Coordinated by Bobby Christensen, O.D., F.A.A.O.

therapeutic insights
Vigamox: A New Weapon
The fourth-generation fluoroquinolone offers efficacy and safety across a broad population.
By Alan G. Kabat, O.D., F.A.A.O., Fort Lauderdale, Fla.

The landscape of ocular infection has changed drama-tically since the introduction of the topical fluoroquinolones in the early 1990s. The newest addition to this drug class, fourth-generation Vigamox (moxifloxacin 0.5% ophthalmic solution, Alcon Laboratories), will have an even greater impact on the treatment of ocular infection.

We need three things

Whenever we deal with ocular infection, we're potentially "playing with fire." Few ocular surface disorders carry such potential for rapid and irreversible vision loss. Permanent corneal scarring and even corneal perforation can occur in poorly managed bacterial infections. So it's imperative that practitioners use a therapeutic regimen that addresses the following points:

Speed. The drug must work quickly to eradicate the infectious organism and to prevent mutation and resistance.

Spectrum. A broad spectrum of activity is essential for today's antibiotics because culturing has become less common and many of the more common ocular flora (e.g., Staphylococcus aureus) have developed significant resistance to other commonly used antibiotics.

Safety. Above all, we must be sure that the agents used to treat ocular disease are safe and nontoxic to ocular tissues.

	Alcon's Vigamox received FDA approval in April.

Fluoroquinolones lead

While many antibiotics are available on the market, a lot of the more commonly used agents now have significant drawbacks. Sulfacetamide, tobramycin and other historically outstanding antibiotics have, in recent years, encountered a great deal of bacterial resistance and a high rate of ocular hypersensitivity reactions. It's not surprising that over the past 10 years, fluoroquino-lones have emerged as the leader in ophthalmic antibiosis. In managing conjunctivitis, fluoroquin-olones have proven to be extremely potent agents. For pre- and postoperative prophylaxis, virtually all surgeons today use a fluoroquinolone agent such as Ciloxan (ciprofloxacin 0.3% ophthalmic solution, Alcon) or Ocuflox (ofloxacin 0.3% ophthalmic solution, Allergan).

However, the real strength of this class of drugs is in managing bacterial keratitis.

How they work

The fluoroquinolones are so effective because they work by inhibiting the function of crucial bacterial enzymes involved in cellular replication. This leads to disruption of the DNA and prevents the bacterial colony from replicating, resulting in rapid death of the invading organism.

Specifically, fluoroquinolones target DNA gyrase and/or topoisomerase IV; Gram-negative bacteria are more susceptible to damage at the DNA gyrase site, while topoisomerase IV is more critical to Gram-positive bacteria. The new fourth-generation fluoroquinolones such as Vigamox have the capacity to block both of these enzymes simultaneously, making them more effective than some of the predecessors in this drug category.

Vigamox to the rescue

Another great benefit to Vigamox is its enhanced activity against a broader range of bacterial pathogens. Most would agree that the current "gold standard" among fluoroquinolones is ciprofloxacin. However, since the introduction of this drug, a fairly high resistance rate has developed among Gram-positive bacteria to ciprofloxacin and other second- and third-generation fluoroquinolones.

The fourth-generation fluoroquinolones differ chemically and pharmacologically from previous generations with respect to side chains located at the C-8 position. This side chain enhances bactericidal activity and prevents bacterial defenses from rendering the drugs inert. Additionally, Vigamox has a unique "bulky" side chain at the C-7 position that inhibits the cell's efflux pump mechanism, further enhancing its potency.

Subsequently, drugs such as Vigamox have excellent intrinsic activity against common Gram-positive pathogens as well as Gram-negative pathogens. Comparing Vigamox to our current "best" antibiotics, we've seen evidence of greatly enhanced activity against Gram-positive isolates. Many of the bacterial strains that have developed resistance to ciprofloxacin and ofloxacin over the past 10 years are fully susceptible to the active ingredient in Vigamox.

Better solubility, resistance

Vigamox works much faster to eradicate bacterial colonies than even ciprofloxacin, as demonstrated by time-kill curves. In addition, because it has a pH of 6.8, which is close to neutral (by comparison, cipro-floxacin has a pH of 4.5), it's more soluble in an ophthalmic formulation. This means that the drug can be formulated at a higher concentration than previous fluoroquinolones, which translates as greater bioavailability and ocular penetration. It also means greater comfort upon instillation.

Vigamox is also far less likely to contribute to bacterial resistance, a growing public health issue today. Not one, but two simultaneous mutations are required at the DNA gyrase and topoisomerase IV sites to achieve resistance, and the likelihood of this occurring naturally is practically infinitesimal.

A number of studies have shown that moxifloxacin is more potent than any of the existing fluoroquinolones. Mather and associates evaluated 93 specific bacterial isolates against ofloxacin, ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin. The minimum inhibitory concentration -- the lowest concentration of drug necessary to inhibit bacterial growth -- was determined for each of these isolates. Vigamox was equivalent or superior to the other four drugs tested in virtually all categories and was the clear leader against Gram-positive organisms overall.

Check out the competition

Vigamox will likely be compared to Zymar (gatifloxacin 0.3% ophthalmic solution, Allergan), the other fourth generation fluoroquinolone that received FDA approval. Gatifloxacin offers excellent efficacy and has been shown to be superior to most available antibiotics.

Mather's study showed that, overall, Vigamox is more potent against Gram-positive pathogens than any other topical fluoroquinolone. In considering concentration, Vigamox is formulated at 0.5% as compared to 0.3% for gatifloxacin.

Doctors can also dose Vigamox less frequently than other fluoroquinolones and still effectively eradicate ocular pathogens. In Phase III clinical trials, Vigamox was successful in treating bacterial conjunctivitis when administered t.i.d. for four days. By comparison, patients must use gatifloxacin every two hours for the first two days, and then q.i.d. thereafter for another five days.

As mentioned, Vigamox maintains a pH of 6.8, compared to a pH of 6.0 for gatifloxacin.

Self-preserving solution

Vigamox is the only fluoroquinolone that is self-preserved -- that is, the drug concentration is high enough that the solution doesn't require additional preservatives. Finally, Vigamox has been tested in adults and children as young as three days. Other fluoroquinolones are approved for one year of age and up. Erythromycin ointment and trimethroprim are available for those older than two months.

Off-label possibilities

While Vigamox is FDA approved for the treatment of bacterial conjunctivitis only, there's already speculation that many practitioners will use this particular agent in an off-label capacity almost immediately. Much in the same way that prostaglandin drugs became "first line" for glaucoma therapy even before the FDA approved that use, many practitioners will likely use Vigamox for corneal infections and peri-operative prophylaxis because of its superior efficacy and enhanced safety.

Other practitioners will likely hesitate to accept the new fourth-generation fluoroquinolones for routine care because of the "big gun" theory and fear of creating resistant strains of bacteria. In fact, this concern is an even greater argument for adopting drugs such as Vigamox as the standard of care for ocular infection. We've already witnessed resistance to second-generation fluoroquinolones, and continuing to use drugs such as ciprofloxacin and ofloxacin will undoubtedly further contribute to resistant bacterial strains.

In contrast, the development of Vigamox-resistant bacteria is exceedingly unlikely anytime in the near future because of the way the drug has been engineered. Unlike past fluoroquinolones, Vigamox shouldn't be kept on the shelf to be used "only in case of emergencies." In all situations we should consider where an effective therapeutic or prophylactic antibiotic is indicated.

Dr. Kabat is associate professor of Optometry and director of Residency Programs at Nova Southeastern University. You can reach him at (954) 262-1470 or at kabat@nova.edu.

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.

Editor's note: This month, "Therapeutic Insights" concludes its coverage of the new fourth-generation fluoroquinolones. In June, OM covered gatifloxacin 0.3% (Zymar by Allergan).