New anti-infectives under development will boast broader spectrum activity

Issue: July 2000

While fluoroquinolones have surpassed aminoglycosides and antibiotics as many practitioners’ first choice for the treatment of ocular infections, concerns about reports of microbial resistance and a lack of adequate gram-negative and gram-positive coverage have prompted researchers to seek alternative treatments.

Ciprofloxacin and ofloxacin, quickly becoming the gold standards of fluoroquinolone treatment, may soon be joined by a variety of other choices, said Ron Melton, OD, in private group practice in Charlotte, N.C. “There have been reports about a lot of resistance developing against Pseudomonas aeruginosa and Staphylococcus aureus, which are two organisms that concern us in eye care,” he said. “Staphylococcus is the most common, and Pseudomonas is the most devastating. With this evolving resistance, companies are looking for alternative medications.”

Bausch & Lomb is one such company. A combination of loteprednol/tobra-mycin is undergoing phase 2 clinical trials and should begin phase 3 trials later this year, said Brian Levy, OD, MSc, vice president of biological and clinical research at Bausch & Lomb. “One of our strategies is to look for new actives, much of which is currently in the feasibility research phase,” he said.

Echelon, based in Wayne, Pa., is currently studying Betadine (povidone-iodine, 2.5%) for the prevention of ophthalmia neonatorum (newborn conjunctivitis), said Dr. Melton. “They are in phase 3 trials with this,” he said. “It is something new and interesting. There have been some reports that povidone-iodine may even be beneficial against adenoviral conjunctivitis.”

Broader spectrum levofloxacin

Santen Pharmaceutical Co. filed a New Drug Application with the U.S. Food and Drug Administration (FDA) on March 1 for Quixin (levofloxacin 0.5%) with the proposed indication as treatment of bacterial conjunctivitis. “It is a levo-isomer of ofloxacin, which gives its major benefit of increased potency and, possibly, once-a-day dosing,” said Dr. Melton.

The solubility factor of levofloxacin allows the drug to be available in different formulations, said Terrence P. O’Brien, MD, director of ocular infectious diseases at the Wilmer Eye Institute in Baltimore. “The feature that makes it attractive is its solubility, allowing it to be formulated at higher concentrations than the current commercial quinolone anti-infectives, which are at 3 mg/mL. Thus, one could have a sort of fortified quinolone with levofloxacin,” said Dr. O’Brien.

“The drug has gone through phase 3 FDA trials in the United States for therapy of acute bacterial conjunctivitis and has been shown to be safe and as effective as other current treatments for conjunctivitis,” he continued. “Trials are beginning now for the indication of bacterial keratitis; it will be interesting to see how levofloxacin compares to the other compounds.”

Gatifloxacin, moxifloxacin

Tequin (gatifloxacin, Bristol-Myers Squibb), currently available as a systemic medication, is also undergoing phase 3 clinical trials as a treatment for bacterial conjunctivitis, said Dr. Melton. “It seems to have a broad spectrum of activity against gram-positive bacteria, specifically staph, but it’s not very effective against Pseudomonas,” he noted. “So it more than likely will not be approved for the treatment of corneal ulcers as a result of its lack of covering Pseudomonas, but it looks like it will be a very good antibiotic drug for the “garden variety” bacterial conjunctivitis.”

Dr. O’Brien agreed that gatifloxacin boasts an expanded spectrum of activity and that it “possibly may be less prone to the development of resistance,” he said. “But that remains to be seen.”

Moxifloxacin, an oral antibiotic recently approved by the FDA under the name of Avelox (Bayer), may also provide additional coverage, said Dr. O’Brien. “Moxifloxacin has a broad spectrum of activity in vitro and improved coverage for certain organisms against which current fluoroquinolones are not completely effective, including strep, in particular,” he said.

Effects of trovafloxacin on the eye

Dr. O’Brien said that he has participated in studies with the expanded-spectrum fluoroquinolone trovafloxacin, which garnered favorable results. “It has a similar spectrum of activity to some of the current commercial fluoroquinolones with respect to its coverage of gram-negative ocular pathogens,” he said. “When we tested it in vitro, screening against gram-negative ocular isolates, the activity was comparable to that of ciprofloxacin; there was no significant difference.

“The exciting thing about it is its broader spectrum of gram-positive coverage, which not only includes staphylococci, but improved coverage of streptococci, anaerobic organisms, enterococci and some gram-negative organisms that are not covered well by the current commercial fluoroquinolone,” he continued. “It does indeed appear to offer this expanded spectrum of activity.”

In vivo studies were performed on experimental rabbit models with Staphylococcus, Streptococcus pneumoniae and P. aeruginosa keratitis; trovafloxacin was compared to ciprofloxacin and ofloxacin, Dr. O’Brien said. “We found that the activity of trovafloxacin was comparable to that of ciprofloxacin therapy of P. aeruginosa keratitis but superior to that of either ciprofloxacin or ofloxacin therapy of S. pneumoniae and Staphylococcus keratitis,” he said. “So it does indeed appear to offer an expanded spectrum of activity.”

He added that, in observing the pharmacokinetics, it was noted that trovafloxacin penetrated well into the corneal tissue. While slightly less soluble than either levofloxacin or ofloxacin, he said, a parenteral formulation is available from Pfizer, who manufactures Trovan, the systemic medication. When studies had been completed, he said, there was some concern regarding potential toxicity stemming from systemic usage of the drug, which has been associated with liver enzyme abnormalities.

“So now, its use is somewhat restricted systemically, and what this will do to the development of a topical formulation is somewhat uncertain,” Dr. O’Brien said. “The company was initially interested in proceeding with the development of an eye drop formulation, but, based on their concerns about systemic toxicity, the development of an eye drop is now on hold.”

New anti-infectives on horizon

According to Dr. O’Brien, the ophthalmic industry will witness much activity with these new products in the near future, due in part to a desire to keep the incidence of microbial resistance down. “This is an exciting time in the development of ocular anti-infectives,” he said. “The industry and researchers are working together to develop newer compounds, and I think we will see some of them come onto the ophthalmic scene in the near future.”

For Your Information:

Ron Melton, OD, is in private group practice and is a member of the Editorial Board of Primary Care Optometry News. He may be reached at 1918 Randolph Rd., Charlotte, NC 28207. Dr. Melton has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Brian Levy, OD, MSc, is vice president of biological & clinical research at Bausch & Lomb. He may be reached at 1400 North Goodman St., PO Box 450, Rochester, NY 14603-0450; (800) 828-1430; (716) 338-0273

Terrence P. O’Brien, MD, is director of ocular infectious diseases at the Wilmer Eye Institute, 600 N. Wolfe St., Wilmer Woods 255, Baltimore, MD 21287-9121; (410) 955-1671; fax: (410) 614-0682. Primary Care Optometry News could not confirm whether or not Dr. O’Brien has a direct financial interest in any of the products mentioned in this article or whether he is a paid consultant for any companies mentioned.