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An emerging approach that uses aqueous chlorhexidine to prevent infections after intravitreal injections to deliver drugs into the eye is as effective as the long prevailing method that uses povidone iodine, a retrospective, single-center study of more than 300,000 injections has found.

The study “adds to my comfort,” for using aqueous chlorhexidine with intravitreal injections, Sunir Garg, MD, co-director of Retina Research at Wills Eye Hospital in Philadelphia, who has published multiple studies evaluating the antisepsis agents, told Medscape Medical News.

Endophthalmitis, an inflammatory infection of the tissues inside the eye, is a rare but devastating complication of intravitreal anti-VEGF injections, often leading to blindness. Previous studies have reported the rate of endophthalmitis after intravitreal anti-VEGF injections ranging from 0.095% (1 in 1050) to 0.0053% (1 in 19,000).

For the new study, published in Ophthalmology Retina, researchers at the Dell Medical School at The University of Texas at Austin analyzed 302,474 intravitreal injections of anti-VEGF drugs from March 2015 to November 2023. Among 267,190 injections with povidone iodine, the rate of endophthalmitis was 0.022% or 1 in 4592 injections. Among 35,284 injections for which aqueous chlorhexidine was used, the rate of endophthalmitis was 0.014% or 1 in 7057 injections (P = .34).

Topical 5%-10% povidone iodine has long been the go-to method for antisepsis for anti-VEGF injections, “the gold standard,” as lead study author Brandon Bates, MD, and colleagues at The University of Texas at Austin noted. “Although [povidone iodine] demonstrates a consistent record as an effective antiseptic, it is not always well tolerated by patients,” Bates and colleagues wrote.

Povidone iodine can cause significant eye irritation in some patients to the point that they want to discontinue anti-VEGF injections, Garg said. “The problem we run into is that some patients really hate it because it irritates their eye so much; it damages the corneal epithelium,” he said.

Garg led a 2019 study that reported povidone iodine demonstrated greater corneal epitheliopathy than aqueous chlorhexidine. A 2024 study from Israel found 1% povidone iodine caused less damage to the corneal epithelium than the 5% solution.

Bates’ group acknowledged other studies have reported similar effectiveness of aqueous damage. But the new study found no difference in the rate of endophthalmitis between the two agents regarding time to presentation, the number of injections patients had before the infection, or visual acuity when patients got the causative injection, upon diagnosis of their endophthalmitis or at 3-month follow-up.

The study authors acknowledged the retrospective design as a limitation, and some patients who developed endophthalmitis may have sought care from outside providers. While the study involved a single center, 12 physicians participated, each using their own protocols for injections, such as speculum use and where they placed the injection in the eye, but the researchers found no variation in rates of endophthalmitis among clinicians.

The study also analyzed outcomes with prefilled syringes, noting that some studies have shown they have lower endophthalmitis rates compared with injections drawn from vials. During the study data collection period, practice shifted from nonprefilled syringes to prefilled syringes, Bates and colleagues wrote, but when they controlled for syringe status, they found no difference in the rates of endophthalmitis between povidone iodine and aqueous chlorhexidine.

If Cost Were an Issue

The study did not compare the cost of the two approaches, or issues with the production source or shelf life. The study noted that retina practices historically had to contract with compounding pharmacies to get aqueous chlorhexidine until 2021, when the FDA approved a commercial formulation called chlorhexidine gluconate (CHG). Garg, who last year led a study comparing the cost of povidone iodine and commercial CHG, said obtaining aqueous chlorhexidine from a compounding pharmacy “is really expensive,” and that commercial CHG is a cheaper alternative.

Commercial CHG comes in a 450 mL bottle. The label states bottles should be discarded 24 hours after they are opened. Garg’s study found the weekly cost of 5% povidone iodine was $16.73 vs $463.25 for CHG when a new bottle was opened daily.

However, Garg’s study also found that 0.05% CHG divided into 1 mL syringes had a 30-day shelf life when stored at room temperature or refrigerated, dropping the weekly cost to $23.16. “If you can open a bottle and use it within a month in a busy practice like ours, it becomes functionally the same cost as povidone iodine,” Garg said.

But significantly larger studies are needed to provide more definitive data on the effectiveness of the two antisepsis agents, Garg said. “Because the endophthalmitis rate is really rare anyway, on the order of 1 in 5000 injections, a case or two here can really affect the take-home message,” he said. “We’ll definitely need a larger study with hundreds of thousands of injections in each group before we can really tease out what that small difference might be between the two.”

Bates and Garg reported having no relevant financial conflicts of interest.

Richard Mark Kirkner is a medical journalist based in Philadelphia.