Preservatives Role in Topical Ocular Drugs

Lisa B. Samalonis, Contributing Editor 9/14/2006

The role of preservatives in topical ophthalmic products is multifaceted. Unlike most medication used in other specialties, many ophthalmic products with preservatives are topical. The preservatives could therefore cause toxicity to the surface of the eye; they could help penetration of the drugs into the target organism; or they could be an additive.

Francis S. Mah, MD, assistant professor of ophthalmology and co-director of the Charles T. Campbell Eye Microbiology Laboratory at the University of Pittsburgh, explains, "Even though the preservatives are 'inactive ingredients,' they could actually play a role in what the medication's job is supposed to be." In eye care, medication preservatives have long been seen as a "necessary evil." Preservatives were used to prevent contamination of the product in the bottle and also used to keep the drug stable. The "evil part" was in order to be preservative it has to kill viruses, bacteria, fungi, or parasites, and invariably it was going to cause a little bit of toxicity to the ocular surface, Dr. Mah explains. "Historically, if you could get away without a preservative that would be better as long as you could assure that the drug was going to be stable and that there was not going to be any contamination in the drug's container. Less is thought to be better. For example in chronic medications, such as artificial tears or glaucoma medications that are going to be used everyday indefinitely, if you could get away with decreasing the preservatives or eliminating the preservatives that would be preferred," he says. Dr. Mah notes that in the ophthalmic antibiotic arena it is conceivable that a preservative would be a benefit. "If you have bacteria on the surface and the preservative helps eliminate some of the bacteria all by itself and you have the therapeutic (the actual drug) also killing, then potentially it could be a benefit," he says, noting that the risks and benefits of potential toxicity would need to be weighed.

Benzalkonium Chloride The most common preservative in ophthalmic care products is benzalkonium chloride (BAK). "The literature has shown that the more BAK you have does cause epithelial cells to stop mitosis and it causes cell death. Therefore it is best to minimize that, however, making sure that there is no contamination occurring," Dr. Mah says. As far as antibiotics are concerned, dilution also becomes an issue. "When the antibiotic is placed in the eye, there is dilution of the antibiotic and the preservative," he adds. "There is so much antibiotic that you

are probably not going to dilute it appreciably, but the BAK, if it is 0.005% you will have diluted it significantly. We have done studies that show the difference when you have a petri dish, or a test tube with bacteria. If you dilute it, even 1:10 or 1:100, you can eliminate the benefit. All of a sudden, it is as if there is not enough BAK to make a difference." A recent study, conducted by Dr. Mah and his colleagues at the University of Pittsburgh, demonstrated that clinically BAK can make a difference in an antibiotic. (Mah FS, et al. IOVS 2006;47:ARVO E-Abstract 1905) "In this study, sponsored by Allergan, we used Zymar (gatifloxacin ophthalmic solution 0.3%, Allergan) with and without BAK in rabbit eyes," says Dr. Mah. Studying methicillin-resistant Staph aureus, "We showed that we could get rid of the infection faster and better with Zymar with BAK than we could with the Zymar minus BAK. In that controlled environment, we showed that BAK can make a difference." Robert W. Snyder, MD, PhD, professor of biomedical engineering at the University of Arizona, believes there's a lot of confusion as to whether having a preservative in a topical antibiotic is advantageous. "I believe it is advantageous," he says. "There is significant laboratory evidence that BAK can add to the potency of an antibiotic by increasing the speed of killing potential pathogens and lowering the MIC of the commercial formulation for known pathogens," says Dr. Snyder, who is also in private practice in Tucson, Arizona. He cites two ARVO studies: (Eser I, et al. IOVS 2004; 45:ARVO E-Abstract 4921, and Blondeau JM, et al. IOVS 2006;47:ARVO E-Abstract 1903). "It is not widely appreciated that the MIC levels that are performed and reported by your hospital are done so using only a solution of the active antibiotic ingredient," adds Dr. Snyder. "The commercial antibiotic preparation and that includes the BAK is not tested nor reported. When we are dealing with antibacterial effect of a commercial formulation of antibiotic on the surface of the eye the activity of the BAK should add to the potency of the antibiotic in the formulation. Zymar with BAK has been shown in the lab to be able to kill pathogens that would be considered resistant to the antibiotic alone."

Contamination Originally preservatives such as BAK were added to antibiotic formulations to keep them sterile. "In general, I believe that having a preservative in a bottle of medication that is going to go onto an eye with a fresh cataract wound is advantageous," explains Dr. Snyder. Preservatives are intended to keep the bottle sterile over the course of multiple uses, notes Dr. Snyder. "For example, elderly, post-cataract surgery patients may not have as much dexterity with their hands. It is

probably pretty common that they have their fingers all around the bottle and frequently touch the bottle tip," he says. In a recent study researchers from Tennent Institute of Ophthalmology, Gartnavel General Hospital, Glasgow, UK, found that preservative-free eye drops in multiple application containers are at risk of contamination by potentially pathogenic microorganisms.1 "The majority of eye drops used in the United Kingdom contain preservatives and are bottled in plastic containers, says Dr. MamunRahman, BSc, one of the study's investigators. "Preservative-free drops are used to avoid ocular irritation and allergies in certain individuals. Contamination should always be an issue, especially when prescribing to elderly patients who are at more risk of infections. For example, those who have recently undergone eye surgery, or whose eye surface defenses may be compromised in some other way." For the study, eye drop bottles were collected from patients attending the Tennent Institute's outpatient and inpatient ophthalmology departments. The bottles were collected on day three (for inpatients) and day seven (for outpatients) of use. The drops were inoculated onto different culture plates and the resulting microbial growth was identified using standard microbial identification techniques. Ninety-five eye drop bottles were collected, containing a variety of 10 different eye drops. Significant bacterial growth was found in eight bottles. In total, seven different types of organism were identified from the eye drops. The organisms identified were Staphylococcus aureus(most common), coagulase-negative Staphylococcus, Bacillus spp., Serratiaspp., Klebsiellaoxytoca, Enterobacter cloacae and alpha Staphylococcus. The longer the duration of use, the greater the chance that eye drops may become contaminated. Preservative-free medications may be at a greater risk of contamination than preserved drops, Dr. Rahman concludes.

Staphylococcus aureuswas most commonly implicated in one study of contaminated bottles of ocular medications.

Innovative bottle design may hinder such bacterial contamination. In 2005, Pfizer debuted its Airless Antibacterial Dispensing System in Visine Pure Tears. This bottle design allowed for the first preservative-free artificial tears formula to be available in a multi-dose bottle. The dispenser includes several features designed to prevent bacteria from entering the container and contaminating the contents, such as a dual-wall reservoir. Currently, no other Pfizer topical ophthalmic products use this bottle design in the United States. The company declined to comment on future plans for the use of the bottle design with other ophthalmic products.

Is Preservative-Free Better? "While it is a sound concept to have a preservative in topical eye medication, I am often asked if the preservatives in topical antibiotics are safe or whether it is advantageous to be 'preservative-free'?" says Dr. Snyder. "There is no question that BAK at the concentration and pH used in the Zymar formulation is safe if you compare side by side healing studies in PRK or cornea transplant patients with Zymar and Vigamox. [He also cites an ARVO report: (Solomon R, et al. IOVS 2005; 46:ARVO E-Abstract 4895)]. There is no consistent evidence that of any deleterious healing effect from the BAK in Zymar." A host of preservative-free products are commercially available. "There has been a move afoot for some time to develop drugs without preservatives," says Richard A. Lewis, MD. "Some of the fluoroquinolones are marketed this way, as are some artificial tears. There is a perception that preservatives impair surface tissues of the eye leading to inflammation and dry eye.

"There is no more important market for this than glaucoma, a condition requiring chronic, long-term eye drop application. This will also play a role in the response of the eye during cataract and glaucoma surgery," says Dr. Lewis, who practices in Sacramento, Calif. In another ARVO report that has been accepted for publication in the Journal of Glaucoma, Dr. Lewis and his colleagues found that travoprost BAK-free is the equivalent to travoprost 0.004% (Travatan, Alcon) in both safety and efficacy. (Lewis RA, et al. IOVS 2006;47:ARVO E-Abstract 452) The double-masked, randomized, parallel group, multicenter, non-inferiority design study compared the new formulation of travoprost 0.004% without benzalkonium chloride (travoprost BAK-free) to that of the marketed formulation of travoprost 0.004% in patients with open-angle glaucoma or ocular hypertension. Adult patients with OAG or OHT and with qualifying IOP (24 to 36 mmHg at 8 a.m.; 21 to 36 mmHg at 10 a.m. and 4 p.m. following appropriate washout of previous ocular hypotensives) in at least one eye on two eligibility visits received either travoprost 0.004% preserved with BAK (n=346) or travoprost BAK-free (n=344) dosed once-daily each evening. Study patients were followed for three months. "The 95 percent confidence limits for the difference in mean IOP were within 0.8 mmHg at nine of nine study visits, and times in both the per protocol and intent-to-treat data sets," explains Dr. Lewis. "Mean IOP reductions, across all nine study visits and times in both the per protocol and intent-to-treat data sets, ranged from 7.3 to 8.5 mmHg for travoprost BAK-free and from 7.4 to 8.4 mmHg for travoprost 0.004%." Statistical equivalence was also demonstrated for the comparison of mean IOP changes. In a study accepted for publication in Advances in Therapy, Richard W. Yee, MD, of Houston, and colleagues also looked at travoprost without BAC.2They compared the relative toxicity of travoprost without BAC (Travatan w/o BAK) and latanoprost (Xalatan, Pfizer) in an immortalized Human Cornea Epithelial Cell Culture System (HEC). They found that all three agents showed evidence of epithelial cell toxicity, with Travatan without BAK being significantly less toxic than Xalatan and gentamicin. "A noted difference between travaprost without BAK and Xalatan is the use of the preservative BAK in Xalatan," says Dr. Yee. "There may be important ramifications on the ocular surface, wound healing after LASEK, PRK, corneal ulcers and persistent epithelial defects in patients chronically using these IOPlowering drugs." For the study, tissue culture plates containing 10.014 pRSV-T HEC (2000-3000 cells/well) were divided into six groups (each with 48 wells). Two groups served as the live control. HEC were left in corneal epithelial culture media until the assay and Systane (Alcon), shown previously to be relatively non-toxic to epithelium.

The two test groups were exposed to 100 l of undiluted IOP lowering drugs and assayed after 25 minutes. A live/dead assay quantified the effects of Travatan without BAK and Xalatan on HCE compared to cells treated with Systane, gentamicin and the live and dead controls. "The least amount of HCE death was associated with the untreated live control and with the cultures treated with Systane," Dr. Yee says. "All other ophthalmic agents tested showed a statistically significant epithelial cell toxicity. Between the two agents, Travatan preserved without BAK showed significantly less toxicity than Xalatan as well as gentamicin and the negative control (methanol). Xalatan and gentamicin were similar in the amount of toxicity observed."

Additional Considerations Much of the use of antibiotics in ophthalmology is off-label for preventing infection perioperatively. "In the perioperative setting there could be a potential advantage when using an antibiotic with a preservative," says Dr. Snyder. "The enhanced killing rate may assist in sterilizing the operative field in those patients who begin their drops just before surgery, and the enhanced and effectively lower MIC may help maintain a sterile tear film free oF otherwise resistant organisms during the postoperative period while the wound is healing." The enhanced killing speed and the lower MIC levels may also be valuable when initiating therapy with a corneal- ulcer patient. "In bacterial keratitis, a fast-acting agent may translate into less tissue damage," he adds. "Therefore, it seems very intuitive that you would want the more potent combination of antibiotic and BAK as in Zymar. With the gatifloxacin plus BAK formulation of Zymar you can be certain that you deliver both components at the same time to optimize the opportunity for synergy."

1. Rahman MQ, et al. "Microbial contamination of preservative free eye drops in multiple application containers." Br J Ophthalmol. 2006 Feb;90:139-41. 2. E.G. Norcom, X.C. Zhao, R.W. Yee, A. Chunag, C. Mitchell. Comparison of the Relative Toxicity of Travoprost without BAC (Travatan w/o BAC) and Latanoprost (Xalatan) in an immortalized Human Cornea Epithelial Cell Culture System.(Accepted for future publication in Advances in Therapy.)