Diabetic Retinopathy Clinical Research Network The Importance of Using Povidone-Iodine and Elimination of Topical Antibiotics for Intravitreous Injections: Update from the DRCR.net 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, Department of Health and Human Services; EY14231 and EY018817 

Financial Disclosure DRCR.net: Principle Investigator, research funds Allergan: Advisory Board No relevant financial relationships for this presentation.

Background DRCR.net has previously reported low rates of endophthalmitis via a protocol requiring topical povidone-iodine, a sterile lid speculum, and topical anesthetic, but not requiring topical antibiotics, sterile gloves, or a sterile drape1,2 A total of 24,065 intravitreous injections have now been administered to 2,598 eyes across DRCR.net trials. Bhavsar AR, Googe JM, Jr., Stockdale CR, et al. Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinolone clinical trials. Arch Ophthalmol. 2009;127(12):1581-3. Bhavsar AR, Stockdale CR, Ferris FL III, et al. Update on Risk of Endophthalmitis After Intravitreal Drug Injections and Potential Impact of Elimination of Topical Antibiotics. Arch Ophthalmol. 2012;130(6):809-810.

Purpose Update of a non-randomized comparison of endophthalmitis rates after intravitreal injection with and without use of topical antibiotics in six DRCR.net Trials: Phase II Bevacizumab for DME (Protocol H) Laser-Ranibizumab-Triamcinolone for DME (Protocol I) Laser-Ranibizumab-Triamcinolone for DME + PRP (Protocol J) Intravitreal Ranibizumab vs Saline for VH from PDR (Protocol N) Prompt PRP vs Ranibizumab+Deferred PRP for PDR (Protocol S) Aflibercept, Bevacizumab and Ranibizumab for DME (Protocol T) Treatment for CI-DME with Very Good VA Study (Protocol V) A new look at development of endophthalmitis without use of povidone-iodine

Standardized DRCR.net Injection Procedure Requires application of topical anesthetic drops or gel (sub-conjunctival injection discouraged) Requires use of a sterile eyelid speculum Requires application of topical povidone-iodine to conjunctiva Does not require topical antibiotics prior to, on day of, or after injection Does not require sterile gloves, sterile drape, or face mask Product was required to be drawn up by investigator from single-use vial at time of injection (bevacizumab, ranibizumab, aflibercept, saline)

Pre- and Post-Injection Antibiotic Use Number of Injections (%) No Pre-Injection and No Post-Injection Antibiotics 13608 (57%) Pre-Injection OR Post-Injection Antibiotics 10,444 (43%) No Povidone Iodine 13 Total 24,065

Evolution of Antibiotic Use in DRCR.net Over Time

Use of Povidone Iodine Use of pre-injection povidone-iodine is strictly required The procedure requires topical povidone-iodine allowed to be present for at least 30 seconds over the injection site, use of a sterile lid speculum, and topical anesthetic Omission of povidone-iodine is a protocol violation For eyes in which povidone-iodine cannot be used (e.g. allergy), study injections should not be given per protocol

Povidone-Iodine Use 24,065 Intravitreal Injections (2,598 eyes) without Povidone-Iodine (protocol violation) 15% of injections without Povidone-iodine developed endophthalmitis

Intravitreal Injections without Povidone-Iodine Povidone-Iodine Use 24,065 Intravitreal Injections (2,598 eyes) 13 injections (2 eyes) without Povidone-Iodine (protocol violation) 100% of eyes developed endophthalmitis

Rates by Antibiotic Use 24,052* Intravitreal Injections (2,596 eyes) 9 Cases of Endophthalmitis 6 (0.06%) With Topical Antibiotics 3 (0.02%) Without Topical Antibiotics p = 0.19 *Excluding injections given without povidone iodine (13 injections in 2 eyes)

Cases of Endophthalmitis Intravitreal Product Injected Culture Results Povidone-Iodine Use Pre-op Antibiotics Post-op Antibiotics 1 Bevacizumab Coagulase negative staphylococcus Yes No 2 Ranibizumab 3 Culture negative 4 No* * Since this event, the DRCR.net has clarified to participating investigators that no study injections may be performed without use of povidone-iodine over the injection site, even as a protocol deviation.

Cases of Endophthalmitis Intravitreal Product Injected Culture Results Povidone-Iodine Use Pre-op Antibiotics Post-op Antibiotics 5 Ranibizumab Streptococcus viridans† Yes No 6 Coagulase negative staphylococcus 7 Saline Culture negative 8 † Scant growth of methicillin resistant staphylococcus aureus also was reported.

Cases of Endophthalmitis Intravitreal Product Injected Culture Results Povidone-Iodine Use Pre-op Antibiotics Post-op Antibiotics 9 Ranibizumab Coagulase negative staphylococcus No* No 10 Aflibercept Culture Negative Yes 11 Bevacizumab Staphylococcus epidermis * Against DRCR.net policy, an injection was performed without povidone-iodine due to severe betadine allergic reaction experienced with prior injections (Shur-Clens was used for prep).

Discussion The standardized intravitreal injection protocol in the DRCR.net trials offers an opportunity to evaluate the role of topical antibiotics and povidone-iodine use on the risk of endophthalmitis following intravitreal injection As reported in multiple previous studies, a low rate of post-injection endophthalmitis has occurred in the DRCR.net trials Topical antibiotic use no longer is standard in a majority of injections given as part of Network protocol

Conclusions Not including topical povidone-iodine substantially increases the risk of endophthalmitis Current data suggest that it is extremely unlikely that omitting topical antibiotics prior to, on the day of, or after injection has a moderate or large increase on the risk of endophthalmitis

Thank You!

References Bhavsar AR, Googe JM, Jr., Stockdale CR, et al. Risk of endophthalmitis after intravitreal drug injection when topical antibiotics are not required: the diabetic retinopathy clinical research network laser-ranibizumab-triamcinolone clinical trials. Arch Ophthalmol. 2009;127(12):1581-3. Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards A, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmal. 2007;114(10):1860-7. The Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064-77 e35. Googe J, Brucker AJ, Bressler NM, et al. Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011;31(6):1009-27. Diabetic Retinopathy Clinical Research Network. An Evaluation of Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy. http://drcrnet.jaeb.org/Studies.aspx?RecID=186. Accessed October 25, 2011. Meagan – please update