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Therapeutics | Jan 2024

Preservatives in Multidose Topical Ophthalmic Drops

Recent product recalls emphasize the safety concerns.

The critical need for sterile, topical ophthalmic drops was underscored by recent FDA actions. In October 2023, the agency recalled more than 20 different products owing to bacterial contamination and issued a warning that the use of these drops could lead to partial or complete vision loss.1 Eye drops are integral to the treatment of many ophthalmic diseases. Preservatives in liquid ophthalmic formulations can ward off microbial contamination and significantly prolong the usability of multidose bottles.2 These preservatives enhance product safety, potentially reducing costs and increasing convenience, for example, by allowing medication to be stored at room temperature. This article explores the preservatives commonly found in topical ophthalmic drops, details their mechanisms of action and safety profiles, and examines reasons why a clinician might opt for a preservative-free eye drop.


  • Eye drops often include preservatives to ward off microbial contamination, but these additives can have adverse ocular effects, necessitating the evolution of safer alternatives.
  • The recent recalls by the FDA of multiple eye drop brands owing to contamination highlights the importance of the sterility and effective preservation of eye care products.
  • The market is experiencing a surge in demand for preservative-free eye drops driven by a desire to avoid preservative-induced ocular side effects. Innovations include single-use vials and advanced multidose bottles that can enhance user safety.


First-generation ophthalmic preservatives are characterized by broad-spectrum activity and small molecular structure.3

Thimerosal. A mercury-based agent, thimerosal disrupts calcium influx into cells. It exhibits efficacy against gram-positive and gram-negative bacteria, fungi, and, to a lesser extent, Acanthamoeba.3 Thimerosal’s side effects include stinging, corneal staining, infiltrates, and limbal epithelial cell changes attributed to direct toxicity and delayed immune reactions. This led manufacturers to discontinue the use of thimerosal in topical ophthalmic drops.3

Chlorhexidine. This bacteriostatic preservative acts by disrupting cell membranes. It is effective against bacteria, fungi, and Acanthamoeba. Although chlorhexidine does not cause hypersensitivity reactions, it is extremely irritating to the eye, leading manufacturers to phase out its use in ophthalmic drops.3 There is also evidence suggesting bacterial resistance to chlorhexidine.3

Benzalkonium chloride. This preservative is found in about 70% of currently available ophthalmic topical drops. The continued popularity of benzalkonium chloride (BAK) can be attributed to its long shelf-life and effectiveness against various bacteria and fungi.4 As a cationic surfactant, BAK disrupts outer membranes, reduces ocular surface tension, and inhibits DNA synthesis.4 Its toxicity varies according to its concentration and the frequency and duration of use. The instillation of BAK-containing drops should not exceed four times daily, especially if the duration of treatment is prolonged.5 Exposure to BAK can cause corneal cell apoptosis, leading to symptoms such as redness, inflammation, discomfort, foreign body sensation, and dryness.4,5


Modern preservatives in ophthalmology typically feature high–molecular-weight molecules, offering both a robust safety profile and broad-spectrum activity against microorganisms. Their larger size is advantageous, particularly in the context of contact lens use, as it reduces the likelihood of absorption into the lenses.6

Polyhexamethylene biguanide. Biguanides, with their high molecular weight, disrupt DNA function, leading to cell death.3 The acronym PHMB is often used to refer to a group of biguanide-based preservatives that includes variants such as polyaminopropyl biguanide and alexidine.3 These preservatives are effective against a wide range of bacteria, such as Pseudomonas aeruginosa and Staphylococcus aureus. PHMB-based preservatives typically are not effective against Acanthamoeba, fungi, or yeasts.3 The correlation between PHMB and corneal toxicity varies by formulation and study, with some indicating potential toxicity.

Polyquaternium-1. This bactericidal preservative is based on quaternary ammonium. Polyquaternium-1 (PQ-1; Polyquad, Alcon) acts by denaturing microbial cell wall proteins.2,3 Like PHMB, PQ-1 is less effective against Acanthamoeba, fungi, and yeasts. This preservative is often used in conjunction with agents such as myristamidopropyl dimethylamine (Aldox, Alcon) that target fungi and amoebae. PQ-1 is generally safe but has been linked to mild corneal toxicity.7

Stabilized oxychloro complex. This preservative acts as an oxidating agent. Stabilized oxychloro complex (SOC; Purite, Allergan) may exert its antimicrobial properties by disrupting protein synthesis or intracellular lipids.2,7 SOC also acts against bacterial and fungal species. It is only a mild ocular irritant, and studies suggest that SOC is well tolerated when administered frequently.7

Sodium perborate. When mixed with water, sodium perborate (GenAqua, Alcon) transforms into water and hydrogen peroxide.2 The resulting hydrogen peroxide oxidizes microbes by altering the permeability of their cell membranes.3 Sodium is a mild ocular irritant but is generally well tolerated.7


Spurred on by the recognition of preservatives’ potential ocular side effects, the trend toward preservative-free ocular drops has gained momentum in recent years.8 One alternative is single-use vials, which are disposed of immediately after application and thus eliminate the need for preservatives. Multidose preservative-free drops are another option, which was recently introduced. Innovative cap designs help avert microbial contamination. Patient feedback suggests both of these delivery systems are user-friendly and efficient but that they prefer multidose bottles because they can be recycled.8


Each year, approximately 30,000 cases of microbial keratitis occur in the United States and require ophthalmic drops for treatment.9 A nuanced understanding of patient characteristics, medical conditions, and treatment adherence is pivotal to the selection of topical therapy. Patients with a history of poor adherence to prescribed medical therapy are at increased risk of drug contamination.

Preserved drops are recommended if dosing will be infrequent (< four times daily) or therapy will be short term.5 Preservative-free options may be preferable for the treatment of chronic conditions such as dry eye disease and glaucoma.

Current limitations in nonpreserved options suggest that preserved drops will remain a mainstay in eye care for the foreseeable future.

1. Food and Drug Administration. FDA warns consumers not to purchase or use certain eye drops from several major brands due to risk of eye infection. Updated November 15, 2023. Accessed November 20, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-consumers-not-purchase-or-use-certain-eye-drops-several-major-brands-due-risk-eye#eyedrops

2. Steven DW, Alaghband P, Lim KS. Preservatives in glaucoma medication. Br J Ophthalmol. 2018;102(10):1497-1503.

3. Bradley CS, Sicks LA, Pucker AD. Common ophthalmic preservatives in soft contact lens care products: benefits, complications, and a comparison to non-preserved solutions. Clin Optom (Auckl). 2021;13:271-285.

4. Coroi MC, Bungau S, Tit M. Preservatives from the eye drops and the ocular surface. Rom J Ophthalmol. 2015;59(1):2-5.

5. Pucker AD. A review of the compatibility of topical artificial tears and rewetting drops with contact lenses. Cont Lens Anterior Eye. 2020;43(5):426-432.

6. Pucker AD, McGwin G, Franklin QX, Nattis A, Lievens C. Application of Systane Complete for the treatment of contact lens discomfort. Cont Lens Anterior Eye. 2021;44(5):101399.

7. Kaur IP, Lal S, Rana C, Kakkar S, Singh H. Ocular preservatives: associated risks and newer options. Cutan Ocul Toxicol. 2009;28(3):93-103.

8. Pucker AD, Lievens C, McGwin G Jr, Franklin QX, Logan A, Wolfe GS. Quality of life in digital device users who are treated with Systane Hydration PF. Clin Optom (Auckl). 2023;15:45-54.

9. Wilhelmus KR. Review of clinical experience with microbial keratitis associated with contact lenses. CLAO J. 1987;13(4):211-214.

Andrew D. Pucker, OD, PhD
  • Senior Director, Clinical and Medical Science, Lexitas Pharma Services
  • andrew.pucker@lexitas.com
  • Financial disclosure: Consultant (Alcon Research, CooperVision, HanAll Biopharma, Kala Pharmaceuticals, Lexitas Pharma Services, Nevakar, Optikal Care); Employee (Lexitas); Research funding (Alcon, Art Optical, ScienceBased Health)
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