-1 (RP1), retinitis pigmentosa GTPase regulator (RPGR), retinitis pigmentosa GTPase regulator interacting protein (RPGR-IP), as well as the Usher, Bardet-Biedl, and nephronophthisis genes. Other systemic disorders associated with retinal degenerations that may also involve ciliary abnormalities include: Alstrom, Edwards-Sethi, Ellis-van Creveld, Jeune, Meckel-Gruber, Orofaciodigital Type 9, and Gurrieri syndromes. Understanding these conditions as ciliopathies may help the ophthalmologist to recognize associations between seemingly unrelated diseases and have a high degree of suspicion that a systemic finding may be present.

Bardet-Biedl Syndrome in an African-American patient: should the diagnostic criteria be expanded to include hydrometrocolpos?

Bardet-Biedl Syndrome (BBS) is a multisystemic disorder diagnosed on the basis of a combination of primary and secondary clinical features that include retinal dystrophy, obesity, polydactyly, cognitive dysfunction, and renal malformations. We report a unique case of BBS in a 13-year old girl of African-American descent who presented with retinitis pigmentosa, obesity, polydactyly, learning disabilities, precocious puberty, hypertension, renal cysts, and Hirschprung disease. Further evaluation revealed a history of precocious puberty, which is antithetical to the common manifestations of BBS, while neuroimaging was suggestive of periventricular leukomalacia and neuro-electrophysiologic studies revealed diffuse cerebral disturbance, which may contribute to her neurological abnormalities. The patient was also diagnosed with hydrometrocolpos, a finding typical of McKusick-Kaufman Syndrome (MKKS) but infrequent in other disorders. This observation, together with recent findings in some mouse models of BBS, raises the question of whether hydrometrocolpos should be considered as an additional diagnostic criterion for BBS to be used in females in parallel to the criterion of hypogonadism in males, thereby improving diagnostic sensitivity.

Recurrent vitreous hemorrhage secondary to haptic-induced chafing.

CASE REPORT: After cataract extraction and placement of a posterior chamber intraocular lens, a 70-year-old man had 5 vitreous hemorrhages over 3 years. Iris transillumination defects and apposition of the nasal haptic and ciliary body were found. COMMENTS: Iris chafing is a rare complication of cataract extraction. Vitreous hemorrhage presumably resulted from iris erosion caused by the IOL haptic.

Antimicrobial resistance and ophthalmic antibiotics: 1-year results of a longitudinal controlled study of patients undergoing intravitreal injections.

OBJECTIVE: To determine antibiotic susceptibility patterns of conjunctival flora from patients undergoing intraocular injection for choroidal neovascularization after repeated exposure to ophthalmic antibiotics. METHODS: We conducted a randomized, controlled, longitudinal study of 48 eyes of 24 patients undergoing unilateral intraocular injection for choroidal neovascularization. Bilateral conjunctival cultures from the treated eye and untreated (control) fellow eye were taken at baseline and after each injection (before the application of povidone-iodine). Patients were randomized to ofloxacin, 0.3%; azithromycin, 1%; gatifloxacin, 0.3%; or moxifloxacin hydrochloride, 0.5% and used only their assigned antibiotic after each injection. Bacterial isolates were tested for antibiotic susceptibility to 16 different antibiotics, and analysis of bacteria DNA was performed using pulse-field gel electrophoresis. Main outcome measures included changes in antibiotic susceptibility patterns of conjunctival flora after 1 year. RESULTS: Coagulase-negative staphylococci (CNS) cultured from eyes repeatedly exposed to fluoroquinolone antibiotics demonstrated significantly increased rates of resistance to older-generation (P = .002) and newer-generation (P < .01) fluoroquinolones. In contrast, CNS isolated from azithromycin-exposed eyes demonstrated significantly increased resistance to macrolides (95%; P < .001) and decreased resistance to older-generation (P = .03) and newer-generation (P < .001) fluoroquinolones. There were significant increases in multiple-drug resistance of CNS isolated from treated eyes, with 81.8% and 67.5% of isolates resistant to at least 3 (P = .01) and at least 5 (P = .009) antibiotics, respectively. CONCLUSION: Repeated exposure of conjunctival flora to ophthalmic antibiotics selects for resistant strains. APPLICATION TO CLINICAL PRACTICE: Repeated use of ophthalmic antibiotics after intraocular injection promotes the emergence of antimicrobial resistance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00831961.

Reduced choroidal neovascular membrane formation in cyclooxygenase-2 null mice.

PURPOSE: To assess the degree of laser-induced choroidal neovascular membrane formation in wild-type (WT) and COX-2 null mice and to measure vascular endothelial growth factor (VEGF), interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α levels in the retina and choroid. METHODS: Four laser burns were placed in each eye of WT and COX-2 null mice to induce choroidal neovascularization. Fluorescein angiography (FA) was performed at 14 days, and retinal pigment epithelium-choroid-sclera (choroidal) flat mounts were prepared. The retina and choroid were isolated from WT and COX-2 null mice at 24, 72, and 168 hours after laser photocoagulation and from unlasered eyes and were tested for VEGF, IL-1ß, and TNF-α. RESULTS: COX-2 null mice demonstrated 58% (P = 0.001) and 48% (P = 0.001) reductions in CNV formation on FA and choroidal flat mounts, respectively, compared with WT mice. For unlasered mice, mean VEGF concentrations in the retina and choroid were 1.2 ± 0.42 pg/mg protein for WT but only 0.42 ± 0.2 pg/mg protein for COX-2 null mice (P < 0.05). After laser photocoagulation, WT mice showed significantly greater VEGF and IL-ß expression in the retina and choroid by 168 hours (P < 0.05) and 72 hours (P < 0.05), respectively, compared with COX-2 null mice. CONCLUSIONS: COX-2 null mice exhibited significantly less choroidal neovascular membrane formation associated with reduced expression of VEGF. The results of this study suggest that COX-2 modulates VEGF expression in CNV and implicates a potential therapeutic role for nonsteroidal anti-inflammatory drugs.

Inhibition of choroidal neovascularization by intravitreal ketorolac.

OBJECTIVE: To determine the inhibitory effect of intravitreal nonsteroidal anti-inflammatory drugs on choroidal neovascularization (CNV) in an animal model of age-related macular degeneration. METHODS: Six laser burns of sufficient power to rupture the Bruch membrane were induced in the peripapillary area of each eye of 18 adult Brown Norway rats. Both eyes of each animal received the same 5-microL intravitreal injection of 30 mg/mL of ketorolac tromethamine, 40 mg/mL of triamcinolone acetonide, or balanced salt solution. Fluorescein angiography was performed on days 14 and 21 after injection, animals were euthanized, and retinal pigment epithelium-choroid-sclera (choroidal) flat mounts were prepared. Areas of abnormal vascular leakage on fluorescein angiography and vascular budding on choroidal mounts were measured and quantified using an image analysis program. RESULTS: Intravitreal ketorolac significantly reduced CNV leakage on fluorescein angiography at 2 (P < .001) and 3 (P = .006) weeks compared with eyes injected with balanced salt solution, but intravitreal triamcinolone was a more potent inhibitor of CNV leakage than ketorolac (P < .001). Vascular budding on choroidal mounts was almost entirely suppressed with triamcinolone (P < .001) and significantly inhibited with ketorolac (P = .009). CONCLUSION: Intravitreal ketorolac significantly reduced laser-induced CNV leakage and vascular budding as determined by fluorescein angiography and choroidal flat mounts, respectively, although this effect was less than that of triamcinolone. CLINICAL RELEVANCE: Intravitreal nonsteroidal anti-inflammatory drugs may be useful in the treatment of CNV owing to age-related macular degeneration or other causes and offer distinct clinical advantages over corticosteroids because of their lack of association with cataract formation or glaucoma.

Cancer-associated retinopathy with retinal periphlebitis in a patient with ovarian cancer.

PURPOSE: To describe a case of cancer-associated retinopathy (CAR) due to ovarian cancer presenting with retinal periphlebitis and a negative-type pattern electroretinogram (ERG). DESIGN: Case report. METHODS: Retrospective chart review. RESULTS: A negative-type ERG in the setting of progressive vision loss and retinal periphlebitis led to the discovery of metastatic ovarian cancer and ultimately the diagnosis of CAR. CONCLUSIONS: CAR can present with periphlebitis and a negative-type ERG. Greater awareness of these associations may allow for earlier detection of future cases.

Safety of intravitreal ketorolac and diclofenac: an electroretinographic and histopathologic study.

OBJECTIVE: To determine the clinical, histologic, and electroretinographic effects in the rabbit retina of escalating doses of two intravitreally delivered nonsteroidal anti-inflammatory drugs (NSAIDs): ketorolac and diclofenac. METHODS: Right eyes received a single 0.1 mL injection of either ketorolac (500-6000 microg/0.1 mL) or diclofenac (300-1500 microg/0.1 mL) prepared in balanced salt solution (BSS). Left eyes served as controls and received BSS. Dark- and light-adapted electroretinograms (ERG) were obtained at baseline and 4 and 8 weeks postinjection. Enucleated eyes were examined histologically. RESULTS: Ophthalmic examinations demonstrated no signs of intraocular inflammation or retinal toxicity. Intraocular pressure measurements remained similar between NSAID injected and control eyes. Histologic and ERG studies of eyes injected with 6000 microg ketorolac and >or=500 microg diclofenac demonstrated toxicity. In contrast, doses up to 3000 microg ketorolac demonstrated enhanced b-wave amplitude responses. Delayed drug toxicity was observed for the highest doses of both NSAIDs. CONCLUSIONS: Intravitreal 3000 microg ketorolac and 300 microg diclofenac were nontoxic in this animal study, and may offer an effective and safer alternative to intravitreal corticosteroids.