Intravitreal administration
Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration, diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.
Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.
Epidemiology
s were proposed over a century ago, however the number performed remained relatively low until the mid 2000s. Until 2001, intravitreal injections were mainly used to treat end-ophthalmitis. The number of intravitreal injections stayed fairly constant, around 4,500 injections per year in the US. The number of injections tripled to 15,000 in 2002, when triamcinolone injections were first used to treat diabetic macular oedema. This use continued to drive an increase to 83,000 injections in 2004. In 2005, bevacizumab and ranibizumab intravitreal injections for the treatment of wet-AMD caused a rise in injections to 252,000. In 2008, over 1 million intravitreal injections were performed. This doubled to 2 million just 3 years later in 2011 when aflibercept became available for the treatment of wet AMD. Intravitreal injections hit an all-time high in 2016, reaching over 5.9 million injections in the US.History
Intravitreal injection was first mentioned in a study in 1911, in which the injection of air was used to repair a detached retina. There were also investigations evaluating intravitreal antibiotics injection using sulfanilamide and penicillin to treat endophthalmitis in the 1940s, yet due to the inconsistency of results and safety concerns, this form of drug delivery was only for experimental use and not applied in patients. It was until 1998, that fomivirsen, the first intravitreal administered medication, was approved by the U.S. Food and Drug Administration.In 2004, when Aiello et al. published the first guidelines for intravitreal injection in the journal Retina, fomivirsen was still the only medication licensed by the FDA for intravitreal injection. At the end of the year, on December 17, the first intravitreal anti-VEGF drug pegaptanib was also licensed by FDA for treatment of wet age-related macular degeneration.
Intravitreal injection has then become more common and a surge in the number of injections performed could be seen. Six extra medications, namely triamcinolone acetonide, ranibizumab, aflibercept, dexamethasone, ocriplasmin and fluocinolone acetonide were approved for this injection by the end of 2014. There are also increasing off-label use of bevacizumab for the management of various ophthalmologic diseases, like AMD, retinal vein occlusion and diabetic macular edema. On top of that, the number of intravitreal injections has escalated from less than 3000 per year in 1999, to an estimation of near 6 million in 2016.
Uses
Intravitreal injection is used to inject a drug into the eye to reduce inflammation, inhibit the growth and development of new blood vessels, or lower the permeability of blood vessels, in turn curing various eye diseases.Disorders/diseases that can be treated with intravitreal injection include:
- Age-related macular degeneration / Macular Degeneration: An eye disorder that slowly destroys sharp, central vision
- Uveitis: Swelling and inflammation within the eyeball
- Retinal vein occlusion: A blockage of the veins that carry blood away from the retina, the back part of your eye, and out of the eye
- Macular edema: Swelling or thickening of the macula due to abnormal fluid accumulation
- * Diabetic macular edema: Poorly controlled diabetes mellitus could lead to diabetic retinopathy, i.e., damages to the retina. The damage to the small blood vessels there causes leakage of fluid
- * Pseudophakic cystoid macular edema
- * Macular edema secondary to retinal vein occlusion
- * Macular edema secondary to uveitis
- Infections, such as endophthalmitis and retinitis
- Noninfectious vitritis
Antimicrobials
s are intravitreally injected to treat eye infections, such as endophthalmitis and retinitis. The medication used depends on the pathogen responsible for the disease.Antibiotics
This type of drug targets on bacterial infection. The first use of intravitreal antibiotics was dated back to experiments in the 1940s, in which penicillin and sulfonamides were used to treat the rabbit endophthalmitis models. Later, more studies proved the beneficial effects of intravitreal antibiotics on acute postoperative endophthalmitis. In the 1970s, Peyman's research on the suggested doses for the medications was published. Intravitreal antibiotics then has gradually become the major treatment to manage bacterial endophthalmitis. Some common antibiotics administered nowadays are vancomycin and ceftazidime.The dosage of antibiotics injected intravitreally is usually low to avoid possible retina toxicity. Some alternative antibiotics have also been tested to replace those that have a higher risk of causing macular toxicity. In light of the raised occurrence of antibiotics resistance, the medications should be chosen and evaluated with the support of bacterial culture and antibiotics sensitivity test results. Sometimes, combinations of different antibiotics may be needed to treat polymicrobial infections, or as an empirical treatment.
Antibiotics, such as moxifloxacin, vancomycin, etc., are used perioperatively and postoperatively as a common method of endophthalmitis prevention in cataract surgery. Researches show such injection of antibiotics is more useful to prevent infection as compared to chemoprophylaxis given topically. However, it has recently been controversial whether it has sufficient efficacy for endophthalmitis prophylaxis, and whether it improves the effectiveness in preventing endophthalmitis by perioperative povidone-iodine when used in combination with the antiseptic.
Antifungals
If the endophthalmitis is suspected to be a fungal infection, antifungals, such as amphotericin B and voriconazole, could be intravitreally injected to treat the disease. Although amphotericin B has a broad spectrum, voriconazole is more commonly used now as it has a higher efficacy and lower toxicity.Antivirals
Since the 1990s, intravitreal antivirals have been used to treat cytomegalovirus retinitis in immunodeficient patients, such as AIDS patients. Some medications that could be used include ganciclovir, foscarnet, and cidofovir. The amount and frequency of the intravitreal agent injected varies among the drug chosen: for example, foscarnet has to be given more frequently than ganciclovir as it has a shorter intravitreal half-life. If the traditional antiviral therapy fails, a combination of these two medications may be injected. On the other hand, antiviral drugs could also be administered for patients with acute retinal necrosis due to varicella-zoster virus retinitis.Anti-VEGF
The most common reason intravitreal injections are used is to administer anti-vascular endothelial growth factor therapies to treat wet age related macular degeneration and diabetic retinopathy. Both of these conditions cause damage to the retina leading to vision loss. There are three widely used Anti-VEGF drugs to treat these conditions: ranibizumab, bevacizumab, and aflibercept. Bevacizumab has not been FDA approved to treat wet AMD, however in the US it is the first line anti-VEGF therapy for over half of ophthalmologists due to its efficacy and drastically lower cost. These three drugs bind to VEGF molecules preventing them from binding to VEGF receptors on the surface of endothelial cells thereby stopping the abnormal angiogenesis that causes wet AMD. All three of these therapies have vastly improved outcomes for sufferers who had limited treatment options prior to their invention but must be administered via intravitreal injection.Vascular endothelial growth factor is a type of protein the body cells produce to stimulate the growth of new blood vessels. Anti-VEGF agents are chemicals that could inhibit these growth factors to reduce or prevent the abnormal growth of blood vessels, which could lead to damage to the eye and vision.
Steroids
Steroids may be administered via intravitreal injection to treat diabetic and vasculo-occlusive macular edema, exudative macular degeneration, pseudophakic cystoid macular edema, and posterior uveitis. Common steroids used to treat these conditions include dexamethasone and triamcinolone acetonide. Steroid implants, such as the dexamethasone implant, are used for long-term treatment of macular edema. Both of these steroid work by modulating inflammatory cytokines.The primary use of the corticosteroids is to reduce the inflammation by inhibiting the inflammatory cytokines. It could be used to treat numerous eye disorders, such as diabetic retinopathy and retinal vein occlusion.
Below are some examples of this type of medication: