To Preserve or Not to Preserve?
That is the ophthalmic anti-infective question.

In ophthalmology, preservatives can act as both friend and foe. We rely on them to protect against microbial contamination, while remaining vigilant for the rare instance of cytotoxicity, especially with long-term use.

In the case of the ocular preservatives used in ophthalmic anti-infectives, the toxicity risk is minimal because the medications typically are used for a short duration. Still, we always need to balance a preservative's efficacy with its biocompatibility and tolerability.

Equally important is the need to recognize a little-known benefit: Besides protecting against contamination, the most commonly used ocular preservative, benzalkonium chloride (BAK), which is in Allergan's gatifloxacin ophthalmic solution 0.3% (Zymar), enhances a medication's absorption rate, and in some cases increases the speed of microbial killing and prevents contamination of the bottle.

The first fourth-generation fluoroquinolones approved by the FDA occupy opposite sides of the preservative debate. Gatifloxacin is preserved with 0.005% BAK, while Alcon's moxifloxacin ophthalmic solution 0.5% (Vigamox) is preservative-free.

The rationale for the nonpreserved product appears to be avoidance of toxicity. Clinical practice, however, suggests that this concern may be largely unfounded. Remember, ofloxacin 0.3% (Ocuflox) and ciprofloxacin 0.3% (Ciloxan) -- which both contain preservatives -- were widely applied without incident in millions of eyes undergoing ophthalmic surgeries before the newer fluoroquinolones appeared.

It's also worth noting that, in order to be marketed in the United States, ocular anti-infectives must pass U.S. Pharmacopoeia (USP) criteria, which are somewhat less stringent than those of the European Pharmacopoeia.

Moxifloxacin has passed USP criteria. These criteria, however, require stasis only (not killing) of yeast and fungal test organisms. Nor do they stipulate logarithmic reductions of bacteria at 6 and 24 hours.

Gatifloxacin has passed the more-stringent European criteria -- which test Staphylococcus aureus, a Gram-positive bacterium, Escherichia coli and Pseudomonas aeruginosa, a Gram-negative enteric and a nonfermentative bacteria respectively, Candida albicans, a yeast, and Aspergillus niger, a filamentous fungus.

We can expect to see other fluoroquinolone agents at similar concentrations pass USP requirements for stasis -- possibly even without an added preservative. Still, the question arises: Does adding a preservative agent increase protection from contamination and add more antimicrobial effects, resulting in cidal activity and more rapid rates of organism killing?

Clinical studies and time will provide further insight -- if not definitive answers -- about the overall benefits of ocular anti-infective preservatives. Meanwhile, no evidence has surfaced to implicate cytotoxicity when preservatives are used as an adjunct in short-term anti-infective regimens.

Still, the debate is worth pursuing. This series of articles explores pertinent issues surrounding the use of preservatives in anti-infective agents:

• I open with an overview of the clinical benefits of BAK.
• Henry D. Perry, M.D., then describes a study performed in his clinic comparing the ocular side effects of gatifloxacin and moxifloxacin.
• Frank Price, M.D., explores the pros and cons of preservatives in topical ocular medications.
• Randall J. Olson, M.D., wraps up by explaining the contamination risk associated with nonpreserved topical ocular medications.

Bear in mind that the studies mentioned in this supplement used the commercial preparations of gatifloxacin and moxifloxacin, not only the molecules themselves. This distinction is significant from research and clinical viewpoints.

Dr. O'Brien is an internationally recognized expert in refractive surgery, anterior segment and eye infections. He practices at the External Diseases and Cornea service at Johns Hopkins Wilmer Eye Institute.