An Ophthalmologist’s Guide to Preservatives in Topical Medications
By Marguerite McDonald, MD, FACS
Preservatives are vital to topical ophthalmic solutions. Without them, patients risk exposure to any number of microbial agents, with potentially serious infections the result. But while preservatives effectively prevent infection, they are not without risks of their own.
In this newsletter, and the next two, we’ll examine different types of preservatives used in topical ophthalmic medications, and the benefits and drawbacks, including potential side effects, of each.
Preservatives were required in topical ophthalmic medications beginning in the early 1960s, after severe eye infections were linked to long-term use of eye drops. Theories on the source of those infections included repeated exposure of the medications to ambient air, or germs transmitted through a user’s hand. The findings also identified the most common infectious agents as Staphylococcus aureus coagulase negative and pseudomonas.
The initial class of preservatives was derived from quaternary ammonium compounds, most commonly benzalkonium chloride (BAK). BAK was widely used and effective, but produced numerous side effects, including disruption of the lipid layer of the tear film. Thimerosal, an organomercury compound, also was widely used in a variety of products including antivenins and, somewhat controversially, vaccines, as well as ophthalmic topical medications. Thimerosal is rarely used now due to toxic and/or allergic reactions, particularly neurotoxic reactions, in a significant percentage of patients.
Current preservatives can be classified into four main categories: detergents, oxidants, chelating agents and metabolic inhibitors.
Cetrimonium. Developed after BAK, cetrimonium has been used in artificial tears, but is now used mostly as a softening agent in hair treatments and in preservation of antifungal creams. However, its toxic effects include keratinization and inflammatory infiltrates at the limbus and within the conjunctival stroma and epithelium. It also manifests cell toxicity similar to that of BAK.
Chlorobutanol. Used as an active ingredient in sedatives, chlorobutanol has also been used in artificial tears, and demonstrates extensive antimicrobial activity. However, it has been shown to cause significant keratitis and ocular surface irritation, although the toxic effect from chlorobutanol is slower to manifest in human corneas than that caused by BAK. In addition, human corneal epithelial cells exposed to this preservative display decreased amounts of mitosis and deterioration of overall cell integrity. Another unexpected finding: it does not affect the stability of the lipid layer of the tear film. Its use is limited because it becomes unstable when stored at room temperature for long periods.
Polyquad. This detergent-type preservative, derived from BAK, was developed in the mid-1980s as a preservative for contact lens storage solutions. It was intended to replace BAK, which by the 1980s had been found to become concentrated in contact lens solution. The result of that concentration was that the contact lens could act as a reservoir of preservative, which could be released when placed on the eye. Polyquad does not become concentrated in contact lens solution and has many other properties that distinguish it from BAK: bacterial cells attract it, while human corneal cells repel it; it is less toxic to the ocular surface. However, it does reduce the density of conjunctival goblet cells, which decreases aqueous tear film production.
Stay tuned for more discussion of preservatives in topical ophthalmic medications next month!
Marguerite McDonald, MD, FACS, with OCLI on Long Island, NY, is clinical professor of Ophthalmology at NYU Langone Medical Center, NY, and clinical professor of Ophthalmology at Tulane University Health Sciences Center, New Orleans, Louisiana.