New drugs best weapons against changing pattern of post-LASIK infections

Unusual infectious agents are emerging as a concern, and new fluoroquinolones are rising to the challenge.

When refractive surgeons think about the prophylaxis and treatment of infections, the major issues that come to mind are effectiveness, safety and concerns about growing drug resistance. Considering these factors and the growing number of opportunistic infections after LASIK, the new generation of fluoroquinolones are the best drugs for today’s “bugs.”

Prophylaxis rationale

The best strategy to prevent infection in LASIK patients is to do the same things we do in cataract surgery: examine the lids and lacrimal sac and aggressively treat any blepharitis or dry eye, concentrating on eliminating the gram-positive bacteria that come from the normal flora of the eye by using prophylactic antibiotics.

Whatever antibiotics we use for prophylaxis, we want to use them in a way that will give us adequate tissue concentrations of drug in a timely fashion prior to surgery. We know that the organisms that cause infection are most likely to get into the eye at the time of surgery. We also have to consider patient convenience and demands on the office staff.

Several studies have looked at the role of preoperative antibiotics starting several days before surgery. In this approach, the patient is sent home with a bottle of antibiotics and instructed to start using them between 3 and 5 days before surgery, typically four times a day. Other studies have looked at starting the antibiotics on the day of surgery. Certainly there are advantages and disadvantages to each method, and surgeons are divided into two camps.

Change of approach

Starting the antibiotics several days before surgery will help us achieve as high a level of drug as possible in tissue and intraocularly by the time of surgery. That is the approach I used previously. But there are disadvantages to that method, including dependence on the patient to remember to administer the medication and the potential risk of corneal toxicity, which can occur with any preserved medication.

The route I now take is to start the medications on the day of surgery. The staff administers the antibiotic along with the other preoperative medications, every 5 to 10 minutes for three doses. Studies have shown that this gives excellent levels of drug in the conjunctiva, cornea and anterior chamber. Moreover, patients do not have to worry about taking the drops, and the office staff does not have to take phone calls from patients who forget when and how to use the medication. After surgery, the patient is sent home with the same bottle and is instructed to continue using the drops four times a day for 5 to 7 days.

Antibiotic of choice

The best method of antibiotic administration before LASIK may still be under debate, but the fluoroquinolones have clearly emerged as the preferred class of drug. The early-generation ophthalmic fluoroquinolones — principally ofloxacin and ciprofloxacin — were wonderful improvements to the armamentarium when they were introduced. They are well tolerated by ocular tissues because of their low toxicity, which is especially important for a prophylactic agent used in elective surgery.

The inhibition of the supercoiling action of DNA gyrase by the fluoroquinolones is an excellent method to halt the colony-forming activity of the most common ophthalmic pathogens. This route of action is effective enough to make the fluoroquinolones bactericidal, and we certainly want a bactericidal medication rather than one that is simply bacteriostatic. The spectrum of this bactericidal activity is also fairly wide, offering a good defense against gram-negative organisms.

But there is a gap in the coverage of gram-positive organisms, especially Streptococcus, by ofloxacin and ciprofloxacin. We are now beginning to see subsequent generations of fluoroquinolones — levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, and others — becoming available in ophthalmic preparations. It is exciting to see the corneal and anterior chamber concentrations that these drugs are achieving or, in the case of drugs under development, have the potential to achieve. It is even more exciting to see the spectrum of activity of these new drugs.

Latest ophthalmic quinolone

Quixin (levofloxacin, Santen) is the first topical ophthalmic fluoroquinolone to become commercially available since ofloxacin and ciprofloxacin. It is a pure formulation of the active L-isomer of ofloxacin, so levofloxacin provides the same safety profile as ofloxacin. But levofloxacin has improved antimicrobial activity against gram-positives, including Streptococcus, as reported by Graves et al.

One important factor in the usefulness of any topical ophthalmic antibiotic is solubility. We know that ofloxacin is more soluble than ciprofloxacin. Studies have found that levofloxacin is even more soluble than ofloxacin. This is one reason levofloxacin can be formulated in the 0.5% concentration of Quixin, whereas ofloxacin is formulated as a 0.3% concentration in Ocuflox (ofloxacin, Allergan).

Laboratory studies show that at a pH of 7, which is the physiologic pH of ocular tissues and the anterior chamber, levofloxacin is more soluble than ofloxacin and ciprofloxacin. In the eye, this gives levofloxacin a concentration in tear fluid almost twice that of ciprofloxacin and slightly greater than ofloxacin 4 hours after instillation.

Tissue concentration

The greater solubility of levofloxacin allows it to achieve higher peak concentrations in the parts of the eye where it is needed. Studies measuring the concentration of levofloxacin in aqueous humor and bulbar conjunctiva found that levofloxacin outperformed ofloxacin.

We recently performed a study measuring the concentration of drug achieved in corneal tissue by various fluoroquinolones in eyes about to undergo penetrating keratoplasty. Those results, which are being prepared for publication, showed superior corneal tissue penetration by levofloxacin. Using an antibiotic that penetrates corneal tissue is essential for refractive surgery.

Question of resistance

Drug resistance is a long-term issue that more than ever affects our short-term decisions about antibiotic selection. As microbes adapt, we must improve our antibiotics.

We should not use long-term, low-dose antibiotics, for example, in patients with a persistent epithelial defect. But long-term, low-dose drug regimens are still being used, particularly after surgery, because of concerns about ocular surface toxicity. Dropping the dose to once or twice a day for several weeks, however, is exactly the way to promote resistance. Three times a day is the lowest dosing frequency I use, based on the most recent studies of long-term antibiotic use. I also limit the duration of treatment. Gone are the days when I would keep a patient on a single drug for months.

We need to use antibiotics in a fashion that will prevent bacterial growth. One way to do that is to aggressively use high concentrations of antibiotic. A drug that achieves high tissue levels and is bactericidal rather than bacteriostatic will be less likely to allow resistance strains to emerge. The data from clinical studies and animal models show that levofloxacin meets these criteria for prophylaxis.

Infections after LASIK

Refractive surgeons also need to be aware of a new pattern of opportunistic infections after LASIK. Reports of these infections have begun to appear in the peer-reviewed literature in the past year. Based on what refractive surgeons are reporting at major meetings, the incidence of these infections seems even higher than the published reports suggest.

Infections after LASIK seem to have a bimodal pattern of presentation. First, there are the early cases showing a relatively rapid, progressive inflammatory reaction within about 1 week after surgery. Those are the familiar cases with gram-positive bacterial infections.

But surgeons should also be alert for less inflamed infections, often with a multifocal pattern, that present at about 2 weeks or later — sometimes much later — after surgery. These cases are opportunistic infections that most anterior segment surgeons are not used to seeing. They are often misdiagnosed as diffuse lamellar keratitis (DLK) or mild forms of conventional bacterial infections, but they are actually caused by Mycobacterium, fungus, Nocardia and other unusual pathogens. Without proper diagnosis and treatment, these infections can progress to the point where therapeutic keratoplasty is necessary.

These late opportunistic infections generated a lot of discussion last year at the meetings of the Refractive Surgery Interest Group of the American Academy of Ophthalmology and the Castroviejo Society. More recently, Chandra et al described mycobacterial infections in seven eyes of eight patients.

These were all cases of hyperopic LASIK using a contact-lens mask that were performed by one surgeon at one surgery center. These patients were all treated as early-onset DLK because of the appearance of interface inflammation. They received increased doses of steroid, which of course exacerbated the real problem.

It is not difficult to understand the misdiagnosis of DLK. The classic picture of mycobacterial infection is an eye that is not severely inflamed, as it would be with a bacterial infection. The fact that mycobacterial infection typically is multifocal and relatively late in presentation can also lead to misdiagnosis.

Clearly, this group represents a threat to every refractive surgical practice. Because of the growing importance of early diagnosis and treatment of post-LASIK infection, I believe that any atypical inflammatory reaction in a LASIK patient justifies culturing without delay.

My treatment of choice for suspected mycobacterial keratitis is combination therapy with amikacin and clarithromycin in addition to levofloxacin. We are now alert to this new pattern of post-LASIK infection, and the office staff has been cautioned to consider this possibility when patients call in with complaints after surgery. The combination of preoperative prophylaxis and postoperative vigilance should keep this new infectious threat in abeyance.

For Your Information:

• Edward Holland, MD, is a professor of clinical ophthalmology at the University of Cincinnati and director of the Cornea Service at the Cincinnati Eye Institute, 10494 Montgomery Road, Cincinnati, OH 45242 U.S.A.; +(1) 513-984-5133, ext. 3151; fax: +(1) 513- 984-4870. Dr. Holland has no direct financial interest in the products mentioned in this article. He is a paid consultant for Santen.

• Santen Inc., makers of Quixin, can be reached at 555 Gateway Drive, Napa, CA 94558 U.S.A.; Web site: www.santeninc.com.
• Allergan, makers of Ocuflox, can be reached at 2525 Dupont Drive, Irvine, CA 92612 U.S.A.; +(1) 714-246-4500; fax: +(1) 714-246-5913; Web site: www.allergan.com.

References:

• Bucci FA. A prospective comparison of four methods of pre-phacoemulsification antibiotic treatment using ofloxacin and ciprofloxacin. IOVS. 2000;41:5768.
• Chandra NS, Torres MF, Winthrop KL, et al. Cluster of Mycobacterium chelonae keratitis cases following laser in-situ keratomileusis. Am J Ophthalmol. 2001;132:819-830.
• Graves A, Henry M, O’Brien TP, et al. In vitro susceptibilities of bacterial ocular isolates to fluoroquinolones. Cornea. 2001;20:301-305.
• Helm CJ, Holland GN, Lin R, et al. Comparison of topical antibiotics for treating Mycobacterium fortuitum keratitis in an animal model. Am J Ophthalmol. 1993;116:700-707.
• Jain S, Azar DT. Eye infections after refractive keratotomy. J Refract Surg. 1996;12:148-155.
• Lin R, Holland GN, Helm CJ, et al. Comparative efficacy of topical ciprofloxacin for treating Mycobacterium fortuitum and Mycobacterium chelonae keratitis in an animal model. Am J Ophthalmol. 1994;117:657-662.
• Perez-Santonja JJ, Sakla HF, Abad JL, et al. Nocardia keratitis after laser in situ keratomileusis. J Cataract Refract Surg. 1997;13:314-317.
• Stevens RK, Holland GN, Paschal JF, et al. Mycobacterium fortuitum keratitis: A comparison of topical ciprofloxacin and amikacin in an animal model. Cornea. 1992;11:500-504.