Do You Welcome BAK? Weighing the Toxicity Risk
We must decide if the likelihood of ocular surface toxicity from a preserved antibiotic outweighs the contamination risk of one that's unpreserved.
By Frank Price, M.D., Indianapolis

Preservatives play a key role in maintaining the sterility of ocular antibiotics and other topical ocular medications through multiple uses. They protect against bacterial or fungal contamination of ophthalmic solutions that can occur when the dropper tip touches skin, eyelids, fingers or other nonsterile surfaces. Once the tip is contaminated, the offending agent may be aspirated back into the bottle, or it may blend into the solution with the next use as the medication collects on the tip before dropping into the eye.

Preservatives are active ingredients that retard or prevent the growth of bacterial and fungal contaminants. Ophthalmic drops commonly contain preservatives, while ophthalmic ointments are often supplied nonpreserved, presumably because they're not as susceptible to contamination from retrograde flow back into the tube.

This article reviews the potential toxicity of preserved ophthalmic antibiotics in light of the benefits of preservation, and discusses the relative merits of the unpreserved alternative.

Ocular surface toxicity

The major problem with preservatives is that in high concentrations they can be toxic to the ocular surface. The most common finding is a diffuse punctate keratitis over the cornea, especially over the inferior cornea where the tears pool.

Eyes with preexisting ocular surface disease are especially sensitive to this toxicity. In particular, eyes with decreased tear production may not wash away the preservative as effectively as normal eyes.

Since antibiotics are commonly used for short courses of treatment, toxicity usually is limited to punctate keratitis. However, some eyes with significant ocular surface disease can develop epithelial erosions, particularly if the antibiotic has intrinsic ocular toxicity. For example, the aminoglycoside antibiotics -- especially neomycin -- are toxic to the ocular surface. The fluoroquinolone antibiotics, on the other hand, are reputed to confer minimal risk of significant corneal surface toxicity.

Chronic use of preserved ophthalmic medications to control glaucoma has been associated with more serious problems such as chronic inflammation and scarring of the conjunctiva. These changes seem to be caused by long-term exposure to the preservative rather than to the medication itself.

Benzalkonium chloride (BAK) is the most frequently used preservative in ophthalmic solutions. It's the preservative found in the fourth-generation antibiotic solution gatifloxacin 0.3% (Zymar).

BAK is essentially a detergent that disrupts the cell walls of bacteria and fungi. While the damage to human cells is minimal compared with its effect on microbial cells, BAK disrupts the corneal epithelial barrier function and may allow more absorption of a medication into the eye.

Corneas treated with gatifloxacin. Scanning electron microscopy demonstrates moderate diffuse loss of microvilli, cell peeling between 2% and 25% of cells and increased number of dark cells.

The unpreserved alternative

Theoretically, unpreserved ocular solutions are desirable to avoid the risk of toxicity. Without a preservative, patients are at risk of contamination from nonsusceptible bacteria and fungi if they use the solution for a number of days. This risk is even greater if the bottle is opened and then put aside for an extended period for later use, which often happens.

Another alternative to using preservatives is to package medications in unit doses as is often the case with artificial tear solutions. The downside there is that providing medications in unit doses is generally more costly, and multiple ampules are bulky compared with a single bottle.

The fourth-generation fluoroquinolone antibiotic solutions -- gatifloxacin 0.3% and unpreserved moxifloxacin 0.5% (Vigamox) -- unleash widespread activity against many bacteria, but not specifically against fungi. The FDA approved moxifloxacin for 7-day use. It comes in a 3-mL bottle, which is smaller than normal, presumably because there is no preservative.

Weighing the pros and cons

Gatifloxacin and moxifloxacin each have their tradeoffs when it comes to safety and the risk of complications. The choice of whether to prescribe a preserved or unpreserved medication must depend on factors specific to the case at hand. Clinicians can take comfort in the fact that preservatives are only known to cause toxic reactions primarily when used in high concentrations.

A corneal specialist in private practice, Dr. Price is also a lecturer and an inventor.