Intravitreal injections are the most common procedures performed in the United States today: it is estimated that 7 million intravitreal injections are performed yearly,¹ compared to 3.7 million cataract surgical procedures.² Therefore, retina specialists are using prophylactic antiseptic techniques multiple times daily to attempt to thwart the devastating complication of postinjection endophthalmitis (PIE).

Historically, based on a landmark prospective study that demonstrated successful endophthalmitis prophylaxis before cataract surgery,³ retina specialists have typically been using bactericidal povidone-iodine (PI) for PIE prophylaxis. PI is a water-soluble iodophor (iodine-releasing agent); iodine quickly penetrates microorganisms’ cell walls and oxidizes key proteins, nucleotides, and fatty acids, eventually leading to cell death.⁴ Conjunctival application of 5% PI for a period of 30 seconds yields a significant reduction in the bacterial colony–forming units.⁵

Preinjection or postinjection topical antibiotics added to PI antisepsis do not decrease the risk of PIE compared to PI alone.^6-8 Additionally, the use of topical antibiotics is associated with increased bacterial resistance of ocular surface flora.⁹ Therefore, topical antibiotic use for PIE prophylaxis following intravitreal injection is not standard of care.

Although PIE prophylaxis is an essential consideration with each intravitreal injection, and PI seems to be an ideal agent for this purpose, there are patients who have difficulty tolerating side effects of topically administered PI to the eye. Corneal epithelial changes may occur with its use and cause ocular irritation, perhaps due to the glycerine, alkyl phenol ether sulphate, and citric acid (known to be chemical irritants) in the solution, rather than the iodine or polyvinylpyrrolidone (povidone) carrier. In any case, the patient may ask for an alternative antiseptic or be relatively intolerant to PI.

Some patients may claim to be allergic to PI, but allergy to iodine itself does not exist. Iodine cannot be an allergen because it is necessary for thyroid function. Iodine may cause adverse reactions such as “iodide mumps” or iododerma (acneiform eruption), but such reactions are usually related to large amounts of iodine and are not allergic in nature. Allergic reactions to seafood have mistakenly been blamed on the iodine in seafood, but are actually from tropomysin proteins in crustaceans and mollusks and parvalbumin proteins in fish.^10,11  

Povidone is a polymer similar to dextran. There are reports of noniodinated povidones causing contact dermatitis and (rarely) anaphylaxis; “allergy” to PI may theoretically then be due to povidone, but not iodine.¹² A “patch test” of PI could be performed in a patient for whom true povidone allergy needs to be ruled out.

Chlorhexidine (CHX), classically used as a contact lens disinfectant, has been investigated as an alternative for PIE prophylaxis. Chlorhexidine has been shown to induce less discomfort than PI when administered topically to the ocular surface.¹³

CHX destroys bacterial cell wall integrity. Its positive charge is attracted to the negative charge of the phosphate-containing molecules on the bacterial cell wall, followed by penetration through the wall, ultimately resulting in bactericidal effects. On the skin surface, studies have shown that CHX 70% is more effective than 10% PI when used prior to an invasive procedure, perhaps due to the skin being exposed to bodily fluids that could deactivate iodine-containing topical antiseptic agents.¹⁴  

A much lower concentration of CHX solution is used for topical ophthalmic use: 0.05% or 0.1%, ideally prepared according to strict aseptic compounding technique in a laminar airflow hood in a cleanroom or via isolation barrier technology.¹⁵ When applied topically on the eye for PIE prophylaxis, the results have been mixed. In 2016, 2 retrospective case series of patients using topical CHX 0.05% or 0.1% for PIE prophylaxis reported similar (with 4,322 injections)¹⁶ or lower (with 40,535 patients)¹⁷ rates of PIE compared to historic series that used PI. 

A prospective, single-center randomized controlled trial published in 2021 showed no cases of PIE in 100 eyes randomized to either PI 5% or CHX 0.1% undergoing bilateral intravitreal injections; PI demonstrated greater ocular surface discomfort and epitheliopathy. In the study, conjunctival sterilization rates for cultures collected 10 minutes after intravitreal injection indicated that both were similarly effective in reducing conjunctival bacterial colony-forming units.¹⁸ 

Two retrospective cohort studies were reported in 2023. In one, there was no statistically significant difference in PIE when PI 5% was used (13 cases in 32,802 injections) compared to 0.05% CHX (9 cases in 34,893 injections).¹⁹ However, in the other, 0.064% of 31,135 patients in the 0.05% CHX group compared to 0.021% of 139,817 patients in the 10% PI group had PIE, a statistically significant increase in PIE risk in the CHX group, prompting the authors to conclude that CHX is “now a second-line agent in our center.”²⁰ Perhaps the increased rate of PIE in CHX-prepared eyes in the latter study was due to the fact that 10% PI was used, rather than 5% PI?

What are the implications (medical and medicolegal) of the evidence? Should we consider using CHX as PIE prophylaxis in our clinics as either a first-line or a second-line agent? If so, how should it be prepared (0.05%, 0.1%, by the physician or a compounding pharmacy)?

Harry Flynn, MD, professor of ophthalmology and retina service director at Bascom Palmer Eye Institute at University of Miami and Jason Fan, MD, vitreoretinal fellow at Bascom Palmer working with Dr. Flynn, as well as Sunir Garg, MD, FACS, FASRS, professor of ophthalmology at Wills Eye Hospital of Thomas Jefferson University, offer their insights regarding this important issue.

Chlorhexidine vs Povidone Iodine for Postinjection Endophthalmitis Prophylaxis

Jason Fan, MD, PhD, and Harry W. Flynn Jr., MD

The application of topical antiseptic is a crucial step in the prevention of PIE. Previous studies have clearly demonstrated its efficacy, with 1 series showing that PI pretreatment decreases the rate of PIE from 11.9% to 0.0019%.²¹ Multiple recent publications have explored the adoption of topical chlorhexidine (CLX) as an alternative to povidone iodine. However, evidence in the literature has been conflicting, likely due to the retrospective nature of many of the studies, as well as differences in dosage, exposure time, and preparation technique.^18-20,22 

Our institution uses PI exclusively for preinjection antisepsis. The benefits of PI include a short application time for bactericidal activity,⁵ lack of microbial resistance,^23,24 penetration of biofilms,²⁵ efficacy of dilute concentrations,²⁶ and minimal toxicity to the retina.^27,28 Disadvantages include ocular irritation and corneal epitheliopathy. True allergy to PI is rare (0.4% in susceptible patients with a history of atopy), and anaphylaxis after ophthalmic use has never been described.²⁹ 

CLX is a polycationic biguanide with broad-spectrum antimicrobial activity. Although it causes less ocular discomfort and may have a more sustained effect over time due to its ability to bind the outermost layer of mucous membranes,^30,31 it appears to have a delayed onset of action when compared to PI.^32,33 And though some retrospective series have found no difference in the rate of PIE when comparing CLX and PI,^18,19,22 others have found them to be higher with CLX.²⁰ Finally, severe allergy and anaphylaxis, though uncommon, have been reported after ophthalmic use of CLX.^34,35 We therefore consider it a second-line antiseptic for the prevention of PIE. Large-scale prospective randomized clinical trials are needed to determine whether CLX is truly noninferior to PI for the prophylaxis of PIE.

Chlorhexidine Preparations for Injection Antisepsis

Sunir Garg, MD, FACS, FASRS

Retina specialists perform many injections each year, and even a small incidence of endophthalmitis can lead to many affected patients. Reducing the incidence of endophthalmitis is critical.^36,37 Topical antisepsis, most commonly with PI, is key. Most of our patients who receive intravitreal anti-VEGF injections have very little to no discomfort with topical PI, but a smaller percentage of patients have moderate discomfort, and some patients feel like they’re being tortured from the PI. I’ve even had a few patients that have told me they would rather go blind than “feel like that.” I use a number of strategies (not all of which are evidence based) to minimize this, including painting a quadrant with PI; using a minimal amount of PI, flushing the fornices copiously after the injection; giving them nonsteroidals^38-42; and using pledgets as well as subconjunctival lidocaine. Often these strategies help, but for some, it’s not enough. 

Having read an article from 2016 looking at topical chlorhexidine, I have been using this selectively in a few patients.¹⁷ It is a game changer for some people. I and colleagues performed a study that randomized patients receiving bilateral same-day injections to 1 eye receiving aqueous chlorhexidine and the other eye receiving topical iodine. Half the patients had no pain with either drop, but of those that did, the vast majority had significantly less pain in the eye that received aqueous chlorhexidine. Grading their corneal epithelium, the eyes with PI had meaningfully higher amounts of epitheliopathy. We also cultured the fornices before and after, and both agents seemed to sterilize the ocular surface similarly.¹⁸

It is challenging that chlorhexidine needs to be obtained from a compounding pharmacy. This is patient specific and has a beyond use date (BUD) of 28 days, which means patients have to buy a new bottle every time they come in. The average cost is around $100 per bottle, which is not sustainable.

Other groups have used commercially available chlorhexidine.²² My colleague Matt Tennant from Canada uses alcohol-based chlorhexidine.²⁰ His recent studies suggest that it should be a second-line agent due to a higher-than-expected endophthalmitis rate. However, due to corneal toxicity concerns, this group painted only the quadrant and did not copiously douse the surface of the eye. One of my former fellows has done work using commercially available alcohol-free aqueous chlorhexidine.¹⁹ This study showed a PIE rate comparable with PI; however, the BUD on these bottles is 24 hours.

It would be helpful to have stability of commercially available aqueous chlorhexidine that would allow us to more appropriately use a commercially available bottle for 2 weeks or even 4 weeks at a time. Doing so would likely make the cost comparable to PI. Once that occurs, I would likely use it on many more patients. Having a larger number of patients in the literature who have received alcohol-free aqueous chlorhexidine would also be very helpful for me in making aqueous chlorhexidine my primary agent for antisepsis. RP

Michael Colucciello, MD, is a clinical associate at the University of Pennsylvania School of Medicine in Philadelphia, and a retina specialist with the South Jersey Eye Physicians Division of PRISM Vision Group in Moorestown, New Jersey. Dr. Colucciello reports no relevant disclosures.

Jason Fan, MD, PhD, is a vitreoretinal fellow at Bascom Palmer Eye Institute of the University of Miami in Miami, Florida. He reports no relevant disclosures.

Harry W. Flynn Jr., MD, is a professor of ophthalmology and the director of the retina service at the Bascom Palmer Eye Institute of the University of Miami. He reports no relevant disclosures.

Sunir Garg, MD, FACS, FASRS, is a professor of ophthalmology at Wills Eye Hospital of Thomas Jefferson University in Philadelphia. He reports no relevant disclosures.

References

1. Martin DF. Evolution of intravitreal therapy for retinal diseases — from CMV to CNV: the LXXIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 2018;191:xli-lviii. doi:10.1016/j.ajo.2017.12.019

2. Rossi T, Romano MR, Iannetta D, et al. Cataract surgery practice patterns worldwide: a survey. BMJ Open Ophthalmol. 2021;6(1):e000464. doi:10.1136/bmjophth-2020-000464

3. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology. 1991;98(12):1769-1775. doi:10.1016/s0161-6420(91)32052-9

4. Lachapelle J-M, Castel O, Casado AF, et al. Antiseptics in the era of bacterial resistance: a focus on povidone iodine. Clin Pract. 2013;10(5):579-592. doi:10.2217/cpr.13.50.

5. Friedman DA, Mason JO 3rd, Emond T, McGwin G Jr. Povidone-iodine contact time and lid speculum use during intravitreal injection. Retina. 2013;33(5):975-981. doi:10.1097/IAE.0b013e3182877585

6. Bhatt SS, Stepien KE, Joshi K. Prophylactic antibiotic use after intravitreal injection: effect on endophthalmitis rate. Retina. 2011;31(10):2032-2036. doi:10.1097/IAE.0b013e31820f4b4f

7. Moss JM, Sanislo SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology. 2009;116(8):1498-1501. doi:10.1016/j.ophtha.2009.02.024

8. Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC. Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012;119(8):1609-1614. doi:10.1016/j.ophtha.2012.02.014

9. Kim SJ, Toma HS. Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections. Ophthalmology. 2011;118(7):1358-1363. doi:10.1016/j.ophtha.2010.12.014

10. Puchalski AR, Chopra IJ. Radioiodine treatment of differentiated thyroid cancer despite history of 'iodine allergy.' Endocrinol Diabetes Metab Case Rep. 2014;2014:130084. doi:10.1530/EDM-13-0084

11. Schabelman E, Witting M. The relationship of radiocontrast, iodine, and seafood allergies: a medical myth exposed. J Emerg Med. 2010;39(5):701-707. doi:10.1016/j.jemermed.2009.10.014

12. van Ketel WG, van den Berg WH. Sensitization to povidone-iodine. Dermatol Clin. 1990;8(1):107-109.

13. Oakley C, Allen P, Hooshmand J, Vote BJT. Pain and antisepsis after ocular administration of povidone-iodine versus chlorhexidine. Retina. 2018;38(10):2064-2066. doi:10.1097/IAE.0000000000001800

14. Darouiche RO, Wall MJ Jr, Itani KM, et al. Chlorhexidine-alcohol vs povidone-iodine for surgical-site antisepsis. N Engl J Med. 2010;362(1):18-26. doi:10.1056/NEJMoa0810988

15. Allen LV. Chlorhexidine 0.04% ophthalmic solution. US Pharm. 2015; 40(6):53-54.

16. Oakley CL, Vote BJ. Aqueous chlorhexidine (0.1%) is an effective alternative to povidone-iodine for intravitreal injection prophylaxis. Acta Ophthalmol. 2016;94(8):808-809. doi:10.1111/aos.12981

17. Merani R, McPherson ZE, Luckie AP, et al. Aqueous chlorhexidine for intravitreal injection antisepsis: a case series and review of the literature. Ophthalmology. 2016;123(12):2588-2594. doi:10.1016/j.ophtha.2016.08.022

18. Ali FS, Jenkins TL. Boparai RS, et al. Aqueous chlorhexidine compared with povidone-iodine as ocular antisepsis before intravitreal injection: a randomized clinical trial. Ophthalmol Retina. 2021;5(8):788-796. doi:10.1016/j.oret.2020.11.008

19. Ton NS, Goncharov V, Zapata I, Adam MK. Endophthalmitis after anti-VEGF intravitreal injections with aqueous chlorhexidine vs povidone-Iodine as ocular antiseptics. Ophthalmol Retina. Published online December 18, 2023. doi:10.1016/j.oret.2023.12.004

20. Mishra AV, Tong CM, Faes L, et al. Comparison of endophthalmitis rates after alcohol-based chlorhexidine and povidone-iodone antisepsis for intravitreal injection. Ophthalmol Retina. 2024;8(1):18-24. doi:10.1016/j.oret.2023.08.007

21. Modjtahedi BS, van Zyl T, Pandya HK, Leonard RE 2nd, Eliott D. Endophthalmitis after intravitreal injections in patients with self-reported iodine allergy. Am J Ophthalmol. 2016;170:68-74. doi:10.1016/j.ajo.2016.07.010

22. Stephenson KA, Merkur A, Kirker A, Albiani D, Pakzad-Vaezi K. Rates of endophthalmitis before and after transition from povidone-iodine to aqueous chlorhexidine asepsis for intravitreal injection. Can J Ophthalmol. Published online February 20, 2024. doi:10.1016/j.jcjo.2024.01.012

23. Houang ET, Gilmore OJ, Reid C, Shaw EJ. Absence of bacterial resistance to povidone iodine. J Clin Pathol. 1976;29(8):752-755. doi:10.1136/jcp.29.8.752

24. Hsu J, Gerstenblith AT, Garg SJ, Vander JF. Conjunctival flora antibiotic resistance patterns after serial intravitreal injections without postinjection topical antibiotics. Am J Ophthalmol. 2014;157(3):514-518. doi:10.1016/j.ajo.2013.10.003

25. Johani K, Malone M, Jensen SO, et al. Evaluation of short exposure times of antimicrobial wound solutions against microbial biofilms: from in vitro to in vivo. J Antimicrob Chemother. 2018;73(2):494-502. doi:10.1093/jac/dkx391

26. Berkelman RL, Holland BW, Anderson RL. Increased bactericidal activity of dilute preparations of povidone-iodine solutions. J Clin Microbiol. 1982;15(4):635-639. doi:10.1128/jcm.15.4.635-639.1982

27. Trost LW, Kivilcim M, Peyman GA, Aydin E, Kazi AA. The effect of intravitreally injected povidone-iodine on Staphylococcus epidermidis in rabbit eyes. J Ocul Pharmacol Ther. 2007;23(1):70-77. doi:10.1089/jop.2006.0076

28. Whitacre MM, Crockett RS. Tolerance of intravitreal povidone-iodine in rabbit eyes. Curr Eye Res. 1990;9(8):725-732. doi:10.3109/02713689008999567

29. Hinkle JW, Wykoff CC, Lim JI, et al. "Iodine allergy" and the use of povidone iodine for endophthalmitis prophylaxis. J Vitreoretin Dis. 2019;4(1):65-68. doi:10.1177/2474126419865991

30. Romano V, Ferrara M, Gatti F, et al. Topical antiseptics in minimizing ocular surface bacterial load before ophthalmic surgery: a randomized controlled trial. Am J Ophthalmol. 2024;261:165-175. doi:10.1016/j.ajo.2024.01.007

31. Anderson MJ, Horn ME, Lin YC, Parks PJ, Peterson ML. Efficacy of concurrent application of chlorhexidine gluconate and povidone iodine against six nosocomial pathogens. Am J Infect Control. 2010;38(10):826-831. doi:10.1016/j.ajic.2010.06.022

32. Abdeyazdan Z, Majidipour N, Zargham-Boroujeni A. Comparison of the effects of povidone-iodine and chlorhexidine solutions on skin bacterial flora among hospitalized infants. J Educ Health Promot. 2014;3:16. doi:10.4103/2277-9531.127596

33. Koburger T, Hübner NO, Braun M, Siebert J, Kramer A. Standardized comparison of antiseptic efficacy of triclosan, PVP-iodine, octenidine dihydrochloride, polyhexanide and chlorhexidine digluconate. J Antimicrob Chemother. 2010;65(8):1712-1719. doi:10.1093/jac/dkq212

34. Okuda T, Funasaka M, Arimitsu M, et al. Anaphylactic shock by ophthalmic wash solution containing chlorhexidine. Article in Japanese. Masui. 1994;43(9):1352-1355.

35. Opstrup MS, Jemec GBE, Garvey LH. Chlorhexidine allergy: on the rise and often overlooked. Curr Allergy Asthma Rep. 2019;19(5):23. doi:10.1007/s11882-019-0858-2

36. Pancholy M, Storey PP, Levin HJ, et al. Endophthalmitis following intravitreal anti–vascular endothelial growth factor therapy: changes in incidence and outcomes over a 9-year period. Curr Eye Res. 2021;46(9):1370-1377. doi:10.1080/02713683.2021.1874023

37. Writing committee for the Post-Injection Endophthalmitis Study Group, Patel SN, Tang PH, et al. The influence of universal face mask use on endophthalmitis risk after intravitreal anti–vascular endothelial growth factor injections [published correction appears in Ophthalmology. 2022;129(8):962]. Ophthalmology. 2021;128(11):1620-1626. doi:10.1016/j.ophtha.2021.05.010

38. Makri OE, Tsapardoni FN, Pagoulatos DD, Pharmakakis N, Georgakopoulos CD. Diclofenac for pain associated with intravitreal injections: a prospective, randomized, placebo-controlled study. Clin Exp Ophthalmol. 2017;45(9):867-874. doi:10.1111/ceo.12988

39. Georgakopoulos CD, Tsapardoni F, Makri OE. Effect of bromfenac on pain related to intravitreal injections: a randomized crossover study. Retina. 2017;37(2):388-395. doi:10.1097/IAE.0000000000001137. PMID: 27442130.

40. Makri OE, Tsapardoni FN, Plotas P, Aretha D, Georgakopoulos CD. Analgesic effect of topical nepafenac 0.1% on pain related to intravitreal injections: a randomized crossover study. Curr Eye Res. 2018;43(8):1061-1064. doi:10.1080/02713683.2018.1461908

41. Georgakopoulos CD, Plotas P, Kagkelaris K, Tsapardoni F, Makri OE. Analgesic effect of a single drop of nepafenac 0.3% on pain associated with intravitreal injections: a randomized clinical trial. J Ocul Pharmacol Ther. 2019;35(3):168-173. doi:10.1089/jop.2018.0113

42. Shtayer C, Lily Okrent Smolar A, Elmalak M, Abayev L, Grzybowski A, Moisseiev E. Post-intravitreal injection pain reduction using topical NSAIDS: a comparative study. Eur J Ophthalmol. Published online September 10, 2023. doi:10.1177/11206721231201176