therapeutic insights
An Irresistible Antibiotic
An in-depth look at Allergan's new fourth- generation fluoroquinolone, gatifloxacin.
By Marc Bloomenstein, O.D., F.A.A.O., Phoenix, Ariz.

Survival of the fittest is the term Charles Darwin used to describe the manner in which species of living organisms allow only the strongest and most resilient genes to flourish. Because all species undergo mutations, only those genes that can withstand the rigorous environment will burgeon and endure.

Today's bacteria

The theory of survival of the fittest is most evident in the strains of bacteria and viruses that scour the earth. They survive by overcoming every obstacle thrown in their path through adaptation, change and even incorporation of the enemy into their own gene pool. This ability keeps physicians and chemists aimed at staying one step ahead of the bacteria and viruses.

We're fortunate to have a whole host of antibiotics to ward off these evil, durable bugs. In this war, we need to become more fit than our enemy -- and that includes expanding our pharmaceutical armamentarium.

Third-generation quinolones popped up in the early 1990s and quickly became our antibiotic of choice. Now the newest generation fluoroquinolones make up more than 70% of all topical antibiotic prescriptions that eyecare practitioners write.

Unfortunately, certain strains of bugs have found a way to foil even the most stalwart of antibiotics. For instance, researchers have shown that the incidence of resistance of Staphylococci aureus isolates among keratitis and conjunctivitis in the last 6 years is 19.4% -- a 166% increase from the first 6 years after the introduction of ciprofloxacin.

Miami's Bascom Palmer Eye Institute analyzed minimum inhibitory concentration (MIC) susceptibility profiles for 1,182 culture-positive patients who had S. aureus keratitis and conjunctivitis. The researchers concluded that there is an emergence of fluoroquinolone resistance among methicillin-sensitive S. aureus keratoconjunctivitis isolates. These findings, as well as others, prompted a demand for newer drugs less resistant to these isolates, which led to the development of fourth-generation fluoroquinolones such as gatifloxacin, by Allergan.

Getting to know gatifloxacin

Gatifloxacin is a synthesized 6-fluoro-8methoxy quinolone with a broader antibacterial spectrum against Gram-positive and Gram-negative organisms than third-generation quinolones.

Results from ongoing clinical trials prove that gatifloxacin is superior to its third-generation predecessor, oflocaxin (Ocuflox, also by Allergan), in regard to greater absorption, higher penetration capabilities and superior pharmacodynamics and kill curves. Furthermore, gatiflox-acin has good water solubility, stable metabolism, low phototoxicity and a low degree of interaction with nonsteroidal anti-inflammatory drugs.

Confirming suspicions

During in-vitro studies, researchers found that gatifloxacin had a broader range of coverage and that organisms resistant to the second- and third-generation fluoroquino lones are sensitive to this new drug. Moreover, an in-vitro study performed at the University of Pittsburgh demonstrated that coagulase-negative Staphylococci isolates that were resistant to oflocaxin were statistically susceptible to gatifloxacin. They also confirmed that gatifloxacin is more potent against Gram- positive bacteria than the second- and third-generation fluoroquinolones.

Equally important is the new ability of gatifloxacin to hold off mutations that typically lead to resistance. Gatifloxacin targets the DNA enzymes responsible for replicating organism resistance, which in turn produces less frequent spontaneous bacterial resistance.

Waiting in the wings

The newer fluoroquinolones need a double mutation to enable resistance whereas the third-generation antibiotics only needed a single mutation. This may become important in the continuous use of these drugs with cataract and keratorefractive surgery. For example, we currently use third-generation fluoroquinolones pre- and post-op and although we haven't had a bacterial infection in the more than 35,000 laser-assisted in situ keratomileusis (LASIK) procedures we performed, the resistance percentage may rise with continual exposure and continued growth in LASIK cases. When resistance to these third-generation drugs becomes a problem, that's when we'll need to turn to gatifloxacin.

Promising applications

Gatifloxacin may hold the greatest potential for protecting the eye from intraocular infections after surgery. Using gatifloxacin, with its greater absorption, we hope that more of the drug is reaching the anterior chamber, ultimately penetrating into the vitreous and reaching therapeutic levels.

Ocular infections with the Gram-negative pathogen Pseudomonas aeruginosa, as demon-strated by U.S. and Canadian researchers, require aggressive therapy. These researchers evaluated gatifloxacin vs. ciprofloxacin in a corneal ulcer model of P. keratitis in rabbits. These researchers reported that gatifloxacin 0.3% is at least as effective as ciprofloxacin at healing corneal ulcers infected with P. aeruginosa, even when gatifloxacin is dosed less frequently. This greater potency combined with increased patient compliance will allow greater protection and less toxicity with quicker healing.

Turning to the big guns

Traditionally we've saved our big guns for the really ugly battles, but with patents for third-generation fluoroquinolones set to expire between 2003 and 2004, Allergan and Alcon will then have new big guns to provide eyecare practitioners with fight the resistant bugs. Because bacteria is constantly adapting and changing to survive, we need to reinvent our pharmacologic thought processes accordingly. Gatifloxacin (with the increase in absorption, potency and less frequent spontaneous resistance) is a prototypical Darwinian medication possessing all of the elements to keep even the most resilient isolates at bay.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.

Dr. Bloomenstein is the Refractive Clinic medical director at the Barnet Dulaney Perkins Eye Center. He lectures and writes on numerous refractive topics and is currently working with the FDA as a clinical investigator on different refractive procedures. He's also past president of the Arizona Optometric Association. Dr. Bloomenstein does not have any financial interest in any product mentioned in this article.