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New NSAID Speeds Resolution of Corneal Ulcer
In this case study, patient comfort was a priority.
BY KEITH LIANG, M.D., F.A.C.S.

Severe acute corneal infections present a persistent challenge because of the need to initiate aggressive treatment immediately on the basis of a differential diagnosis alone. We must also take into account the dual and potentially conflicting therapeutic goals of reducing inflammation and making the patient comfortable as quickly as possible.

While fourth-generation quinolones are effective against most bacterial infections, our choices of anti-inflammatory agents must be guided by the potential for a viral etiology and, until recently, our willingness to trade immediate patient comfort for inflammation control. Available data on recently introduced bromfenac ophthalmic solution 0.09%, (Xibrom, ISTA Pharmaceuticals), suggest that it is a potent NSAID that rapidly reduces postsurgical inflammation and pain and yet is well tolerated on instillation. These properties proved advantageous in the following case.

Case history/presentation: A 51-year-old female patient came to the office complaining of pain and foreign body sensation in her left eye. She reported that these symptoms had persisted for 1 week and that after 4 days the eye had also become very red. She said the pain was worse in the afternoon. She had undergone surgery 9 days prior to presentation for an infection in her left foot and was still taking oral amoxicillin (Augmentin, Glaxo SmithKline). She was positive for contact lens wear and had a history of thyroid disease, Sjogren's syndrome and arthritis, but denied having diabetes.

Examination: The patient's best-corrected visual acuity was 20/30 in the affected (left) eye and 20/20 in the right eye. Slit lamp examination of her left eye revealed neovascularization � 1.5 mm along the superior limbus with corneal edema and an epithelial defect at the 1 o'clock position. There were no cells or flare in the anterior chamber, confirming that the infection was confined to the cornea at presentation.

Treatment: We initiated therapy with moxifloxacin HCl ophthalmic solution 0.5% (Vigamox, Alcon) as base) q.i.d. and asked the patient to return the following day.

Follow-up Day 1: Best-corrected visual acuity in the affected eye had returned to 20/20. Slit lamp examination revealed that the corneal defect had healed. However, the patient complained of intense pain and photophobia, presumably due to persistent inflammation. We added Xibrom b.i.d. and continued q.i.d. Vigamox.

Follow-up Day 4: Patient reported tremendous improvement in pain and photophobia. Slit lamp examination revealed similar picture, with vessels evident but no epithelial defect and no cells or flare. Patient directed to continue Vigamox q.i.d. and Xibrom b.i.d.

Follow-up Day 8: Best-corrected visual acuity in the affected eye 20/20. No patient complaints of pain or photophobia. Slit lamp showed continued presence of vessels. We continued Vigamox q.i.d., Xibrom b.i.d., and added loteprednol etabonate ophthalmic suspension 0.5% (Lotemax, Bausch & Lomb) q.i.d.

Follow-up Day 14: Patient felt well and her affected eye was clear, with best-corrected visual acuity at 20/20. There was no evidence of corneal edema, though some vessels did persist. We discontinued both Vigamox and Lotemax, concluding that infection had been eradicated and that we had obtained appropriate anti-inflammatory activity. We asked the patient to continue using Xibrom b.i.d. for 7 more days to control inflammation and for comfort.

Discussion: Faced with a serious and painful corneal infection, the goal of therapy is to decrease inflammation and alleviate the patient's discomfort as quickly as possible. Particularly in the office setting, culturing to positively identify the pathogen prior to initiating therapy is impractical, so we must rely on a thorough examination and our skill with the differential diagnosis. Once therapy is initiated, improvement, or at least no worsening, of signs and symptoms within the first few days generally confirms the accuracy of the diagnosis and provides a rationale for completing the chosen treatment course.

In this case, we considered four common culprits in our differential: gram-positive staph, gram-negative organisms secondary to contact lens wear, herpes virus, and superior limbal keratitis due to her history of thyroid disease. The decision to initiate therapy with a fourth generation fluoroquinolone with good coverage of both gram-negative and gram-positive pathogens addressed a likely bacterial etiology. This initial suspicion was validated by the rapid resolution of the corneal defect while the presence of continued inflammation and pain, typically associated with marginal staph infection, narrowed the presumed diagnosis further.

However, at this point, the patient remained in significant discomfort due to the evident inflammation and therapy needed to be broadened appropriately. We could not completely rule out viral or other etiologies during the early course of treatment. Steroids could improve symptoms while masking vital physical findings that may present later in the treatment course, so a corticosteroid was avoided. The well documented anti-inflammatory and analgesic properties of NSAIDs make this class an obvious choice; however, NSAIDS may cause significant burning and stinging on instillation in patients already in considerable discomfort. Not only did this reduce patient satisfaction with therapy but we suspect it also had a negative impact on compliance, a potentially critical issue in serious ophthalmic infections.

A New NSAID Option

Recent presentations on the new NSAID Xibrom suggested it might make an attractive alternative. Clinical trials of Xibrom in patients following cataract surgery demonstrated rapid reductions in cells and flare and, although its indication is limited to treatment of postoperative inflammation, it provided rapid resolution of ocular pain. Without any preoperative dosing in patients with relatively high inflammation scores, b.i.d. therapy with Xibrom, initiated a full day after cataract surgery, produced statistically significant reductions in inflammation compared with placebo by day 3 and at all subsequent time points. The estimated median time to resolution of ocular pain was 2.0 days, with nearly all patients (95.8%) pain free by day 3. Xibrom was also well tolerated, with an incidence of burning and stinging of only 1.4%.1-2

We also had to consider the well-documented cases of corneal toxicity with older NSAIDs, particularly in patients with compromised epitheliums. Class labeling for all ophthalmic NSAIDs recommends caution in patients with conditions including epithelial defects and ocular surface disease. However, in addition to our own experience using NSAIDs in the treatment of corneal ulcers and the fact that in this case, the epithelial defect had healed prior to initiation of NSAID therapy, we thought the unique pharmacokinetic properties that make Xibrom the first b.i.d. NSAID might further minimize this concern. According to data provided by the company, b.i.d. dosing is possible because Xibrom is a highly lipophilic molecule that penetrates ocular tissue rapidly and maintains active concentrations over a sustained period.3 It is also a more potent inhibitor of the COX-2 enzyme, which is most responsible for inflammation and pain, than either diclofenac or amfenac.4

With this background, we hoped that adding Xibrom at follow-up Day 1 would allow us to address the remaining inflammation and make the patient feel better quickly.

By follow-up Day 8, we felt comfortable adding a steroid, But probably due to long-term contact lens wear, the residual vessels were not responsive to dual anti-inflammatory therapy and the steroid was discontinued.

A Favorable Outcome

In summary, this case suggests that Xibrom may be a useful addition to our therapeutic arsenal against serious acute ophthalmic infections, providing rapid anti-inflammatory activity and resolution of pain without compromising patient comfort or masking physical findings required in the daily assessment of acute corneal infections. Indeed, our patient felt much better after only 2 days (4 doses) of Xibrom treatment. Our experience with this agent in corneal ulcers, particularly its beneficial comfort profile, has encouraged its use in our refractive procedures as well.

Keith Liang, M.D., F.A.C.S., is medical director for Center for Sight and Sacramento Eye SurgiCenter in Sacramento, Calif. He can be reached at (916) 446-2020 or by e-mail at kliang@liangvision.com. Dr. Liang has no financial or consulting relationship with ISTA Pharmaceuticals.

References:

1. Donnenfeld ED, Holland EJ, Stewart R, Grillone LR, for the Bromfenac Study Group. Topical Xibrom 0.1%, an investigational NSAID for post-cataract surgery inflammation, markedly decreases inflammation. Abstract 36245. Presented at ASCRS, Washington, D.C.ASCRS, April 15-20, 2005. Abstract 36245.

2. Donnenfeld ED, Holland EJ, Stewart R, Grillone LR, for the Bromfenac Study Group. Topical Xibrom 0.1%, an investigational NSAID, significantly and rapidly decreased post-cataract surgery inflammation and reduced ocular pain. Presented at ARVO, Fort Lauderdale, Fla., May 1, 2005. Session/Poster 791/B765

3. Data on File. ISTA Pharmaceuticals.

4. Data on File. ISTA Pharmaceuticals; Data from U.S. Patent.

5. Data on File. ISTA Pharmaceuticals.