Symposium: Ocular Surface Disease Management: The Role of Next Generation Combination Agents

Richard L. Lindstrom, MD: Ophthalmologists have a variety of options to treat eye inflammation caused by surgery, infection, allergy, and other conditions. Available corticosteroids help reduce inflammation in the eye, and antibiotics treat infections caused by bacteria. Combination agents containing corticosteroids and antibiotics are available for patients suffering from inflammation with the risk of bacterial infection.

How do ophthalmologists diagnose patients with ocular surface disease?

John D. Sheppard, MD: In all of medicine, one in 20 patients has a complaint about the eye, and the majority of those complaints concern red eye. Ophthalmologists must be careful when categorizing conditions that are a concern to the patient but are non-vision-threatening as opposed to vision-threatening conditions or conditions associated with systemic illness. Ophthalmologists must distinguish conditions that are common and mitigated by immediate intervention, conditions that can lead to vision loss, or conditions affecting the rest of the body that may have significant morbidity.

Patients are most afflicted by allergic or infectious disease. Allergic disease is often overtreated with antibiotics, and infectious disease is often undertreated with antibiotics and ignored by practitioners. The most common external diseases ophthalmologists diagnose that cause red eye are allergy, blepharitis, infectious conjunctivitis and dry eye, and it is important to differentiate between those conditions with the patient’s history and an examination.

“Allergic disease is often overtreated with antibiotics, and infectious disease is often undertreated with antibiotics and ignored by practitioners." —John D. Sheppard, MD

Diagnosing ocular surface disease

Lindstrom: How can ophthalmologists differentiate between vision-threatening and non-vision-threatening diseases?

Edward J. Holland, MD: The most common symptom of ocular surface disease is patient discomfort. Fluctuation in vision also occurs, however, due to unstable tear film and punctate erosions of the cornea. In advanced cases of ocular surface disease, cornea involvement can lead to sight-threatening complications such as scarring and neovascularization. Ophthalmologists can differentiate between vision-threatening and non-vision-threatening diseases by carefully evaluating the cornea for punctate staining, epithelial defects, anterior stromal opacification and neovascularization.

Eric D. Donnenfeld, MD: Clinicians can also differentiate between vision-threatening and non-vision-threatening diseases by reviewing the patient’s history. A history of decreased vision, pain and previous ocular surface or intraocular surgery in the involved eye are suggestive of conditions that may be vision threatening. The clinician must ensure that the patient has a thorough evaluation.

Some symptoms, however, are generally non-vision threatening. Itching is a common symptom, and it is the primary manifestation of allergic conjunctivitis. Other symptoms suggestive of non-vision-threatening problems include foreign body sensation, grittiness, dryness, tearing, redness without any other significant symptoms or pain.

Lindstrom: When treating patients with non-vision-threatening symptoms, should ophthalmologists be conservative and treat with a simple topical lubricant, or is it reasonable for ophthalmologists to treat patients more aggressively?

Stephen S. Lane, MD: Ophthalmologists must understand the difference between common eye problems and potentially vision-threatening conditions. It is the ophthalmologist’s obligation to make the correct diagnosis based on clinical findings and the patient’s history, and treatment should be determined by that diagnosis. For example, if the diagnosis is allergic conjunctivitis, blepharitis or keratitis, the ophthalmologist should institute an aggressive treatment. The difficulty is that often, depending on the ophthalmologist’s experience and the patient’s clinical presentation, the diagnosis may not be easily determined.

“Combination therapy is indicated when the ophthalmologist suspects an infectious component to an ocular surface inflammatory condition.” —Edward J. Holland, MD

When the diagnosis is difficult to ascertain, I believe the safety of using an anti-inflammatory and antibiotic combination medication is reassuring for the treating doctor. Physicians, particularly those with less experience, can feel confident in their treatment plan even given the worst case scenario: infectious keratitis. While combinations may not be the ideal first line treatment in the case of infectious keratitis, the antibiotic component of the combination agent should treat the infectious component.

Lindstrom: When diagnosing a patient, how does the ophthalmologist determine if a patient is in need of combination therapy? For example, I have seasonal allergic conjunctivitis, mild blepharitis and mild dry eye. When my eye becomes irritated, I know I have a red, irritated eye, but I am not always certain of the primary cause of the irritation. How often do ophthalmologists encounter an eye condition that is difficult to diagnose?

Sheppard: Difficulty in diagnosing a patient is common for ophthalmologists, which raises an important point. Patients as educated as an ophthalmologist do not know exactly what is wrong with their eyes, unless a foreign body has entered the eye or the patient knows he or she was exposed to infection. Diagnosing a patient based on symptoms, gross appearance and patient history often can be difficult for ophthalmologists, particularly recalcitrant referral cases ophthalmologists often see. Less-difficult cases are readily handled by primary care practitioners or remedy spontaneously, and never appear in the ophthalmology office.

Use of combination agents

Lindstrom: Combination agents are useful for ophthalmologists having difficulty diagnosing patients because these agents provide both an anti-inflammatory and an antibiotic. When is it appropriate for the ophthalmologist to treat a patient with combination therapy?

Holland: Combination therapy is indicated when the ophthalmologist suspects an infectious component to an ocular surface inflammatory condition, such as blepharoconjunctivitis or blepharokeratoconjunctivitis. In addition, any condition such as corneal epithelial defect with a risk of infection, is often best treated with combination therapy.

In addition, combination agents are effective in postoperative prophylaxis. Ophthalmologists should use a combination agent that includes a steroid, which treats the inflammation, and an antibiotic, which treats a potential secondary infection following recent surgery.

Sheppard: Blepharitis and conjunctivitis secondary to infection are two important global causes of non-vision-threatening red eye that, in my experience, respond better to a combination agent than to an anti-inflammatory or anti-infective alone.

A common scenario is a patient with dry eye and irritation who rubs his or her eyes with a contaminated finger, or a patient with blepharitis or an allergic irritation who rubs his or her eyes and introduces organisms creating a secondary infection. That secondary bacterial conjunctivitis is the most common complication of dry eye in my practice, and I find combination agents are the most effective treatment.

“Combination agents allow ophthalmologists to effectively treat patients with two agents and cover any potential misdiagnosis.” —Stephen S. Lane, MD

Lindstrom: What treatment option is best for a patient diagnosed with bacterial conjunctivitis: a simple antibiotic, a separate antibiotic and steroid combination or a combination agent?

Sheppard: I believe a combination agent, specifically tobramycin-loteprednol (Zylet, Bausch & Lomb), is the best current treatment option for a patient with bacterial conjunctivitis. My concerns when prescribing tobramycin-loteprednol are whether the patient is allergic to tobramycin and whether the patient has uncontrolled steroid-responsive glaucoma. The majority of patients qualify for treatment with tobramycin-loteprednol, which is the medication I most often prescribe.

Lane: Bacterial conjunctivitis is difficult to diagnose unless the ophthalmologist performs eye cultures. The ophthalmologist often treats presumed bacterial conjunctivitis when the condition is most frequently a mixed-mechanism disease or viral conjunctivitis. With combination agents, ophthalmologists can effectively treat with two agents and cover the potential misdiagnosis. A clinician can be confident a patient’s condition will improve when using a combination agent.

Sheppard: I do not routinely perform eye cultures if the condition is inherently obvious and there is no risk factor such as immunocompromise or recent operative procedure.

The first 5 years of my career was in family practice and pediatrics, and the prototypic conjunctivitis patient was a child whose eye was sealed shut with a puffy discharge and who suffered from an upper respiratory infection. Many of these ocular problems resolved with systemic antibiotics. If the condition appears to be an isolated ocular infection with yellowish-green mucopurulent discharge and a red eye, then I would recommend treatment with tobramycin-loteprednol.

Today, my patient with prototypic bacterial conjunctivitis is an older woman with more than routine dry eye or blepharitis. This patient has one eye sealed shut in the morning with a green and yellow mucopurulent discharge. I would also recommend treating this patient with tobramycin-loteprednol.

Case study: Nonspecific conjunctivitis Stephen S. Lane A 32-year-old patient with a 10-year history of soft contact lens wear complained of discomfort and redness in the right eye of 2 days duration (Figure). In those 2 days he also reported a mild mucoid discharge present upon awakening in the morning. Vision was unchanged, and contact lens wear was discontinued those 2 days. The patient reported sleeping in the contacts the night before the onset of symptoms. Examination showed the conjunctiva to be diffusely inflamed but with increased injection nasally. Further examination found that tarsal conjunctival follicles were present and that the cornea was clear. Intraocular inflammation was not observed. A mild mucoid discharge was noted in the inferior conjunctival cul-de-sac. Figure. The patient was diagnosed with irritation and redness, which are symptoms of nonspecific conjunctivitis. Source: Lane SS Although I thought the most likely diagnosis for this patient was nonspecific conjunctivitis related to contact lens overwear, I was concerned about the possibility of bacterial infection resulting in the mild mucoid discharge. Under these circumstances I thought that the most appropriate treatment regimen primarily demanded anti-inflammatory steroid coverage. Because mucoid discharge was present, however, I also wanted some broad spectrum antibiotic coverage. Tobramycin-loteprednol (Zylet, Bausch & Lomb) four times a day offered this patient the ideal combination of convenience (single bottle of drops), broad spectrum antibiotic coverage (tobramycin), and anti-inflammatory treatment (loteprednol). Additionally, I was reassured that the loteprednol component would achieve the potent anti-inflammatory action this patient required without concern of a steroid response elevation in IOP. After 4 days of treatment, the inflammation and mucoid discharge completely resolved and tobramycin-loteprednol was discontinued. The patient resumed contact lens wear with the warning to avoid sleeping in them again.

Concerns of steroid use

Lindstrom: Unless the patient has a specific allergy, the topical antibiotic in a combination agent will not have an adverse effect. Ophthalmologists, however, have concerns about the potential adverse effects of topical steroids. What safety concerns should ophthalmologists consider when determining if a patient should use a combination agent that includes a topical steroid?

Donnenfeld: The ophthalmologist can observe some symptoms when examining patients with ocular disease to determine whether they should be treated with a steroid. A majority of patients with mixed-mechanism disease find relief when treated with combination agents if a component of the disease is inflammation and another component is infectious disease.

At times, however, the ophthalmologist needs to be concerned about the corticosteroid. An ophthalmologist should check whether the patient’s history suggests treatment with agents other than steroids. The ophthalmologist should be cautioned against treating with a steroid if a patient has a history of herpetic eye disease or ocular trauma. Patients with ocular, organic trauma should not be treated with steroids. Organic trauma may increase the risk of infectious keratitis and non-bacterial keratitis, such as fungus, that will not respond to the antibiotics or will be worsened by steroids.

Immunosuppressed patients should not be treated with steroids unless a complete ocular examination indicates otherwise.

Lane: It is important to note that family practice physicians and pediatricians often do not have the equipment or experience to diagnose all potential problems on the front part of the eye. Family practice physicians and pediatricians generally perform a pen light examination and an external examination, and many have fluorescein and a blue light. If the physician or pediatrician finds a problem with the cornea, I advise him or her to refer the patient to an ophthalmologist. Although combination agents may treat some corneal conditions, patients with corneal problems should be referred to an ophthalmologist who has the tools for making the diagnosis and recommending the correct regimen of medications.

Lindstrom: When can the ophthalmologist feel comfortable treating a patient with steroids?

“Corticosteroids are the most effective agent ophthalmologists can prescribe for treating ocular inflammation.” —Edward J. Holland, MD

Donnenfeld: Steroids are often successful when treating bilateral disease. Most bilateral disease will be due to allergy, blepharitis or dry eye, and steroids will help all three. Rarely will the condition of a patient who has bilateral disease worsen with the addition of steroids. Treating monocular disease with steroids, however, increases the risk of harmful side-effects.

Holland: Corticosteroids are the most effective agent ophthalmologists can prescribe for treating ocular inflammation. Corticosteroid treatment is the preferred method for the majority of patients with inflammation, whether due to immunologic, infectious or post surgical conditions.

Lindstrom: How does a patient’s history of contact lens wear influence an ophthalmologist’s decision to use a steroid in the treatment of ocular disease?

Donnenfeld: A history of contact lens wear in a patient with ocular surface disease is often an indication of bilateral disease. It is uncommon to find a contact lens wearer with monocular disease. In consideration of the recent epidemic of fungal keratitis related to contact lenses, an ophthalmologist should not treat a patient with monocular red eye who has a history of contact lens wear until a thorough examination is performed.

Monocular disease is rare in patients who wear contact lenses, however. A majority of contact lens wearers have inflammatory processes that need corticosteroids to improve.

Lindstrom: Conditions such as herpes simplex keratitis or fungal ulcer in a single eye of patients who wear extended-wear contacts may cause an acute problem when steroid treatment is administered. In addition, ophthalmologists should be aware of other long-term side effects of steroids. What are the long-term side effects of steroids? Are the newer steroids safer?

Holland: The most common concerns ophthalmologists have with long-term use of topical steroids are increased IOP, cataract formation and secondary infection.

Lane: In the past, the potential increase in IOP and the development of cataracts were concerns when prescribing topical steroids. The ketone group of steroids, including prednisone, prednisolone and dexamethasone, was often used and found to increase IOP in approximately 10% of the population.¹ It was important for the ophthalmologist to monitor patients on a ketone group steroid because of this potential increase in IOP.

“I prescribe the newer generation of steroids...much more frequently today than in the past, and I am more comfortable with them.” —Richard L. Lindstrom, MD

Loteprednol etabonate is classified as an ester steroid. Ophthalmologists need not be as concerned about the potential increase of IOP or the formation of cataracts with ester group steroids as they are with ketone group steroids. The significant difference between the two groups of steroids is how the medications break down (Figure 1). The ketone group of steroids breaks down into active molecules of steroid. With ester steroids, the esterases that break down the steroid into non-active components leave less active steroid and none of the additive effect of the metabolites that can cause complications. This breaking down of the steroid into non-active components decreases the increase in IOP effect as well as minimal inducement of cataracts.

Lindstrom: I find myself using the newer generation of steroids such as loteprednol much more frequently today than in the past, and I am more comfortable with them, as well. Is that a justifiable change in therapy, and do you agree with the change? Are you now less hesitant to prescribe steroids than you were trained to be in your residency?

Sheppard: I trained at the Proctor Foundation at the University of California in San Francisco, where a number of researchers were concerned that the available steroids had a number of deleterious effects, including the induction of cataract, glaucoma and herpetic diseases, in susceptible individuals. In short-term pulse therapy, steroid responders can quickly develop a high-pressure spike. I have observed this high-pressure spike often with dexamethasone and prednisolone.

Figure 1 Ketone and ester steroids at position 20 Ketone steroids break down into active molecules of steroid, while ester steroids break down into non-active components of steroids. Source: Bausch & Lomb

In a standard 10-day to 14-day course of a combination steroid, such as loteprednol-tobramycin, with a safe steroid profile, the eye does not have enough time to produce a pressure spike. In the few patients I have observed who develop severe pressure rises in long-term use of steroids, I was often able to mitigate the effect with topical agents. In the few patients I have observed with moderate pressure rises while on loteprednol, I have been able to reverse the effect pharmacologically. In my experience with traditional ketone agents, reversal of steroid induced glaucoma requires significantly more time compared with ester steroids, and is more likely to lead to laser treatment, such as selective laser trabeculoplasty, or to surgical treatment, such as trabeculectomy.

Lindstrom: Do data support loteprednol’s safety profile? Have studies concluded the agent is safer?

Sheppard: I believe the safety studies are irrefutable. Charles Slonim, MD, observed hundreds of patients administered loteprednol etabonate 0.2% (Alrex, Bausch & Lomb) over a period of 3 years and found virtually no significant pressure rises.² A number of studies show that topical loteprednol 0.5% (Lotemax, Bausch & Lomb) administered four times a day over 6 weeks compared with topical prednisolone produces one-seventh the risk of a pressure rise and fewer high pressure rises.^1,3-5 Findings from animal studies show cataractogenesis is less likely on a molecular basis from use of loteprednol compared with use of other steroids. Many of my colleagues who have administered thousands of prescriptions of loteprednol have not found any association with cataractogenesis. A cataract study, however, will be more difficult and expensive to conduct because cataract density changes take longer to develop and require frustratingly precise methodology for quantification.

In terms of efficacy, our laboratory presented a study 2 years ago in the Journal of Ocular Pharmacology and Therapeutics documenting that in a rabbit model with uveitis, the loteprednol molecule given in the standard 0.5% concentration is more potent than prednisolone and all of the other topical ketone steroids.¹ Loteprednol improved protein levels in the aqueous humor in the uveitis model. The study also found an improvement in white cell infiltration into the eye, cornea and anterior chamber by confocal microscopy, and a Western blot analysis showed superior glucocorticoid receptor internalization, the true molecular marker for steroid efficacy.

“I believe loteprednol should be used to treat any ocular surface disease, such as allergic conjunctivitis, blepharitis, ocular irritation and allergies.” —Eric D. Donnenfeld, MD

I use loteprednol regularly in my practice, and I believe the efficacy of loteprednol is well-documented and will be supported by more long-term, double-masked studies.

Donnenfeld: The physician’s decision to use a medication includes consideration of risk:benefit ratios. The number one rule for a physician is to do no harm. The risk:benefit ratio for loteprednol swings strongly toward benefit compared with other corticosteroids. The efficacy is comparable with that of ketone corticosteroids, such as dexamethasone and prednisolone acetate, while avoiding most of the safety concerns associated with ketone corticosteroid.

When an ophthalmologist treats intraocular inflammation due to uveitis, allograft rejection or cataract surgery, loteprednol is a reasonable corticosteroid to prescribe. When patients have more significant inflammation, I believe other steroids can be used. Patients who suffer from significant inflammation are rare, however.

I believe loteprednol should be used to treat any ocular surface disease, such as allergic conjunctivitis, blepharitis, ocular irritation and allergies. The efficacy of loteprednol is sufficient to treat ocular surface diseases, and the side effects are minimal compared with effects of the ketone corticosteroids.

Case study: Blepharokeratoconjunctivitis Edward J. Holland A 45-year-old man with a recurrent chalazion developed blepharokeratoconjunctivitis (Figure). Slit lamp examination revealed meibomian gland disease with telangiectasia and inspissation of the meibomian gland ortices of all four lids. Both eyes demonstrated a palpebral and bulbar conjunctiva injection. In addition, the patient had a marginal corneal infiltrate and an overlying epithelial defect in his right eye causing significant discomfort. Figure. Patient suffering from blepharoconjunctivitis. Source: Holland EJ Meibomian gland disease is a chronic inflammatory condition of the eye lids. Patients with meibomian gland disease complain of recurrent chalazia and chronic ocular injection. Most importantly, these patients complain of chronic low-to-moderate discomfort. Corneal involvement with marginal infiltrates, scarring and neovascularization can lead to significant vision loss. These patients also suffer from vision fluctuation due to the unstable tear film and evaporated tear loss. Treatment for this patient began with a lid hygiene regimen including warm compresses and lid scrubs twice daily. In addition, oral doxicycline 50 mg every day was initiated to stabilize the meibomian gland secretions. Due to the keratoconjunctivitis findings, which include the marginal infiltrate with an overlying epithelial defect, the patient was treated with tobramycin-loteprednol (Zylet, Bausch & Lomb) four times a day. The patient responded well to the treatment, with resolution of the infiltrate and healing of the epithelial defect. Tobramycin-loteprednol is an effective choice in the management of marginal keratitis, secondary to blepharitis. In my experience, loteprednol etabonate is an effective topical steroid, and tobramycin is useful in prophylaxis for secondary infection. The safety parameters make tobramycin-loteprednol an ideal topical steroid for the management of acute and chronic keratoconjunctivitis. I find that loteprednol has a significantly lower risk of IOP rise and cataract formation when compared with prednisolone or dexamethosone. In addition, my clinical experience shows that tobramycin is an effective broad spectrum antibiotic for treating bacterial conjunctivitis and prophylaxis against secondary infection.

Antibiotic component

Lindstrom: Discuss the antibiotic component of combination agents.

Lane: When treating a patient, the ophthalmologist must be aware of conditions involving mixed-mechanism disease. For example, a patient with blepharitis may also have an infection and a seasonal allergy. For best results, the ophthalmologist should safely treat these conditions at the same time. The judicious use of a combination antibiotic and steroid is important when treating a combination of conditions.

Patients often have a single condition, such as a nonspecific corneal infiltrate that is localized near the limbus, often due to blepharitis. Inflammation around the limbus is a condition for which a combination agent is more effective than a separate steroid and separate antibiotic. The combination agent has the antibiotic that provides broad coverage for organisms causing the condition along the limbus as well as the steroid used to treat the inflammation.

Sheppard: When selecting a generic agent, I prefer to use the antibiotic tobramycin for ocular surface infection. Tobramycin achieves low minimum inhibitory concentrations on the ocular surface to eradicate gram positive organisms that are common in ocular infections, as well as Haemophilus influenza (Figure 2). In 2002, our Association for Research in Vision and Ophthalmology (ARVO) posters of common conjunctivitis pathogens showed that tobramycin was as efficacious as a polymyxin B-trimethoprim (Polytrim, Allergan) combination with an 82% gram positive sensitivity and an 83% gram negative sensitivity.⁶ In addition, tobramycin was superior to sulfa antibiotics. In our clinical population, we also find topical aminoglycosides, such as tobramycin, extremely useful with methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis.

Figure 2 Common ocular bacterial pathogens that respond to tobramycin
Source: Bausch & Lomb

Economic viability and compliance

Lindstrom: I am a strong advocate of combination agents. I believe they are economically appropriate and enhance compliance. Why do ophthalmologists prefer combination agents to other treatment options, and why are combination agents useful?

Lane: From a compliance standpoint, combination products are useful because the patient does not need two separate medications. Using one agent reduces the amount of time a patient needs to set aside for using the medications, because separate medications must be taken at different times.

Economically, the combination agent is beneficial for patients because purchasing one medication is significantly less expensive than purchasing two.

I find that combination agents improve compliance. Prescribing a combination agent, however, restricts an ophthalmologist from separating and timing when he or she wants to use the separate components.

Donnenfeld: The two most important concerns for patients are compliance and cost. A third component is that when a patient uses two different medications, the patient is exposed to twice as much preservative. Four drops a day of a medication containing a preservative is not nearly as significant as eight drops a day of a medication with the same preservative. Patients using separate medications may have increased sensitivity to the preservative. Ophthalmologists should prescribe as little preservative as possible. Doubling exposure to the preservative is a concern.

“I am a strong advocate of combination agents. I believe they are economically appropriate and enhance compliance.” —Richard L. Lindstrom, MD

I do not consider treating one disease process at a time ideal. The ophthalmologist should treat all of a patient’s conditions and not ignore some. Treating all components of a disease should be a simple premise when managing patients, and a combination agent provides that treatment.

Combination agents are also useful for patients who have an inflammatory process and are at risk of infectious complications. For example, in the perioperative surgical arena, inflammation is the primary concern. A one in 1,000 risk of infection exists, however. I am unwilling to accept that great a risk, and, therefore, I will often use a combination antibiotic and steroid.

Sheppard: Combination agents are patient friendly. A patient is grateful to receive a single prescription rather than multiple prescriptions. Some societies and some patients expect more drugs, but I prefer the simplicity of combination agents.

Absorption profiles with the same drop regimen vary greatly. Absorption depends on administration technique, the patient’s blink reflex, the amount of the drop put in the eye, how the drop bounces off the cornea, whether the eye is closed and many other compounding factors. Ophthalmologists may observe high-tear or low-tear, conjunctival and intracameral levels associated with the therapeutic agent. With this variety, ophthalmologists add the additional variable of consecutive or simultaneous drops that perform two different actions. The second drop may not be effective because the first drop may displace it. The opposite is also a possibility, when the second drop dilutes the first. An ophthalmologist adds another variable of indeterminate concentration in the target tissue when prescribing multiple medications.

In addition, difficulty arises if a patient is unable to administer the drops and requires another person to administer them. Administering the second and third medication on the patient’s four times a day multi-drug schedule is often a daunting task, because the patient should wait 10 minutes between each drop. A significant amount of dissatisfaction may result, not only for the patient who experiences some consternation in self-administration, but possibly for the patient’s family, usually a more active and preoccupied younger generation caregiver who must dedicate considerable time to administer multiple drops to the patient.

Case study: Bacterial keratitis John D. Sheppard A 45-year-old patient developed a severe ring infiltrate while working in southern Florida after a hurricane (Figure 1). The patient returned to Viriginia with blinding pain and Proteus mirabilis on his corneal scraping. I immediately began fluoroquinolone plus tobramycin-loteprednol therapy to provide synergistic antimicrobial therapy while mitigating tissue destruction with the topical loteprednol. The patient’s infection cleared within 2 weeks. Corneal opacification and ectasia were limited by the anti-inflammatory regimen, starting first with tobramycin-loteprednol, then followed with loteprednol 0.5% (Lotemax, Bausch & Lomb) for another 6 weeks. The scarring was minimal (Figure 2), but did create difficulty when working outdoors. The patient was prescribed a tinted contact lens which permitted full visual function in all lighting conditions, and delayed corneal transplantation by several years (Figure 3). Figure 1. Acute Proteus mirabilus corneal ulcer with ring infiltrate sensitive to fluoroquinolones and tobramycin. Figure 2. After 2 weeks of treatment with gatifloxacin (Zymar, Allergan) and tobramycin-loteprednol, the patient showed improved vision and reduced corneal edema. Figure 3. Patient recovered 20/40 vision with reduced glare using a deeply tinted soft contact lens. Source: Sheppard JD I am comfortable prescribing a topical steroid, such as loteprednol, for bacterial keratitis unless the organism is Pseudomonas aeruginosa, which can lead to perforation or reactivation in the presence of any steroid. All keratitis patients should be followed closely until full resolution of the infectious phase of their illness.

Choosing a combination agent

Lindstrom: There is a multitude of combination agents on the market, including sulfa-steroid combinations, neomycin-steroid combinations, tobramycin-dexamethasone (Tobradex, Alcon) and tobramycin-loteprednol. How should the ophthalmologist choose a combination agent?

“Tobramycin has significant coverage as a bactericidal drug compared with a static drug such as a sulfa.” —Stephen S. Lane, MD

Lane: The only combination antibiotic steroid I use is the tobramycin-loteprednol combination. The steroid component and safety features of the combination outweigh the steroids from any of the other groups. Alone, loteprednol is useful in the treatment of ocular disease. Loteprednol in combination with tobramycin is ideal, because tobramycin has significant coverage as a bactericidal drug compared with a static drug such as a sulfa.

The only instance when I do not use tobramycin-loteprednol is when I prefer to apply a medication directly to the lid. In some circumstances, an ointment is easier to apply to the lid.

Lindstrom: Do you prescribe the sulfa-steroid combinations, neomycin-steroid combinations or dexamethasone combinations?

Sheppard: I have not prescribed topical neomycin in 15 years. I believe it is the most hypersensitizing agent in ophthalmology, and it is a disservice to patients. I have had many emergency room referrals for patients who were prescribed ophthalmic neomycin which created a hypersensitivity reaction that is entirely avoidable.

The sulfa drugs pose a wide range of problems, including resistance. Resistance is higher because of the common and almost indiscriminate use of sulfa drugs for problems such as cystitis, urinary tract infections, sinusitis, cutaneous infections and otitis media prophylaxis in the pediatric age group. The resistance problem of sulfa drugs includes sulfacetamide. Sulfacetamide is a also a sensitizing agent and is associated with Stevens-Johnson syndrome.⁷

I do not like to use dexamethasone because it has none of the front-runner characteristics ophthalmologists prefer in an agent, such as potency, ocular surface penetration, limited glaucoma risk, efficacy in uveitis or well-documented aqueous concentrations. I do not believe dexamethasone is a particularly strong or safe steroid.

“When comparing combination agents, I believe it is important to find which combination agnt is the most effective with the lowest risk.” —Eric D. Donnenfeld, MD

A number of steroid and fluoroquinolone combinations are in development. Several pharmaceutical companies are attempting to produce sufficient data to convince the FDA that the sum of the parts is greater than the agents given individually and that the combination provides a protective effect. I believe the companies will have a difficult time with the argument. These companies are primarily studying staphylococcal marginal keratitis or peripheral ulceration, thus recruiting an orphan indication. The objection of the FDA is that the medication will produce increased resistance to the stronger fluoroquinolones, at least on the ocular surface. Fluoroquinolones are often reserved as the agents of last resort for severe infections because of their perceived power or their status as preferred prophylactic agents for elective surgery. If these fluoroquinolone steroid agents do become available, ophthalmologists may have a difficult decision when choosing a preferred combination.

Donnenfeld: When comparing combination agents, I believe it is important to find which combination agent is the most effective with the lowest risk. Neomycin carries an allergic risk and is a potent sensitizing agent with 15% to 20% of patients experiencing allergic responses. The ophthalmologist should not want to incorporate an antibiotic that has that sensitizing potential.

Sulfacetamide is mild, will not kill many bacteria or be effective against gram-positive organisms found on the ocular surface.⁶

The other component is the steroid, and loteprednol is as effective as dexamethasone on the ocular surface with less risk of steroid- associated side effects. Loteprednol will not have significant problems with cataractogenesis or glaucoma that is found with dexamethasone or prednisolone acetate.

Lindstrom: How does tobramycin-loteprednol compare with tobramycin-dexamethasone in safety studies?

“The use of tobramycin- loteprednol for treatment of ocular inflammation associated with the need for combination therapy may result in fewer cases of increased IOP.” —Edward J. Holland, MD

Holland: I presented an abstract at ARVO comparing the ocular tolerance and IOP effects of tobramycin-loteprednol and tobramycin-dexamethasone.⁸ The treatments were administered four times a day for 4 weeks in healthy volunteers. In the study, 306 patients were randomized, with 156 patients receiving tobramycin-loteprednol and 150 patients receiving tobramycin-dexamethasone in a double-masked, multicenter parallel group clinical trial. Patients received either tobramycin-loteprednol or tobramycin-dexamethasone four times a day in both eyes for 28 days.

Results for the tobramycin-loteprednol group were statistically significant. Pain relief was noted in mean change from the baseline to the final week of patient diary assessment. In the tobramycin-dexamethasone group, patients reported a significant deterioration of light sensitivity. Overall, tobramycin-loteprednol was not inferior to tobramycin-dexamethasone for all comfort/tolerability parameters evaluated.

Changes in comfort/tolerability from baseline to each subsequent study visit revealed a statistically significant difference between the treatment groups for all comfort/tolerability parameters. All of these changes favored tobramycin-loteprednol in terms of better comfort/tolerability.

Increases from baseline IOP greater than 10 mm Hg were seen in both treatment groups (Figure 3). The difference in the rate of IOP increase was significant in the tobramycin-dexamethasone group, as nearly four times as many patients in the tobramycin-dexamethasone group experienced this degree of IOP elevation. The use of tobramycin-loteprednol for treatment of ocular inflammation associated with the need for combination therapy may result in fewer cases of increased IOP, with ocular comfort/tolerability profile that is favorable when compared with tobramycin-dexamethasone.

Figure 3 Percentage of patients in each treatment group with IOP changes of >10 mm Hg over baseline3

Source: Bausch & Lomb

Lindstrom: Patients undoubtedly benefit from the use of combination agents in the treatment of ocular surface disease. Combination agents are used to treat inflammation with the risk of bacterial infection. With the addition of new combination agents, such as tobramycin-loteprednol, ophthalmologists have another safe option when treating ocular surface disease.

I would like to thank the panel for their comments, Ocular Surgery News for organizing this symposium and Bausch & Lomb for providing its support.

References

1. Samudre SS, Lattanzio FA Jr., Williams PB, Sheppard JD Jr. Comparison of topical steroids for acute anterior uveitis. J Ocul Pharmacol Ther. 2004;20:533-547.
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