During the past few years, several articles have reported rising endophthalmitis rates.1 Whether this phenomenon is caused by the advent of clear corneal cataract surgery or by the bacteria's increasing rates of resistance against the older fluoroquinolones ciprofloxacin, ofloxacin, and levofloxacin, the following conclusion is logical: ophthalmologists need stronger weapons to protect their patients against postoperative infections. The arrival of the fourth-generation fluoroquinolones is therefore timely.

Given that, today, nearly all ophthalmic surgeons have decided to abandon the second and third generations for these more advanced fluoroquinolones, the question now is which of the two fourth generations provides the best protection against postoperative infection. At first glance, one might consider moxifloxacin (Vigamox; Alcon Laboratories, Inc., Fort Worth, TX) and gatifloxacin (Zymar; Allergan Inc., Irvine, CA) to be rather similar. However, a closer look at these two agents reveals significant differences in their attributes that translate into clinically significant distinctions in their advantages and benefits. The undisputable, tangible differences between moxifloxacin and gatifloxacin are found in their molecular structures as well as in their commercial formulations.

STRUCTURAL DISTINCTIONS

Both moxifloxacin and gatifloxacin have a methoxy group at the C-8 position that allows the two fluoroquinolones to bind with equal affinity to topoisomerase II and IV, thereby offering increased potency against gram-positive organisms compared with older fluoroquinolones. Only moxifloxacin, however, has a bicyclic side-chain at the C-7 position (Figure 1). This modification allows moxifloxacin to inhibit the bacterial cell's efflux pump mechanism and allows the drug to stay in the pathogens for a longer period of time. The longer the antibiotic stays in the cells, the greater the kill rate is. This important distinction may help explain why moxifloxacin offers greater potency and susceptibility when compared to gatifloxacin against gram-positive organisms, whether they are susceptible or resistant to fluoroquinolones.5,6 Vigamox, in fact, has a broader spectrum of activity than Zymar (Figure 2).

DIFFERENCES IN FORMULATION

Vigamox is concentrated at 0.5%, and Zymar at 0.3%. The higher the concentration of the active fluoroquinolone in each drop, the greater the likelihood of the drug's achieving larger concentrations throughout the ocular tissues. Additionally, Vigamox is formulated at a nearly neutral pH of 6.8, whereas Zymar has a pH of 6.0. This disparity can lead to significant differences in the solubility of the two agents at the normal ocular pH level near neutrality. These differences may explain why Vigamox achieves therapeutic concentrations at the target sites (cornea and aqueous) even against the fluoroquinolone-resistant pathogens, whereas Zymar does not.

Lastly, Vigamox is sufficiently robust not only to meet but to exceed all US Pharmacopoeia tests without the need for benzalkonium chloride (BAK).7 That Vigamox does not need a preservative is a direct result of the inherent antibacterial and antifungal activity of the moxifloxacin formulation. Zymar, on the other hand, is formulated with 0.005% BAK, a potentially toxic ingredient.

What do these differences mean to ophthalmologists in terms of selecting one antibiotic instead of the other? A fluoroquinolone's clinical efficacy is determined by potency and penetration. Relevant potency measures include the agent's spectrum and activity against the pathogens of most concern to ophthalmologists, and penetration is defined as the antibiotic's ability to reach the target sites, the cornea and aqueous, at therapeutic levels.

PATIENT PROTECTION

My colleagues and I are currently comparing the commercial preparation of Vigamox (moxifloxacin HCL ophthalmic solution 0.5%) to the commercial preparation of Zymar (gatifloxacin ophthalmic solution 0.3%). In a double-masked, randomized fashion, on the day prior to cataract surgery, patients are dosed q.i.d. with one of the two antibiotics. On the day of surgery, patients receive one more drop 1 hour prior to a cataract surgeon's entering the anterior chamber. We determine concentrations by high-performance liquid chromatography, which we perform in our laboratory. Results from this ongoing study indicate that Vigamox penetrates significantly better than Zymar. These initial findings confirm those reported by all other investigators who have evaluated the differences in penetration between these two topical agents.9,10

When comparing the MICs of moxifloxacin and gatifloxacin for the most common infection-causing endophthalmitis pathogens to the agents' achieved concentrations in the anterior chamber, we found that Vigamox achieved penetration levels that exceed the gatifloxacin MICs by a factor of 10 against susceptible strains. This level of penetration is of particular significance, because, as the literature shows, in order to be effectively and rapidly bacteriocidal and prevent bacterial mutations, the antibiotic must be at a concentration 10 times the MICs.11,12 Although Zymar's concentrations are inhibitory, they do not reach levels high enough to consistently kill such pathogens. Vigamox's concentrations meet the MICs for at least some of the most common resistant strains (ie, fluoroquinolone-resistant Staphylococcus aureus), although Zymar fails to reach therapeutic levels against such resistant pathogens (Figure 2).6

BIOCOMPATIBILITY OF FOURTH-
GENERATION FLUOROQUINOLONES

Although potency and penetration define a fluoroquinolone's clinical efficacy, before adding any new product to your therapeutic armamentarium, it is of critical importance to validate the safety and overall biocompatibility of such agents. We ophthalmologists are very fortunate to have a fluoroquinolone class of products that is very safe, with little-to-no ocular toxicity. The safety of both Vigamox and Zymar have been investigated during their FDA trials as well as in postapproval surveillance. Animal and human models have also validated their biocompatibility in settings most relevant to ophthalmic surgeons.13-18 Sami et al14 compared Vigamox's and Zymar's safety. The study model evaluated potential differences in corneal wound healing patterns with the topical use of commercial formulations of these two agents in patients undergoing bilateral PRK. Results showed no difference in the time of wound closure between the Vigamox and Zymar groups. There was also no difference in haze grading or postoperative UCVA (Figure 3). These findings underline the clinical safety of these new fourth-generation agents and confirm the work done by others, as well as the clinical experience of ophthalmologists such as myself who have been routinely relying on these fourth-generation agents for well over a year now.13-19

WHY I CHOOSE VIGAMOX

Although Vigamox's lack of BAK may enhance its biocompatibility, I believe that both it and Zymar offer excellent clinical safety. My selection criteria therefore relate to which of these two agents best protects the cornea and aqueous against the pathogens of most concern to ophthalmologists. Vigamox's superior spectrum of activity against such pathogens (Table 1) as well as its solubility translate to more efficacy at the target sites.

The fourth generation arrived, bringing a promise of efficacy even against some of the fluoroquinolone-resistant pathogens. Due to its superior potency and penetration, Vigamox is the only topical fluoroquinolone capable of maintaining such activity all the way to and through the anterior chamber. All of the aforementioned factors make me confident that Vigamox is the best line of defense against postoperative infection and are the reasons why I choose Vigamox.

James P. McCulley, MD, is Professor and Chairman of the Department of Ophthalmology at The University of Texas Southwestern Medical Center in Dallas. He is a paid consultant for Alcon Laboratories, Inc., but states that he holds no financial interest in any product or other company mentioned herein. Dr. McCulley may be reached by fax at (214) 648-9061; james.mcculley@utsouthwestern.edu.

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