As you know, preservatives are a mixed blessing. The Food and Drug Administration requires that multidose bottles of medications include a preservative to kill bacteria and fungi that may contaminate the fluid in the bottle; as a result, for several decades our medications have contained preservatives specifically designed to keep the medications sterile during patient use and the life cycle of the bottle.

Unfortunately, while these pre-servatives are very effective against pathogens, they were not specifically designed to be friendly to the eye. They tend to consist of harsh chemicals that stop bacterial growth but also harm corneal and conjunctival epithelial cells. After chronic use of medications containing these preservatives, the deleterious effect on anterior segment epithelial cells leads to poor production and maintenance of the tear film, resulting in problems such as dry-eye syndrome. Long-term use can also roughen the surface of the cornea and conjunctiva because of loss of epithelium and inflammation, which can then lead to foreign body sensation and deteriorating vision. So there’s a good and bad side to preservatives—especially the older, soap-like preservatives in the quaternary ammonium family of chemicals, which include benzalkonium chloride, or BAK. These preservatives do a good job of protecting the multidose bottle of medication, but they have the potential for long-term deleterious effects on the eye.

Alternative Options

Partly for that reason, we’ve seen an influx of several new types of preservatives into glaucoma medications over the past few years. Some of these preservatives are well-known in the dry-eye world. For example, Polyquad (Polyquaternium-1) has historically been used in artificial tears; it was originally formulated by Alcon to replace BAK in contact lens solutions. (BAK concentrates in contact lenses during lens storage; Polyquad does not.)

Now Polyquad has found its way into several glaucoma formulations that are available outside the United States, including Travatan and a product that combines travaprost and timolol. Like BAK, Polyquad falls into the soap-like quaternary ammonium preservative family, but it’s a much larger molecule. As a result, it’s not internalized by the epithelial cells on the eye, so it doesn’t cause the kind of toxicity that BAK causes. At the same time, it’s just as effective against pathogens, altering the stability of the bacteria’s cell wall, so it kills the pathogens but does not kill the epithelial cells.

Other new preservatives include SofZia, an ionic-buffered preservative that’s found in Travatan-Z, and Purite, a preservative that breaks down upon contact with the air, found in Alphagan P. They act in a much different way than the quaternary ammonium compounds; Purite oxidizes microbial cellular components, but has no significant effect on human ocular tissues. SofZia causes oxidative damage and subsequent death in bacteria that lack the enzymes cytochrome oxidase or catalase. (Human cells possess these enzymes and are thus not similarly harmed.) These preservatives are effective enough to pass all of the FDA requirements for preserving a multidose bottle of medication, and it’s been proven both in cell cultures and clinical trials that they are much gentler to the eye than alternatives such as BAK.

Another approach to avoiding contamination is to eliminate the need for a preservative via single-dose packaging. Some medications are now available in unit doses that are intended to be used once and then thrown away; this eliminates any concern about contamination of the contents after the unit has been opened. There has been a significant increase in the number of medications available in this type of format, including Cosopt Preservative Free and Timolol Preservative Free.

Why Is BAK Still So Popular?

The existence of these alternatives raises an important question: If these alternative preservatives are equally viable options, why don’t more medications use them instead of relying on BAK? There are a number of reasons, ranging from a few positive side effects of BAK to a lack of universal damage to patient convenience. Despite the downsides of BAK, manufacturers, ophthalmologists and patients all have reasons for not rushing to replace it.

For example, in some situations, BAK does have a positive effect. When the first medications for the treatment of glaucoma appeared, such as beta-blockers, it was understood that the penetration of these medications into the eye would be enhanced by something like BAK. BAK affects the cell-to-cell junctions on the cornea and conjunctiva, allowing more of the active ingredient to get into the eye. This results in a greater concentration of the drug in the aqueous humor, enhancing its effect. This effect encouraged companies to keep BAK in the drug formulation.

Many companies still view this as a positive and a reason to continue using BAK, despite the drawbacks associated with it. Consider the recent introduction of the higher-BAK formulation of Lumigan. The concentration of the active ingredient has been lowered from 0.03% to 0.01%, but the amount of BAK in the solution has been quadrupled. This allows more of the drug to get into the eye, even though the product has a lower concentration of the active ingredient.

This same rationale explains different levels of BAK in other products. For example, Vigamox (moxifloxacin) is preservative-free while Zymar (gatifloxacin) contains BAK.

That makes sense because moxifloxacin has been shown to penetrate the cornea better than some of the other fluoroquinolones, including gatifloxacin.1-3 The BAK in some multidose antibiotic formulations, in addition to acting as a preservative, enhances the penetration of the active ingredient into the eye.

Another reason BAK remains widely used is that the alternative preservatives don’t always meet all countries’ preservative requirements, which in some cases are more stringent than those in the United States. Since most companies are global in their reach, they choose preservatives that can be used anywhere around the globe, and that’s true of BAK. Another factor discouraging companies from venturing into milder alternative preservatives is the cost of developing them. Creating new preservatives and getting them through the different approval processes takes money and effort. BAK, in contrast, is familiar and inexpensive, so companies continue to opt for using it.

It's possible that after some amount of exposure to a preservative like BAK the damage will become irreversible; we simply don't know. That's all the more reason to keep a close eye on your patients' corneas.
Ophthalmologists also have not been rushing to move patients off of BAK-preserved drops, for several reasons. For one thing, it’s extremely difficult to clinically quantify the differences between the version of a given drug that incorporates BAK and the version that doesn’t. We don’t have very sensitive methods for measuring and comparing the differences that might exist. Basic science research shows that a quaternary ammonium compound like BAK can have an effect on the cells on the eye; but when you try to measure that effect clinically, it’s not always measurable and reproducible. That lack of clinical differentiation helps to keep the message from getting through to physicians: Patients who are being treated with chronic drops might very well benefit from avoiding BAK-preserved drops.

Another reason BAK remains widely used is that the problems it may cause are not seen in every patient. Many of our patients who have been using BAK-preserved drops for multiple years seem to tolerate it very well, so there’s little incentive to switch them over to a drug that’s alternatively preserved. In addition, the reality is that when it comes to treating glaucoma, intraocular pressure control is king. If we’re seeing the IOP reduction that we want to see, and the patient is stable and not exhibiting any noticeable signs of a problem with BAK, we typically don’t change the medication.

Last but not least, drugs that do use alternative preservatives have a few downsides from the patient’s perspective. First of all, these drugs are not generics, so they force the patient to pay brand-name prices. Also, the packaging of the single-dose, nonpreserved formulations may cause practical problems for some patients. The unit doses are small, and I’ve had patients complain about misplacing some of them and not being able to find them. Some patients with physical limitations have a hard time using them. Furthermore, in an attempt to save money, some patients will attempt to save an opened single-dose unit in order to get a second or third dose out of it later, which may lead to contamination of the contents, defeating the purpose of the single-dose packaging.

Working With What We’ve Got

Given that we’re likely to have patients using drops that contain BAK for some time to come, here are a few strategies that may help you minimize the problems that can accompany its use:

• Examine your patients carefully for signs of ocular surface damage. Because we tend to be so focused on IOP, I advocate for examining our patients carefully to see what the ocular surface looks like. If a patient has significant ocular surface disease and is showing signs of epithelial breakdown, that’s a patient I would switch from a BAK-preserved drop to an alternatively preserved or nonpreserved drop. It’s important to take that added stress on the ocular surface out of the equation. After a few weeks I would bring the patient back in for an IOP check and re-evaluation of tear breakup time and surface staining.

In our practice, when we note that a patient is having this problem and switch him to a different drop, we frequently see a measurable improvement in the ocular surface status. If the cornea doesn’t improve, it may require a more intensive treatment for dry eye like Restasis or a mild steroid.

• Remember that it may take weeks to reverse BAK-related corneal damage. We don’t know how long it will take a given eye to recover once the patient is switched to a drop without BAK. We conducted a study in which it took eight weeks to see the reversal of the effects on the eye. (The difference was measurable.) At the same time, other studies have found that it took 12 weeks to see a measureable change in tear-film breakup time and staining of the corneal epithelium. Either way, it’s clear that it may take multiple weeks before the patient notices any difference and before the physician can actually measure any improvement.

It’s also possible that after some amount of exposure to a preservative like BAK the damage will become irreversible; we simply don’t know. That’s all the more reason to keep a close eye on your patients’ corneas, so none of them end up with potentially irreversible damage.

• If a patient will be undergoing glaucoma surgery such as a trabeculectomy, consider stopping BAK-preserved drops before the surgery. It’s a good idea to do this when a glaucoma patient has a very hyperemic and inflamed conjunctiva with evidence of ocular surface disease. In this situation, it’s not unusual for us to stop all glaucoma drops (if possible) before doing the filtration surgery, and place the patient on mild steroids for a week or two in order to reduce the conjunctival inflammation.

Remaining Vigilant

Of course, the use of topical drops comes with many problems besides preservative toxicity, among them the well-known issue of patient compliance. So it’s likely that at some point in the future we’ll be getting away from the use of topical drops as a mainstay of glaucoma treatment, eliminating concerns about preservative toxicity. Options such as laser trabeculoplasty, minimally invasive glaucoma surgeries (MIGS), new long-term drug delivery depots and other developments will hopefully allow us to move away from relying so heavily on drops.

Unfortunately, developments that might lead to eliminating drops have been slow in coming, and the regulatory approval process is long. Given those realities, topical therapies will probably be a key part our glaucoma treatments for years to come, and that means we’ll be dealing with the issues surrounding preservatives such as BAK for the foreseeable future. But as long as we stay on the lookout for signs of trouble, and switch patients to alternatives when necessary, the benefits of drops should continue to outweigh the pitfalls.  REVIEW

Dr. Kahook is a consultant for Alcon and Allergan and has patent interests with Abbott Medical Optics, Oasis, New World Medical, Glaukos, ClarVista and Mile High Ophthalmics.

1. Chung JL, Lim EH, Song SW, Kim BY, Lee JH, Mah FS, Seo KY. Comparative intraocular penetration of 4 fluoroquinolones after topical instillation. Cornea 2013;32:7:1046-51.
2. Güngör SG, Akova YA, Bozkurt A, Yasar Ü, Babaoğlu MÖ, Çetinkaya A, Çolak M. Aqueous humour penetration of moxifloxocin and gatifloxacin eye drops in different dosing regimens before phacoemulsification surgery. Br J Ophthalmol 2011;95:9:1272-5.
3. Holland EJ, Lane SS, Kim T, Raizman M, Dunn S. Ocular penetration and pharmacokinetics of topical gatifloxacin 0.3% and moxifloxacin 0.5% ophthalmic solutions after keratoplasty. Cornea 2008;27:3:314-9. doi: 10.1097/ICO.0b013e3181608561.