Point/Counterpoint: Self-Preserved Vs Preserved - PART I

Terrence P. O'Brien, MD
Moxifloxacin 0.5% is formulated as a preservative-free or self-sterilizing solution, as opposed to gatifloxacin 0.3%, which contains BAK. There are certain clinical or surgical situations in which a preservative-free solution is desirable, particularly when toxicity to the ocular surface is relevant with frequent and prolonged application. In other situations, however, preservatives are beneficial, especially if a medication will be used for an extended period of time, posing a significant risk for exogenous contamination. For instance, in glaucoma therapy, an eyedropper's tip may come into contact with the eyelashes or lid margins and will be used for a period of at least 30 days. Therapy for ocular infectious diseases typically involves short-term dosing with abrupt cessation, so eliminating a preservative may have some benefit. On the other hand, preservatives are effective at killing microorganisms and may contribute an additive antimicrobial effect to the antibacterial agent. We try to avoid excessive exposure with preservatives to the ocular surface in cataract and refractive patients, as they are often very sensitive to chemicals and prone to dry eye.

Lisa Brothers Arbisser, MD
The FDA recently approved two new fourth-generation fluoroquinolone antibiotics for ophthalmic use. These agents afford ophthalmologists a chance to get another jump ahead of the pathogenic flora that populate our patients' ocular surfaces and potentially complicate our sterling surgical outcomes. The methoxy group at the C8 position of these designer molecules distinguishes these drugs from those that came before and confers important characteristics that affect potency and discourage the development of microbial resistance.

ZYMAR (gatifloxacin) is the new drug from Allergan, Inc. (Irvine, CA), and VIGAMOX (moxifloxacin) is the new agent by Alcon Laboratories, Inc (Fort Worth, TX). Because these antibiotics have the ability to foil bacterial enzymes at two sites, they are lethal to the wide range of developing, resistant gram-positive organisms that have learned how to survive the previous generations of fluoroquinolones. It is imperative for ophthalmologists to eradicate these organisms while we still have antibacterial agents to which they are naïve. The only question in my mind is which fourth-generation fluoroquinolone is the drug of choice.

There are subtle differences between moxifloxacin and gatifloxacin based on their differing side chains on the C7 position of the molecules. Researchers are presently accumulating data with which to be able to compare the agents' MIC 90s for various organisms. Also, we have only early comparative data on penetration and pharmacodynamics for these drugs, and as of this writing, we await a head-to-head study to directly compare these data.

One clear difference in the formulation between gatifloxacin and moxifloxacin as approved by the FDA is their respective modes of preservation. Interestingly, in the battlefield upon which companies are forced to play, there is no unanimity of opinion as to how to interpret this difference.

As I understand it, the FDA conducts a specific test with outcome criteria to meet the US Pharmacopeia requirements for antimicrobial efficacy. Bacterial and fungal isolates' growth must be retarded over a period of 28 days to pass this test. Moxifloxacin met these criteria and, I am told, even caused some death of fungal isolates without an added preservative. VIGAMOX is therefore considered to be “self-preserved.” This status differs from that of unpreserved drugs, which, not having met the criteria, must be individually packaged by dose. Gatifloxacin, on the other hand, was approved by the FDA with the addition of BAK for ZYMAR to meet the same standards. I presume this addition was required, albeit at a very low concentration of 0.005%.

BAK is well known to ophthalmologists for being toxic to the corneal endothelium and noxious, in a dose-dependent manner, to the epithelium. Surgeons accept the preservative as a necessary evil in most ophthalmic preparations, including steroidal and nonsteroidal topical medications. Therefore, reason would dictate that a medication used effectively peri- and intraoperatively that lacks this toxic substance would be advantageous for ocular surgery. This dictum may hold particularly true for LASIK patients regarding the health of exposed keratocytes as well as their epithelium. We certainly do not want the endothelium of immediate postoperative cataract patients exposed to BAK in any way.

There are, however, those who interpret the lack of BAK in VIGAMOX as a risk for contamination and point out that, for reasons obscure to me, the product information insert states that the patient should not touch the tip of the medication's dropper to his eye. All ophthalmologists recognize this proviso as proper technique and strive to warn patients about it with the use of all topical medications. Despite the presence of BAK, it is possible for organisms to grow in mishandled solution containers of all types.

I must assume that the FDA would not have approved VIGAMOX, with a competitive shelf life to ZYMAR, for multidosing if routine patient self-administration posed a significant risk of contamination. Also, I have come to grips with the concept of self-preservation and accept that such a thing is possible with an anti-infective agent.

Harold R. Katz, MD
Preservatives are required in most drops that are not in unit-dose containers so that the drops meet the US Pharmacopeia requirement for the Antimicrobial Efficacy Test. In this test, three different types of bacteria and two fungal organisms are introduced into a bottle of topical ophthalmic drops after the bottle is opened in order to simulate a clinical situation in which the bottle's tip may become contaminated with the patient's ocular surface flora. Samples of the contaminated drops are then taken at various time periods for up to 28 days.

VIGAMOX is the first topical ophthalmic antibiotic drop that has passed the rigorous Antimicrobial Efficacy Test without the use of an added preservative. The drug's self-preservation will have important consequences whenever toxicity of a preservative is an issue in a clinical setting, such as in refractive surgery. Preservatives offer no advantages if they are not required to prevent the growth of bacteria and fungi in an opened bottle of drops. BAK in particular has been shown to have cytotoxic properties and may detrimentally affect healing of the ocular surface. This is always an undesirable effect. It is important to realize that VIGAMOX has passed the exact same testing as other topical ophthalmic drops such as ZYMAR. There is, in fact, no decrease in the shelf life of VIGAMOX because of the absence of added preservatives. VIGAMOX is not unpreserved, it is self-preserved. The potency of this antibiotic allows it to also serve as the preservative, and offers a tremendous clinical advantage by not exposing the cornea to toxic agents such as BAK.

Terrence P. O'Brien, MD, serves as Director of Ocular Infectious Diseases and Ocular Microbiology Laboratory at The Wilmer Ophthalmological Institute at Johns Hopkins University School of Medicine in Baltimore. He holds no direct financial interest in any product discussed herein but serves as an ad hoc consultant to Alcon Laboratories, Inc., Allergan, Inc., Novartis Ophthalmics, Inc., Pfizer Inc., and Santen, Inc. Dr. O'Brien may be reached at (410) 583-2842; tobrien@jhmi.edu.
Lisa Brothers Arbisser, MD, is in private practice in Davenport, Iowa, and is immediate past President of the American College of Eye Surgeons. She holds no direct financial interest in any product mentioned herein. Dr. Arbisser may be reached at (563) 323-8888; drlisa@arbisser.com.
Harold R. Katz, MD, is Director of Cornea and Refractive Surgery at The Krieger Eye Institute in Baltimore. He holds no financial interest in any product mentioned herein. Dr. Katz may be reached at (410) 601-5991; hal1999@aol.com.