Intravitreal injection of anti-vascular endothelial growth factor, or VEGF, agents has become the standard of care for the treatment of a number of retinal diseases, including exudative macular degeneration; retinal vein occlusions; diabetic macular edema; proliferative diabetic retinopathy; and neovascular glaucoma. The most serious complication from intravitreal injection of anti-VEGF agents is endophthalmitis. Although rare, endophthalmitis can result in devastating loss of vision or loss of the eye. 

Biennial Medicare claims for intravitreal injections of pharmacological treatments.

Although the incidence is low, endophthalmitis most commonly occurs as a complication following cataract surgery due to the large number of cataract surgeries performed annually. The incidence of post-cataract endophthalmitis varies between 0.09 percent and 0.33 percent.¹ Recently, the number of cases of endophthalmitis occurring as a result of intravitreal anti-VEGF injections has increased, largely due to the dramatic increase in the number of injections performed annually. Between 1997 and 2001, fewer than 5,000 intravitreal injections were performed annually, while more than 800,000 were performed in 2007 (See table).² The number of injections has increased so much that intravitreal injection is now second to only cataract surgery as the most common treatment procedure across most tertiary centers in Europe and the United States.³

Several groups have reported their experience regarding the incidence of endophthalmitis after intravitreal injection and found rates of endoph-thalmitis ranging between 1/1,300 to 1/10,000; however, these studies were limited by their retrospective nature and relatively small sample size.^4-8 Recently, a large, single-center, consecutive case series with a prospective surveillance log found the incidence of clinically suspected endophthalmitis to be approximately 1/1,500.⁹ However, the incidence may indeed be lower than 1/1,500, as the culture-positive rate in the largest study to date was only 34 percent,⁹ in contrast to the 69 percent culture-positive rate in the Endophthalmitis Vitrectomy Study.¹⁰

There are several possible reasons for this lower culture-positive rate. All patients who were felt to have clinically suspected endophthalmitis after intravitreal injection underwent vitreous tap with injection of antibiotics, thus patients who may have had a sterile inflammatory reaction to either bevacizumab or ranibizumab may have been included in this series. Alternatively, patients with post-injection endophthalmitis often underwent in- office vitreous and/or anterior chamber tap only, while many patients in the EVS had a vitreous biopsy with a vitrectomy instrument. The larger vitreous sample may have increased the culture yield.

Patients with endophthalmitis typically present with decreased vision and pain. In a recent series, all cases of intravitreal injection-related endophthalmitis presented with pain, decreased visual acuity and vitritis on average 3.4 days after injection. In addition, 18 of 23 cases (78 percent) had a hypopyon.⁹ However, the presence or absence of pain, vitritis, decreased vision and hypopyon did not distinguish between culture-positive and culture-negative cases, suggesting one should maintain a low threshold to treat presumed infectious endophthalmitis. Fortunately, most cases returned to baseline vision within several months, although a few had significant visual loss. 

Clinicians have looked at a number of risk factors for the development of endophthalmitis following intravitreal anti-VEGF injection. Much attention has been given to topical antibiotic use before, during and after the injection. Studies have failed to show direct evidence that topical antibiotics given prior to the intravitreal injection reduce the risk of endophthalmitis. The best study on topical perioperative drops demonstrated that topical povidone 5% reduced the incidence of endophthalmitis occurring after cataract surgery; extrapolating this data, povidone should be used during the prep for intravitreal injections.¹¹ The evidence concerning the efficacy of topical antibiotic use is conflicting. One study found that compared to topical antibiotic drops started three days prior to eye surgery, 5% povidone-iodine solution as part of the procedural prep resulted in a similar decrease in the number of bacterial colonies and species cultured from the conjunctiva; however, when used together they produced a synergistic effect and yielded the greatest reduction in bacterial colony counts.¹²

In contrast, more recent work suggests that although bacterial colony counts can be reduced by the use of topical antibiotic drops administered several days prior to the procedure, topical antibiotic drops did not appear to reduce colony counts significantly more than topical povidone as part of the prep alone.¹³ Another recent paper from the DRCR.net group found a low rate of endophthalmitis in a protocol that did not use topical antibiotics other than topical povidone as part of the procedure prep.¹⁴ Although the study size was small, this prospective data suggests that the benefit of topical antibiotic use is at best limited. 

The manner in which topical povidone is used is also important. After administration of a topical anesthetic such as proparacaine, povidone should be placed so that it is in direct contact with the conjunctiva prior to administration of any viscous anesthetic gel (if used by the treating physician). If the topical viscous anesthetic is placed onto the conjunctiva before betadine use it acts as a barrier to sterilization.¹⁵ A recent clinical study found no cases of infectious endophthalmitis in a consecutive series of 4,690 patients receiving anti-VEGF agents using topical betadine immediately before and after instillation of 2% topical lidocaine gel anesthesia.¹⁶

The VEGF Inhibition Study In Ocular Neovascularization (VISION) trial suggested the risk of endophthalmitis could be modified by vigilance to an aseptic injection technique. In addition, use of a lid speculum was suggested as a prevention strategy.¹⁷ However, bladed lid speculum use, displacement of the conjunctiva, hemisphere of injection and type of anti-VEGF agent (i.e., bevacizumab vs. ranibizumab) did not affect risk in a large retrospective study.⁹

The most common organisms to cause endophthalmitis after cataract surgery are coagulase-negative Staphylococcus and Staphylococcus aureus, which make up approximately 75 percent of isolated bacteria.¹⁸ Most bacteria originate from the patient’s native flora.¹⁹ The EVS study found that one of the major predictors of visual outcome in patients who developed endophthalmitis was microbial etiology.¹⁰ Cases that were culture-positive for Staph epidermidis had better visual outcomes than cases positive for more virulent organisms such as Streptococcus or gram negative organisms. 

The microbial spectrum seen in cases of endophthalmitis following cataract surgery differs from the microbial spectrum seen following intravitreal injection of anti-VEGF agents. Of note, several studies have shown an increased rate of streptococcal cases following intravitreal injections of anti-VEGF agents. In the EVS study, 9 percent of the culture-positive isolates were Streptococcus species,¹⁰ and another study found 8.2 percent of the culture-positive isolates following clear cornea cataract surgery were Streptococcus species.¹⁸ In contrast, a meta-analysis of endophthalmitis after intravitreal injection of anti-VEGF agents found 30.8 percent of culture-positive isolates to be Streptococcus species.²⁰ The preponderance of Streptococcus endophthalmitis after intravitreal injection was confirmed by two other studies.^9,21

This variation in the microbial spectrum has generated several hypotheses regarding the origin of the organisms. Adult salivary flora is made up of at least 41 percent Streptococcus species^22,23 and aerosolization or droplet spread can serve as potential contaminates in the operative field.^24-28

This method of transmission has been best studied for lumbar puncture. Although the incidence of meningitis after dural puncture is much lower than the incidence of endoph-thalmitis after intravitreal injection, there are several similarities between the procedures: Both involve insertion of a needle into a nutrient-rich body in a non-operating room setting, and both the spinal fluid and the vitreous are immunologically privileged sites.²⁰ Because of the potentially fatal outcome associated with meningitis, risk factors for the development of post-spinal tap meningitis have been extensively studied, especially regarding use of a surgical mask. Two studies found that the absence of a surgical mask was associated with a significant increase in colonies per exposed plate.^27,29 Other studies have shown that there is an increase in colony counts when not wearing a facemask and talking, as opposed to wearing a facemask or not talking.^20,26

Another study concerning meningitis after dural puncture demonstrated an increased risk of bacterial spread during times of concurrent viral upper respiratory tract infection in a health-care provider.²⁵ Furthermore, the authors found a surgical mask was effective in decreasing spread of bacteria during the study.25 Comparisons to intraarticular knee injection have also been made, and studies have shown that failure to wear a facemask resulted in increased infection with alpha-hemolytic Streptococcus organisms.³⁰ Given the support these studies provide for mode of transmission of bacteria via aerosolization or droplet spread, it may be advisable to wear a facemask during the procedure or avoid talking, sneezing, or coughing in order to prevent transmission of upper respiratory tract organisms.^9,20,31

Fortunately, the incidence of end-ophthalmitis after intravitreal injection is low, and most eyes regain lost vision over time. However, some patients have poor outcomes, partly due to organism virulence. Clinicians should maintain a low threshold for treatment of suspected endophthalmitis as pain, vitritis, decreased vision and hypopyon do not appear to differentiate between culture-positive and culture-negative cases.⁹ Povidone-iodine should continue to be the mainstay of endophthalmitis prevention, as peri-procedural use of topical antibiotics, use of lid speculum, hemisphere of injection, and use of bevacizumab versus ranibizumab do not appear to affect risk. Finally, work remains to be done to better reduce the incidence of endophthalmitis following an increasingly common procedure.   REVIEW