New combinations, formulations at the forefront of anti-infective treatment

The area of ocular anti-infective treatment continues to advance, with many of the major pharmaceutical companies currently developing new drugs or combinations. The recent Food and Drug Administration approvals of Zymar (gatifloxacin ophthalmic solution 0.3%) from Allergan and Vigamox (moxifloxacin ophthalmic solution 0.5%) from Alcon were a large part of these advances.

Currently, Bausch & Lomb, Alcon and Santen have antibiotic/steroid combination drugs in the pipeline. In addition, Allergan recently received FDA approval for a new formulation of its nonsteroidal anti-infective drug Acular (ketorolac tromethamine) that can be used in combination with fourth-generation fluoroquinolone Zymar.

Representatives of Alcon and Santen told Primary Care Optometry News that they felt it would be premature to discuss their upcoming products at this time.

Loteprednol etabonate and tobramycin

Bausch & Lomb has developed a combination drug using the steroid loteprednol etabonate and the antibiotic tobramycin.

“This is an ophthalmic suspension product containing loteprednol etabonate and tobramycin,” said Rob Meyering, vice president of pharmaceutical business for Bausch & Lomb. “We are looking forward to filing a new drug application this year, and we hope it will be approved in 2004.”

Mr. Meyering explained that loteprednol etabonate is a steroid currently marketed in the United States under the brand name Lotemax (Bausch & Lomb). Tobramycin is an aminoglycoside antibiotic, marketed both as a single entity, Tobrex (Alcon), and as part of existing combinations. The most popular of these combinations is a product called TobraDex (tobramycin/dexamethasone, Alcon), Mr. Meyering said.

“The primary difference between TobraDex and our new combination is that we are putting in Lotemax rather than dexamethasone,” Mr. Meyering said.

Ketone steroids and ester steroids

Mr. Meyering said loteprednol is designed to be a “site active” corticosteroid and contains an ester group in its molecular structure. Lotemax has been widely used since 1998 and possesses a broad range of indications.

“All other steroids, such as prednisolone, dexamethasone and fluorometholone, are in the ketone class of steroids,” he told Primary Care Optometry News. “And because it is from an entirely new class of steroids, loteprednol has remarkably improved safety advantages vs. ketone steroids.”

The structural difference allows for naturally occurring esterases in the eye to break down loteprednol into inactive metabolites after loteprednol exerts its effect.

Among the safety benefits of loteprednol is a lower incidence of intraocular pressure increases, Mr. Meyering said.

In studies of 28 days or longer sponsored by Bausch & Lomb, prednisolone acetate 1% was found to produce a clinically significant increase in IOP (>10 mm Hg) in 6% of patients, vs. 1% of patients on Lotemax.

“One of the more significant safety advantages, which has been proven over 4 years of clinical use, is that there has been nowhere near the number of intraocular pressure spikes that you would normally have expected from certain steroid-responding types of patients,” he said. “There is an increased margin of safety that has proven to be clinically significant over the past 4 years on the market, as well as in our clinical trials.”

Mr. Meyering also discussed the role played by tobramycin, which is classified as an aminoglycoside antibacterial.

Aminoglycosides are antibacterials used primarily to treat infections caused by susceptible aerobic gram-negative bacteria.

“Aminoglycosides are good agents, are time-tested and cover a broad spectrum of both gram-positive and gram-negative pathogens,” he said. “Tobramycin has been a real workhorse over the past decade in general ophthalmic anti-infective treatment.”

Allergan’s reformulation of Acular

Allergan plans to launch a reformulation of its nonsteroidal anti-inflammatory drug (NSAID) Acular, which can be used with the fluoroquinolone Zymar and the steroid Pred Forte (prednisolone acetate, Allergan).

According to a company press release, Acular LS 0.4%, which received FDA approval in early June, is a new formulation of ketorolac tromethamine indicated for the reduction of ocular pain and burning/stinging following corneal refractive surgery. A third-quarter 2003 launch is anticipated.

According to Jane Wolf, marketing manager for Zymar, the new, optimized formulation of Acular LS will likely be used along with Zymar and Pred Forte. She said it is common for physicians to prescribe an anti-infective, a steroid and an NSAID.

“Fluoroquinolones have really become standard of care for eye care practitioners,” said Ms. Wolf.

Zymar will now provide better coverage of gram-positive pathogens and atypical organisms, she said. “By prescribing Zymar, practitioners may be able to extend the life of fourth-generation fluoroquinolones by slowing the mutation of the first step in the development of bacterial resistance.”

Vigamox and Zymar

One of the most notable recent developments in anti-infective treatment is the FDA approvals of fourth-generation fluoroquinolones Vigamox and Zymar.

These approvals come at a time when the newest fluoroquinolones are better than ever, boasting improved solubility, improved penetration and greater spectrum of activity. Both of these new fluoroquinolones have an increased affinity for topoisomerase IV and are also effective for DNA gyrase.

Vigamox is a topical fourth-generation fluoroquinolone approved for treatment of bacterial conjunctivitis. Clinical trials showed Vigamox to be effective in the treatment of gram-positive bacteria, including Staphylococcus and Streptococcus. It is also highly active against Chlamydia, according to Alcon.

Pediatric patients with bacterial conjunctivitis can be safely treated with moxifloxacin, according to a study released by the drug’s manufacturer at the Association for Research in Vision and Ophthalmology meeting held in Ft. Lauderdale this spring.

In a poster presented by members of the Alcon research team, moxifloxacin was studied in a group of 728 patients dosed with the drug either twice or three times daily, to evaluate adverse effects. The pediatric population consisted of 336 patients ranging from newborn (age 0 to 27 days) up to adolescents (age 12 to 17). The nonpediatric patient population consisted of 352 adults between 18 and 64 years of age and 40 elderly people.

Overall, there were few differences in safety and tolerability between pediatric and nonpediatric patients, the study showed. The pediatric patients exhibited more ocular discomfort (1.8%) and upper respiratory infection (2.7%), but there was no indication that Vigamox was associated with these symptoms. These symptoms were similar in incidence in the placebo group.

There were no safety concerns observed in any age group based on the measured ocular and nonocular safety parameters, including visual acuity, ocular signs, fundus parameters and cardiovascular parameters.

Zymar was approved for treating bacterial conjunctivitis caused by susceptible strains of bacteria.

In an Allergan-sponsored study presented at ARVO, researchers concluded that substantial percentages of gram-positive species isolated from bacterial conjunctivitis patients in the study were resistant or intermediately resistant to levofloxacin and ciprofloxacin; however, the same isolates were susceptible to gatifloxacin.

M. Long and H.G. Jensen stated: “Compared to older fluoroquinolones, gatifloxacin displays clearly improved activity against gram-positive ocular bacteria in vitro.”

Gatifloxacin also contains the preservative benzalkonium chloride.

“Oftentimes, people think of a downside to preservatives and forget about the up-side,” said Randall J. Olson, MD, of the University of Utah School of Medicine. “But benzalkonium chloride has been around for a long time, and is a tried-and-true standard of preservative for multi-use drop bottles.”

Dr. Olson told Primary Care Optometry News that this preservative can be very useful against yeast, fungus and various types of bacteria.

For Your Information:

• Rob Meyering is vice president of pharmaceutical marketing for Bausch & Lomb. He can be reached at 8500 Hidden River Pkwy., Tampa, FL 33637; (813) 975-7700; fax: (813) 975-7701.
• Jane Wolf is product manager for Zymar. She can be reached at Allergan, 2525 Dupont Drive, Irvine, CA 92612-1599; (714) 246-4500; fax: (714) 246-4214.
• Randall J. Olson, MD is a professor at the University of Utah School of Medicine. He can be reached at 50 North Medical Drive, Salt Lake City, UT 84132; (801) 581-2352; fax: (801) 581-3357.