A cluster of presumed, noninfectious endophthalmitis after intravitreal injection of bevacizumab: long-term follow-up

Abstract

Purpose-To report the outcome of 5 consecutive cases of presumed, noninfectious endopththalmitis following intravitreal injection of bevacizumab (IVB).Methods-Ten pre-loaded syringes of bevacizumab (1.25 mg/50 µL) furnished by a compounding pharmacy were injected intravitreally. Treatments were performed in the operating room by the same surgeon on 2 consecutive days.Results-Of 10 eyes, 5 showed moderate to severe ocular inflammation within a few days of injection. All patients were treated in the same surgical session. Vitreous tap performed in the patient presenting with the most severe grade of inflammation was negative for bacteria and fungi. At the time of the vitreous biopsy, this patient was injected with vancomycin 1 mg/100 µL in the vitreous cavity. Other eyes with moderate inflammation received topical and systemic antibiotics and topical steroid treatment. Visual acuity returned to pre-endophthalmitis or better levels in all eyes within 1 month. The other 5 patients treated with IVB from the same batch in the other surgical session did not develop inflammation.Conclusions-IVB can induce noninfectious endophthalmitis. The use of compounded syringes can explain clustering of the inflammation. We were unable to identify the reasons for the variable grade of inflammation we observed in our patients.Bevacizumab (Avastin; Roche, Basel, Switzerland) is a humanized monoclonal antibody binding vascular endothelial growth factor (VEGF) that was originally developed to treat metastatic carcinoma of the colon and rectum. Michels et al 1 used intravenous bevacizumab infusions as an off-label treatment for neovascular age-related macular degeneration (n-AMD). Its efficacy in this context led to off-label intravitreal bevacizumab (IVB) administration and eventually widespread use as a treatment for ocular diseases associated with retinal neovascularization and edema, including macular edema secondary to retinal vein occlusion (RVO), n-AMD myopic choroidal neovascularization (m-CNV), CNV secondary to angioid streaks, diabetic macular edema (DME), and neovascular glaucoma. 2 IVB can cause procedure-related complications (traumatic cataract, retinal detachment, hemovitreous, and infectious endophthalmitis) and drug-related systemic and local side effects, including noninfectious endopththalmitis, 3 which must be distinguished from infectious endopththalmitis, 4-16 because management and prognosis of these two entities differs greatly. We report a cluster of noninfectious endophthalmitis ranging in severity from mild inflammation to severe vitritis with or without retinal involvement after IVB. In our patients, we employed single-use syringes of bevacizumab from the same batch, prepared by a single compounding pharmacy.

An Introduction to Biosimilars for the Treatment of Retinal Diseases: A Narrative Review

“…Also, ziv-aflibercept, an anti-VEGF drug approved for treating colorectal cancer, has been investigated as a treatment for nAMD [37], despite the fact that in the EU intravitreal use of ziv-aflibercept is contraindicated because of its hyperosmotic properties [38]. In addition to their off-labeldriven limitations, both products require additional compounding prior to use in retinal diseases, which may increase the risk of intraocular infections [39][40][41][42].…”

“…Some physicians may query why they should use biosimilars when payers will reimburse reference products, or when bevacizumab or zivaflibercept is available to them. The fact that the use of both bevacizumab and ziv-aflibercept in ophthalmology is off-label, together with concerns regarding inflammation and infection following intravitreal administration of both products, may create a sense of uncertainty with prescribers [39][40][41][42]126]. Furthermore, the use of bevacizumab is not available in all countries, or even uniformly within countries, reflecting diverging opinions of governments and clinical societies on its use [127].…”

Particulate Matter From Syringes Used for Intravitreal Injections

“…Given the fact that the vitreous is a small, contained space and that neovascular retinal diseases typically require ongoing treatment, the risks associated with injecting particulate matter (including silicone oil) into the vitreous may be cumulative, 4 , 5 and particles may have association with complications such as floaters, sustained increase in intraocular pressure, and endophthalmitis. 6 – 9 …”

“…Given the fact that the vitreous is a small, contained space and that neovascular retinal diseases typically require ongoing treatment, the risks associated with injecting particulate matter (including silicone oil) into the vitreous may be cumulative, 4,5 and particles may have association with complications such as floaters, sustained increase in intraocular pressure, and endophthalmitis. [6][7][8][9] On-label injectable drug products are required, according to United States Pharmacopeia chapter ,790., to be "essentially free" of visible particles and USP ,789. strictly limits subvisible particles in ophthalmic solutions. However, USP ,789. is subject to interpretation.…”

Ophthalmic biosimilars and biologics—role of endotoxins

“…The cases include patients invoking immune reaction to the biological drug itself, an entity known as anti-drug antibody; or reaction to the impurities present in the drug formulation [6]. There have been several reports of cluster sterile endophthalmitis arising from intravitreal bevacizumab therapy [7][8][9]. Wang et al reported cluster of sterile endophthalmitis (69%) due to counterfeit bevacizumab.…”