Comprehensive Ocular and Systemic Safety Evaluation of Polysialic Acid-Decorated Immune Modulating Therapeutic Nanoparticles (PolySia-NPs) to Support Entry into First-in-Human Clinical Trials.

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation.

Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial.

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 (P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:327-335.].

Effect of Bevacizumab vs Aflibercept on Visual Acuity Among Patients With Macular Edema Due to Central Retinal Vein Occlusion: The SCORE2 Randomized Clinical Trial.

IMPORTANCE: Studies have established the efficacy and safety of aflibercept for the treatment of macular edema due to central retinal vein occlusion. Bevacizumab is used off-label to treat this condition despite the absence of supporting data. OBJECTIVE: To investigate whether bevacizumab is noninferior to aflibercept for the treatment of macular edema secondary to central retinal or hemiretinal vein occlusion. DESIGN, SETTING, AND PARTICIPANTS: The SCORE2 randomized noninferiority clinical trial was conducted at 66 private practice or academic centers in the United States, and included 362 patients with macular edema due to central retinal or hemiretinal vein occlusion who were randomized 1:1 to receive aflibercept or bevacizumab. The first participant was randomized on September 17, 2014, and the last month 6 visit occurred on May 6, 2016. Analyses included data available as of December 30, 2016. INTERVENTIONS: Eyes were randomized to receive intravitreal injection of bevacizumab (1.25 mg; n = 182) or aflibercept (2.0 mg; n = 180) every 4 weeks through month 6. MAIN OUTCOMES AND MEASURES: The primary outcome was mean change in visual acuity (VA) letter score (VALS) from the randomization visit to the 6-month follow-up visit, based on the best-corrected electronic Early Treatment Diabetic Retinopathy Study VALS (scores range from 0-100; higher scores indicate better VA). The noninferiority margin was 5 letters, and statistical testing for noninferiority was based on a 1-sided 97.5% confidence interval. RESULTS: Among 362 randomized participants (mean [SD] age, 69 [12] years; 157 [43.4%] women; mean [SD] VALS at baseline, 50.3 [15.2] [approximate Snellen VA 20/100]), 348 (96.1%) completed the month 6 follow-up visit. At month 6, the mean VALS was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, -0.14; 97.5% CI, -3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority. Ocular adverse events in the aflibercept group included 4 participants with intraocular pressure (IOP) more than 10 mm Hg greater than baseline; ocular adverse events in the bevacizumab group included 1 participant with endophthalmitis (culture negative), 9 with IOP more than 10 mm Hg greater than baseline, 2 with IOP higher than 35 mm Hg, and 1 with angle-closure glaucoma not attributed to the study drug or procedure. CONCLUSIONS AND RELEVANCE: Among patients with macular edema due to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to visual acuity after 6 months of treatment.

Metallic intraocular foreign bodies: characteristics, interventions, and prognostic factors for visual outcome and globe survival.

PURPOSE: To describe metallic intraocular foreign body (IOFB) injuries and identify prognostic factors for visual outcome and globe survival. DESIGN: Interventional, consecutive, retrospective case series. METHODS: setting: Wills Eye Hospital. study population: Ninety-six eyes of 96 patients with metallic intraocular foreign bodies. procedures: Metallic IOFB injuries between January 1991 to June 2002 were reviewed for clinical characteristics, surgical intervention, and outcome. Univariate and multivariate analyses were performed to identify prognostic variables. main outcome measures: Final visual acuity and globe survival. RESULTS: The average patient age was 33.0 years with a male predominance (94%). Forty percent of eyes had a presenting vision of 20/50 or better. Following IOFB removal, 40% of patients required additional interventions. Thirty-one percent of eyes had a final acuity of 20/50 or better. Eight percent of patients ultimately required enucleation or evisceration. Excellent visual outcome (defined as > or =20/50) was associated with multiple variables, including normal lens at presentation and anterior segment IOFB (P< .003). Factors associated with poor visual outcome (defined as <20/200) included uveal prolapse and posterior segment IOFB (P < .0003). Globe loss was associated with younger age, presenting light perception (LP) or no light perception (NLP) vision, BB/pellet injury, and the presence of an afferent pupillary defect (P < .01). CONCLUSIONS: Multiple prognostic factors were identified in this large analysis of metallic IOFB injuries, which may help predict visual outcome and globe survival. Most of these variables were independent of intervention and can be identified at the time of initial presentation.

Incidence of endophthalmitis after 20- and 25-gauge vitrectomy.

PURPOSE: To assess the incidence rate of endophthalmitis after 25-gauge pars plana vitrectomy and to compare it with the endophthalmitis rate after 20-gauge pars plana vitrectomy. DESIGN: Retrospective, interventional, comparative cohort study. PARTICIPANTS: Eight thousand six hundred one consecutive pars plana vitrectomy surgery patients. METHODS: Surgeries performed at a single institution between January 1, 2004, and September 1, 2006, were reviewed. MAIN OUTCOME MEASURES: Incidence of postvitrectomy endophthalmitis. RESULTS: Endophthalmitis developed in 1 of 5498 eyes after 20-gauge vitrectomy (0.018%) and in 7 of 3103 eyes after 25-gauge vitrectomy cases (0.23%; P = 0.004). Median final visual acuity was counting fingers or hand movements (range, 20/50-no light perception), with comparable results between 20-gauge and 25-gauge endophthalmitis cases. CONCLUSIONS: The visual outcomes of vitrectomy-associated endophthalmitis, for both 20-gauge and 25-gauge vitrectomy, is poor. In this study population, 25-gauge vitrectomy had a statistically significant 12-fold higher incidence of endophthalmitis compared with 20-gauge vitrectomy.

Endophthalmitis after open globe injury: microbiologic spectrum and susceptibilities of isolates.

PURPOSE: To present the microbiologic spectrum and susceptibilities of isolates in posttraumatic endophthalmitis, and to provide a review of the literature. DESIGN: Retrospective consecutive case series. METHODS: A review of 1182 consecutive open globe injuries was performed, identifying 10 patients with culture-proven endophthalmitis. RESULTS: Thirteen organisms were isolated from 10 eyes with posttraumatic endophthalmitis. Isolated organisms included Streptococcus species (46.2%), coagulase-negative Staphylococcus (23.1%), and Bacillus cereus (15.4%). All organisms tested were susceptible to vancomycin and tobramycin. The most commonly isolated organisms from an aggregate posttraumatic endophthalmitis pool of 372 cases obtained by literature-based meta-analysis were coagulase-negative Staphylococcus (21.5%) and Bacillus cereus (18.5%). CONCLUSION: We report a high prevalence of gram-positive pathogens and a notable prevalence of Bacillus cereus in posttraumatic endophthalmitis. Susceptibility results suggest that posttraumatic endophthalmitis isolates are generally susceptible to vancomycin and tobramycin.

Relationship between clinical presentation and visual outcome in postoperative and posttraumatic endophthalmitis in south central India.

PURPOSE: To determine risk factors for poor visual outcome in postoperative and posttraumatic endophthalmitis in a large referral center in south central India. METHODS: In this prospective observational series the authors examined 388 patients of postoperative (n= 206) and posttraumatic (n= 182) endophthalmitis at the L V Prasad Eye Institute in Hyderabad, India between 1991 and 1997. The analysis was confined to 236 patients-128 (62.1%) postoperative and 108 (59.3%) posttraumatic patients who were followed for a minimum period of 3 months. A detailed protocol was followed. Chi-square and logistic regression analysis were used to determine risk factors for visual outcome worse than 6/18 and worse than 6/120. RESULTS: Postoperative endophthalmitis: In univariate analysis the features associated with poor visual acuity (grouped as < 6/18 and < 6/120) included intracapsular cataract surgery, poor presenting visual acuity, presence of vitreous cells, inability to visualise the optic disc on indirect ophthalmoscopy, presence of vitreous membranes on ultrasonography, and a culture-positive vitreous biopsy. In the multivariate analysis, visual acuity of less or equal light perception (LP) at presentation was associated with a 3-month postoperative visual acuity of < 6/18, with an odds ratio of 5.85 [1.25 - 27.42, 95% CI], and vitreous membranes seen on ultrasonography was associated with a final visual acuity of < 6/120, with an odds ratio of 2.47 [1.05 - 5.83, 95% CI]. Posttraumatic endophthalmitis: In univariate analysis the features associated with poor visual acuity (grouped as < 6/18 and < 6/120) included a retained intraocular foreign body (IOFB), trauma by needle (hypodermic or sewing), poor presenting visual acuity, inability to visualise the optic disc on indirect ophthalmoscopy, presence of vitreous membranes on ultrasonography, and a culture-positive vitreous biopsy. In multivariate analysis, IOFB was associated with a 3-month follow-up visual acuity of < 6/18, with an odds ratio of 5.90 [1.85 - 18.78, 95% CI], and trauma by a needle (hypodermic or sewing) and retained IOFB was associated with a final visual acuity of < 6/120, with an odds ratio of 4.47 [1.22 - 16.38, 95%CI] and 3.76 [1.36 - 10.37, 95% CI] respectively. CONCLUSION: This is the largest, single-centre, prospective study on risk factors for poor visual outcome in postoperative and posttraumatic endophthalmitis. The independent risk factor for 3-month follow-up visual acuity of < 6/18 was the presenting visual acuity of < or =LP in postoperative endophthalmitis and a retained IOFB in posttraumatic endophthalmitis. The independent risk factor for 3-month visual acuity of < 6/120 was the presence of vitreous membranes on ultrasonography in postoperative endophthalmitis, and trauma by a needle (hypodermic/ sewing) and retained IOFB in posttraumatic endophthalmitis.

Cataract extraction following penetrating keratoplasty.

OBJECTIVE: To assess the safety of cataract extraction following penetrating keratoplasty for corneal graft survival and to evaluate visual and refractive outcomes in corneal graft patients undergoing cataract extraction. METHODS: Retrospective chart review of 29 eyes of 24 patients with corneal grafts who underwent cataract extraction from January 1, 1993 to December 31, 2002, followed on the Cornea Service at Wills Eye Hospital. RESULTS: The mean time from penetrating keratoplasty to cataract extraction was 8.4 years (range 2 months to 36 years). Following cataract extraction, the corneal grafts remained clear in all but 1 eye (3%), during an average follow-up time of 44.5 months (range 3-118 months). All of the remaining patients benefited from improved visual acuity, with 15 of 28 patients having a postoperative best-corrected visual acuity of 20/30 or better. Patients also benefited from decreased absolute spherical refractive error, with a preoperative mean value of 6.6 +/- 3.4 D compared with 2.4 +/- 1.6 D postoperatively, while cylindrical refractive error remained relatively stable at 3.2 +/- 2.9 D preoperatively and 2.8 +/- 2.4 postoperatively. The patient who developed graft failure had 3 episodes of preoperative endothelial rejection and a clear corneal graft at the time of cataract surgery. CONCLUSIONS: Cataract surgery following penetrating keratoplasty is a safe and effective procedure, with a low but definite risk of corneal graft failure. In patients with clear grafts and visually significant cataracts, cataract extraction alone is preferred over repeat penetrating keratoplasty and cataract extraction.

Endophthalmitis after penetrating keratoplasty: microbiologic spectrum and susceptibility of isolates.

PURPOSE: To present the microbial spectrum and susceptibilities of isolates in endophthalmitis following penetrating keratoplasty. DESIGN: Interventional case series. METHODS: The 1,074 consecutive cases of endophthalmitis presenting to Wills Eye Hospital between 1989 and 2000 were reviewed. Fourteen patients with endophthalmitis after penetrating keratoplasty were identified, and vitreous biopsy isolates from these patients were examined. RESULTS: Eleven (78.6%) of 14 vitreous samples were culture-positive, and two others (14.3%) had organisms viewed on pathology specimen, for a total of 13 (92.9%) organism-proven cases of endophthalmitis. Isolates included 10 (76.9%) gram-positive cocci (six Streptococcus sp., three Staphylococcus sp., one identified on pathology specimen only) and three (23.1%) gram-negative organisms (Proteus mirabilis, Serratia marcescens, one identified on pathology specimen only). Susceptibilities to organism-appropriate antibiotic testing are reported, including cefazolin (six of eight, 75.0%), ciprofloxacin (four of seven, 57.1%), nafcillin (four of six, 66.7%), and vancomycin (seven of seven, 100.0%). CONCLUSION: This is the largest series on microbial susceptibilities in postpenetrating keratoplasty endophthalmitis. We report a high percentage of culture-positivity, and a high incidence of gram-positive species, and in particular Streptococcus species, with all tested gram-positive organisms susceptible to vancomycin.

Evaluation of corneal scraping smear examination methods in the diagnosis of bacterial and fungal keratitis: a survey of eight years of laboratory experience.

PURPOSE: To determine the sensitivity, specificity, and predictive values of Gram and potassium hydroxide with calcofluor white (KOH+CFW) stains in the diagnosis of early and advanced microbial keratitis, a retrospective analysis of comparative data from a prospectively collected database was done. METHODS: Patients with nonviral microbial keratitis seen at L.V. Prasad Eye Institute between February 1991 and December 1998 were included in the study. The type of bacteria seen on Gram stain was determined from 251 corneal scrapings from patients with early keratitis and 841 corneal scrapings from patients with advanced keratitis. The presence of fungi in corneal scrapings was determined by KOH+CFW stain of 114 and 363 scrapings from patients with early and advanced keratitis, respectively. The smear findings were compared with culture results to analyze specificity, sensitivity, and predictive values of the staining techniques. RESULTS: The sensitivity of Gram stain in the detection of bacteria was 36.0% in early and 40.9% in advanced keratitis cases; however, the specificity was higher in both groups (84.9% and 87.1%, respectively). Comparatively, the sensitivity and specificity of fungal detection were higher using KOH+CFW in early (61.1% and 99.0%, respectively) as well as advanced keratitis (87.7% and 83.7%, respectively). Predictive values were high for KOH+CFW in fungus detection, while they were poor for Gram stain in bacteria detection. In advanced keratitis cases, the false positives were higher in fungal detection (16.3%) than in bacterial detection (10.3%), while the false negatives were significantly higher in bacterial detection compared with fungal detection (59.1% versus 12.3%, p< 0.0001). In early keratitis, on the other hand, both false positives and false negatives for bacterial detection were significantly higher than fungal detection. CONCLUSIONS: Decisions can reliably be based on KOH+CFW stain of corneal scrapings for initiation of antifungal therapy in mycotic keratitis. The results of Gram stain, on the other hand, have limited value in therapeutic decisions for bacterial keratitis. Therefore, the search for a better modality for early and efficient diagnosis of bacterial keratitis needs to continue.