Allergy to Ophthalmic Preservatives

Jison Hong; Leonard Bielory


Curr Opin Allergy Clin Immunol. 2009;9(5):447-453. 

In This Article

Benzalkonium Chloride

Benzalkonium chloride, also known as BAC, is a quaternary ammonium, which is a highly hydrosoluble bipolar compound with surfactant properties. Their mechanism of action primarily involves its intrinsic detergent activities depending on its concentration (ranges from between 0.004 and 0.02% in most topical products) leading to dissolution of bacterial cell walls and membranes. The spectrum of activity is mainly focused on Gram-positive bacteria. BAC is used in a wide range of commonly used products, such as soaps, cosmetics, cleaning products, ophthalmic preparations, disinfectants, and spermicides. BAC is known to cause damage/toxicity in almost all ocular structures.

Animal Studies

Although the use of BAC does not appear to interfere with the absorption of the therapeutic agent in animal models,[6•] Becquet et al.[7] performed a study using rats to demonstrate the toxic and immunoallergic reactions that take place in the corneo-conjunctival surface after subjecting the eyes to the application of various preservatives. They found that even at low concentrations of a single instillation of BAC, toxic effects on the corneo-conjunctival surface were noted most likely due to its intrinsic detergent properties that can alter tear fluid stability, particularly in its lipid phase. In rats treated with various other preservative solutions (BAC 0.01%, methyl parahydroxybenzoate 0.05%, and thiomersal 0.004%) there was an infiltration of immunocompetent cells into the limbus and bulbar conjunctiva that expressed class II and CD11b membrane HLA antigens (leukocyte integrin). Similar results were reported later by Baudouin[8] in rats treated by timolol 0.5% containing BAC (0.01%) with abnormal expression of antigens human leukocyte antigen-DR and clusters of designation 23.

Human Studies

Human in-vitro studies performed by Becquet et al.[7] showed that unpreserved β-blockers showed no toxic effects on cultured human Tenon's capsule fibroblasts, whereas preserved β-blockers showed toxicity and inhibition of fibroblast proliferation. Mietz et al.[9] also demonstrated that instillation of another β-blocker, metipranolol 0.3% preserved in BAC, produced deterioration of the composition of the extracellular matrix and the organization of the conjunctival stroma, combined with an increase in the number of activated subepithelial fibroblasts, in the deposits of collagen and the thickening of the basal membrane of the endothelium. In a tissue culture model utilizing immortalized corneal and conjunctival epithelial cells, toxicity was observed with all preservatives, but dependent upon concentration with the order of decreasing toxicity observed for thimerosal (0.0025%) more than BAC (0.025%) more than chlorobutanol (0.25%) more than methylparaben (0.01%) more than sodium perborate (0.0025%).[10•] Goto et al.[11] performed a study in which human lens epithelial cells were cultured in medium containing different dilutions of latanoprost, timolol maleate, and BAC and then assessed using phase-contrast microscopy after 7 days' culture to determine the morphological changes that take place. The experiment showed that there is a dose-dependent toxic effect of BAC induced by the expression of prostaglandin E2 (PGE2), IL-1α and IL-6, resulting in the inhibition of the proliferation and elongation of the human lens cell and then to cell death.

The effects of preservatives on the eye are sometimes obscured by the chronic disease process, for which topical ophthalmic medications are used. A study performed by Hamard et al.[12] showed that BAC played a role in trabecular cell death in glaucoma patients from the chronic use of topical ophthalmic medications containing BAC. In the study, normal and glaucomatous trabecular cell lines were treated for 15 min with antiglaucoma drugs (1/100 and 1/10 dilutions): timolol BAC+ or BAC-, betaxolol BAC+ or BAC-, latanoprost BAC+ or pure BAC. Apoptotic marker (Apo2.7) expression, annexin V binding and DNA content were evaluated by flow cytometry and confocal microscopy. They found that benzalkonium-containing β-blockers and prostaglandin analogue triggered mild expression of one out of three apoptotic markers, whereas the proapoptotic effect observed with BAC appeared to be largely hindered by active compounds in the preserved eyedrops. The use of BAC may be worse in patients with more chronic ocular disorders as patients with atopic dermatitis had an increased sensitivity to preservatives, such as thimerosal, parabens, and BAC.[5] However, when actually trying to assess the impact of BAC in cell-mediated responses, a recent study[13] tested 42 898 patients with BAC 0.1% in petrolatum (topical drugs, ophthalmics, and disinfectants; between 1996 and 2006 demonstrated 0.6–1.5% reactions with a total of 41 stronger positive reactions.

Although human in-vivo studies have generated rare reports of BAC induced IgE-mast cell type reactions, a recent study[14] demonstrated bronchoconstriction in asthmatics when challenged with BAC suggesting a nonspecific trigger. Specifically relating to the eye, a study by Ishibashi et al.[15] evaluated preserved and nonpreserved topical timolol and noted that the NIBUT (noninvasive breakup time) of the precorneal tear film was significantly shortened. They evaluated precorneal tear film stability without fluorescein instillation that facilitates the in-vivo noninvasive observation of precorneal tear film breakup and found that eye exposure to preserved timolol resulted in significant instability in the precorneal tear film at 30 min after instillation, whereas the preservative-free timolol had no such effect suggesting that even a single exposure to 0.005% BAC may produce precornealtear film instability.