Fig. 14.1
S. epidermidis growth in a patient after intravitreal injection of Avastin. (Top) Gram stain at 100× magnification showing gram-positive cocci in groups; (bottom) blood (left) and chocolate (right) agar showing moist colonies without hemolysis (courtesy: Joveeta Joseph, Ph.D.)
In spite of the extensive use of injections, evidence on relative safety with regards to endophthalmitis risk is limited. Rayess et al. studied 183 cases of endophthalmitis from approximately 500,000 anti-VEGF injections (overall rate of 0.036%) [9]. The rates of endophthalmitis were 0.039% in bevacizumab group, 0.035% in ranibizumab group, and 0.035% in aflibercept group (Table 14.1). These differences were not significant. Coagulase-negative Staphylococcus and Streptococcus species were the commonly isolated organisms in all three groups (Table 14.1). Overall, visual outcomes were better in culture-negative than culture-positive cases at 3 months follow-up. Furthermore, culture-positive cases due to coagulase-negative Staphylococcus had better visual outcomes at 3 months than those related to Streptococcus species for all groups.
Molecule | Total injections | Endophthalmitis n | Rate | Common organisms |
|---|---|---|---|---|
Bevacizumab | 153,812 | 60 | 0.039% | Staphylococcus (69.6%) Streptococcus (21.7%) |
Ranibizumab | 309,722 | 109 | 0.035% | Staphylococcus (43.9%) Streptococcus (22%) |
Aflibercept | 40,356 | 14 | 0.035% | Staphylococcus (50%) Streptococcus (50%) |
Endophthalmitis was reported after a mean of approximately 4 days from the day of injection. Mean logMAR visual acuity was 0.74 ± 0.54 (Snellen equivalent: 20/110) before the injection (baseline) and decreased to logMAR 2.27 ± 0.86 (Snellen equivalent: counting fingers, P < 0.001) at diagnosis of endophthalmitis. At 3 months follow-up, the visual acuity improved to logMAR 1.14 ± 1.04 (Snellen equivalent: 20/276, P = 0.005 compared to baseline vision). Although the average visual acuity improved after treatment for endophthalmitis, it was worse than the mean pre-injection visual acuity. Similar results have been shown by a study from the Bascom Palmer Eye Institute at Florida, USA [10].
The risk of endophthalmitis after an intravitreal steroid injection is much higher compared with an anti-VEGF agent injection [11]. A total of 75,249 beneficiaries in a large national US medical claims database representing 406, 380 intravitreal injections were studied. Approximately 400,000 anti-VEGF injections and 19,000 steroid injections were performed. There were 73 cases of endophthalmitis following intravitreal anti-VEGF injections (rate = 0.019% or 1 in 5283 anti-VEGF injections) and 24 cases of endophthalmitis after corticosteroid injections (rate = 0.13% or 1 in 778 steroid injections). After controlling for diagnosis, age, race, and gender, the odds ratio (OR) for occurrence of endophthalmitis was 6.92 (95% confidence interval, 3.54–13.52, P < 0.001) times higher post-corticosteroid injection compared with anti-VEGF injections [11] (Table 14.2).
Table 14.2
Comparison of endophthalmitis rates after anti-VEGF injection and intravitreal steroid injection [11]
Molecule | Total injections | Endophthalmitis | Rate |
|---|---|---|---|
Anti-VEGF | 387,714 | 73 | 0.019% |
Steroid | 18,666 | 24 | 0.13% |
There is a debate on whether the distribution of bevacizumab through compounding pharmacies increases the risk for endophthalmitis compared to the distribution of single-use vials of ranibizumab from the manufacturer. Vander Beek et al. reported their 8-year results (January 2005–December 2012) of intravitreal injections [12]. This analysis included 296,565 bevacizumab injections to 51,116 patients and 87,245 ranibizumab injections to 7496 patients. There were 71 cases of endophthalmitis (49 in the bevacizumab cohort and 22 in the ranibizumab cohort) for an endophthalmitis rate of 0.017% for bevacizumab and 0.025% for ranibizumab. There was no significant association with development of endophthalmitis after a bevacizumab injection compared with ranibizumab (odds ratio, 0.66 [95% CI, 0.39–1.09]; P = 0.11) [12].
Preoperative Prophylaxis
There are currently no randomized clinical trials evaluating the role of prophylactic topical antibiotics in this setting. Many large series have reported that topical antibiotics do not decrease the rate of endophthalmitis. This may be related to changes in the conjunctival flora due to repeated exposure to antibiotics. At this time, povidone-iodine, rather than antibiotics, is preferred for the majority of patients undergoing intravitreal injections [13].
Location of Operating Room vs. Outpatient Clinic
In the 2013 American Society of Retinal Specialists (ASRS) Preferences and Trends (PAT) Survey, over 98% of USA-based specialists reported performing injections in an office setting, compared with only 47% of international specialists [14]. In Germany and other parts of Europe, more number of injections were performed in the operating room (OR) [15]. The endophthalmitis rate has been reported to be 0.12% for office-based injections compared to 0% for OR-based injections [16].
Gloves
Even though no study has been done to analyze the role of gloves, complete aseptic precautions should be taken during intravitreal injections, as is the standard for any other intraocular surgical procedure. Since the vitreous is an avascular protein-rich tissue, even minimal bacterial contamination could lead to serious infection.
Face Mask
Surgical facemask is essential to eliminate any accidental bacterial contamination of the eye from the surgeon’s mouth or nasopharynx [17]. Facemask should be even worn by those assisting in the injection procedure. As per the 2013 ASRS PAT survey, 14% of ophthalmologists reported wearing a mask during intravitreal injections [14]. In a meta-analysis of over 100,000 injections, McCannel found that almost a third of the cases were due to Streptococcus species. This was threefold higher than earlier studies of endophthalmitis after cataract surgery [18]. Streptococcus contamination is associated with poor visual acuity and an increased likelihood of enucleation. Streptococcus viridans are normal commensals of the upper respiratory tract and oral cavity [18, 19]. Since they are uncommonly found as part of the normal conjunctival flora, the contamination could occur from aerosolization [7, 18].
A mask may also offer protection in the event of an inadvertent cough or sneeze. The needle should remain capped until immediately before the injection [5]. Patients should be instructed to minimize talking before or during the procedure.
Povidone-Iodine
Povidone-iodine is a complex of iodide and polyvinylpyrrolidone (PVP), which acts as a reservoir of “free” iodine, and is the active component [20, 21]. The iodine penetrates cell membranes and inactivates intracellular proteins, fatty acids, and nucleotides. It has broad-spectrum antimicrobial activity with negligible bacterial resistance. A recent survey found that over 99% of retinal specialists use povidone-iodine before intraocular injections [22].
In a randomized study, 5% povidone-iodine instilled into the conjunctival sac prior to ophthalmic surgery reduced the number of bacterial colonies by 91%, compared to a 33% reduction in control eyes [23]. In an open-label nonrandomized trial, Speaker and Menikoff found that the incidence of culture-positive endophthalmitis was 0.06% using 5% povidone-iodine, compared to 0.24% using silver protein solution [24]. In contrast, using a 2-min contact time, Ferguson et al. [25] found that 5% povidone-iodine was more effective than 1% povidone-iodine at reducing the number of colony-forming units, particularly in the presence of a heavier initial bacterial load.
Antibiotics
In the ASRS PAT Surveys, the percentage of respondents using pre-injection topical antibiotics has reduced from 40% in 2008 to 27% in 2011. The percentage using postinjection topical antibiotic has also reduced from 86% in 2008 to 62% in 2011. In 2013, 78% of US respondents indicated no use of pre- or postinjection topical antibiotics.
Pre-injection Antibiotics
No studies have shown any substantial benefit of pre-injection topical antibiotics to reduce the risk of endophthalmitis. Using antibiotics just 1–2 h preoperatively conferred no additional benefit over povidone-iodine alone in two studies [26, 27].
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