Fourth-generation fluoroquinolones used aggressively for treating corneal ulcers

Issue: September 2004

Dosing depends on ulcer severity

Joseph P. Shovlin, OD, FAAO: To provide a response consistent with the question, I’ll assume that the patient has a presumed microbial event rather than a sterile ulcer like that found in an indolent (sterile) shield ulcer from vernal disease or contact lens peripheral ulcer.

Unfortunately, fourth-generation fluoroquinolones have yet to receive Food and Drug Administration approval or labeling for corneal indications, such as ulcerative keratitis. Nonetheless, these highly effective anti-infective agents are quickly becoming the standard of care in treating infectious corneal ulcers. They are attractive for several reasons, including a reliable therapeutic index, exceedingly capable pharmacokinetics, acceptable corneal toxicity and a decreased potential for resistance to develop. The ability of fluoroquinolones to eliminate replicating bacteria is unsurpassed, allowing practitioners to often employ empiric, monotherapy.

Recently, Kowalski and colleagues found that most keratitis isolates showed no difference in in vitro susceptibility to the five commercially available fluoroquinolones. The minimal inhibitory concentrations (MICs) for the fourth-generation fluoroquinolones were statistically lower than earlier-generation fluoroquinolones for all gram-positive organisms without sacrificing gram-negative coverage. (Kowalski RP, et al: Am J Ophthalmol. 2003;9(136):500-506.)

Sadly, I’m not yet aware of any in vivo studies comparing the efficacy and safety of fourth-generation fluoroquinolones to earlier-generation fluoroquinolones. Surprising to some, fourth-generation agents probably have a greater potential to create corneal toxicity than past-generation fluoroquinolones. Dosing is dependent on ulcer severity, and the taper (amount and duration) is based upon signs of improvement and the organism encountered (presumptive or determined by culture).

Appropriate initial pre-loading doses are almost always recommended and are generally administered in the office. Patients are instructed thereafter to instill one to two drops every 15 to 30 minutes for the first 5 to 6 hours, then every 30 minutes to 1 hour the first day. Patients are often asked to awaken at least twice at 4 and 6 hours. The next day, the dosing regimen depends less upon how things look but more on what organism(s) is believed responsible for the infection. Most often, patients are asked to use one drop hourly from early morning to late evening.

Practitioners are advised not to make any early abrupt changes to therapy because some infections, especially gram-negatives, look worse the next day in spite of appropriate therapy.

A taper to one drop six to eight times per day will generally follow shortly thereafter, depending on the response to therapy. Improvement is measured by the blunting of the perimeter of stromal suppuration, reduced density of the infiltrative process and surrounding edema and re-epithelialization and reduction in anterior chamber reaction. A final taper should not result in less than four-times-daily dosing and may be required for 14 days and beyond for some organisms. Prolonged therapy is generally necessary for certain organisms such as Pseudomonas, Nocardia and Mycobacterium.

Joseph P. Shovlin, OD, FAAO, is a Primary Care Optometry News Editorial Board member and in practice at Northeastern Eye Institute. He can be reached at 200 Mifflin Ave., Scranton, PA 18503; (570) 342-3145; fax: (570) 344-1309; e-mail: jshovlin@aol.com.

Every 2 hours for 24 hours

John Coble, OD: Fourth-generation fluoroquinolones are very effective. I realize that the effectiveness of this class is strong enough that twice-daily dosing has been shown adequate in most infections and it is indicated for three times daily dosing.

However, we know that corneal ulcers are not “most infections.” We take them very seriously. I will begin a corneal ulcer patient on a fourth-generation fluoroquinolone every 2 hours for the first 24 hours. When I see the patient on the second day, he or she is usually much better. In fact, the patient is usually so much better that I reduce him or her to four times daily for 4 more days before discontinuing the medication.

For a central corneal ulcer, depending on the severity, I may even begin every hour for the first day. However, every 2 hours seems to be enough, even for the worst case. But for a really bad central ulcer, hit it hard and often. All central ulcers are really bad.

Another consideration is compliance from the patient. Patients may only use the drops half as much as prescribed, even when you educate and scare them. So when I think the patient may not be the compliant type, I may tell him or her a more frequent dosage so he or she will get an ample amount.

John Coble, OD, is in private practice in Greenville, Texas. This year he was named the TOA Optometrist of the Year and the American Optometric Association Optometrist of the Year. He can be reached at Eyecare of Greenville, 3005 A Joe Ramsey Blvd., Greenville, TX 75401; (903) 454-1886; fax: (903) 455-3055; e-mail: DrCoble@EyeCareofGreenville.com; Web site: www.eyecareofgreenville.com.

Severity, compliance play a role

Andrew S. Gurwood, OD, FAAO: The strategy for eradicating bacterial microbial keratitis is to exterminate the underlying pathogen while simultaneously controlling or mitigating the inflammatory process. This is accomplished by instilling topical antibiotic drops, topical cycloplegic preparations and possibly the judicious use of topical anti-inflammatory drops.

In combating any infection, some basic rules include the following:

Organisms must be susceptible to the agent chosen (appropriate use) and the agent must be able to gain access to the offending organisms (penetration to the site of infection).
The drug must be dosed at levels that not only stop replication (minimum inhibitory concentration [MIC]), but also prevent mutations from surviving (minimum prevention concentration [MPC]), producing a high minimum inhibitory quotient (ratio of tissue concentration to MIC).
The medicine must remain at MIC and MPC levels long enough to completely eliminate the pathogen (prevention of resistance and superinfection).
The drug should not irreparably harm the host (avoid toxicity).
Cultures remain the gold standard for identifying organisms and determining susceptibility.

Published loading regimens range from the very aggressive, which includes drops every 15 minutes for a number of hours followed by every hour for some time, followed by every 2 hours for some time working toward the goal of a four-times-daily maintenance for at least 14 days, to less aggressive, straightforward hourly dosing until lesion resolution can be seen, then moving to a four-times-daily modality for at least 14 days, to no loading at all with every-2-hour administration until improvement is seen followed by four times daily maintenance for 14 days.

Style, severity, experience and compliance all play a role. Topical antibiotics should not be tapered below four-times-daily dosing. Following lesion resolution and dosage completion (minimum of 7 days in ulcer cases) they should be discontinued.

While levofloxacin is officially approved by the FDA for treating corneal ulcers, moxifloxacin and gatifloxacin are approved for bacterial conjunctivitis.

Andrew S. Gurwood, OD, FAAO, is an associate professor of clinical sciences and an attending optometric physician at The Eye Institute of the Pennsylvania College of Optometry. He can be reached at Pennsylvania College of Optometry, 1200 West Godfrey Ave., Philadelphia, PA 19141; (215) 276-6134; fax: (215) 276-1329; e-mail: Agurwood@pco.edu.

Loading dose, every 15 min., every hour

Bruce E. Onofrey, OD, RPh. FAAO: Currently, fourth-generation fluoroquinolones are not approved for treating bacterial ulcers. Therefore this means that this would be an off-label use, and there are no specific dosing guidelines when treating off label.

Having said that, these drugs have the best efficacy against most of the gram-positive ulcer-producing pathogens and are at least as good as older fluoroquinolones in treating susceptible gram-negative ulcer pathogens. Their real forte is their efficacy against fluoroquinolone-resistant organisms and, in particular, the non-tuberculin mycobacteria that are the most common ulcer-producing pathogens following LASIK surgery.

My protocol is as follows:

Culture the organism on blood and chocolate agar.
Get a Gram’s stain.
Initiate therapy with one drop every minute for five doses in the office.
One drop every 15 min. until bed on day 1.
One drop every 1 to 2 hours overnight.
Day 2: one drop every hour.
When healing begins, reduce the dose eventually to four times daily and initiate Tobrex (tobramycin, Alcon) or polysporin ointment before bed until the ulcer is completely resolved.
Treatment is altered based on cultures and susceptibility reports and on the clinical success of the empiric therapy.

Bruce E. Onofrey, OD, RPh, FAAO, is a Primary Care Optometry News Editorial Board member and chair of primary care eye services at Lovelace Medical Center, Eye Clinic. He can be reached at 5150 Journal Center Blvd. NE, Albuquerque, NM 87109; (505) 262-7000, ext. 8328; fax: (505) 262-3366;
e-mail: Eyedoc3@aol.com.