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1
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Han F, Li X, Tao T, Wang J. A pharmacovigilance study on the safety of faricimab in real-world scenario using FDA adverse event reporting system database. Expert Opin Drug Saf 2025; 24:657-664. [PMID: 39825687 DOI: 10.1080/14740338.2025.2456173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/17/2024] [Accepted: 01/02/2025] [Indexed: 01/20/2025]
Abstract
BACKGROUND Faricimab is predominantly prescribed for conditions such as age-related macular degeneration (AMD), diabetic macular edema (DME), and macular edema related to retinal vein occlusion (RVO-ME). Currently, a notable absence of large-scale, real-world studies focusing on the adverse reactions of faricimab exists. METHODS This study assesses the side effects of faricimab by analyzing reports of adverse events (AEs) from the FDA's AE Reporting System (FAERS) database. Through disproportionality analysis, this study substantiates the drug's safety oversight. RESULTS Our study revealed 2,746 instances of adverse events linked to faricimab, spanning 21 system organ classes (SOCs). The study retained 121 significant disproportionality preferred terms (PTs) that met criteria across all four analytical methods. Faricimab-associated AEs not documented in the drug instructions included visual impairment, blindness, retinal hemorrhage, anterior chamber inflammation, keratic precipitates, dry eye, chorioretinitis, diabetic retinopathy, and others. CONCLUSION The majority of our results align with earlier clinical studies and the details outlined in the product's manual. Additionally, we identified several unforeseen and potential AE signals related to faricimab use. These insights are instrumental for ongoing clinical surveillance and risk assessment associated with the drug.
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Affiliation(s)
- Furong Han
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Xiang Li
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tao Tao
- Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Jiawei Wang
- Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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2
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Comcali S, Tasci YY, Onen M, Gulhan B, Sahin M, Cavdarli C, Bilgic OM, Yorgun MA, Toklu Y, Alp MN, Yazar Z. Endophthalmitis following intravitreal injections at a tertiary center: real-life data on incidence, risk factors, management strategies, and visual outcomes. BMC Ophthalmol 2025; 25:278. [PMID: 40335933 PMCID: PMC12057116 DOI: 10.1186/s12886-025-04093-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 04/21/2025] [Indexed: 05/09/2025] Open
Abstract
PURPOSE To investigate the incidence, contributing factors, management, and long-term outcomes of endophthalmitis following intravitreal injections performed in our clinic. METHODS This retrospective study included all patients who received intravitreal bevacizumab, aflibercept, ranibizumab, or dexamethasone injections between 2019 and 2024 at four retina clinics of Ankara Bilkent City Hospital. Demographic characteristics of the patients, visual acuity, intravitreal injection etiology, comorbidities, and treatments applied were recorded. Patients who received antibiotic prophylaxis after intravitreal injections (IVI) were categorized as Group 1, while those who did not receive prophylaxis were classified as Group 2. RESULTS A total of 4171 patients and 21,339 intravitreal injections were evaluated. Of the participants, 47.2% were female and 52.8% were male, with a mean age of 66.3 ± 10.3 years (range: 40-98). Group 1 included 13,121 injections (61%), while Group 2 had 8,218 injections (39%). Endophthalmitis was observed in 13 patients (3.0 per 1000 patients-8.1 per 10,000 injections). Patients who developed endophthalmitis had an average of 6.1 ± 4.1 prior injections (range: 2-16), and the mean time to presentation after the last injection was 7.6 ± 3.4 days (range: 2-14). Endophthalmitis cases were distributed as 7 in Group 1 (5.3 per 10,000) and 6 in Group 2 (4.4 per 10,000). The endophthalmitis rate in Group 1 was not statistically significantly different from Group 2 (p > 0.05). All patients received vitreous taps and intravitreal vancomycin-ceftazidime injections at initial presentation. Eleven patients (85%) underwent a pars plana vitrectomy within 24 h. The mean follow-up period was 32 ± 20 months, and any case did not require evisceration surgery. CONCLUSION Early surgical intervention in cases of endophthalmitis is the most critical approach for preserving the eye and achieving visual rehabilitation. Notably, endophthalmitis was more common in people who got intravitreal bevacizumab or dexamethasone injections, and antibiotic prophylaxis did not appear to reduce the risk of its occurrence.
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Affiliation(s)
- Sebile Comcali
- Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey.
| | - Yelda Yildiz Tasci
- Department of Ophthalmology, Ankara Bilkent City Hospital Ankara, Yildirim Beyazit University, Ankara, Turkey
| | - Mehmet Onen
- Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey
| | - Busra Gulhan
- Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey
| | - Muzaffer Sahin
- Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey
| | - Cemal Cavdarli
- Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey
| | | | - Mucella Arikan Yorgun
- Department of Ophthalmology, Ankara Bilkent City Hospital Ankara, Yildirim Beyazit University, Ankara, Turkey
| | - Yasin Toklu
- Department of Ophthalmology, Ankara Bilkent City Hospital Ankara, Yildirim Beyazit University, Ankara, Turkey
| | - Mehmet Numan Alp
- Department of Ophthalmology, Ankara Dunyagoz Hospital, Ankara, Turkey
| | - Zeliha Yazar
- Department of Ophthalmology, University of Health Sciences, Ankara Bilkent City Hospital, Ankara, Turkey
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Guo S, Li M, Jia Z, Xu D, Yu C, Mei Y, Zhao Y, Duan X, Guo X, He P, Cui C, Wang C, Li L, Du J, Xu G, Cao S, Qi Z, Wu H, Wang L. Establishment of a subvisible particle profile in ophthalmic recombinant fusion protein and antibody formulations to control and monitor drug quality. Int J Pharm 2025; 675:125500. [PMID: 40139452 DOI: 10.1016/j.ijpharm.2025.125500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/20/2024] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Abstract
The presence of subvisible particles in intravitreal injection ophthalmic formulations may affect drug efficacy and safety. Although Chapters 788 and 789 of the United States Pharmacopeia limit the concentration of particles ≥ 10 μm, particles less than 10 μm may cause blurred vision and floaters in the injected eyes. Due to limited access to ophthalmic protein formulations, few studies investigated the profile of subvisible particles in these formulations. In this study, the subvisible particle concentration, size distribution, and morphology of 11 intravitreal injection ophthalmic recombinant fusion protein and monoclonal antibody formulations at different drug clinical trial stages were characterized. In addition, there was significant difference in particle morphology, (circularity, compactness and etc) between unexpired and expired batches using Mann Whitney test, which was probably associated with the proportion change of protein and silicone oil particles and could be used for drug quality control at different clinical trial stages or on the market.
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Affiliation(s)
- Sha Guo
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Meng Li
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Zhe Jia
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China; School of Pharmacy, Yantai University, Shandong, China
| | - Dongze Xu
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Chuanfei Yu
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Yuting Mei
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Yuhao Zhao
- NMPA Key Laboratory for Quality Control of Therapeutic Monoclonal Antibodies, Shanghai Institute for Food and Drug Control, Shanghai, China
| | - Xuhua Duan
- NMPA Key Laboratory for Quality Control of Therapeutic Monoclonal Antibodies, Shanghai Institute for Food and Drug Control, Shanghai, China
| | - Xiang Guo
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Pengfei He
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Chunbo Cui
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Cui Wang
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Lingkun Li
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Jialiang Du
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Gangling Xu
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China
| | - Sixian Cao
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Zhiyun Qi
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China
| | - Hao Wu
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, China.
| | - Lan Wang
- State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, National Institutes for Food and Drug Control, Beijing, China.
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Baghban R, Namvar E, Attar A, Mortazavi M. Progressing nanotechnology to improve diagnosis and targeted therapy of Diabetic Retinopathy. Biomed Pharmacother 2025; 183:117786. [PMID: 39753094 DOI: 10.1016/j.biopha.2024.117786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 02/08/2025] Open
Abstract
The inherent limitations of traditional treatments for Diabetic Retinopathy (DR) have spurred the development of various nanotechnologies, offering a safer and more efficient approach to managing the disease. Nanomedicine platforms present promising advancements in the diagnosis and treatment of DR by enhancing imaging capabilities, enabling targeted and controlled drug delivery. These innovations ultimately lead to more effective and personalized treatments with fewer side effects. This review highlights the progress, challenges, and opportunities in developing effective diagnostics and therapeutics for DR. Additionally, it explores innovative engineering techniques that leverage our growing understanding of nano-bio interactions to create more potent nanotherapeutics for patients.
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Affiliation(s)
- Roghayyeh Baghban
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ehsan Namvar
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Alireza Attar
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mojtaba Mortazavi
- Department of Biotechnology, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran
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5
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Khristov V, Weber SR, Caton-Darby M, Campbell G, Sundstrom JM. Diagnostic and Therapeutic Utility of Extracellular Vesicles in Ocular Disease. Int J Mol Sci 2025; 26:836. [PMID: 39859553 PMCID: PMC11765869 DOI: 10.3390/ijms26020836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 01/11/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Extracellular vesicles (EVs) are lipid bilayer particles released by virtually all cells, with prominent roles in both physiological and pathological processes. The size, number, and molecular composition of released EVs correlate to the cells of origin, modulated by the cell's environment and pathologic state. The proteins, DNA, RNA, and protein cargo carried by EVs are protected by degradation, with a prominent role in targeted intercellular signaling. These properties make EVs salient targets as both carriers of biomarkers and potential therapeutic delivery vehicles. The majority of EV research has focused on blood, urine, saliva, and cerebrospinal fluid due to easy accessibility. EVs have also been identified and studied in all ocular biofluids, including the vitreous humor, the aqueous humor, and the tear film, and the study of EVs in ocular disease is a new, promising, and underexplored direction with unique challenges and considerations. This review covers recent advances in the diagnostic and therapeutic use of ocular EVs, with a focus on human applications and key preceding in vitro and in vivo animal studies. We also discuss future directions based on the study of EVs in other organ systems and disease sates.
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Affiliation(s)
- Vladimir Khristov
- Penn State Hershey College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA; (V.K.); (G.C.)
| | - Sarah R. Weber
- Department of Ophthalmology, Penn State University, Hershey, PA 17033, USA; (S.R.W.); (M.C.-D.)
| | - Mireille Caton-Darby
- Department of Ophthalmology, Penn State University, Hershey, PA 17033, USA; (S.R.W.); (M.C.-D.)
| | - Gregory Campbell
- Penn State Hershey College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA; (V.K.); (G.C.)
| | - Jeffrey M. Sundstrom
- Department of Ophthalmology, Penn State University, Hershey, PA 17033, USA; (S.R.W.); (M.C.-D.)
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Khandelwal A, Gowthamarajan K, Nirmal J, Ponnusankar S. Exploring the Therapeutic Potential of Anti-VEGF Drugs for the Management of Diabetic Retinopathy: An Overview. Curr Diabetes Rev 2025; 21:e160424228951. [PMID: 38629377 DOI: 10.2174/0115733998294968240405091023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/23/2025]
Abstract
The discovery of antivascular endothelial growth factor medications has resulted in a substantial change in diabetic retinopathy treatment. The most common cause of diabetic retinopathy blindness is Diabetic Macular Edema. The pathophysiology of Diabetic Macular Edema is thought to include the well-known pro-angiogenic and pro-permeability factor vascular endothelial growth factor. Over the past decade, drugs that impede the functions of vascular endothelial growth factors have established themselves as a standard-of-care treatment for a range of ocular ailments and improved patients' clinical results with diabetic retinopathy and Diabetic Macular Edema, and their frequency has grown exponentially with the introduction of these agents Pegaptanib, Ranibizumab, and Aflibercept which are approved for ophthalmic indications, while Bevacizumab is used off-label. These medications delivered intravitreally have halted the vascular development of diabetic retinopathy. Various randomized trials have proven that antivascular endothelial growth factor medication is safe and effective in preserving vision. Following an extensive period of preclinical development aimed at enhancing and defining its biological impacts, these drugs were shown in clinical trials to be effective in treating diabetic retinopathy and other ophthalmic conditions. Data from various sources suggest that Pegaptanib, Ranibizumab, and Aflibercept are costly, while Bevacizumab is cost-effective, and in low and middle-income nations, it is thus a desirable therapy choice. However, issues with compounding, counterfeiting, and off-label usage restrict its availability in many nations. The pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, and contraindications of antivascular endothelial growth factor agents are discussed, and the results of clinical trials evaluating their efficacy are summarized.
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Affiliation(s)
- Aman Khandelwal
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Kuppusamy Gowthamarajan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Jayabalan Nirmal
- Department of Pharmacy, Translational Pharmaceutics Research Laboratory, Birla Institute of Technology and Science (BITS)-Pilani, Hyderabad, India
| | - S Ponnusankar
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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7
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Khan H, Aziz AA, Khanani Z, Khan H, Mojumder O, Gahn GM, Khanani AM. Approved treatments for neovascular age-related macular degeneration: current safety and future directions. Expert Opin Drug Saf 2024; 23:1109-1114. [PMID: 39101834 DOI: 10.1080/14740338.2024.2387318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 07/26/2024] [Indexed: 08/06/2024]
Abstract
INTRODUCTION Age-related macular degeneration (AMD) is a progressive retinal degenerative disease that is implicated as one of the leading causes of visual impairment in the elderly population. Vascular endothelial growth factor (VEGF) has been identified as the main driver of AMD, and various therapeutics have revolutionized the treatment and management of neovascular AMD (nAMD) with favorable visual and anatomical outcomes. AREAS COVERED Physicians have a variety of approved therapeutics in their arsenal for patients with varying disease progression and patient-specific needs, with the ultimate goal of achieving optimal visual and anatomic outcomes. The literature search was conducted using PubMed, Google Scholar, and sources from companies' websites, allowing us to locate findings recently presented at conferences. EXPERT OPINION Scientific advancements in the field have led to newly approved therapeutics and devices, such as the port-delivery system with ranibizumab (PDS), and further investigation is ongoing in the realm of gene therapy for retinal diseases. In addition to efficacy and durability, newer agents must have comparable safety profiles to older agents in order to be used broadly. These options introduce a level of complexity in nAMD treatment; however, physicians to personalize treatment to improve vision in nAMD patients and reduce treatment burden overall.
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Affiliation(s)
- Hannah Khan
- Reno School of Medicine, University of Nevada, Reno, NV, USA
| | - Aamir A Aziz
- Reno School of Medicine, University of Nevada, Reno, NV, USA
| | | | - Huma Khan
- Sierra Eye Associates, Reno, NV, USA
| | | | | | - Arshad M Khanani
- Reno School of Medicine, University of Nevada, Reno, NV, USA
- Sierra Eye Associates, Reno, NV, USA
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8
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Kour V, Swain J, Singh J, Singh H, Kour H. A Review on Diabetic Retinopathy. Curr Diabetes Rev 2024; 20:e201023222418. [PMID: 37867267 DOI: 10.2174/0115733998253672231011161400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 07/08/2023] [Accepted: 08/23/2023] [Indexed: 10/24/2023]
Abstract
Diabetic retinopathy is a well-recognised microvascular complication of diabetes and is among the leading cause of blindness all over the world. Over the last decade, there have been advances in the diagnosis of diabetic retinopathy and diabetic macular edema. At the same time, newer therapies for the management of diabetic retinopathy have evolved. As a result of these advances, a decline in severe vision loss due to diabetes has been witnessed in some developing countries. However, there is a steady increase in the number of people affected with diabetes, and is expected to rise further in the coming years. Therefore, it is prudent to identify diabetic retinopathy, and timely intervention is needed to decrease the burden of severe vision loss. An effort has been made to review all the existing knowledge regarding diabetic retinopathy in this article and summarize the present treatment options for diabetic retinopathy.
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Affiliation(s)
- Vijender Kour
- Consultant Ophthalmology, Department of Ophthalmology, Sub District Hospital, Tral, Pulwama, India
| | - Jayshree Swain
- Department of Endocrinology, IMS and Sum Hospital, Siksha O Anusandhan (SOA) University, Bhubaneswar, India
| | - Jaspreet Singh
- Department of Endocrinology, IMS and Sum Hospital, Siksha O Anusandhan (SOA) University, Bhubaneswar, India
| | - Hershdeep Singh
- Consultant Neurosurgeon, Department of Neurosurgery, Fortis Ludhiana, Bhubaneswar, India
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9
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Zehden JA, Mortensen XM, Reddy A, Zhang AY. Systemic and Ocular Adverse Events with Intravitreal Anti-VEGF Therapy Used in the Treatment of Diabetic Retinopathy: a Review. Curr Diab Rep 2022; 22:525-536. [PMID: 36053385 DOI: 10.1007/s11892-022-01491-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Intravitreal anti-vascular endothelial growth factor (VEGF) agents are used routinely in the management of neovascular conditions including proliferative diabetic retinopathy and diabetic macular edema. While the efficacy of anti-VEGF agents has been well-validated, their ocular and systemic adverse events should always be considered and discussed with patients. The aim of this review is to discuss the most recent literature reports regarding the various ocular and systemic adverse events associated with intravitreal anti-VEGF treatment in diabetic retinopathy. RECENT FINDINGS The most frequently reported adverse ocular events include subconjunctival hemorrhage, vitreous hemorrhage, increased intraocular pressure, uveitis, endophthalmitis, ocular surface disease, and traumatic cataract. Subconjunctival hemorrhage and vitreous hemorrhage are the most common ocular adverse events reported with intravitreal anti-VEGF treatment. The most serious (though rare) ocular adverse events include endophthalmitis and rhegmatogenous retinal detachment. A consensus regarding the association of systemic adverse events (such as myocardial infarction, stroke, and death) with intravitreal anti-VEGF treatments has not been established. Intravitreal anti-VEGF therapy is used in the treatment of diabetic retinopathy, macular degeneration, and other diseases. These agents are associated with a variety of ocular and systemic adverse events that ophthalmologists should always consider.
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Affiliation(s)
- Jason A Zehden
- Department of Ophthalmology, University of North Carolina at Chapel Hill, 2226 Nelson Hwy Suite 200, Chapel Hill, NC, 27517, USA
| | - Xavier M Mortensen
- Department of Ophthalmology, University of North Carolina at Chapel Hill, 2226 Nelson Hwy Suite 200, Chapel Hill, NC, 27517, USA
| | - Ashvini Reddy
- Athena Eye Institute, San Antonio, TX, USA
- University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Alice Yang Zhang
- Department of Ophthalmology, University of North Carolina at Chapel Hill, 2226 Nelson Hwy Suite 200, Chapel Hill, NC, 27517, USA.
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10
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Sharma D, Bisen S, Kaur G, Van Buren EC, Rao GN, Singh NK. IL-33 enhances Jagged1 mediated NOTCH1 intracellular domain (NICD) deubiquitination and pathological angiogenesis in proliferative retinopathy. Commun Biol 2022; 5:479. [PMID: 35589941 PMCID: PMC9120174 DOI: 10.1038/s42003-022-03432-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/29/2022] [Indexed: 01/10/2023] Open
Abstract
Pathological retinal neovascularization (NV) is a clinical manifestation of various proliferative retinopathies, and treatment of NV using anti-VEGF therapies is not selective, as it also impairs normal retinal vascular growth and function. Here, we show that genetic deletion or siRNA-mediated downregulation of IL-33 reduces pathological NV in a murine model of oxygen-induced retinopathy (OIR) with no effect on the normal retinal repair. Furthermore, our fluorescent activated cell sorting (FACS) data reveals that the increase in IL-33 expression is in endothelial cells (ECs) of the hypoxic retina and conditional genetic deletion of IL-33 in retinal ECs reduces pathological NV. In vitro studies using human retinal microvascular endothelial cells (HRMVECs) show that IL-33 induces sprouting angiogenesis and requires NFkappaB-mediated Jagged1 expression and Notch1 activation. Our data also suggest that IL-33 enhances de-ubiquitination and stabilization of Notch1 intracellular domain via its interaction with BRCA1-associated protein 1 (BAP1) and Numb in HRMVECs and a murine model of OIR.
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Affiliation(s)
- Deepti Sharma
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA
| | - Shivantika Bisen
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA
| | - Geetika Kaur
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA
| | - Eric C Van Buren
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Gadiparthi N Rao
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Nikhlesh K Singh
- Integrative Biosciences Center, Wayne State University, Detroit, MI, 48202, USA.
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, 48202, USA.
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11
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Ziaei P, Resnick JL, Stella N, DiLeo MV. Novel Combined Lidocaine/Povidone Iodine Delivery System for Preintravitreal Injection. J Ocul Pharmacol Ther 2022; 38:319-325. [PMID: 35255227 PMCID: PMC9271332 DOI: 10.1089/jop.2021.0095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose: Intravitreal injection has become a popular treatment for various retina disorders and dramatically increased over the past few years. In traditional preintravitreal injection, the preparation steps are time consuming for practitioners who perform a significant number of injections per day. Besides, lidocaine gel (L-Gel) shows a potential absorption barrier on the antibacterial effect of povidone iodine (PI). Methods: In this study, we describe a L/PI gel system as an alternative approach to address these issues for traditional preinjection drug administration. Lidocaine and PI are loaded in a thermoresponsive gel instilled as a liquid to the lower fornix that transitions to a stable, solid gel depot. Results and Conclusion: The gel demonstrated decrease in conjunctival touch sensitivity and sufficient bacteria killing with a single step, suggesting a significant decrease in the time required and less potential for drug inhibition due to sequential administration.
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Affiliation(s)
- Parissa Ziaei
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Jayde L. Resnick
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Nicholas Stella
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Morgan V. DiLeo
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Department of Chemical Engineering, and University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Department of Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.,McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA.,Address correspondence to: Prof. Morgan V. DiLeo, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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12
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Ebrahimi M, Balibegloo M, Rezaei N. Monoclonal antibodies in diabetic retinopathy. Expert Rev Clin Immunol 2022; 18:163-178. [PMID: 35105268 DOI: 10.1080/1744666x.2022.2037420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Diabetic retinopathy (DR), as one of the main complications of diabetes, is among the leading causes of blindness and visual impairment worldwide. AREAS COVERED Current clinical therapies include photocoagulation, vitrectomy, and anti-vascular endothelial growth factor (VEGF) therapies. Bevacizumab and ranibizumab are two monoclonal antibodies (mAbs) inhibiting angiogenesis. Intravitreal ranibizumab and bevacizumab can decrease the rate of blindness and retinal thickness, and improve visual acuity whether as monotherapy or combined with other treatments. They can increase the efficacy of other treatments and decrease their adverse events. Although administered intravitreally, they also might enter the circulation and cause systemic effects. This study is aimed to review our current knowledge about mAbs, bevacizumab and ranibizumab, in DR including superiorities, challenges, and limitations. Meanwhile, we tried to shed light on new ideas to overcome these limitations. Our latest search was done in April 2021 mainly through PubMed and Google Scholar. Relevant clinical studies were imported. EXPERT OPINION Future direction includes detection of more therapeutic targets considering other components of DR pathophysiology and shared pathogenesis of DR and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, the treat-and-extend regimen, and new ways of drug delivery and other routes of ocular drug administration.
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Affiliation(s)
- Moein Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Balibegloo
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),Universal Scientific Education and Research Network (USERN), Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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13
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Dosmar E, Walsh J, Doyel M, Bussett K, Oladipupo A, Amer S, Goebel K. Targeting Ocular Drug Delivery: An Examination of Local Anatomy and Current Approaches. Bioengineering (Basel) 2022; 9:41. [PMID: 35049750 PMCID: PMC8772869 DOI: 10.3390/bioengineering9010041] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/03/2022] [Accepted: 01/10/2022] [Indexed: 01/23/2023] Open
Abstract
Ocular drug delivery remains the focus of much modern research. Primary routes of administration include the surface, the intravitreal space, the subretinal space, and the subconjunctival space, each with its own series of unique challenges, limitations, and advantages. Each of these approaches requires careful consideration of the local anatomy, physical barriers, and key cells as well as the interface between the anatomy and the drug or drug system being delivered. While least invasive, the topical route poses a challenge with the many physical barriers that prevent drug penetration into the eye; while injection into the intravitreal, subretinal, and subconjunctival spaces are direct and targeted but limited due to the many internal clearance mechanisms and potential for damage to the eye. Polymeric-based, sustained-release drug delivery systems have been identified as a potential solution to many of these challenges; however, the design and successful implementation of a sustained-release system that is well-tolerated, bioactive, biocompatible, and degradable remains, in many cases, only in the early stages. The drugs and biomaterials in question also require special attention as small chemical changes could result in vastly different outcomes. This paper explores the anatomy and key cells of these four primary drug delivery routes as well as the interface between drug and drug delivery systems and the anatomy, reviewing the recent developments and current state of research in each area. Finally, this paper also examines the frequently used drugs and biomaterials found in ocular drug delivery and summarizes the primary interactions observed.
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Affiliation(s)
- Emily Dosmar
- Department of Biology and Biomedical Engineering, Rose-Hulman Institute of Technology, Terre Haute, IN 47803, USA; (J.W.); (M.D.); (K.B.); (A.O.); (S.A.); (K.G.)
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14
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Updates on the Current Treatments for Diabetic Retinopathy and Possibility of Future Oral Therapy. J Clin Med 2021; 10:jcm10204666. [PMID: 34682788 PMCID: PMC8537579 DOI: 10.3390/jcm10204666] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 10/04/2021] [Accepted: 10/09/2021] [Indexed: 12/23/2022] Open
Abstract
Diabetic retinopathy (DR) is a complication of diabetes and one of the leading causes of vision loss worldwide. Despite extensive efforts to reduce visual impairment, the prevalence of DR is still increasing. The initial pathophysiology of DR includes damage to vascular endothelial cells and loss of pericytes. Ensuing hypoxic responses trigger the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. At present, the most effective treatment for DR and diabetic macular edema (DME) is the control of blood glucose levels. More advanced cases require laser, anti-VEGF therapy, steroid, and vitrectomy. Pan-retinal photocoagulation for non-proliferative diabetic retinopathy (NPDR) is well established and has demonstrated promising outcomes for preventing the progressive stage of DR. Furthermore, the efficacy of laser therapies such as grid and subthreshold diode laser micropulse photocoagulation (SDM) for DME has been reported. Vitrectomy has been performed for vitreous hemorrhage and tractional retinal detachment for patients with PDR. In addition, anti-VEGF treatment has been widely used for DME, and recently its potential to prevent the progression of PDR has been remarked. Even with these treatments, many patients with DR lose their vision and suffer from potential side effects. Thus, we need alternative treatments to address these limitations. In recent years, the relationship between DR, lipid metabolism, and inflammation has been featured. Research in diabetic animal models points to peroxisome proliferator-activated receptor alpha (PPARα) activation in cellular metabolism and inflammation by oral fenofibrate and/or pemafibrate as a promising target for DR. In this paper, we review the status of existing therapies, summarize PPARα activation therapies for DR, and discuss their potentials as promising DR treatments.
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15
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Li T, Sun J, Min J, Zhou S, Zhu X, Jia H, Sun X. Safety of Receiving Anti-Vascular Endothelial Growth Factor Intravitreal Injection in Office-Based vs Operating Room Settings: A Meta-analysis. JAMA Ophthalmol 2021; 139:1080-1088. [PMID: 34410325 PMCID: PMC8377608 DOI: 10.1001/jamaophthalmol.2021.3096] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Importance Compared with the operating room (OR), office-based intravitreal injection (IVI) is considered a more cost-effective and convenient approach, yet clinical outcomes of IVIs with anti-vascular endothelial growth factor (VEGF) agents in different settings (office-based vs OR) have not been systematically evaluated. Objective To evaluate the safety outcomes of IVI with anti-VEGF agents in the OR vs office-based setting. Data Sources PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to July 2020. Study Selection Eligible studies reporting on patients who received IVIs with anti-VEGF drugs with a clearly stated injection setting of the office or OR. Data Extraction and Synthesis Two reviewers independently screened studies, extracted data, and assessed risk of bias. A meta-analysis was conducted to determine the rates of endophthalmitis (EO) and culture-positive EO. Main Outcomes and Measures Rates of EO and culture-positive EO following anti-VEGF IVIs in the OR and office-based setting. Results Thirty-one studies with a total of 1 275 815 injections were included. Comparative analysis suggested no difference between rates of EO after IVIs performed in the office and OR settings (odds ratio, 3.06; 95% CI, 0.07-139.75; P = .57; I2 = 80%) were identified, yet a higher rate of culture-positive EO was found in the office setting (odds ratio, 21.52; 95% CI, 2.39-193.55; P = .006; I2 = 0%). The pooled rates of EO following anti-VEGF IVIs were 0.03% (95% CI, 0.03-0.04) and 0.02% (95% CI, 0.01-0.04) in office and OR settings, respectively, and the pooled rates of culture-positive EO were 0.01% (95% CI, 0.01-0.02) and 0.01% (95% CI, 0-0.02). The pooled rates of other ocular and systemic adverse events were low. Conclusions and Relevance The rate of clinically suspected or culture-positive EO following anti-VEGF IVIs was low whether the procedure was performed in the office or OR setting. Bacterial spectrum could differ between the 2 settings. This meta-analysis could not determine if it is more appropriate to give treatment in the OR for safety reasons in low-income compared with higher-income regions in the world.
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Affiliation(s)
- Tong Li
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Junran Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Jingyu Min
- Novartis Pharmaceuticals, Shanghai, China
| | | | | | - Huixun Jia
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Ophthalmic Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Ophthalmic Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.,Shanghai Key Laboratory of Fundus Diseases, Shanghai, China
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16
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Al Busaidi A, Al-Hinai A. Postprocedural Endophthalmitis or Postprocedural Intraocular Inflammation: A Diagnostic Conundrum. Case Rep Ophthalmol 2021; 12:418-424. [PMID: 34054495 PMCID: PMC8136315 DOI: 10.1159/000511970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/02/2020] [Indexed: 11/19/2022] Open
Abstract
We experienced an atypical endophthalmitis occurring post consecutively performed in-office procedures; an intravitreal injection (IVI) of ranibizumab followed by an anterior chamber (AC) paracentesis performed twice in an eye with neovascular glaucoma (NVG). A 52-year-old diabetic male who was asymptomatic developed signs of endophthalmitis and decreased vision without pain in his left eye a few days post-IVI and AC paracentesis. The condition worsened after an initial vitreous tap and injection of antibiotics. Cultures of vitreous and aqueous samples were negative. Complete resolution occurred after a pars plana vitrectomy with IVI of antibiotics and steroid with removal of a dense “yellowish-brown” fibrinous plaque. The absence of pain, presence of a peculiar colored fibrin, mild-to-moderate vitritis without retinitis, negative cultures, and complete recovery despite the fulminant presentation; favor a diagnosis of inflammation over infection. We hypothesize that a micro-leak from a 26-gauge AC tap tract might have served as an entry port for 5% povidone-iodine from the ocular surface thus inciting inflammation. However, an exuberant inflammatory response that can be typically seen in NVG eyes after intraocular procedures cannot be excluded. Various causes of inflammation post-procedures, both toxic and nontoxic should be considered in atypical culture-negative fulminant endophthalmitis cases with good outcome posttreatment. Any minor ocular procedure may carry a risk of such complication. Patient counseling and care must be exercised in performing these procedures.
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Affiliation(s)
- Aisha Al Busaidi
- Department of Ophthalmology, Sultan Qaboos University Hospital, Al Khoudh, Oman
| | - Ahmed Al-Hinai
- Department of Ophthalmology, Sultan Qaboos University Hospital, Al Khoudh, Oman
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17
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Reyes-Capo DP, Yannuzzi NA, Smiddy WE, Flynn HW. Trends in Endophthalmitis Associated With Intravitreal Injection of Anti-VEGF Agentsat a Tertiary Referral Center. Ophthalmic Surg Lasers Imaging Retina 2021; 52:319-326. [PMID: 34185586 DOI: 10.3928/23258160-20210528-04] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND OBJECTIVE To report the incidence and clinical features of infectious endophthalmitis after intravitreal (IV) injection of anti-vascular endothelial growth factor inhibitors (VEGF) between 2018 and 2020 and to compare to prior rates. PATIENTS AND METHODS Retrospective analysis of patients with endophthalmitis after anti-VEGF IV injections treated at Bascom Palmer Eye Institute between January 1, 2018, and December 31, 2020. RESULTS Between 2018 and 2020, the rate of clinically diagnosed endophthalmitis was 0.014% (10/71,858) and of culture-positive was 0.008% (6/71,858). Clinically diagnosed endophthalmitis rates per injection were: aflibercept (0.022%); ranibizumab (0.019%); bevacizumab (0%); and brolucizumab (0%). Clinically diagnosed endophthalmitis rates were similar in the present study compared to those from 2005 to 2017 (P = .84). Fifteen eyes were diagnosed with endophthalmitis (10 in-house, five external referrals). Of culture-positive eyes, the organisms were coagulase-negative Staphylococcus (8/11), Streptococcus species (2/11), and Abiotrophia defectiva (1/11). A universal face-masking policy in 2020 did not lower infection rates (P = .73). CONCLUSION Endophthalmitis rates after IV anti-VEGF remain low and are similar to prior reports. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:319-326.].
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Zierden HC, Josyula A, Shapiro RL, Hsueh H, Hanes J, Ensign LM. Avoiding a Sticky Situation: Bypassing the Mucus Barrier for Improved Local Drug Delivery. Trends Mol Med 2021; 27:436-450. [PMID: 33414070 PMCID: PMC8087626 DOI: 10.1016/j.molmed.2020.12.001] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/24/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023]
Abstract
The efficacy of drugs administered by traditional routes is limited by numerous biological barriers that preclude reaching the intended site of action. Further, full body systemic exposure leads to dose-limiting, off-target side effects. Topical formulations may provide more efficacious drug and nucleic acid delivery for diseases and conditions affecting mucosal tissues, but the mucus protecting our epithelial surfaces is a formidable barrier. Here, we describe recent advances in mucus-penetrating approaches for drug and nucleic acid delivery to the ocular surface, the female reproductive tract, the gastrointestinal tract, and the airways.
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Affiliation(s)
- Hannah C. Zierden
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231,Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218
| | - Aditya Josyula
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231,Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218
| | - Rachel L. Shapiro
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231,Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218
| | - Henry Hsueh
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231,Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218
| | - Justin Hanes
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231,Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218,Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287,Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287,Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287
| | - Laura M. Ensign
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231,Department of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218,Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287,Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287,Departments Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287,Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287,Correspondence: (L.M. Ensign)
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19
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Brar AS, Wani VB, Tenagi AL. Outcomes of three intravitreal injections of bevacizumab given monthly for diabetic macular oedema is a viable treatment for an economically disadvantaged population. AFRICAN VISION AND EYE HEALTH 2021. [DOI: 10.4102/aveh.v80i1.618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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20
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Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition. Cell Metab 2021; 33:818-832.e7. [PMID: 33548171 DOI: 10.1016/j.cmet.2021.01.011] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/30/2020] [Accepted: 01/11/2021] [Indexed: 02/07/2023]
Abstract
Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.
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21
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Incidence of Endophthalmitis after Intravitreal Anti-Vascular Endothelial Growth Factor Injections in an Operating Room in China. J Ophthalmol 2021; 2020:5163484. [PMID: 33815833 PMCID: PMC7988740 DOI: 10.1155/2020/5163484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 10/01/2020] [Accepted: 10/24/2020] [Indexed: 11/17/2022] Open
Abstract
Purpose To evaluate the rate of presumed endophthalmitis (EO) after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections performed in an operating room (OR) under sterile conditions in mainland China. Methods Retrospective single-center study between September 2012 and December 2017 at Beijing Tongren Eye Center, Beijing, China. Intravitreal injection database was reviewed. All anti-VEGF injections were performed using a standardized sterile technique in an OR. Injection protocols included antibiotics for 3 days pre-injection, topical 5% povidone-iodine rinsing before the procedure, and post-injection antibiotics for 3 days. Results A total of 37,830 intravitreal injections were performed at Beijing Tongren Eye Center. Three cases were managed as presumed EO (0.0079%). Positive cultures were documented in 2 of 3 cases. EO incidence following ranibizumab and conbercept administration was 0.0088% (3 in 33,930) and 0% (0 in 3,900), respectively. No significant difference was detected between the two drugs (P = 0.745). Conclusions Very low EO rates were seen in mainland China using a standardized sterile technique in an OR. However, EO could not be completely avoided.
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22
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Zina S, Khochtali S, Invernizzi A, Ksiaa I, Hager BA, Viola F, Abroug N, Khairallah M. Results of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Inflammatory Choroidal Neovascularization. J Curr Ophthalmol 2021; 33:68-74. [PMID: 34084960 PMCID: PMC8102949 DOI: 10.4103/joco.joco_128_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 07/08/2020] [Accepted: 08/01/2020] [Indexed: 11/25/2022] Open
Abstract
Purpose: To report the visual outcomes of intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) in inflammatory choroidal neovascularization (iCNV). Methods: A retrospective study of 43 eyes of 38 patients with active choroidal neovascularization (CNV) related to ocular inflammatory disease, treated with IVT injections of anti-VEGF (bevacizumab, ranibizumab, or aflibercept), with or without associated systemic anti-inflammatory therapy, at Fattouma Bourguiba University Hospital, Monastir, Tunisia (24 eyes of 23 patients) and at Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy (19 eyes of 15 patients) from January 1, 2013, to December 31, 2018. Results: The mean age was 35.5 ± 16.4 years. The sex ratio male:female was 0.27. Seventeen eyes (39.5%) of 17 patients (44.7%) had only anti-VEGF injections, and 26 eyes (60.5%) of 21 patients (45.3%) had anti-VEGF injections and associated systemic anti-inflammatory therapy. Bevacizumab was injected in 36 eyes (83.7%), ranibizumab in six eyes (14%), and aflibercept in one eye (2.3%). Mean follow-up was 20.3 ± 19.2 months (range, 6–106 months). Mean visual acuity improved from 0.8 ± 0.37 logMAR (approximate Snellen equivalent 20/125) to 0.51 ± 0.42 logMAR (approximate Snellen equivalent 20/63) (P < 0.001). Mean central macular thickness on optical coherence tomography decreased from 403.7 ± 121.9 to 293.7 ± 82.8 μm (P < 0.001). Mean gain of vision was 2.9 ± 3.1 lines. The mean number of injections was 2.5. Twenty eyes (46.5%) received a single injection. There were no side effects related to the IVT injections of anti-VEGF. Conclusions: CNV is a sight-threatening complication of uveitis. IVT anti-VEGF seems to be an effective and safe treatment for iCNV when inflammation is controlled.
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Affiliation(s)
- Sourour Zina
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Sana Khochtali
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Alessandro Invernizzi
- Department of Biomedical and Clinical Science "Luigi Sacco", Eye Clinic, Luigi Sacco Hospital, University of Milan, Milan, Italy.,Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Imen Ksiaa
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Ben Amor Hager
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Francesco Viola
- Fondazione Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Nesrine Abroug
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Moncef Khairallah
- Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia
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Cox JT, Eliott D, Sobrin L. Inflammatory Complications of Intravitreal Anti-VEGF Injections. J Clin Med 2021; 10:981. [PMID: 33801185 PMCID: PMC7957879 DOI: 10.3390/jcm10050981] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 12/20/2022] Open
Abstract
Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is a commonly used therapy for numerous retinal diseases. The most commonly used of these medications are bevacizumab, ranibizumab, aflibercept, and brolucizumab. However, intravitreal administration of these agents is also associated with several inflammatory and non-inflammatory adverse events. The three inflammatory adverse events are sterile intraocular inflammation, brolucizumab-associated retinal vasculitis, and post-injection endophthalmitis. This narrative review summarizes the current literature regarding these conditions, including their epidemiology, presentation, management, outcomes, and pathogenesis. The inflammatory adverse events also share a number of overlapping features, which can make them difficult to discern from one another in a clinical context. This review discusses certain distinguishing features of these conditions that may aid providers in discerning between them and establishing the correct diagnosis.
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Affiliation(s)
| | | | - Lucia Sobrin
- Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA 02114, USA; (J.T.C.); (D.E.)
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24
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Jang KH, Ahn JY, Sohn JH, Hwang DDJ. Safety Evaluation of Bilateral Same-day Intravitreal Injections of Bevacizumab. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2020. [DOI: 10.3341/jkos.2020.61.10.1164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Jang K, Ahn J, Sohn J, Hwang DDJ. Evaluation of the Safety of Bilateral Same-Day Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents: Experience of a Large Korean Retina Center. Clin Ophthalmol 2020; 14:3211-3218. [PMID: 33116371 PMCID: PMC7567572 DOI: 10.2147/opth.s276620] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 09/21/2020] [Indexed: 01/21/2023] Open
Abstract
Purpose To evaluate the short-term ophthalmic side effects of bilateral same-day intravitreal anti-vascular endothelial growth factor (VEGF) injections. Patients and Methods We retrospectively analyzed patients who received intravitreal bevacizumab, ranibizumab, and aflibercept injections in both eyes on the same day between January 2014 and June 2019. The patients were followed up for 1 day, 1 week, and 1 month after the injections. Results A total of 323 patients (646 eyes) received 1418 bilateral same-day intravitreal anti-VEGF injections. The patients' mean age was 62.47 ± 13.97 years. The most common cause of bilateral injection was age-related macular degeneration (54.80%), followed by complications due to diabetic retinopathy (35.33%), retinal vein occlusion (2.40%), and central serious chorioretinopathy (1.27%). There were 22 cases of subconjunctival hemorrhage, 17 cases of temporary elevation of intraocular pressure, and no case of endophthalmitis. Twenty-one patients showed acute intraocular inflammation after the bilateral injection. All patients showed complete improvement within 2 weeks after the injection. Conclusion Bilateral same-day intravitreal anti-VEGF injection is a well-tolerated procedure on short-term follow-up. It is one of the more convenient approaches for both the patient and ophthalmologist.
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Affiliation(s)
- Kyuhwan Jang
- Department of Ophthalmology, HanGil Eye Hospital, Incheon, Korea
| | - Jayoung Ahn
- Department of Ophthalmology, HanGil Eye Hospital, Incheon, Korea
| | - Joonhong Sohn
- Department of Ophthalmology, HanGil Eye Hospital, Incheon, Korea
| | - Daniel Duck-Jin Hwang
- Department of Ophthalmology, HanGil Eye Hospital, Incheon, Korea.,Department of Ophthalmology, Catholic Kwandong University College of Medicine, Incheon, Korea
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26
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Malakouti-Nejad M, Bardania H, Aliakbari F, Baradaran-Rafii A, Elahi E, Monti D, Morshedi D. Formulation of nanoliposome-encapsulated bevacizumab (Avastin): Statistical optimization for enhanced drug encapsulation and properties evaluation. Int J Pharm 2020; 590:119895. [PMID: 32956821 DOI: 10.1016/j.ijpharm.2020.119895] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 01/01/2023]
Abstract
Bevacizumab (Avastin®), an anti-vascular endothelial growth factor, is one of the most effective drugs widely used to inhibit ocular angiogenesis. Nanoliposomes were recruited to improve the accessibility of bevacizumab (BVZ) during treatment. To optimize drug entrapment efficiency (DEE %), the effect of some independent variables was evaluated utilizing response surface methodology. The optimized formulation containing BVZ (NLP-BVZ) was characterized, and its safety was assessed. Employingarising retinalpigment epithelial (ARPE) cells, the permeability of the nanoliposome was analyzed. Structural stability and integrity of NLP-BVZ were also estimated with different methods. Optimal condition for the maximum DEE (39.9%) was obtained with cholesterol/DPPC (1,2-Dipalimitoyl-Sn-glycero-3-phosphocholine) (%w/w) 13.64, BVZ/DPPC (%w/w) 83.78 and 9 freeze-thaw cycles. Neutral fabricated NLP-BVZ with an average size of 141.5 ± 45.8 nm showed a smooth spherical structure and released the drug in a slow and sustained fashion. The formulation exhibited no obvious effect against human umbilical vein endothelial cells (HUVECs) and ARPEs. Additionally, the pattern of the circular dichroism (CD) and intrinsic fluorescence spectra confirmed the structural integrity of protein remained conserved after encapsulation. Taken together, the analysis indicated that the process of entrapment into nanoliposome meaningfully made the drug safer, more stable, and, therefore, appropriate for treating ocular disorders.
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Affiliation(s)
- Maryam Malakouti-Nejad
- Bioprocess Engineering Department, Institute of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Hassan Bardania
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran; Clinical Research Development Unit, Imamsajad Hospital, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Farhang Aliakbari
- Bioprocess Engineering Department, Institute of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Alireza Baradaran-Rafii
- Ocular Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, No 23, Paydarfard-9th Boostan St., Pasdaran Ave, Tehran, Iran
| | - Elahe Elahi
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Daniela Monti
- Department of Pharmacy, University of Pisa, via Bonanno 33, 56126 Pisa, Italy
| | - Dina Morshedi
- Bioprocess Engineering Department, Institute of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
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27
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Xu K, Mousa R, Loewenstein A, Barak A, Chin EK, Almeida DRP. Management and Visual Outcomes of Acute Bacterial Endophthalmitis Following Intravitreal Injection of Contaminated Bevacizumab in a Single Day. Ophthalmic Surg Lasers Imaging Retina 2020; 51:346-352. [PMID: 32579693 DOI: 10.3928/23258160-20200603-05] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 04/28/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Bevacizumab requires compounding for off-label intravitreal injection, thus creating a risk of possible contamination during preparation. PATIENTS AND METHODS This retrospective, consecutive case series from a single site included patients who developed culture-proven acute endophthalmitis after intravitreal injection with contaminated bevacizumab. All patients suspected of endophthalmitis had vitreous biopsy and microbial cultures prior to initiation of treatment and were managed with immediate tap and injection of antibiotics followed early by pars plana vitrectomy. Main outcome measures included best-corrected visual acuity (BCVA) at 3-month follow-up after treatment. RESULTS Twenty-four patients developed acute bacterial endophthalmitis following intravitreal injection of contaminated bevacizumab single-dose syringes in a single day. Twenty-three cases (95.8%) grew Streptococcus species and one (4.2%) grew Enterococcus species. Six cases (25.0%) had optic nerve atrophy, three (12.5%) developed retinal detachment, one (4.2%) had vitreous hemorrhage, and one (4.2%) had band keratopathy. At 3-month follow-up, compared to BCVA at the time of initial presentation, 11 patients (45.8%) had improved vision, eight (33.3%) had unchanged BCVA, and five (20.8%) had worse BCVA. However, when compared to BCVA prior to endophthalmitis (baseline), 22 cases (91.7%) had significantly worse BCVA at 3-month follow-up. CONCLUSIONS Contamination of off-label bevacizumab poses devastating risk of endophthalmitis following intravitreal injection. Vigilance is needed to ensure all possible safeguards are in place to prevent contamination. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:346-352.].
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28
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Jung E, Jung WK, Park S, Kim HR, Kim J. Aucuba japonica extract inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy, with its bioactive components preventing VEGF-induced retinal vascular hyperpermeability. Food Sci Nutr 2020; 8:2895-2903. [PMID: 32566207 PMCID: PMC7300051 DOI: 10.1002/fsn3.1590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 03/19/2020] [Accepted: 03/30/2020] [Indexed: 12/27/2022] Open
Abstract
Neovascularization in the retina is common pathophysiology of diabetic retinal microvasculopathy and exudative macular degeneration. Our study assessed the inhibitory activity of an ethanol-based extract of Aucuba japonica (AJE) on abnormal angiogenesis in the retina with a hyperoxia-induced neovascular retinopathy model. The inhibitory effects of aucubin, quercetin, and kaempferol, bioactive compounds, from A. japonica, on retinal vascular hyperpermeability were also examined. On the 7th postnatal day (P7), the C57BL/6 pups were exposed to a hyperoxic environment with 75% oxygen to develop the experimental angiogenesis in retinas. On the 12th postnatal day (P12), the pups were then returned to the normal atmospheric pressure of oxygen. From P12 to P16, the administration was intraperitoneal. The dose per day was 250 mg per kg weight. Retinal neovascularization was measured with retinal flat mounts prepared on P17. We also measured the vascular leakage mediated by the vascular endothelial growth factor (VEGF) in retinas. Mice treated with AJE had markedly smaller neovascular lesions, in comparison with vehicle-administered mice. AJE downregulated the expression of both VEGF protein and mRNA. In addition, aucubin, quercetin, and kaempferol ameliorated VEGF-induced retinal vascular leakage. The results of our study suggest that AJE is a potent antiangiogenic substance. AJE could also serve as a therapeutic agent for abnormal growth of vessels in the retina in patients with ischemic retinopathy. The bioactive compounds of AJE may be responsible for its antiangiogenic abilities.
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Affiliation(s)
- Eunsoo Jung
- Laboratory of ToxicologyResearch Institute for Veterinary Science and College of Veterinary MedicineSeoul National UniversitySeoulKorea
| | - Woo Kwon Jung
- Department of Oral PathologySchool of DentistryJeonbuk National UniversityJeonjuKorea
| | - Su‐Bin Park
- Department of Oral PathologySchool of DentistryJeonbuk National UniversityJeonjuKorea
| | - Hyung Rae Kim
- Department of Oral PathologySchool of DentistryJeonbuk National UniversityJeonjuKorea
| | - Junghyun Kim
- Department of Oral PathologySchool of DentistryJeonbuk National UniversityJeonjuKorea
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29
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Amoaku W, Bailey C, Downey L, Gale RP, Ghanchi F, Hamilton R, Mahmood S, Menon G, Nosek J, Pearce I, Yang Y. Providing a Safe and Effective Intravitreal Treatment Service: Strategies for Service Delivery. Clin Ophthalmol 2020; 14:1315-1328. [PMID: 32546938 PMCID: PMC7239611 DOI: 10.2147/opth.s233061] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 04/03/2020] [Indexed: 11/23/2022] Open
Abstract
An aging population leads to increasing demand for medical retina services with chronic diseases being managed in long-term care pathways. Many hospital services struggle to deliver efficient and effective MR care due, at least in part, to infrastructure that does not expand responsively enough to meet the increased demand. A steering committee of retinal specialists from a variety of UK NHS hospital ophthalmology departments with experience of leading and managing NHS retinal services in the intravitreal era came together for the generation of this document to review and compile key aspects that should be considered when optimising intravitreal treatment capacity within MR services. This article aims to provide a useful collation and signposting of key published evidence, consensus and insights on aspects of delivering an intravitreal service, including treatment regimens, virtual clinics, staff training and governance, telemedicine and information technology, and data collection and key performance indicators. The objective is to equip ophthalmologic healthcare professionals with the necessary tools to develop and adapt their local service in the face of current and projected increased demand.
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Affiliation(s)
- Winfried Amoaku
- Academic Ophthalmology, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK
| | - Clare Bailey
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Louise Downey
- Hull and East Yorkshire Eye Hospital, Hull University Teaching Hospital, Hull, UK
| | | | - Faruque Ghanchi
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | | | - Sajjad Mahmood
- Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Geeta Menon
- Frimley Health NHS Foundation Trust, Frimley, UK
| | | | - Ian Pearce
- St Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK
| | - Yit Yang
- Wolverhampton Eye Infirmary, The Royal Wolverhampton NHS Trust, Wolverhampton, UK
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30
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Teo AWJ, Rim TH, Wong CW, Tsai ASH, Loh N, Jayabaskar T, Wong TY, Cheung CMG, Yeo IYS. Design, implementation, and evaluation of a nurse-led intravitreal injection programme for retinal diseases in Singapore. Eye (Lond) 2020; 34:2123-2130. [PMID: 32382144 DOI: 10.1038/s41433-020-0920-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 04/16/2020] [Accepted: 04/21/2020] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND To describe the design, implementation, and evaluation of a nurse-led intravitreal injection (NL-IVT) programme in a Singapore tertiary eye hospital. METHODS Patients requiring anti-vascular endothelial growth factor (VEGF) IVT were recruited. Implementation and evaluation were done in the Singapore National Eye Centre, a tertiary centre. To assess safety, nurse injectors recorded details of procedures performed and complications for an 8-month period from February 2019. To evaluate patient experience, we used a modified patient questionnaire and recorded both patients' waiting time and IVT procedure duration. A retrospective audit of IVTs before and after the introduction of NL-IVT was performed from January 2017 to September 2019. Cost difference between NL-IVT and standard doctor-led (DL) IVT was evaluated. RESULTS A total of 8599 NL-IVTs were performed. No cases of severe complication were detected in the follow-up. A total of 135 patients who received NL-IVT and DL-IVT were surveyed. General satisfaction, interpersonal manner, financial aspect, time spent with injector, and staff competence were higher in NL-IVTs than in DL-IVTs (p < 0.05). There were no differences in terms of technical quality and communication. For 934 patients, waiting time was significantly shorter in NL-IVT (3.6 ± 10.3 min) compared with DL-IVTs (35.3 ± 32.3 min); on average, 19.7 min were saved through NL-IVT (p < 0.01). The cost difference per IVT between NL-IVT and DL-IVT is estimated at 286 SGD (163 GBP). CONCLUSION With a well-designed training programme, NL-IVT is a safe, acceptable, and cost savings procedure. With increasing demand for IVT, NL-IVT provides an alternative model of care for healthcare systems globally.
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Affiliation(s)
- Alvin Wei Jun Teo
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | - Tyler Hyungtaek Rim
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.,Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
| | - Chee Wai Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | | | - Nazurah Loh
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore
| | | | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.,Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
| | - Chui Ming Gemmy Cheung
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.,Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
| | - Ian Yew San Yeo
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore. .,Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
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31
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Tomita Y, Cakir B, Liu CH, Fu Z, Huang S, Cho SS, Britton WR, Sun Y, Puder M, Hellström A, Talukdar S, Smith LEH. Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice. Angiogenesis 2020; 23:385-394. [PMID: 32140799 DOI: 10.1007/s10456-020-09717-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/24/2020] [Indexed: 02/06/2023]
Abstract
To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD). Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (Ffar4+/+) and knock out (Ffar4-/-) mice on a C57BL/6J/6N background. The ex vivo choroid-sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-ĸB/NF-ĸB and qRT-PCR for Il-6, Il-1β, Tnf-α, Vegf, and Nf-ĸb were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from Ffar4+/+ and Ffar4-/- mice were used to assess RPE contribution to inflammation. The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in Ffar4-/- compared to Ffar4+/+ mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1β) via the NF-ĸB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of Ffar4-/- mice compared with Ffar4+/+ RPE. In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV.
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Affiliation(s)
- Yohei Tomita
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Bertan Cakir
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Chi-Hsiu Liu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Zhongjie Fu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Shuo Huang
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Steve S Cho
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - William R Britton
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Ye Sun
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Mark Puder
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, USA
| | - Ann Hellström
- Pediatric Ophthalmology, Sahlgrenska Academy, The Queen Silvia Children's Hospital, Göteborg, Sweden
| | | | - Lois E H Smith
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
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Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models. Int J Mol Sci 2020; 21:ijms21041188. [PMID: 32054022 PMCID: PMC7072824 DOI: 10.3390/ijms21041188] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/06/2020] [Accepted: 02/08/2020] [Indexed: 12/18/2022] Open
Abstract
The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21- or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicle- treated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification.
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Tsirouki T, Steffen J, Dastiridou A, Praidou A, Androudi S. Endophthalmitis in HIV Infection. Ocul Immunol Inflamm 2020; 28:1060-1065. [PMID: 31944150 DOI: 10.1080/09273948.2019.1699580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Purpose: The role of HIV infection in exogenous and endogenous endophthalmitis has not been clarified. We aim to assess the potential role of HIV as a risk factor or a poor prognostic feature in this sight-threatening condition. Methods: Literature review. Review of evidence: Evidence for endophthalmitis in HIV patients is based on scarce retrospective case series and case reports. Infrequency of literature on this topic is owed to the diversity of the different types of endophthalmitis as well as the rarity of the coexistence of the two conditions. Conclusions: Endophthalmitis in HIV patients are a rare but potentially devastating condition. Many forms of endophthalmitis tend to occur in severely immunosuppressed HIV patients with low CD4 counts. Therefore, the early introduction of cART with full immune reconstitution is an essential part of the prevention of endophthalmitis in the HIV population.
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Affiliation(s)
- Theodora Tsirouki
- Department of Ophthalmology, University of Thessaly , Larissa, Greece
| | - Jonel Steffen
- Division of Ophthalmology, University of Cape Town , Cape Town, South Africa
| | - Anna Dastiridou
- Department of Ophthalmology, University of Thessaly , Larissa, Greece
| | - Anna Praidou
- Department of Ophthalmology, Agios Dimitrios Hospital , Thessaloniki, Greece
| | - Sofia Androudi
- Department of Ophthalmology, University of Thessaly , Larissa, Greece
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34
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Patel SN, Gangaputra S, Sternberg P, Kim SJ. Prophylaxis measures for postinjection endophthalmitis. Surv Ophthalmol 2020; 65:408-420. [PMID: 31923477 DOI: 10.1016/j.survophthal.2019.12.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 12/24/2019] [Accepted: 12/30/2019] [Indexed: 12/23/2022]
Abstract
Intravitreal injections have become the most commonly performed ophthalmic procedure, transforming modern retina practice. Postinjection endophthalmitis, while rare, remains the most feared potential complication. Prophylaxis measures including topical antisepsis, hand hygiene, gloves, masks, and drapes have all been proposed to help prevent postinjection endophthalmitis; however, there remains significant variation in protocol, given the lack of agreement among retina specialists on which steps are crucial to prevent endophthalmitis. With millions of injections performed annually, collating data have helped us better understand risk factors for endophthalmitis after intravitreal injection. We summarize the consensus guidelines for intravitreal injection technique and comprehensively review the literature on prevention of postinjection endophthalmitis.
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Affiliation(s)
- Shriji N Patel
- Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
| | - Sapna Gangaputra
- Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Paul Sternberg
- Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Stephen J Kim
- Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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35
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Endophthalmitis Following Intravitreal Injections Performed in the Office Versus Operating Room Setting. CURRENT OPHTHALMOLOGY REPORTS 2019. [DOI: 10.1007/s40135-019-00208-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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36
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Juncal VR, Francisconi CLM, Altomare F, Chow DR, Giavedoni LR, Muni RH, Berger AR, Wong DT. Same-Day Bilateral Intravitreal Anti-Vascular Endothelial Growth Factor Injections: Experience of a Large Canadian Retina Center. Ophthalmologica 2019; 242:1-7. [PMID: 30928983 DOI: 10.1159/000499115] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 02/25/2019] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To evaluate the outcomes and complications of bilateral same-day intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. METHODS This is a single-center, retrospective study that included 524 eyes of 262 patients who received concomitant bilateral intravitreal anti-VEGF injections in 2016 at St. Michael's Hospital, Toronto. If any of the patients were receiving simultaneous bilateral injections on a regular basis prior to 2016, data pertaining to previous injections were also reviewed. Everyone received bevacizumab, ranibizumab, or aflibercept in an office setting. RESULTS A total of 9,798 intravitreal anti-VEGF injections (4,899 bilateral injection sessions) were performed in 524 eyes of 262 patients. The average number of bilateral injection sessions per patient was 18.7 ± 14.1. Ranibizumab was the most commonly used anti-VEGF drug (83.8%). The incidence of endophthalmitis was 0.01%, and there were 2 episodes of acute intraocular inflammation among the 9,798 injections (0.02%). All 3 cases occurred after treatment with ranibizumab. There were 2 deaths (0.76%) due to nonvascular causes but no vascular related systemic adverse events were reported. CONCLUSIONS Same-day bilateral intravitreal anti-VEGF injections present a low rate of complications and are well tolerated by patients. This safe practice may reduce the burden on the health-care system and on the patients.
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Affiliation(s)
- Verena R Juncal
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Carolina L M Francisconi
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Filiberto Altomare
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
| | - David R Chow
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada.,Toronto Retina Institute, North York, Ontario, Canada
| | - Louis R Giavedoni
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Rajeev H Muni
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Alan R Berger
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada.,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada.,Toronto Retina Institute, North York, Ontario, Canada
| | - David T Wong
- Department of Ophthalmology, St. Michael's Hospital, Toronto, Ontario, Canada, .,Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada, .,Department of Ophthalmology, Oakville Trafalgar Hospital, Oakville, Ontario, Canada,
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37
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Management of bacterial postoperative endophthalmitis and the role of vitrectomy. Surv Ophthalmol 2018; 63:677-693. [DOI: 10.1016/j.survophthal.2018.02.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 02/04/2018] [Accepted: 02/06/2018] [Indexed: 11/20/2022]
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38
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Kiss S, Dugel PU, Khanani AM, Broder MS, Chang E, Sun GH, Turpcu A. Endophthalmitis rates among patients receiving intravitreal anti-VEGF injections: a USA claims analysis. Clin Ophthalmol 2018; 12:1625-1635. [PMID: 30214147 PMCID: PMC6124467 DOI: 10.2147/opth.s169143] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Purpose Intravitreal (IVT) injections of the anti-vascular endothelial growth factor (VEGF) agents aflibercept, bevacizumab, and ranibizumab are commonly prescribed to treat neovascular age-related macular degeneration (nAMD). Studies comparing inflammation rates in large populations of patients receiving these agents and the treatment of ocular inflammation post-IVT anti-VEGF injections are scarce. In this study, we compared rates of endophthalmitis claims (sterile and infectious) following IVT anti-VEGF injections to determine the risk factors associated with developing endophthalmitis, and examined the claims for subsequent treatment. Patients and methods This retrospective cohort study of USA claims data examined the risk of developing endophthalmitis following IVT injection of aflibercept, bevacizumab, or ranibizumab in patients with nAMD between 11/18/2011 and 5/31/2013. The primary study outcome was occurrence of endophthalmitis within 30 days of a claim for an IVT anti-VEGF injection. Endophthalmitis rates were calculated separately for aflibercept, bevacizumab, and ranibizumab, followed by pairwise comparisons of endophthalmitis frequencies among the 3 treatments. Results This analysis included 818,558 injections from 156,594 patients with nAMD. The rates (% [n/N]) of endophthalmitis following aflibercept, bevacizumab, and ranibizumab IVT injections were 0.100% (136/135,973), 0.056% (268/481,572), and 0.047% (94/201,013), respectively. In a multivariate analysis, aflibercept was associated with a significantly higher risk of endophthalmitis vs ranibizumab (adjusted odds ratio, 2.19; 95% CI: 1.68–2.85; P<0.0001). The risk of endophthalmitis was similar for bevacizumab and ranibizumab. Within 14 days after endophthalmitis, 38.6% of cases received injectable antibiotics, 15.3% received injectable steroids, and 30.3% underwent vitrectomy. Conclusion The rate of endophthalmitis was very low, but higher following IVT injection with aflibercept compared with both bevacizumab and ranibizumab in patients with nAMD.
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Affiliation(s)
- Szilárd Kiss
- Department of Ophthalmology, Weill Cornell Medical College, New York, NY, USA,
| | - Pravin U Dugel
- Retinal Consultants of Arizona, Phoenix, AZ, USA.,USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Michael S Broder
- Partnership for Health Analytic Research, LLC, Beverly Hills, CA, USA
| | - Eunice Chang
- Partnership for Health Analytic Research, LLC, Beverly Hills, CA, USA
| | - Gordon H Sun
- Partnership for Health Analytic Research, LLC, Beverly Hills, CA, USA
| | - Adam Turpcu
- Genentech, Inc., South San Francisco, CA, USA
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Hunyor AP, Merani R, Darbar A, Korobelnik JF, Lanzetta P, Okada AA. Topical antibiotics and intravitreal injections. Acta Ophthalmol 2018; 96:435-441. [PMID: 28440583 DOI: 10.1111/aos.13417] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 01/13/2017] [Indexed: 12/28/2022]
Abstract
There is increasing evidence that topical antibiotics, given before and/or after intravitreal injections, are ineffective in preventing endophthalmitis and are possibly harmful. In addition to the lack of efficacy and increased development of resistant organisms, the use of topical antibiotics adds significantly to the cost of delivering intravitreal therapy. Despite this, in many countries, it is still common practice to use pre- and/or postinjection topical antibiotics. This review outlines the general principles of effective antibiotic prophylaxis, and the evidence regarding topical antibiotic use as a prophylactic measure for endophthalmitis following intravitreal injections. A key distinguishing feature of intravitreal injections from most other invasive procedures is the fact that they are often repeated on multiple occasions to the same eye. Given the lack of evidence to support topical antibiotics as an effective method of prophylaxis for postinjection endophthalmitis, it appears that more widespread education of ophthalmologists is required to avoid continued inappropriate use. Revision of drug labels in some jurisdictions, and amendment of local/professional society guidelines, may be required to assist in achieving this goal. Emphasis should be placed on antisepsis and aseptic technique, which are the major proven methods of endophthalmitis prevention, rather than antibiotics.
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Affiliation(s)
- Alex P. Hunyor
- University of Sydney; Sydney New South Wales Australia
- Sydney Eye Hospital; Sydney New South Wales Australia
| | - Rohan Merani
- Sydney and Macquarie Universities; Sydney New South Wales Australia
- Concord Repatriation General Hospital; Concord New South Wales Australia
| | - Archie Darbar
- Royal North Shore Hospital; St Leonards New South Wales Australia
| | - Jean-François Korobelnik
- Service d'ophtalmologie; CHU de Bordeaux; Bordeaux France
- Univ. Bordeaux; ISPED; Bordeaux France
- Inserm; U1219 - Bordeaux Population Health Research Center; Bordeaux France
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Antibiotic prophylaxis for preventing endophthalmitis after intravitreal injection: a systematic review. Eye (Lond) 2018; 32:1423-1431. [PMID: 29891901 DOI: 10.1038/s41433-018-0138-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 12/26/2017] [Accepted: 02/19/2018] [Indexed: 12/31/2022] Open
Abstract
PURPOSE To assess the effect of topical antibiotic prophylaxis on the rate of post-operative endophthalmitis after intravitreal injection (IVI). METHODS We conducted a systematic review of studies comparing the rates of endophthalmitis in eyes receiving IVI of different drugs with and without topical antibiotic prophylaxis, by searching MEDLINE and EMBASE up to June 2016. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias tool and the Risk Of Bias in Non-randomized Studies of Interventions (ROBINS-I) for randomized clinical trials (RCTs) and non-randomized studies, respectively. We used a random-effects meta-analysis to compute the odds ratio (OR) of endophthalmitis with antibiotic prophylaxis compared with no prophylaxis and conducted subgroup analyses to compare the efficacy of different regimens and classes of antibiotics on endophthalmitis rates. RESULTS We identified 1 randomized and 12 non-randomized studies that reported 74 cases of endophthalmitis in 147,203 IVIs using antibiotic prophylaxis compared with 55 cases in 211,418 IVIs with no prophylaxis. The overall OR of endophthalmitis for antibiotic prophylaxis vs. no prophylaxis was 1.33 (95% CI 0.75-2.38). Leave-one-out sensitivity analyses showed that the exclusion of the only study with a serious risk of bias significantly increased the risk of endophthalmitis in the antibiotic prophylaxis group compared with control (OR: 1.62, 95% CI: 1.17, 2.34). There was no difference in the endophthalmitis rate associated with any other factor analyzed, including type of antibiotic, type of drug injected, or antibiotic prophylaxis regimen. CONCLUSIONS Antibiotic prophylaxis does not reduce the rate of endophthalmitis following IVI and might potentially be associated with an increased risk of post-operative infection.
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Aster koraiensis Extract and Chlorogenic Acid Inhibit Retinal Angiogenesis in a Mouse Model of Oxygen-Induced Retinopathy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:6402650. [PMID: 29849715 PMCID: PMC5937502 DOI: 10.1155/2018/6402650] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 02/04/2018] [Indexed: 11/17/2022]
Abstract
Aster koraiensis extract (AKE) is a standard dietary herbal supplement. Chlorogenic acid (CA) is the major compound present in AKE. Retinal neovascularization is a common pathophysiology of retinopathy of prematurity, diabetic retinopathy, and wet form age-related macular degeneration. In this study, we aimed to evaluate the effects of AKE and CA on retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Vascular endothelial growth factor- (VEGF-) induced tube formation was assayed in human vascular endothelial cells. Experimental retinal neovascularization was induced by exposing C57BL/6 mice to 75% oxygen on postnatal day 7 (P7) and then returning them to normal oxygen pressure on P12. AKE (25 and 50 mg/kg/day) and CA (25 and 50 mg/kg/day) were administered intraperitoneally for 5 days (P12–P16). Retinal flat mounts were prepared to measure the extent of retinal neovascularization at P17. The incubation of human vascular endothelial cells with AKE and CA (1–10 μg/mL) resulted in the inhibition of VEGF-mediated tube formation in a dose-dependent manner. The neovascular area was significantly smaller in AKE or CA-treated mice than in the vehicle-treated mice. These results suggest that AKE is a potent antiangiogenic agent and that its antiangiogenic activity may, in part, be attributable to the bioactive component CA.
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Xu K, Chin EK, Bennett SR, Williams DF, Ryan EH, Dev S, Mittra RA, Quiram PA, Davies JB, Parke DW, Johnson JB, Cantrill HL, Almeida DRP. Endophthalmitis after Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors: Management and Visual Outcomes. Ophthalmology 2018; 125:1279-1286. [PMID: 29477689 DOI: 10.1016/j.ophtha.2018.01.022] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/13/2018] [Accepted: 01/17/2018] [Indexed: 10/18/2022] Open
Abstract
PURPOSE We describe the presentation of patients developing endophthalmitis after intravitreal injection with vascular endothelial growth factor (VEGF) inhibitors. Moreover, we evaluate the management by comparing the outcomes of immediate tap and injection of intravitreal antibiotics (TAI) versus initial surgical pars plana vitrectomy (PPV). Finally, we analyze the predictive factors of visual outcomes at 6-month follow-up. DESIGN Retrospective, single-center, nonrandomized interventional study. PARTICIPANTS Patients developing endophthalmitis after receiving an intravitreal injection of anti-VEGF agent between 2006 and 2016. METHODS All patients received a vitreous biopsy sent for cultures before the initiation of treatment: TAI group versus PPV with intravitreal antibiotics (PPV group). MAIN OUTCOME MEASURES Best-corrected visual acuity (BCVA) at 6-month follow-up after treatment for endophthalmitis. RESULTS A total of 258 357 intravitreal injections occurred over the course of the 10-year period, of which 40 patients (0.016%) had endophthalmitis within 3 weeks after injection. In total, 34 patients (85.0%) had pain and 25 patients (62.5%) had hypopyon on initial examination. Among 24 culture-positive cases, 66.7% of the causative organisms were coagulase-negative Staphylococcus, followed by Streptococcus species (10.0%). The best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution [logMAR]) at 6-month follow-up was significantly worse for patients who had a positive culture for Streptococcus species (4.0; standard deviation [SD], 0.8) (approximately light perception) compared with those who had a positive culture for coagulase-negative Staphylococcus (0.4; SD, 0.3) (∼20/50) (P < 0.0001). Compared with the TAI group, a higher proportion of samples were culture-positive in the PPV group (90.9% vs. 48.3%, P = 0.03). There was no statistically significant difference in BCVA at 6-month follow-up between the TAI and PPV groups. Younger age (<85 years) and lower intraocular pressure (IOP) (≤25 mmHg) at presentation were predictive of achieving a BCVA of 20/400 or better at 6-month follow-up after treatment. Initial management (TAI vs. PPV), duration of symptoms, presence of pain, presence of hypopyon, presenting BCVA, and culture status (positive vs. negative) were not found to be predictive of visual outcomes at 6-month follow-up. CONCLUSIONS No significant difference in BCVA at 6-month follow-up was detected between the TAI and PPV groups. Younger age and lower IOP at presentation were associated with better visual outcomes at 6-month follow-up.
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Affiliation(s)
- Kunyong Xu
- Department of Ophthalmology, Weill Cornell Medicine, Cornell University, New York, New York
| | - Eric K Chin
- Retina Consultants of Southern California, Redlands, California
| | | | | | - Edwin H Ryan
- VitreoRetinal Surgery PA, Minneapolis, Minnesota
| | - Sundeep Dev
- VitreoRetinal Surgery PA, Minneapolis, Minnesota
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Beri S, Shandil A, Garg R. Stenotrophomonas maltophilia: An emerging entity for cluster endophthalmitis. Indian J Ophthalmol 2017; 65:1166-1171. [PMID: 29133644 PMCID: PMC5700586 DOI: 10.4103/ijo.ijo_314_17] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
PURPOSE This was a study of acute cluster endophthalmitis along with clinical features, culture results, and visual outcomes of 10 eyes of 10 patients after intravitreal injection of Avastin (bevacizumab) in one sitting from a single vial. METHODS Retrospective review of intravitreal injection of 1.25 mg/0.05 ml bevacizumab that was given to 10 eyes of 10 patients on the same day from a freshly opened vial. All patients manifested with endophthalmitis the next day. Vitreous tap for direct smear and culture was done. Intravitreal antibiotics and steroids were injected and appropriate treatment begun. The injection vial of the same batch was sent for VITEKTM identification and antimicrobial susceptibility of isolates. RESULTS Endophthalmitis presented within 24 h of intravitreal injection. There was a remarkable absence of posterior pupillary synechia. Two cases were culture-positive (20%), showing pseudomonoid growth. The vial of the same batch revealed a pseudomonoid bacilli Stenotrophomonas maltophilia using VITEKTM, which was resistant to multiple drugs. Hence, the contaminated vial was identified as the source of infection in our case. Among 10 patients, two underwent pars plana vitrectomy. Visual acuity returned to preendophthalmitis levels in 9/10 eyes after 1 month. One patient was lost to follow-up. Late complications included retinal detachment in one case and neovascular glaucoma in another. CONCLUSION Early recognition and treatment are key factors in improving outcomes. Causative etiology could be microbial contamination of the drug vial. S. maltophilia should be considered a pathogenic organism of postintravitreal endophthalmitis.
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Affiliation(s)
- Sarita Beri
- Department of Ophthalmology, Lady Hardinge Medical College, New Delhi, India
| | - Anurag Shandil
- Department of Ophthalmology, Lady Hardinge Medical College, New Delhi, India
| | - Rajiv Garg
- Department of Ophthalmology, Lady Hardinge Medical College, New Delhi, India
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Munro M, Williams GR, Ells A, Fielden M, Kherani A, Mitchell P, Ruzicki J, Adatia FA. Lid splinting eyelid retraction technique: a minimised sterile approach for intravitreal injections. Br J Ophthalmol 2017; 102:1254-1258. [PMID: 29246893 DOI: 10.1136/bjophthalmol-2017-311081] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/25/2017] [Accepted: 11/21/2017] [Indexed: 11/04/2022]
Abstract
BACKGROUND/AIMS To describe an alternative technique for avoiding contact with the lids and lashes, without the use of a lid speculum, during intravitreal anti-vascular endothelial growth factor injections. METHODS Retrospective case series of all patients undergoing intravitreal injections of bevacizumab and ranibizumab, with the lid splinting retraction technique from January 2010 to December 2015. Injections performed by six vitreoretinal specialists were included. The key preinjection ocular surface preparation includes topical anaesthetic, 5% povidone-iodine and a subconjunctival injection of 2% lidocaine with epinephrine. A second instillation of 5% povidone-iodine is given and the intravitreal injection is then performed. No lid speculum is used. A search of the electronic medical records identified patients diagnosed with postinjection endophthalmitis and charts were reviewed to ensure inclusion criteria were met. The main outcome measure was incidence of postinjection endophthalmitis. RESULTS A total of 78 009 consecutive intravitreal injections were performed, of which 22 207 were bevacizumab and 55 802 were ranibizumab. In this cohort of patients (n=6320), 12 cases of endophthalmitis developed, corresponding to a rate of 0.015%. CONCLUSIONS The technique of eyelid retraction for intravitreal injection has a low rate of endophthalmitis, similar to the reported rates using a metal lid speculum. This is beneficial for both the physician and the patient as it minimises patient discomfort as well as the duration of the procedure. To our knowledge, this is one of the largest studies performed to date evaluating intravitreal injection-related endophthalmitis.
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Affiliation(s)
- Monique Munro
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada
| | - Geoff R Williams
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada.,Southern Alberta Eye Center, Calgary, Alberta, Canada
| | - Anna Ells
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada.,Southern Alberta Eye Center, Calgary, Alberta, Canada
| | - Michael Fielden
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada.,Southern Alberta Eye Center, Calgary, Alberta, Canada
| | - Amin Kherani
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada.,Southern Alberta Eye Center, Calgary, Alberta, Canada
| | - Patrick Mitchell
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada.,Mitchell Eye Centre, Southern Alberta Eye Center, Calgary, Alberta, Canada
| | - Jessica Ruzicki
- Department of Ophthalmology, Queen's University, Kingston, Ontario, Canada
| | - Feisal A Adatia
- Division of Ophthalmology, University of Calgary, Calgary, Alberta, Canada.,Mitchell Eye Centre, Southern Alberta Eye Center, Calgary, Alberta, Canada
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Singh SR, Dogra A, Stewart M, Das T, Chhablani J. Intravitreal Ziv-Aflibercept: Clinical Effects and Economic Impact. Asia Pac J Ophthalmol (Phila) 2017; 6:561-568. [PMID: 28971631 DOI: 10.22608/apo.2017263] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
During the past decade, drugs that inhibit the actions of vascular endothelial growth factor (VEGF) have become standard-of-care treatment for a variety of chorioretinal vascular conditions. The off-label, intravitreal use of ziv-aflibercept (Zaltrap) has provided clinicians with an additional cost-effective drug. The commercial preparation of ziv-aflibercept contains the same aflibercept (VEGF-trap) molecule as Eylea but has a much higher osmolarity (1000 mOsm/kg vs 300 mOsm/kg). Initial concerns regarding cytotoxicity and long-term safety of intravitreal ziv-aflibercept have been largely negated after a series of publications failed to identify adverse ocular and systemic side effects. Both treatment-naive and anti-VEGF‒resistant cases of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), retinal vein occlusion (RVO), and choroidal neovascular membrane (CNVM) may respond as well to ziv-aflibercept as to aflibercept. A higher dose of ziv-aflibercept (2 mg in 0.08 mL) does not cause any adverse effects during short-term follow-up period (1 month). Data from various sources suggest that ziv-aflibercept may be as cost effective as bevacizumab, thereby making it an attractive treatment option in low- and middle-income countries. However, problems with off-label use, compounding, and counterfeiting limit its availability in many countries. Data from prospective, randomized, multicenter clinical trials are still required to convince physicians and regulatory bodies of its clinical efficacy and potential as early therapy.
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Affiliation(s)
- Sumit Randhir Singh
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye institute, Hyderabad, India
| | - Avantika Dogra
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye institute, Hyderabad, India
| | - Michael Stewart
- Department of Ophthalmology, Mayo Clinic, Jacksonville, Florida
| | - Taraprasad Das
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye institute, Hyderabad, India
| | - Jay Chhablani
- Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye institute, Hyderabad, India
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EGHB010, a Standardized Extract of Paeoniae Radix and Glycyrrhizae Radix, Inhibits VEGF-Induced Tube Formation In Vitro and Retinal Vascular Leakage and Choroidal Neovascularization In Vivo. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:1568702. [PMID: 29234364 PMCID: PMC5646325 DOI: 10.1155/2017/1568702] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 08/29/2017] [Indexed: 11/18/2022]
Abstract
EGHB010 is a hot water extract of the rhizome mixture of Paeonia lactiflora Pallas and Glycyrrhiza uralensis Fisch. Choroidal neovascularization (CNV) and vascular leakage are the common pathophysiologies of age-related macular degeneration. In this study, we aimed to evaluate the effect of EGHB010 on retinal vascular leakage and laser-induced CNV in a rat model. Vascular endothelial growth factor- (VEGF-) induced tube formation was assayed in human retinal microvascular endothelial cells. Intravitreal VEGF-induced blood-retinal barrier breakdown was assayed in Sprague-Dawley rats. Experimental CNV was induced by laser photocoagulation in Brown Norway rats. EGHB010 (50 and 100 mg/kg/day) was administered orally for 10 days after laser photocoagulation. Choroidal flat mounts were prepared to measure the lesion size of CNV. Incubation of retinal vascular endothelial cells with EGHB010 (12.5 and 25 μg/mL) resulted in the inhibition of VEGF-induced tube formation in a dose-dependent manner. VEGF-mediated retinal vascular leakage was blocked by the oral administration of EGHB010. The CNV area was significantly lower in EGHB010-treated rats than in vehicle-treated rats. These results suggest that EGHB010 is a potent antiangiogenic agent. Thus, the oral administration of EGHB010 may have a beneficial effect in the treatment of vascular leakage and CNV in patients with age-related macular degeneration.
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Comparative cyto-histological study of needle tip aspirates and entry sites after intravitreal injection using different needle types. PLoS One 2017; 12:e0174467. [PMID: 28692684 PMCID: PMC5503168 DOI: 10.1371/journal.pone.0174467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 03/09/2017] [Indexed: 12/12/2022] Open
Abstract
A comparison of the cellular content of needle tip aspirates and entry sites after transconjunctival intravitreal injection (IVI) using different needle types was performed. White outbred rats and human cadaver eyes were used for IVI by hypodermic 27 gauge (G) and 30G needles, and spinal anesthesia Pencan 27G needles. Aspiration of vitreous for quantitative morphological and cell cultivation analysis, as well as cyto-histological analysis of aspirates and entry sites were carried out. The most common cells in the aspirates from all needle types were conjunctival epithelial-, ciliary body non-pigmented epithelial- and sclerocyte-like cells and granular proteins. Crystallized vitreous specimens were present in each aspirate. The entry sites of hypodermic needles showed marked trauma in all wall layers of rat and human eyes accompanied by cellular destruction and hemorrhages. Pencan 27G needle caused less tissue trauma with partial reposition of sclerocytes. Transconjunctival IVIs with hypodermic 27G and 30G, and Pencan 27G needles result in trauma of all layers of the eyeball. The possible consequences of cellular content being cut and injected into the eye, as well as the entry site wound shape deserve future consideration and improvements.
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Importance of Lid Hygiene Before Ocular Surgery: Qualitative and Quantitative Analysis of Eyelid and Conjunctiva Microbiota. Eye Contact Lens 2017; 42:366-370. [PMID: 26657662 PMCID: PMC5098457 DOI: 10.1097/icl.0000000000000221] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Objective: To evaluate the efficacy of a cleansing eyelid wipe in reducing the microbiota present on the ocular surface before cataract surgery. Methods: A single-center, prospective, single-blind phase IV study was conducted at the University Complutense of Madrid. Forty-five adult patients who were scheduled for ocular surgery after treatment with commercially available eyelid wipes were consecutively enrolled. The study lasted 5 days and the patients were examined at day 0 (D0), day 3 (D3), and day 5 (D5). They received instructions to apply the eyelid wipe only to the eye subject to surgery, using the other eye as a control with no treatment. Lid and conjunctival swabs were taken on each day and microbes identified. Ocular surface microbiota was estimated by measuring the area of the agar plate occupied by the grown colonies with respect to the total available area. Results: Measurements at D3 and D5 showed a percent reduction of 58% and 63%, respectively, in the microbial load on the eyelid in the treated eyes (P=0.0011). There was also a reduction, although nonsignificant, in the microbiota of the conjunctiva of 72% and 69% on D3 and D5, respectively. Conclusions: The degree of microbiota reduction was comparable with that obtained after topical application of antibiotics in other studies. The results suggest the use of these eyelid wipes as a complementary prophylactic method before any ocular surgery.
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Infectious and sterile endophthalmitis after intravitreal injections: differential diagnosis, prevention, treatment. OPHTHALMOLOGY JOURNAL 2017. [DOI: 10.17816/ov10162-69] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Endophthalmitis is a rare but extremely severe complication of different intraocular procedures. In the article, we analyze world literature data on prevalence, differential diagnosis, prevention methods, and treatment of endophthalmitis after intravitreal injections.
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Ruão M, Andreu-Fenoll M, Dolz-Marco R, Gallego-Pinazo R. Safety of bilateral same-day intravitreal injections of anti-vascular endothelial growth factor agents. Clin Ophthalmol 2017; 11:299-302. [PMID: 28203056 PMCID: PMC5295803 DOI: 10.2147/opth.s124282] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Purpose The aim was to evaluate the safety of bilateral same-day injections with intravitreal antiangiogenic drugs for macular diseases. Methods Cross-sectional retrospective review of unilateral and bilateral same-day antiangiogenic injections was conducted between January 2011 and March 2016 in the Unit of Macula, University and Polytechnic Hospital La Fe (Valencia, Spain). A total of 8,172 injections were administered, among which 6,560 were unilateral and 1,612 were bilateral injections. Patients were included in the study regardless of the diagnosis. Ranibizumab and aflibercept were the antiangiogenic drugs used. The presence of endophthalmitis or retinal detachment was evaluated. Results A total of 1 (0.012%) culture-proven endophthalmitis and 19 (0.233%) acute intraocular inflammations were registered. In the unilateral injections group, there were 18 (0.274%) acute intraocular inflammations and 1 (0.015%) culture-proven endophthalmitis. One (0.062%) of the 1,612 bilateral same-day injections had a unilateral acute intraocular inflammation, and there were no culture-proven endophthalmitis in this group. Conclusion Bilateral same-day injections are more convenient for patients and their caregivers than the unilateral injections administered on different days. In our study, the prevalence of culture-proven endophthalmitis and acute intraocular inflammation was lower in the bilateral injections than in the unilateral group. These data support the idea that bilateral same-day injections are a safe and valid treatment to use in our clinical practice.
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Affiliation(s)
- Miguel Ruão
- Department of Ophthalmology, Centro Hospitalar Entre Douro e Vouga, Santa Maria da Feira, Portugal
| | - María Andreu-Fenoll
- Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spain
| | - Rosa Dolz-Marco
- Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spain
| | - Roberto Gallego-Pinazo
- Unit of Macula, Department of Ophthalmology, University and Polytechnic Hospital La Fe, Valencia, spain
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