rx perspective
Refractive Surgery Prophylaxis
New options in fluoroquinolones spark a fresh, and ongoing, body of research to be evaluated.

Atypical Mycobacteria a Major Culprit
By Terrence Kim, M.D.

The incidence of LASIK-associated infections is now quoted in some studies to be as high as 1:1,000. Interestingly, atypical mycobacteria account for about half of the LASIK infections reported in the peer-reviewed literature. Here at Duke, we've had the opportunity to treat a number of LASIK-associated infections, some of which have been caused by unusual organisms. Our limited experience has shown us that they can be very difficult to diagnose and manage.

Better prophylactic coverage against these atypical organisms --as well as gram-positive and fluoroquinolone-resistant organisms -- is a major reason why the new fluoroquinolones are important.

Human Data Emerging

At our facility, we use moxifloxacin (Vigamox) because of its potency and penetration and because it's self-preserved.

Ophthalmologists have been bombarded with numerous studies reporting the potency of various fluoroquinolones. Of these, the Mather study (published in the April 2002 issue of American Journal of Ophthalmology) constitutes a well-designed, independent study highlighting the superior potency of moxifloxacin compared with other fluoroquinolones against gram-positive organisms, notably Streptococcus and Staphylococcus.

In addition, moxifloxacin provides improved coverage of atypical mycobacteria. Ocular isolate studies (such as Shah, et al., ARVO 2003) have demonstrated the increased potency of moxifloxacin over second- and third-generation fluoroquinolones against various atypical mycobacterial species (i.e., M. fortuitum and M. gastri).

The unique formulation of moxifloxacin (with a higher concentration of 0.5% and physiologic pH of 6.8) will result in therapeutic penetration as well as the absence of precipitation. Preliminary results from a multicenter, FDA-approved study of aqueous humor concentrations in human eyes confirm the superior penetration of moxifloxacin previously demonstrated by in vivo rabbit studies (Robertson et al., ARVO 2003).

Human data such as this will reassure ophthalmologists that Vigamox will reach the target tissue in an effective concentration to be bactericidal, providing adequate protection against endophthalmitis and keratitis following cataract and refractive surgery.

Our New Regimen

Also, Vigamox is self-preserved; it doesn't contain benzalkonium chloride (BAK). This will minimize potential toxicity, especially during treatment of an infection where antibiotic loading and dosing may be frequent. An antibiotic that interferes the least with epithelial healing will benefit our patients.

Our current antibiotic dosing regimen for prophylaxis in LASIK involves using Vigamox every 10 to 15 minutes during the hour before surgery, ensuring that the patient receives three to four doses. (While some surgeons may start prophylactic antibiotic dosing 1 to 3 days before surgery, the superior penetration data on Vigamox make us comfortable starting prophylaxis dosing the day of surgery.) We also apply two or three drops of antibiotic directly on the flap at the conclusion of the LASIK procedure, after 2 to 3 minutes of flap drying.

Following surgery, we place our patients on antibiotic four times a day for 4 days.

Hit the "Bugs" Hard

Several studies have confirmed patterns of increasing bacterial resistance to our second- and third-generation fluoroquinolones. In my opinion, this is the most compelling reason to switch to a fourth-generation fluoroquinolone: preventing development of bacterial resistance.

The traditional teaching of reserving the stronger antibiotics for the more severe infections doesn't apply to this advanced generation of fluoroquinolones. Switching over to a new antibiotic like Vigamox sooner will help prevent resistant organisms from becoming a more serious problem.

Terry Kim, M.D., is an associate professor of ophthalmology and associate director of cornea and refractive surgery services at Duke University Eye Center, Duke University School of Medicine, in Durham, NC.

LASIK is Its Own Prophylactic Challenge
By Terrence P. O'Brien, M.D.

Laser vision correction techniques are classified as "surgically clean" rather than completely sterile. The risk of contamination is especially serious in LASIK:

► LASIK involves devices such as microkeratomes and excimer lasers, which can't be completely heat-sterilized.

► LASIK creates a new space between the cornea lamellae, which microorganisms can invade.

► Corneal nerves are temporarily severed, which can impede normal corneal defenses.

► Surgeons may use postoperative agents such as topical anti-inflammatory corticosteroid drugs; these can make the eye more susceptible to infection and reduce its ability to respond adequately to wound contamination. (They can also relieve symptoms temporarily, creating a false impression of clinical improvement.)

Considering the danger of contamination, increased rates of infection associated with LASIK, the frequent appearance of less typical organisms and increasing resistance to existing fluoroquinolones, the need for new antibiotic agents has never been greater.

Potency and the Preservative Question

Analysis of the in vitro susceptibility data or experimental models of infection indicate that gatifloxacin and moxifloxacin are fairly similar with respect to their intrinsic antibacterial activity and effectiveness against commonly encountered gram-positive ocular pathogens. Antibiotic concentration and intraocular penetration are perhaps of less practical importance for refractive surgery than for cataract surgery.

► Vigamox (moxifloxacin 0.5%) comes in a higher concentration than Zymar (gatifloxacin 0.3%), but both are more than capable of significantly reducing contamination of the ocular surface, alone or in combination with a dilute antiseptic such as povidoneiodine 2.5%.

► Similarly, both of these fluoroquinolones have a pharmacokinetic profile that allows sufficient penetration into the corneal epithelium and anterior stroma to be effective for prophylaxis in refractive surgery. In these procedures, the antibiotic is applied mainly for surface decontamination, and the ability of the antibiotic drug to penetrate into the lamellar interface in LASIK. Because the flap is on average only 120 to 160 microns thick, so the drug doesn't have to penetrate very far to be effective.

However, there are a few differences that cause me to favor gatifloxacin for use in refractive surgery:

Efficacy. Compared to moxifloxacin, gatifloxacin has demonstrated slightly superior in vitro activity against the nontuberculous mycobacterial species, like Mycobacterium cheloneae and others that are being seen with increasing frequency after LASIK and other refractive surgeries.

The addition of BAK. Unlike Vigamox, Zymar is formulated with a very low concentration (0.005%) of benzalkonium chloride (BAK). This has two advantages: First, BAK is a potent preservative agent, so it helps protect against the possibility of contamination during patient use. (A number of studies have shown a significant potential contamination of medications used by patients over time.) Second, BAK is also an effective antiseptic agent with rapid bactericidal effects that works in combination with the gatifloxacin to eliminate potential pathogens and to protect the eye during the vulnerable perioperative period.

Of course, BAK is a double-edged sword. Preservatives are known to be potentially cytotoxic, especially when used at higher concentrations and very frequent dosing intervals. However, in refractive surgery we're usually talking about lower frequency dosing over a short period.

In fact, it's been shown that at the 0.005% concentration -- and even somewhat higher concentrations found in other eyedrops -- BAK is not significantly toxic to corneal epithelial cells. Ofloxacin and ciprofloxacin formulations having higher BAK concentrations were used extensively in perioperative topical prophylaxis for a number of years without surgeons noticing excessively adverse toxic effects. Given this fact, I see the inclusion of BAK at this concentration as a potential advantage.

Post-Op Dosing Can Be Reduced

We apply gatifloxacin 0.3% eyedrops every 2 minutes, for a total of 3 doses, before the patient is brought into the laser room. (This is similar to the protocol we used with the older fluoroquinolones.)

Once the patient is in the laser room, we introduce a viscous lubricant such as carboymethylcellulose 1%, followed by a drop of dilute antiseptic povidone iodine 2.5% solution instilled directly onto the ocular surface. (The lubricant helps to protect the epithelium.)

After the excimer laser ablation and flap repositioning, we apply a few additional drops of gatifloxacin to the surface of the cornea while the flap is adhering. (We don't recommend placing any fluoroquinolone antibiotic directly on the stromal bed, to avoid subjecting keratocytes to unnecessary toxicity.)

Postoperatively, because of the increased potency of the new fluoroquinolones, we reduced the frequency of use to three times a day for a period of 3 to 5 days. Of course, we make certain that the patient doesn't taper the antibiotic, which would invite the development of resistance by increasing the selection pressure for resistant organisms.

The broad spectrum of activity and potent bactericidal action of gatifloxacin combined with its favorable formulation and eyedrop characteristics make it an exciting addition to the available ophthalmic antibacterial agents.

Dr. O'Brien is director of refractive eye surgery and ocular infectious diseases at The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Md. He has studied ophthalmic fluoroquinolones in vitro and in vivo extensively in the Wilmer Ocular Microbiology Laboratory that he directs.

Higher Concentration Coming Soon

Based on concentration, penetration, safety and efficacy," says Edward J. Holland, M.D., "levofloxacin (Quixin) is a good choice for the highly demanding refractive surgery patient." And according to Marguerite McDonald, M.D., the soon-to-be-available levofloxacin 1.5% provides three times the highest fluoroquinolone concentration currently available, with no deleterious side effects. "We recently tested levofloxacin 1.5% in a non-human primate penetrating keratoplasty study, dosing the drop in a typical perioperative regimen," she says. "Timed corneal and aqueous humor samples indicated that this concentration is remarkably non-toxic and safe, even when we studied the stromal keratocytes, the most sensitive of all the corneal cell lines."

Debra L. Skelnik, a leading tissue culturist known for her work in cell biology, recently analyzed the cytotoxicity of all five currently prescribed fluoroquinolones in human corneal endothelial cells and human corneal keratocytes. "Levofloxacin was the least cytotoxic across different exposure times and concentrations," Skelnik explains. (For more details, see "A Look at Some Recent Studies".)

Dr. Holland emphasizes three points. "First, the higher concentration means higher fluid and tissue concentrations early in the short-term course that's now being prescribed postoperatively," he says.

"Second, levofloxacin's tissue penetration has been proven in human studies." Dr. Holland reported the results of one of those studies at the 2003 ARVO meeting. "We compared the penetration of levofloxacin, ofloxacin, and ciprofloxacin in aqueous fluid and corneal tissue after topical administration in human volunteers. After dosing with 1 drop at 15 minutes and 1 drop at 10 minutes, levofloxacin achieved significantly higher concentrations in aqueous fluid than ofloxacin or ciprofloxacin. Levofloxacin was also present in corneal stromal tissue in significantly higher concentration than ciprofloxacin." He notes that a lack of human data regarding penetration for the newest fluoroquinolones makes direct comparison impossible.

"Third," he says, "levofloxacin has an excellent safety profile. Trial data have shown a 1% to 3% side effect rate."

In another study reported at ARVO, Shah and colleagues demonstrated that levofloxacin, moxifloxacin, and gatifloxacin were equally effective against M. chelonae and M. gastri in 16 atypical mycobacterial cultures. Other ARVO data from Alfonso et al., demonstrated that 24 isolates of M. chelonae/M. abscessus were all resistant to levofloxacin, moxifloxacin, and gatifloxacin.