Intravitreal Injections and Endophthalmitis

Stephen J. Kim, MD

Disclosures

Int Ophthalmol Clin. 2015;55(2):1-10. 

In This Article

Background

Intravitreal (IVT) injections are the fastest growing procedure in ophthalmology and their expanding use represents one of the most dynamic areas of innovation over the past decade in the treatment of eye disease. IVT drug delivery considerably minimizes systemic exposure and directly bypasses the eye's natural barriers allowing for intraocular levels of drug not obtainable with systemic or even topical administration.[1] Consequently, the number of injections performed in the United States, estimated from Medicare procedure codes, rose from <3000 per year in 1999 to >1 million in 2008. Taking into account the aging population and expanding indications, the number of IVT injections may reach nearly 6 million in 2016.[2]

The rapid growth in IVT injections has resulted from the introduction of novel drug therapies. In 2004, only 2 agents were specifically approved by the United States Food and Drug Administration for IVT delivery: fomivirsen for cytomegalovirus retinitis in association with acquired immune deficiency syndrome (and since removed from the US market) and pegaptanib for the treatment of neovascular age-related macular degeneration (AMD). By the end of 2014, there were 6 additional agents approved for IVT delivery: (1) ranibizumab for the treatment of neovascular AMD, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO); (2) triamcinolone acetonide for the treatment of sympathetic ophthalmia and uveitis; (3) dexamethasone IVT implant for the treatment of RVO, noninfectious uveitis affecting the posterior segment, and DME; (4) aflibercept for the treatment of AMD, RVO, and DME; (5) ocriplasmin for the treatment of vitreomacular traction; and (6) fluocinolone acetonide IVT implant for the treatment of DME. In addition, bevacizumab is commonly used off-label for the treatment of AMD, RVO, and DME. Several other drug classes are routinely compounded for IVT delivery including antibiotics, antiviral medications, and methotrexate. Because of continued innovation and drug development, additional agents will likely be approved for IVT delivery in the near future.

Cataract formation, elevated eye pressure, inflammation, and retinal detachment can be serious complications after IVT injection, but endophthalmitis remains the most feared complication because of its rapid course and potential for severe vision loss (Fig. 1).[3] Its reported incidence after IVT injection ranges from 0.02% to 0.2%, and may depend in part on the specific drug and/or delivery device administered.[4] For example, corticosteroids possess potent anti-inflammatory properties that may actively suppress host immune responses that would normally defend against inoculated pathogens into the vitreous. In addition, commercially available formulations of triamcinolone acetonide are suspensions that typically are injected with bigger gauge needles (to prevent obstruction) in larger volume (0.1 vs. 0.05 mL) than anti-VEGF agents, which may result in greater vitreous reflux and/or incarceration at the time of injection. Taken together, these factors could plausibly explain an increased rate of endophthalmitis with corticosteroids when compared with other agents. In support of this, the earlier literature suggests a much higher rate of endophthalmitis after IVT injection of triamcinolone (nearly 1%), but more contemporary studies report rates approximating those seen with other anti-VEGF agents.[5–7] The large volume of IVT injections performed today has only been a recent phenomenon and improving technique and provider experience may explain a declining incidence. Furthermore, sterile endophthalmitis can result from injection of triamcinolone (with or without preservatives) that may be clinically indistinguishable from infectious endophthalmitis. Nonetheless, it is prudent to be aware of the potentially higher risk for endophthalmitis after injection of corticosteroids.

Figure 1.

Composite photograph of a patient presenting 7 days after intravitreal injection of bevacizumab. A slightly hemorrhagic layered hypopyon (A) is present with fibrin in the anterior chamber (B). Retroillumination demonstrates a yellowish reflex (C) due to dense vitreous opacities, which are demonstrated on B-scan ultrasound (D).

Although most recent large series report rates of endophthalmitis after IVT injection of ≤0.05% (1/2000), the cumulative risk of endophthalmitis per treated patient is far more significant as many inflammatory and retinovascular conditions require long-term serial injections. As an example, the cumulative risk of endophthalmitis per patient after 2 years of treatment in MARINA approached 1%.[8] Furthermore, several recent outbreaks of endophthalmitis have occurred in cities across the United States due to compounded bevacizumab and triamcinolone, which has raised further safety concerns regarding this procedure. The published literature reflects this growing concern. A search of PubMed reveals over 400 articles related to this topic since 2004 and less than half this number in all the preceding years before. With the rapid increase in injections, this subject merits further review and summative insights on best practice.

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