Abstract
Objective
To report the incidence of endophthalmitis following intravitreal injection using a standardized procedure.
Methods
Intravitreal injections of preservative-free triamcinolone acetonide or ranibizumab were performed in two Diabetic Retinopathy Clinical Research Network prospective, randomized clinical trials. The standardized procedure for these trials requires topical povidone-iodine, use of a sterile lid speculum and topical anesthetic, but does not require the use of topical antibiotics prior to, on the day of, or after injection.
Results
As of February 23, 2009, 3226 intravitreal injections of ranibizumab and 612 injections of preservative-free triamcinolone have been administered. Topical antibiotics were given on the day of injection in 361(9%), for several days after injection in 813(21%), on the day of injection and after injection in 1388(36%), and neither on the day of injection nor after injection in 1276(33%). Three cases of culture positive endophthalmitis occurred following ranibizumab injections (0.09%) and no cases occurred following triamcinolone injections. In all three endophthalmitis cases, topical antibiotics were given for several days after the injection but not prior to injection.
Conclusions
The results suggest that a low rate of endophthalmitis can be achieved using a protocol that includes topical povidone-iodine, use of a sterile lid speculum and topical anesthetic but does not require topical antibiotics.
Introduction
Intravitreal injections have become an increasingly common route of administering medications in the treatment of posterior segment disease. Endophthalmitis is one of the most serious complications of intravitreal injection of medication with a reported incidence per injection ranging from 0.02% to 1.9%.1–5 Optimum management of the ocular surface prior to, during, and after intravitreal injections remains controversial.3, 6 Topical povidone-iodine is the only preoperative substance proven in a randomized clinical trial to reduce the risk of endophthalmitis after intraocular surgery.7 To our knowledge, there have not been adequate studies evaluating the role of topical antibiotics; thus, uncertainty still exists as to the efficacy of topical antibiotics in preventing post-injection endophthalmitis. Although combined use of topical povidone-iodine and antibiotics may have a synergistic effect in reducing the preoperative culture positive rate of the conjunctival surface,8, 9 there is little evidence that we have identified to suggest that topical antibiotics reduce the rate of endophthalmitis in humans. In addition, there is little evidence that the pharmacokinetics of the topical regimens provided would result in adequate antibiotic levels which would be expected to have a protective effect.10–13 In spite of this, topical antibiotics prior to the intravitreal injection have been required in several recent clinical trial protocols.14–16 Furthermore, recent surveys have suggested that 40% of retina specialists use topical antibiotics prior to anti-VEGF intravitreal injections, and 86% use topical antibiotics after anti-VEGF intravitreal injections.17
Previous studies have indicated a low rate of endophthalmitis following preservative-free intravitreal triamcinolone injections where prolonged topical antibiotic use for multiple days prior to the injection was not required, and antibiotics were required only on the day of and after the injection.18, 19 We report the endophthalmitis rate in the Diabetic Retinopathy Clinical Research Network (DRCR.net) Laser-Ranibizumab-Triamcinolone (LRT) trials in which topical antibiotics prior to, on the day of injection, and use for several days after the injection were not required but could be administered at the discretion of the investigator.
Methods
The ongoing DRCR.net LRT trials utilize a standardized protocol for the ocular surface preparation and intravitreal injection of ranibizumab or preservative-free triamcinolone. Topical antibiotics may be administered prior to the day of injection or pre-injection on the day of injection at the discretion of the investigator, although this is not required. A drop of topical anesthetic is applied to the eye. Two or three drops of 5% povidone-iodine may be placed in the lower fornix. The use of povidone-iodine lid scrubs is also optional. While the use of additional topical anesthetic on cotton tip applicators is optional, subconjunctival anesthetic and lidocaine gel or other viscous anesthetic is not permitted as part of the protocol. A cotton tipped applicator soaked in 5% povidone-iodine or a 10% povidone-iodine swab is placed directly over the intended injection site or alternatively a 5% povidone-iodine forced stream flush from an angiocatheter is employed. In all cases, a sterile eyelid speculum is used to stabilize the eyelids. Preservative-free triamcinolone acetonide or ranibizumab is injected through the pars plana. Although it is not required, at the discretion of the investigator topical antibiotics may be provided and used for several days post-injection.
Diagnosis of endophthalmitis was based on investigator’s judgment, and a culture was required prior to initiating antibiotic treatment for presumed endophthalmitis. The 95% confidence interval for the incidence of endophthalmitis per injection was computed based on the binomial distribution under the assumption of independence.
Results
As of February 23, 2009, 3838 intravitreal injections in 733 eyes have been administered by 124 physicians as part of the DRCRnet LRT trials. This includes 612 injections of preservative-free triamcinolone in 272 eyes and 3226 injections of ranibizumab in 461 eyes. Topical antibiotics were given on the day of injection but not after the injection in 361 (9%), for several days after injection but not on the day of injection in 813 (21%), both on the day of and for several days after the injection in 1388 (36%), and neither the day of nor after the injection in 1276 (33%) (see table 1). Topical antibiotics were also given for several days prior to the day of injection in 10 of the cases in which topical antibiotics were given both on the day of and for several days after the injection.
Table 1.
Antibiotic regimens used in the laser-ranibizumab-triamcinolone trials
| Number of Injections (%) | Post-Injection Antibiotics | No Post-Injection Antibiotics |
|---|---|---|
| Pre-Injection Antibiotic Eye Drops | 1,388 (36)* | 361(9) |
| No Pre-Injection Antibiotics | 813 (21) | 1,276 (33) |
Includes 10 cases in which antibiotic eye drops also were given at home prior to injection in addition to pre-injection on the day of injection and after injection.
Among the 3226 ranibizumab injections in 461 eyes, there have been three cases of culture positive endophthalmitis (0.09%, 95% confidence interval [CI] 0.02% to 0.27%) in 3 eyes (0.65%, 95% CI 0.13% to 1.89%). In all three cases, antibiotics were not given prior to the injection but were given for several days post-injection. The three cases occurred at two of 60 clinical centers and were from two of 11 lots of ranibizumab. The two cases that occurred at the same clinical center were from different investigators using different lots of ranibizumab. An additional 681 injections were given without incident using the same lot from which two of the three cases occurred. One case occurred after a subject’s first injection and two cases occurred after a subject’s second injection. The bacteria that were isolated by cultures included heavy growth of streptococcus viridans and scant growth of methicillin resistant staphylococcus aureus (MRSA) in case 1 and coagulase negative staphylococcus in cases 2 and 3. Among the 612 triamcinolone injections, there have been no cases of culture positive endophthalmitis. In addition, there have been no cases of culture negative endophthalmitis from either type of injection.
Discussion
The protocol for the injection procedure in the DRCR.net Laser-Ranibizumab-Triamcinolone trials offers an opportunity to evaluate the role of topical antibiotics for potentially reducing the risk of endophthalmitis following intravitreal injection. The standardized injection protocol required the application of topical povidone-iodine to the conjunctival surface as well as the use of a sterile eyelid speculum. The use of topical antiobiotics was optional. Medication was administered from both prefilled syringes (triamcinolone) as well as from syringes which required filling by the investigator from a separate vial at the time of injection (ranibizumab). As in multiple previous studies, a low rate of post-injection endophthalmitis occurred.
Although several retrospective studies have reported relatively low rates of endophthalmitis following intravitreal injections1–3, this report presents data from two large, multicenter, prospective, randomized clinical trials that used a standardized injection protocol that did not require the use of topical antibiotics.
Expanding from a previous DRCR.net intravitreal study that suggested that omitting several days of pre-injection topical antibiotics did not increase the risk of endophthalmitis,20 these current studies suggest it is extremely unlikely that omitting topical antibiotics on the day of or after injection has a moderate or large increase on the risk of endophthalmitis. However, because of the very low incidence of endophthalmitis, no study can rule out the possibility that topical antibiotics might have a minor effect on the risk of endophthalmitis. Therefore, the results of this study do not prove that topical antibiotics have no effect on the risk of endophthalmitis following intravitreal injection.
The results herein indicate that a low rate of endophthalmitis can be achieved using an intravitreal injection protocol that does include topical povidone-iodine, the use of a lid speculum and topical anesthetic but does not require topical antibiotic prophylaxis prior to, on the day of or after the injection.
Acknowledgments
Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services EY14231, EY14269, EY14229.
Footnotes
The funding organization participated in oversight of the conduct of the study and review of the manuscript but not directly in the design of the study, the conduct of the study, data collection, data management, data analysis, interpretation of the data, or preparation of the manuscript.
Allergan, Inc. provided the triamcinolone and Genentech, Inc. provided the ranibizumab. Both companies provided funds for part of the clinical care costs of the DRCR.net Laser-Ranibizumab-Triamcinolone protocols. Allergan, Inc. also has provided unrestricted funds to DRCR.net for its discretionary use. As per the DRCR.net Industry Collaboration Guidelines (available at www.drcr.net), the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.
A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net
An address for reprints is not provided.
The studies are listed on www.clinicaltrials.gov. Identifiers: NCT00444600, NCT00445003.
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