Sterile endophthalmitis following same-day intravitreal aflibercept 8 mg injections: a single-center observational study

Technical Summary: Sterile Endophthalmitis Following Same-Day Intravitreal Aflibercept 8 mg Injections

Problem Statement
Intravitreal aflibercept 8 mg was developed to extend treatment intervals for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). While pivotal clinical trials (CANDELA, PULSAR, PHOTON) demonstrated low rates of intraocular inflammation (IOI) comparable to the 2 mg formulation, post-marketing surveillance has identified clusters of sterile inflammatory events. These events sometimes present with severe features such as retinal vasculitis. The specific etiology of these clusters remains under investigation, with hypotheses ranging from product-specific immunogenicity to handling-related factors (e.g., vial withdrawal techniques). This study addresses the need to characterize a specific, temporally clustered outbreak of sterile endophthalmitis following same-day administration of vial-drawn aflibercept 8 mg at a single tertiary center, distinguishing it from general aseptic procedure failures.

Methodology
This was a retrospective, single-center observational study conducted at Jena University Hospital. The cohort consisted of six consecutive patients who received intravitreal aflibercept 8 mg (Eylea, 114.3 mg/mL) from sealed single-use vials on a single treatment day in May 2024.

• Procedure: All injections were performed in a dedicated operating theatre under standardized aseptic conditions by the same surgeon. The drug was withdrawn using a single-use needle (18 G) from vials disinfected with alcohol. Departmental records indicated all six vials originated from the same commercial batch, though the specific batch identifier was not retained.
• Control Context: On the same day, in the same theatre, and by the same personnel, other anti-VEGF agents (aflibercept 2 mg, faricimab, ranibizumab) were administered without inflammatory sequelae.
• Data Collection: Patients underwent serial examinations including best-corrected visual acuity (BCVA), intraocular pressure (IOP), slit-lamp biomicroscopy, and optical coherence tomography (OCT). Fluorescein angiography (FA) was performed in four affected patients. Vitreous sampling for microbiological culture was conducted in the most severe case (one patient undergoing pars plana vitrectomy).
• Analysis: Given the small sample size, descriptive statistics (mean ± standard deviation) were used. No formal hypothesis testing was performed.

Key Results

• Incidence and Timing: Five of the six patients (83%) developed sterile endophthalmitis within 2 to 4 days post-injection (mean 3.0 ± 0.7 days). The sixth patient remained asymptomatic.
• Clinical Presentation: Symptoms included blurred vision and floaters. Examination revealed anterior chamber cells and vitritis in all affected cases. One patient (Patient 5) developed a hypopyon. Two patients experienced hand-motion vision at the peak of inflammation. IOP remained normal, and no retinal infiltrates, vasculitis, or vascular occlusion were observed clinically.
• Imaging and Microbiology: OCT showed a reduction in central retinal thickness (CRT) from a pre-injection mean of 267 ± 55 µm to 205 ± 36 µm at the time of inflammation. Fluorescein angiography in four patients showed no evidence of retinitis or vasculitis. In the single patient who underwent pars plana vitrectomy, vitreous cultures for bacteria and fungi were negative.
• Treatment and Outcomes: All patients received topical anti-inflammatory and antibiotic therapy; four received systemic corticosteroids. The patient with hypopyon underwent pars plana vitrectomy, anterior chamber washout, and intravitreal antibiotics.
  • Visual Recovery: Mean BCVA worsened from 0.44 ± 0.20 logMAR at baseline to 1.29 ± 0.88 logMAR at diagnosis. By approximately one year, mean BCVA recovered to 0.41 ± 0.20 logMAR. Four of the five eyes returned to or exceeded their pre-injection baseline; one eye showed a minor decline attributed to recurrent exudative disease activity rather than structural damage from inflammation.
• Comparative Safety: Same-day injections of other anti-VEGF agents under identical procedural conditions resulted in no inflammatory events.

Key Contributions
The study provides a detailed clinical characterization of a same-day cluster of sterile endophthalmitis following aflibercept 8 mg administration. Its primary contribution is the observation that the inflammatory events were isolated to a specific batch of vial-drawn aflibercept 8 mg, while other anti-VEGF agents administered simultaneously in the same environment remained unaffected. This pattern helps differentiate the event from a general failure of aseptic technique. The study documents the clinical course, including the rapid onset (2–4 days), the specific inflammatory phenotype (predominantly anterior chamber and vitreous cells without vasculitis in this specific cluster), and the favorable visual prognosis following anti-inflammatory management.

Significance and Claims
The authors claim that this same-day cluster supports the existence of sterile endophthalmitis as a clinically relevant post-marketing event specific to aflibercept 8 mg. The absence of comparable events with other anti-VEGF agents administered on the same day argues against a general aseptic-procedure failure and suggests a factor related to the product, the vial, the handling process (specifically vial withdrawal), or the commercial batch.

The paper emphasizes that while the exact mechanism (e.g., protein aggregation, silicone oil droplets, or batch-specific quality variation) cannot be definitively proven due to the lack of retained batch identifiers and limited microbiological testing, the temporal clustering and negative cultures strongly support a sterile etiology. The authors conclude that prompt recognition, exclusion of infection, anti-inflammatory treatment, and pharmacovigilance reporting are critical. They suggest that meticulous vial preparation, avoidance of agitation, and consideration of pre-filled syringe (PFS) formulations may help mitigate risk, noting that real-world data has previously indicated numerically lower IOI rates with PFS administration compared to vial-drawn methods.