Zymar

How this antibiotic class is becoming a key to treating corneal infections.

Recently, I saw a 34-year-old contact lens wearer who complained of foreign body sensation, light-sensitivity and red eye. He admitted to abusing his contact lenses as a youth. I found the following:

* Slight lid edema

* Normal pupils

* A small peripheral infiltrate in his cornea, with slight staining.

A contact lens wearer with a sterile infiltrate? So it seemed - until I completed a thorough examination and discovered he had gram-negative Pseudomonas aeruginosa keratitis. I treated this patient successfully, but the case illustrates the importance of recognizing a wide range of possibilities involving the cornea. In this article, I'll discuss key diagnostic considerations and important distinctions among treatments, consistent with research results.

Recognizing infection hallmarks

I knew this patient had an infection by recognizing key signs and symptoms including:

* Pain

* Blepharospasm

* Decreased vision

* Mucopurulent discharge

* Grayish-white stromal infiltrate

* Epithelial defect or significant corneal staining

* Thick tear film debris or mucopurulent discharge present

* Significant conjunctival hyperemia and ciliary flush

* Anterior chamber reaction, ranging from few cells and hypopyon.

Typically, we don't see these problems in a patient with a sterile infiltrate unless the infiltrate is a chronic condition, dating back about 1 or 2 months. But the most significant hallmarks - acute pain and decreased vision - are almost always symptoms of an infectious process.

You should never assume a patient has a sterile infiltrate. If you see an anterior chamber reaction and red eye, always assume he has an infection.

Recognize common infections

Although my patient was infected by Pseudomonas aeruginosa, the more common form of bacterial keratitis involves Staphylococcus aureus. Typically, you'll see a well-circumscribed inferior margin and a 2-mm lesion outside the visual axis. When deciding whether to culture, I use the "1, 2, 3" rule:

* 1 mm from the visual axis, which is inside 6 mm of pupil margain.

* 2 or more infiltrates

* 3 mm or greater in size.

I'll also culture if the patient has come from a hospital setting, has just undergone surgery or is immunocompromised.

You may think Staphylococcus is fairly ubiquitous and benign, but an ulcer is never benign. It's an emergency condition. In fact, the number one cause of endophthalmitis is gram-positive, coagulase negative S. aureus. The first resistant bacterium - colonizing in the presence of methicillin - was S. aureus. We'll always have problems with this bacterium, so we need to treat aggressively when we suspect any infection.

Four answers for infections

Not all infections are the same, and should not be treated in a uniform manner. These four options can be used as guidelines for treating infections.

* Tobramycin 0.3% and dexamethasone 0.1% (TobraDex). You should reserve this treatment for confirmed sterile infiltrates.

* Combination loteprednol etabonate 0.5% and tobramycin 0.3% (Zylet). This also is an appropriate combination for a confirmed sterile infiltrate or chronic conditions such as meibomianitis.

* Monotherapy with a fourth generation fluoroquinolone. This is an ideal initial treatment when you suspect an infection.

* A fluoroquinolone combined with prednisolone acetate (Pred Forte). A corticosteroid is never indicated in early treatment of a potential infectious keratitis or for a patient who may be immunocompromised.

I begin treating a suspected infection with a loading dose of gatifloxacin 0.3% ophthalmic solution (Zymar). I use two drops every 15 minutes for 2 to 3 hours, usually in the office instilled by technician. If the ulcer is severe and in the visual axis, I add fortified antibiotics, alternating treatments every 30 minutes. After the loading dose, in a typical case, the patient should use one drop every hour. When he goes to bed, he should awake every 2 hours and administer another drop. I find that ulcers resolve faster with this approach than if I prescribe an ointment for use when the patient is sleeping.

It's very important to see the patient 24 hours after the initial visit. If it's not staining and there is no anterior chamber reaction, the infiltrate is probably sterile. I treat this patient with the combination of medications, specifically loteprednol etabonate 0.5% and tobramycin 0.3% four times daily for 7 days.

If I see a break over the top of the epithelium, I know I'm dealing with classic bacterial keratitis and will increase the gatifloxacin dose. For the second night, I prescribe ointments for when the patient is sleeping. If he's a contact lens wearer, I prescribe tobramycin 0.3% ointment, which is effective against gram-negative infections. If he's not, the infection is probably S. aureus, which calls for bacitracin (Polysporin).

Know your fluoroquinolones

Several factors differentiate the fluoroquinolones we use to manage infections. In terms of structure, they appear very similar, except for a component called methoxy (OCH)1 in gatifloxacin. Both gatifloxacin 0.3% and moxifloxacin hydrochloride 0.5% (Vigamox) are equally potent against gram-positive bacteria, offering comparable minimum inhibitor concentrations (MIC^sub 90^) - levels at which 90% of the pathogens are killed - for the most common sources of infections, such as Staphylococcus pneumoniae, Staphylococcus epidermidis and S. aureus. However gatifloxacin 0.3% offers lower MICs than moxifloxacin 0.5% and has faster killing properties as well.

In short, the fourth generation fluoroquinolones are better, more powerful and achieve greater penetration than earlier generation fluoroquinolones. However, this is where most of the similarities between gatifloxacin and moxifloxacin end. In one comparison, gatifloxacin demonstrated a much swifter effect, killing 16 of 17 strands of S aureus during the first 30 minutes. Moxifloxacin hydrochloride 0.5% killed only 1 of 17 strands during the first 60 minutes.2 I don't know if this is because of gatifloxacin's preservative, benzalkonium chloride (BAK), but the results are convincing.

While associated with fewer reported adverse events, gatifloxacin also was found to be more effective against gram-negative infections, such as P. aeruginosa. In one study, the MIC^sub 90^ levels - at which 90% of the pathogen is destroyed - for gatifloxacin was 1.28 mg/mL vs. 2.60 mg/mL for moxifloxacin.3 Keep in mind that the lower numbers represent faster kill rates. The MIC^sub 90^ levels for gatifloxacin against Klebsiella pneumoniae and Enterobacter aerogenes were 20% to 25% of the values for moxifloxacin in the same study.3

Gatifloxacin may be more effective against atypical bacteria, such as Mycobacterium. This genus is present in 5% or less of the general population, however, studies have implicated it in more than 50% of all infections cultured after cataract and refractive surgery. Because of this, I recommend treating patients with gatifloxacin before and after cataract surgery or after refractive surgery. Research has shown that changes in intraocular pressure after clear corneal incisions may cause poor wound apposition, allowing fluid to flow back into the wound.1,4 This is one more reason to treat preoperatively.

Evaluating ocular biocompatibility

Another important distinction among fourth generation fluoroquinolones is their ocular biocompatibility or tolerability. At the 2004 meeting of the Association for Research in Vision and Ophthalmology (ARVO), Eric D. Donnenfeld, M.D., presented data from a tolerability study of 30 healthy volunteers who were randomized between gatifloxacin and moxifloxacin hydrochloride 0.5%.5

Dr. Donnenfeld found comparable results when either drop was used four times a day. But when he administered the drops more frequently, as you would for a patient with a corneal ulcer, pupil size was affected and most patients developed erythema, indicating gatifloxacin was better tolerated.

Better corneal wound healing

An important consideration when comparing fourth generation fluoroquinolones is penetration, which may affect the healing rate in patients. An unpublished, prospective study of 46 patients by Majid Moshirfar, M.D., found the following advantages of gatifloxacin over moxifloxacin after penetrating keratoplasty:

* Wound size on day 4 was 23.9 mm^sup 2^ for patients treated with moxifloxacin vs. 10.6 mm^sup 2^ for those treated with gatifloxacin.

* Wound size on day 7 was 3.8 mm^sup 2^ for patients treated with moxifloxacin vs. 0.85 mm^sup 2^ for those treated with gatifloxacin.

* Four patients didn't heal at all with moxifloxacin. All patients on gatifloxacin healed within 21 days, and the average healing time was 5 days.

Make the right choices

To summarize my approach to treating corneal ulcers in this era of fourth generation fluoroquinolones: I always look for infectious signs anterior chamber involvement, redness and a drop in vision. For treatment, I use the fourth generation fluoroquinolones that have been proven effective. When you use these drugs on a fairly regular basis treating a lot of ulcers in a cornea practice, for example - that's when you see some of these differences, which may influence your therapeutic choices in certain cases.

References

1. McDonnell PJ, Taban M, Sarayba M, et al. Dynamic morphology of clear corneal cataract incisions. Ophthalmology. 2003;110:2342-2348.

2. Eser, et al. ARVO, 2004.

3. Callegan MC, Ramirez R, Kane ST, et al. Antibacterial activity of the fourth-generation fluoroquinolones gatifloxacin and moxifloxacin against ocular pathogens. Adv Ther. 2003;20:246-252.

4. Taban M, Rao B, Reznik J, et al. Dynamic morphology of sutureless cataract wounds effect of incision angle and location. Sun Ophthalmol. 2004;49 Suppl 2:S62-S72.

5. Donnenfeld E, Perry HD, Chruscicki DA, et al. A comparison of the fourth-generation fluoroquinolones gatifloxacin 0.3% and moxifloxacin 0.5% in terms of ocular tolerability. Curr Med Res Opin. 2004;20:1753-1758. Erratum in: Curr Med Res Opin. 2005;21:643.

By Paul Karpecki, O.D., F.A.A.O., Kansas City, Mo.

Copyright Boucher Communications, Inc. Oct 2005
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