BAK Story

A short summary of the long history of benzalkonium chloride.

BY MARK B. ABELSON, M.D., AND GREGG J. BERDY, M.D.

There has been significant concern in recent years about the presence of benzalkonium chloride (BAK) in glaucoma medications and fluoroquinolones because of BAK's potential for corneal toxicity, but we would like to remind readers of two studies that we think bring needed perspective. In 1963, Robert Kohn investigated ophthalmic preservative effectiveness in Philadelphia. Forty-three years later, in 2006, Colin Chanock conducted a study with the same goal in Oslo, Norway.

The two men were separated by both the Atlantic ocean and a generation, yet their conclusions were remarkably similar: of all the preservatives they tested, solutions containing BAK most effectively resisted microbial contamination. And today, despite the recent trend toward BAK-free medications, BAK remains the most common preservative used in multi-use ophthalmic solutions, in part because of its long history of safety and efficacy. We would like to review that history, up to the present day.

Medications, B.P. (Before Preservatives)

In the old days, many ophthalmic solutions were kept unpreserved in corked glass bottles and were administered with a pipette.¹ Studies showed that the solutions stored this way were almost always (94%) contaminated.¹ In retrospect, this finding is not particularly surprising. It's easy to imagine ways a loose pipette, an open bottle or a removed cork could come in contact with a pathogenic microorganism, even in a clean clinic. As Louis Pasteur famously demonstrated in 1864, with a curved-neck glass flask, sterile broth, a flame and a little time, contamination from microorganisms can be prevented with savvy packaging.² By 1969, containers resembling the modern eye drop bottle were in common use.¹

In the late 1940s and 1950s, investigators searched intensively for appropriate ophthalmic preservatives.¹ It was, in some ways, a difficult search. Ophthalmic preservatives needed to be many things at once: microbiocidal, easily soluble, chemically stable and compatible with all components of formulations, while minimizing ocular toxicity.¹ BAK was one of the first preservatives to be added to an eye drop, with references dating back 60 years; in 1949, McPherson and Wood published a study of BAK-containing eye drops in the American Journal of Ophthalmology.³

BAK vs. Other Preservatives

In 1963, BAK quickly distinguished itself among the 7 preservatives studied (BAK, chlorobutanol, thimerosal, methylparaben/propylparaben, phenylmercuric nitrate, phenylethyl alcohol and polymyxin B sulfate). Kohn and colleagues tested BAK in vitro against 13 different strains of Pseudomonas aeruginosa.⁴ At its highest concentration, BAK was bacteriocidal in only 45 minutes, significantly less time than all other preservatives including chlorobutanol (9 hours), thimerosol (6 hours) and phenylmercuric nitrate (6 hours).⁴ BAK's efficacy was so impressive, in fact, that it became the standard for evaluating the efficacy of potential preservatives. In a subsequent experiment by Kohn, chemicals were discussed as an "improvement" or "not an improvement" over BAK.⁵

In 2006, Colin Charnock, of the Department of Health Sciences at Oslo University College, evaluated five brands of preserved artificial tears for antimicrobial efficacy, using tests specified by the European Pharmacopoeia.⁶ Six hours after inoculation, Candida albicans cell counts were reduced to undetectable levels in a solution containing a BAK/EDTA combination preservative, days before other preservatives. BAK/EDTA also reduced P. aeruginosa and Staphylococcus aureus inoculums to undetectable concentrations within 15 minutes — hours before other preservatives.⁶

Safety and Efficacy Today

BAK is still the most commonly-used preservative in ophthalmic medications, and the FDA requires that topical ophthalmic medications in multidose bottles be preserved. In other words, a bottle of eye drops is most likely preserved with BAK in a concentration ranging from 0.004% to 0.25%.⁷ So what does BAK's popularity imply about its safety and efficacy?

One way to review the safety and efficacy of BAK would be to summarize studies investigating both these factors. For example, the previously-mentioned studies by Kohn and Charnock found BAK was effective against Pseudomonas, Staphylococcus and Candida. A study conducted by Berdy and colleagues found a mild regimen of preservative-free artificial tears was not significantly less toxic to rabbit eyes compared to BAK 0.02% on a quantitative scale of corneal epithelial morphologic change.⁷

In a way, though, many unpublished reviews of BAK's safety and efficacy have already been completed. When considering the composition of a new topical, multi-use ophthalmic solution, formulators conduct their own independent reviews of BAK's safety and efficacy. The areas generally considered are: antimicrobial efficacy, toxicity to ocular tissue, optimal pH range for antimicrobial efficacy and ocular tolerance, ingredient compatibility and processing conditions.⁸

The United States Pharmacopoeia National Formulary (USPNF) specifically states that ophthalmic solutions in multidose containers intended for individual use on intact ocular surfaces must contain a suitable substance or mixture of substances to prevent the growth of, or to destroy, micro-organisms accidentally introduced when the container is opened during use.⁹ In most cases, the substance selected is BAK.

In addition, the USP-NF states that "all useful antimicrobial agents are toxic substances."⁹ The choice of ophthalmic preservative is therefore a kind of optimization problem: a preservative's toxicity to pathogenic microbes should be maximized and its toxicity to the ocular surface should be minimized. The marketplace has already found a solution to this balance of microbial and human toxicity. If 78% of preserved eyedrops include BAK, that implies that 78% of the time, formulators have decided BAK was the most appropriate antimicrobial, and regulatory agencies have approved of their choice.

Toxicology Lesson

As for the question of toxicity, researchers from Switzerland's Institute of Medical Chemistry at the University of Lausanne report that ophthalmic preservatives can be nonspecifically toxic.⁸ At lower, clinically common concentrations, preservatives are generally toxic only to their intended targets: pathogenic bacteria, yeasts and fungi.⁸ If exposure is extreme, preservatives can be toxic both to pathogenic microbes and to the ocular tissues they are meant to protect.⁸ At certain concentrations, Bequet and colleagues found cetrimonium chloride, BAK, benxododecinium bromide, thiomersal and methyl parahydroxybenzoate all induced similar histopathological and inflammatory changes in the rat ocular surface.¹¹ Although nonspecific toxicity is a possibility with most preservatives, it's not always a clinically relevant possibility.

Researchers from Schepens Eye Research Institute at Harvard Medical School, for example, found that when rabbits were given two drops of 0.02% BAK every three minutes for one hour, cytotoxic morphological changes were observed in the corneal epithelium.⁷ However, in the clinic, it is unlikely a patient would ever be given the human equivalent of two preserved eye drops every three minutes for one hour. Under less excessive dosing (two drops every 30 minutes for 2 hours), researchers found BAK induced only minimal cytotoxic corneal damage not significantly different than control (phosphate-buffered saline).⁷

The cytotoxicity profile of BAK has been particularly well documented due to its long history and extensive use. Multiple studies, primarily conducted on rabbit and human conjunctival epithelial cells in vitro, have demonstrated BAK's ability to increase epithelial cell permeability, growth arrest and apoptosis.^12-14 By their in vitro nature, though, most of these studies do not accurately mimic ocular surface conditions.

BAK is cytotoxic at exaggerated concentrations and can facilitate increased penetration of the drug and epithelial cell death. However, dilution by the normal tear film and nasolacrimal drainage minimizes any ocular surface effects of typical (~0.01%) BAK concentrations. In patients with severe dry eye or pre-existing corneal surface disease, though, the diminished tear film can prevent drop dilution, facilitating BAK-induced cytotoxicity.

The Real Threat

Ultimately, the greatest threat to the epithelial surface comes from microbes, not from any ingredient listed on the label of an ophthalmic preparation. For example, Staphylococcus, one of the most common bacterial isolates of blepharoconjunctivitis and keratitis,¹⁵ produces σ, β, γ and δ toxins, the shiga toxin, toxic shock syndrome toxin, exfoliating toxin A and B, leukocidin, coagulase and the enterotoxins A, B, C, D and E2. Among other things, this long, intimidating list of toxins can cause multifactorial lysis of ocular cells.²

Although ophthalmic solutions are no longer kept in small glass bottles closed with corks and drops are no longer administered with separate syringes, microbial contamination continues to be a problem, as a group of British researchers demonstrated last year. After only a few (3 to 7) days, 8 of 95 bottles containing 10 different drugs formulated for experimental purposes without preservatives were contaminated with bacteria, including Staphyloccocus, Bacillus species, Serattia species, Klebsiella oxytoca, Enterobacter cloacae and Alpha streptococcus.¹⁶ Perhaps more alarmingly, in 1992 Schein et al. reported 64 of 220 (29%) of medications used by 101 patients with non-microbial OSD were contaminated with micro-organisms.¹⁷

BAK to the Future

The choice of ophthalmic preservative is essentially a balance of toxicity. The "good" antimicrobial toxicity should be balanced against "bad" collateral toxicity to ocular tissues. Today, the vast majority of ophthalmic solutions are preserved with BAK, and while we're often concerned about recommending or prescribing medications with BAK, that concern is not always warranted. As two researchers from Johns Hopkins Hospital put it, "Benzalkonium chloride… is nonirritating in concentrations necessary to achieve bactericidal effects."³

Those researchers, Samuel McPherson and Ronald Wood, made that statement 60 years ago, but for most patients, it remains true today. BAK is still the preservative of choice: it is bactericidal and bacteriostatic, effective and has stood the test of time. After decades of progress and innovation in ophthalmology, millions of prescriptions and millions of instillations, the evidence still suggests BAK is a safe and effective preservative when used as recommended.

When prescribing BAK-containing medications, be sure to explain to the patient the necessity of dose compliance in order to avoid the potential downsides of BAK. Also explain that while complications are uncommon, the patient should be on the lookout for ocular dryness, pain, redness or foreign body sensation, particularly right after dosing. Such signs and symptoms may be the result of mis- or over-use, and may warrant a re-evaluation of the dosing regimen. OM

References

1. Barkman R, Germanis M, et al. Preservatives in eye drops. Acta Ophthalmol. 1969;47:461-475.
2. Madigan MT, Martinko JM. Biology of Microorganisms. 11th ed. Upper Saddle River, NJ: Person Prentice Hall; 2006.
3. McPherson SD, Wood RM. Self-sterilizing ophthalmic solutions. Am J Ophthalm. 1949;32:675.
4. Kohn, SR, Gershenfeld L, et al. Effectiveness of Antibacterial Agents Presently Employed in Ophthalmic Preparations as Preservatives against Pseudomonas Aeruginosa. J Pharm Sci. 1963;52 967-974.
5. Kohn, SR, Gershenfeld L, et al. Antibacterial Agents Not Presently Employed as Preservatives in Ophthalmic Preparations Found Effective against Pseudomonas Aeruginosa. J Pharm Sci. 1963;52:1126-1129.
6. Charnock, C. Are multidose over-the-counter artificial tears adequately preserved? Cornea. 2006;25:432-437.
7. Berdy, GJ, Abelson MB, et al. Preservative-free artificial tear preparations. Assessment of corneal epithelial toxic effects. Arch Ophthalmol. 1992;110:528-532.
8. Furrer P, Mayer JM, et al. Ocular tolerance of preservatives and alternatives. Eur J Pharm Biopharm. 2002;53:263-280.
9. United States Pharmacopoeia National Formulary, 2008 Version (official 12/1/07-4/30/08).
10. Abelson MB, Fink K. How to handle BAK talk. Rev Ophthal. 2002;9:12.
11. Becquet F, Goldschild M, et al. Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface. Curr Eye Res. 1998;17:419-425.
12. Uematsu M, Kumagami T, Kusano M, et al. Acute corneal epithelial change after instillation of benzalkonium chloride evaluated using a newly developed in vivo corneal transepithelial electric resistance measurement method. Ophthalmic Res. 2007;39:308-314.
13. De Saint Jean M, Brignole F, Brinquier AF, et al. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci. 1999;40:619-630.
14. McCarey B, Edelhauser H. In vivo corneal epithelial permeability following treatment with prostaglandin analoges with or without benzalkonium chloride. J Ocul Pharmacol Ther. 2007;23:445-451.
15. Mah F. Bacterial Clamydial and Mycobacterial Infections. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. 3rd ed.Elsevier Inc. 2008.
16. Rahman, MQ, Tejwani D, et al. Microbial contamination of preservative free eye drops in multiple application containers. Br J Ophthalmol. 2006;90:139-141.
17. Schein OD, Hibberd PL, et al.. Microbial contamination of in-use ocular medications. Arch Ophthalmol. 1992 ;110:82-85.