BLEPHARITIS MANAGEMENT

Transcription

1 BLEPHARITIS MANAGEMENT CURRENT THINKING AND BEST PRACTICES Report of a SECO Roundtable moderator Kirk Smick, OD panelists Marc Bloomenstein, OD, FAAO Milton M. Hom, OD, FAAO, FACAAI(Sc) Katherine M. Mastrota, MS, OD, FAAO Bruce E. Onofrey, OD, RPh, FAAO sponsored by

2 ROUNDTABLE PARTICIPANTS* MODERATOR PANELISTS Kirk Smick, OD, is chief of optometry services at Clayton Eye Center in Morrow, GA. Marc Bloomenstein, OD, FAAO, practices at Schwartz Laser Eye Center in Scottsdale, AZ. Milton M. Hom, OD, FAAO, FACAAI(Sc), practices in Azusa, CA. Katherine M. Mastrota, MS, OD, FAAO, is the center director of Omni Eye Surgery in New York, NY. Bruce E. Onofrey, OD, RPh, FAAO, is professor and executive director of continuing education programs at the University of Houston College of Optometry in Houston, TX. *SECO 2016 This discussion centers on the management of the common, often poorly defined and misunderstood set of conditions that comprise blepharitis. This term, which simply indicates an inflammation of the eyelids, encompasses a host of interrelated conditions involving the pilosebaceous unit of the anterior lid and the meibomian glands of the posterior lid. 1 Inflammation and/or infection of these functional ocular surface components, while seldom sight-threatening, is detrimental to ocular comfort, and visual performance. Blepharitis can often affect the cornea and conjunctiva, resulting in punctate keratitis and inflammation. Over the long term, chronic blepharitis can incite permanent structural changes, including loss of lashes and scarification of meibomian gland orifices. Blepharitis can also lead to contact lens intolerance or compromise the results of ocular surgery. 1 Fortunately, the attention of researchers and clinicians has focused increasingly in recent years on the inflammatory and infectious conditions of the lid margin, offering insights into their prevalence, pathophysiology, and the means by which they can be treated. This roundtable brought together a group of optometric ocular surface experts to discuss the latest thinking on the diagnosis and treatment of both anterior and posterior blepharitis. The objective of the panelists was to create guidelines and offer pearls that will enable clinicians to better manage a lid margin disease that virtually all of us see daily in our practices. 2

3 SCOPE OF PROBLEM Dr. Kirk Smick Before we try to define them, let us begin by discussing the frequency with which we see the different forms of blepharitis in our practices. Dr. Bloomenstein, how often do you see blepharitis, whether we label it anterior, posterior, mixed or meibomian gland disease (MGD) or staphylococcal blepharitis? Dr. Marc Bloomenstein In my practice, more than half of the patients over age 30 have some form of blepharitis. I believe that I am identifying it more often now than in the past simply because I am looking more closely for it. But importantly, not all of the patients in whom I see blepharitis are symptomatic, nor have they come to me seeking relief from lid disease or its ocular surface sequelae. Although blepharitis is detectable through signs, the patient is either unaware of, or unconcerned by, its presence. Dr. Bruce Onofrey Patients with MGD, a common form of posterior blepharitis, frequently have a chronic, low grade lid disease process, often going on for months or years without producing symptoms (or producing only transitory symptoms when subject to environmental stress such as being outdoors on a dry windy day). Then, some event or activity (e.g., initiation of contact lens wear, increased time working at a computer) may exacerbate the condition and produce more frequent and troubling symptoms. But because symptoms can be intermittent, patients may not bring them up without prompting at the examination. FIGURE 1 Meibomian gland expression is central to the diagnosis of posterior blepharitis (MGD). Healthy meibum is a free-flowing, clear to yellow fluid; thickened, pasty meibum, like that shown here, is indicative of gland dysfunction. (Image copyright Bausch & Lomb Incorporated.) This, combined with the complexity of defining the conditions we refer to as blepharitis, has resulted in a good deal of confusion and uncertainty about the disease s prevalence. But blepharitis is certainly very common, particularly in older patients. Dr. Milton Hom Both anterior blepharitis and posterior blepharitis/mgd are associated with significant ocular disease. For example, Lemp and coworkers looked at 159 dry eye patients and found that 86% had signs of evaporative dry eye caused by MGD. Clearly, posterior blepharitis/mgd is an important factor in the creation of dryness symptoms. 2 In our practice, we found that 77 out of 166 consecutive patients had dry eye. Of those patients, similarly, 52 (67.5%) had evaporative dry eye due to MGD. Interestingly, about two-thirds of these MGD cases were mild. 3 Were they not part of a dry eye study, it is possible that many of these patients blepharitis/mgd would have gone undiagnosed and untreated. I honestly think that based on symptoms alone, without performing expression, we are missing a huge amount of MGD (Figure 1). I honestly think that based on symptoms alone, without performing expression, we are missing a huge amount of MGD. MILTON M. HOM, OD, FAAO, FACAAI(SC) Bloomenstein It is becoming increasingly clear that MGD plays a role in many, if not most, cases of symptomatic dry eye disease. And what is also becoming clear is the prevalence of asymptomatic or nonobvious MGD. 4 A study conducted in Spain of an age-stratified adult patient population (N = 619) found a higher prevalence of asymptomatic MGD patients (21.9%) than symptomatic MGD patients (8.6%). 5 Of course, asymptomatic patients with signs of blepharitis may not want (or adhere to) treatment, but I think that it is important that we appreciate the prevalence of the condition. Because there is significant hidden pathology in our patient population, we need to start focusing closely on the eyelids, looking for blepharitis, so that we can treat it early, before there is significant corneal and conjunctival involvement, in the case of anterior blepharitis. In the case of posterior blepharitis/mgd, the goal is to treat while the glands are still healthy enough to recover. Ultimately, blepharitis can degrade patients vision our mission is to prevent that. Onofrey I agree. As we know, signs of MGD can be subtle, even when the patient is symptomatic. So without careful attention to the lid margin, which includes performing meibomian gland expression, a clinician may provide incomplete treatment for a patient s symptoms (e.g., with lubricant drops only), without recognizing or addressing the underlying cause. EXAMINATION AND DIAGNOSIS Smick Research findings published over the last decade have caused most of us to regard the eyelid margin much differently than we did before: we are examining the lids more carefully, becoming a great deal more specific in our diagnoses and targeting our treatments more carefully. But before we 3

4 discuss the management of blepharitis, let us discuss what is necessary for a thorough lid examination. Dr. Onofrey: How do you proceed? Onofrey When I look at the lids and ocular surface, I think in terms of functional anatomy. Each tissue, or part of the ocular adnexa, has a function and an anatomic structure to support that function. I work systematically, from front to back, looking at each component of the tissue to determine which components, if any, look as if they may not be performing their physiologic function appropriately. I look first at the eyelid anatomy and structure and then at the quality of the tears and meibum to determine whether there is an evident cause for the patient s symptoms, if any. Inflammation, of course, produces hyperemia and tissue changes, which can include cicatrization; but these can also be signs of infection. With bacterial activity, we tend to see changes in the production of the meibum; you can see, for example, saponification, the formation of bubbles foaming across the lid margin, which suggests a bacterial overgrowth. This sign is not pathognomonic for infection, but it is highly suggestive (Figure 2). FIGURE 2 In certain blepharitis presentations, it is thought that bacterial lipases break down meibum and result in the soapy tears pictured here. (Image copyright Bausch & Lomb Incorporated.) Dr. Katherine Mastrota While I think the eyelids, as part of the ocular surface unit, are rising in importance to our colleagues, I think many may still move too quickly past the lids and lashes unless there is frank injection, inflammation, or noticeable scurf or debris. It is essential to look carefully and, as Dr. Onofrey stated, to note specifically the anatomical location and nature of any irregularity. I too work systematically, anterior to posterior, in my ocular surface exam; and I start with the skin of the eyelid and periorbital area, looking for any (even subtle) abnormalities. For example, are the lids swollen, sagging, or inflamed? Are there any areas of incomplete lid closure upon blink? Then I move to the eyelashes: Are they normal in color, quality, and resiliency? Are they nestled firmly and robustly into the eyelash follicle? Any infectious or inflammatory process may compromise the appearance and function of these structures: The eyelashes within an inflamed or dysfunctional follicle may be brittle or absent altogether, pointing, possibly, to an anterior blepharitis. At this point, further probing is necessary to determine whether the cause is infectious, perhaps atopic/allergic, or seborrheic (Figure 3). FIGURE 3 Greasy lash debris such as that pictured here is common in seborrheic blepharitis. (Image copyright Bausch & Lomb Incorporated.) I continue moving back, everting the lids and checking for concretions, other lesions, or signs of chronic inflammation which may or may not be related to blepharitis. And I pay close attention to the quality of the lid margin itself, looking for vascularization, keratinization, as well as at the position of the mucocutaneous junction and punctum. Then, looking at the meibomian glands, I determine whether the orifices are visible. The appearance of normal, healthy meibomian glands is marked by their location at regular intervals and by a clearly defined cuff of epithelial tissue around each orifice. I check whether the glands appear small, irregular, or atrophied, or, conversely, whether they are visibly plugged and capped. I also use transillumination to obtain an image of the glands. And, most important, as Dr. Hom mentioned, is to express the glands. Bloomenstein It might be useful to highlight something Dr. Mastrota touched on that in addition to simply paying more careful attention to the lids and meibomian glands, a relatively new skill set is evolving in optometry for lid margin examination. These new skills include meibomian gland expression and performing meibomography with a transilluminator. Hom There are tools available to facilitate meibomian gland expression, but I prefer my thumbs or in some cases, a cotton swab. I think the angle of illumination is important when viewing the expression. Oblique direct illumination adds reflections to the expression, as opposed to straight-on direct illumination. If I move the slit lamp illumination at around 45 degrees temporally, I can judge the clarity of the meibum better. I have missed MGD by not moving the light beam to an oblique angle. The report of the International Workshop on Meibomian Gland 4

5 A SYSTEMATIC APPROACH TO EYELID EXAMINATION Starting with anterior structures, move in a posterior direction Begin with periocular and external lid skin; look for: Laxity Lesions Inflammation Swelling Tenderness Rosacea Telangiectasia Examine lash line; look for irregularities in: Color Quantitiy (i.e., missing lashes) Quality/resiliency (i.e., brittle or broken lashes) Look for crusting, scurf, or debris along the lash line Colarettes may indicate staphylococcal blepharitis Cylindrical dandruff suggests Demodex mites Evert lids; look for: Lesions Enlarged papillae Vascularization Concretions Look along lid margin for: Telangiectasia Change in position of punctum Keratinization Visible meibomian gland orifices Irregularity of gland position Plugged, capped, or atrophied glands Perform gland expression Note fluid color and consistency Note ease/difficulty of expression If available, perform Meibomography by transillumination Tear film interferometry Dysfunction includes a scheme for grading meibomian gland function based on expression, which takes both the effort required to express the glands and the quality/texture of meibum into consideration. 6 We integrated a similar scale into the study I discussed earlier; suffice it to say that anything other than a clear, motor oil-like fluid upon expression should raise our suspicions. Because there is significant hidden pathology in our patient population, we need to start focusing closely on the eyelids, looking for blepharitis, so that we can treat it early, before there is significant corneal and conjunctival involvement, in the case of anterior blepharitis. In the case of posterior blepharitis/mgd, the goal is to treat while the glands are still healthy enough to recover. MARC BLOOMENSTEIN, OD, FAAO Smick Can we discuss symptoms in this context? What should we be listening for, or asking about? Onofrey Patients are frequently unaware of their own lid disease. Just as detecting subtle signs of blepharitis often requires that we actively look for them, it is similarly often necessary to probe for subtle symptoms. I think it is valuable to consider administering one of the available validated survey tools in order to systematically identify and help patients become conscious of symptoms that may be low-grade or intermittent. While we are focusing, for the most part, on the lids in this discussion, we are really talking about ocular surface disease, which is very complex. When we make a diagnosis and a treatment decision, we need to incorporate both signs and symptoms, and a questionnaire is a good way to start. I believe in the regular use of surveys for all patients, but I am in an atypical setting (a teaching institution) and so must reinforce to students the importance of covering all the possible etiologies with patients who come in with nebulous or intermittent complaints. A standardized survey is a good place to begin; though individual practitioners may wish to adapt an established survey tool to align its focus with the practice s scope and capabilities. A contact lens specialty practice or a disease-oriented practice could, for example, individualize the questionnaire for its own patient base. In general, I think we have to be cognizant of the waxing and waning nature of these conditions, and remember that symptoms may change from season to season, day to day and even hour to hour. KATHERINE M. MASTROTA, MS, OD, FAAO 5

6 Hom Indeed, for MGD specifically, there is evidence that some symptom survey tools may be somewhat improperly directed. Keeping in mind that signs and symptoms do not always correlate in ocular surface disease, I have seen cases in my practice which scored as mild on symptom surveys but were clearly significant (and symptomatic) MGD. Researchers are working to identify some symptoms specific to MGD (e.g., ocular fatigue, foreign body sensation), which might be helpful to include on a custom symptom survey. 7 Mastrota We also have to appreciate that symptoms not only vary in severity from patient to patient, but can also be affected by seasonal, dietary, or lifestyle changes that are often difficult for a patient to pinpoint. For example, a patient might get eyelash extensions and decide she cannot remove her eye makeup as diligently as she did before; another patient might decide to become a vegan and eliminate fish from his diet, or might go on a 2-month ski trip, during which the cold, wind, and sun aggravates previously subclinical symptoms. In general, I think we have to be cognizant of the waxing and waning nature of these conditions, and remember that symptoms may change from season to season, day to day and even hour to hour. Onofrey We must respect the complexity of the condition. Ocular surface disease in general, and blepharitis specifically, may be progressive. Every patient needs a complete and accurate diagnosis whether the patient is highly symptomatic or relatively asymptomatic if we are to make appropriate treatment determinations. Symptoms are a notoriously unreliable indicator of severity in dry eye and ocular surface disease. Whatever symptoms a patient presents with itching, dryness, reduced vision quality a workup of the ocular surface must encompass the constellation of signs and symptoms affecting all the interrelated components of the tissue complex. 8 A proper evaluation of the lids to determine what, if any, role blepharitis might have in the disease process, is essential to ensure that treatment, if it is warranted, is directed as much as possible at the cause. MANAGEMENT Smick Understanding that blepharitis is a complex condition, let us talk about disease management, starting with the conundrum of patients who are relatively asymptomatic but show signs of anterior or posterior blepharitis. Should we intervene in these cases, and, if so, how? Hom It is not always clear. In the prevalence study I mentioned earlier, we analyzed the distribution of MGD severity. 3 Again, about two-thirds of the patients had grade 1 to grade 2 disease. So many patients with MGD are likely to be minimally symptomatic, with low-grade disease. Obviously, we want to minimize the risk of disease progression in these cases; but it is challenging to treat patients without symptoms and motivate them to adhere to therapy. And I do believe there is a progression few patients come in having developed MGD or lid disease overnight. Bloomenstein When I want to encourage patients with few symptoms to cooperate with therapy, I show them the signs that concern us. Tools are readily available that allow us to both photograph and display ocular pathology, and a photo can go a long way toward helping patients understand why treatment might be indicated (Figure 4). FIGURE 4 A capped meibomian gland on the superior lid. Such a photo, especially when compared to a normal presentation, can provide helpful education for the affected patient. (Image copyright Bausch & Lomb Incorporated.) Mastrota I do exactly that: I display photos on a big screen in my exam room, and whether it be capped glands, lid debris, broken lashes, or empty follicles, I say to the patient: You see that? That s not good. And here is what you have to do to help with that. When patients come back for follow-up, they ask: How does my lid margin look? How do my lashes look? I think showing pathology gives patients greater ownership over their treatment and care, just as glaucoma patients who are well-informed and motivated will pay attention to their intraocular pressures (IOPs) over time. We must respect the complexity of the condition. Ocular surface disease in general, and blepharitis specifically, may be progressive. Every patient needs a complete and accurate diagnosis whether the patient is highly symptomatic or relatively asymptomatic if we are to make appropriate treatment determinations. BRUCE E. ONOFREY, OD, RPH, FAAO 6

7 Smick How do you stage treatment for lid disease, especially where symptoms are mild or transient? What do you start with? Bloomenstein Lid hygiene is always first, as well as regular follow-ups to determine whether the condition is improving or getting worse. I then modify therapy as needed. For many patients, hygiene may be all the therapeutic intervention necessary. On the other hand, those whose disease has progressed may require intervention that is prompt, aggressive, and thorough. Mastrota Eyelid hygiene is necessary not only to clear bacteria and their byproducts, but also to remove allergens, lid scurf, cosmetic creams and makeup residue and to dampen the Demodex mite population in some individuals. To me, instruction on cleaning the lids with a commercially prepared product or just in the shower, with greater attention to the lid margin is a baseline requirement for patients with any stage of lid or ocular surface disease. TREATMENT GOALS Anterior blepharitis Decrease bacterial load Reduce inflammation Restore ocular surface homeostasis Improve patient symptoms Posterior blepharitis (MGD) Reduce inflammation Improve meibomian gland function Reduce bacterial load Improve ocular surface symptoms Hom I agree; and I think patients require some instruction: A simple explanation and demonstration can help them to be mindful of lid hygiene. Even those patients who consider themselves to be diligent about facial hygiene may be missing their lids, because the eyes and eyelids are set into the orbit and can be missed in cleaning the cheeks, nose, and forehead. I like to look at things in stages. In addition to hygiene, for patients with mild signs and mild symptoms, I like to emphasize the use of warm compresses and artificial tears. Where signs and/or symptoms are more severe, I turn to pharmaceutical interventions. Onofrey Like Dr. Hom, in general, I take a staged approach to treating blepharitis, depending on the severity of the disease. My basic plan for blepharitis, in addition to the hygiene we have discussed, always includes artificial tears to help lubricate the ocular surface and normalize tear film quantity. I also recommend warm compresses and, for MGD patients, try to encourage meibomian gland massage, but that is often difficult for patients to comply with at home. At the next level of treatment, if there is inflammation of the conjunctiva or the cornea and I am concerned about infection, I may consider short-term use of a topical steroid/antibiotic combination. This can address acute inflammation, reduce the bacterial load on the ocular surface, and bring patients to a place where maintenance therapy with the other treatments I have mentioned can be of greater benefit. I am very cautious about the duration of treatment with any steroid-containing agent. Because they are rapidly effective, patients may be tempted to continue or re-initiate therapy with them in the absence of a clinician s instruction. Even though the loteprednol etabonate in ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension 0.5%/0.3%) has a proven safety profile, all patients on corticosteroid therapy should be closely monitored for adverse events. 9 Smick Let us dig deeper into combination antibiotic/steroid formulations. Their effectiveness in cases of blepharitis stems from the fact that, when we detect inflammation and there is the possibility of bacterial overgrowth, it can be difficult to discern whether the problem is primarily infectious or inflammatory. A combination drug covers both concerns, and is simple for patients to administer. Dr. Mastrota, could you discuss your use of combination antibiotic/steroid drops in more detail? Mastrota When choosing a combination antibiotic/steroid drop, I think carefully about the desired characteristics of each component. First, the antibiotic: in ZYLET, we have tobramycin, an aminoglycoside antibiotic with good activity against bacteria commonly cultured from the conjunctiva particularly staphylococcal species, which are often implicated in anterior blepharitis and blepharoconjunctivitis. 10,11 Microbial resistance is rising, but over the last decade we have not seen a drastic increase in resistance to tobramycin among common ocular isolates. 10 When we detect inflammation and there is the possibility of bacterial overgrowth, it can be difficult to discern whether the problem is primarily infectious or inflammatory. A combination drug covers both concerns, and is simple for patients to administer. KIRK SMICK, OD 7

8 INDICATIONS AND USAGE ZYLET (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) is a topical anti-infective and corticosteroid combination for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies. The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye. The particular anti-infective drug in this product (tobramycin) is active against the following common bacterial eye pathogens: Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae, and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species. Important Safety Information continued on page 9. Onofrey Combination anti-infective/anti-inflammatory medications should, of course, be used only when each component is needed in the treatment of the disease. In my clinical experience, this is typically the eye that is inflamed and at-risk of further inflammatory consequences. There are a number of ocular surface inflammatory conditions that may develop in response to blepharitis, including secondary allergic conjunctivitis associated with staphylococcal blepharitis and corneal conditions such as phlyctenular disease or marginal infiltrates. All of these respond well and quickly to a steroid. But when we put a steroid on an eye where there is active bacterial growth even just normal lid flora, such as Staphylococcus epidermidis, we risk promoting active infection due to the immunosuppressive effects of the steroid. 12 Thus, adding a drug like tobramycin, which we know to be quite effective against staphylococci even against methicillinresistant Staphylococcus aureus (MRSA) helps reduce the risk of activating a secondary bacterial infection in an already compromised eye. 13 Reducing the bacterial load on the lids can also help speed relief from the acute phase of blepharitis with an infectious component. Mastrota The safety profile of a combination agent s steroid component is critically important: the risks associated with ophthalmic steroids (IOP elevation, cataractogenesis, and immunosuppression) are serious. Indeed, a multicenter, randomized, investigator-masked study comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% to dexamethasone 0.1%/tobramycin 0.3% found both combinations to be effective in the treatment of blepharokeratoconjunctivitis; but more patients experienced significant IOP increases with the dexamethasone than the loteprednol combination. 9 Smick I think you bring up a very important point. In casual discussions with colleagues and in panels like this one, I commonly encounter a degree of caution among optometrists regarding the prescription of corticosteroids. Of course, this attitude is not unfounded: we have all encountered patients with IOP elevations in response to steroid therapy, and we know that any patient taking a steroid for more than 10 days requires regular follow-up and IOP monitoring. The risks of steroid use are serious, and we must be thoughtful about both the need for steroid and the risk profile of the particular drug we select. I think this applies especially to combination formulations, which we may reach for reflexively without giving much thought to their constituents. As Dr. Mastrota notes, studies comparing loteprednol etabonate 0.5%/ tobramycin 0.3% to dexamethasone 0.1%/tobramycin 0.3% have found equivalent efficacy and reduced risk of significant IOP elevations with the loteprednol etabonate combination. 12,15 Onofrey When I use a steroid/antibiotic combination, it is usually for acute disease of the ocular surface that results from significant lid inflammation (e.g., the blepharokeratoconjunctivitis treated in the studies just mentioned). I do not treat the lid inflammation, per se, with a topical steroid/antibiotic combination and certainly do not use it for long-term maintenance. I do favor strategies like lid hygiene and warm compresses, as these are directed at the primary site of the disease. But for those situations in which the ocular surface, and especially the cornea, is affected by the inflammatory and infectious process going on 8

9 in the lid, I think a combination drop is indicated and can be very effective. Smick Most optometrists see a large number of contact lens patients. Because contact lens wear is itself a risk factor for microbial keratitis, and because the irritation and discomfort associated with blepharitis may, over time, discourage patients from continuing their contact lens wear, it is critically important for optometrists to find and address lid disease in current or prospective contact lens wearers. 16 Hom Evidence suggests that contact lens wear can compromise the lids (particularly the meibomian glands) and ocular surface. Arita and colleagues published a study in 2009 examining the meibomian gland function of contact lens wearers, which found a significant correlation between contact lens wear and meibomian gland loss. 17 In the study, a meiboscore was determined for each subject (from 0 = no loss of meibomian glands to 3 = glands are nonfunctional in more than two-thirds of the total glandcontaining area). The average meiboscores of the contact-lens wearing study subjects (mean age years) were similar to those of an older (60- to 69-year-old) population that did not wear lenses. This study also found a correlation between duration of contact lens wear and meiboscore. 17 So when evaluating contact lens wearers particularly those who have been in lenses over a long term pay close attention to the lid margin and expression. Smick In treating contact lens patients with lid disease, it can be a significant challenge to just get them to take a break from their lenses. If treatment with an antibiotic/steroid agent is indicated, we aim for the shortest possible duration of therapy to quell the acute disease. Dr. Mastrota, you work in a referral practice: Are contact lens patients with moderate lid disease referred to you and if so, why? Instruction on cleaning the lids with a commercially prepared product or just in the shower, with greater attention to the lid margin is a baseline requirement for patients with any stage of lid or ocular surface disease. KATHERINE M. MASTROTA, MS, OD, FAAO Mastrota Sometimes a contact-lens wearing patient will be referred because of a red eye; and often the referring clinician will say, We prescribed an antibiotic, and the patient has been taking it for 4 days without noticeable improvement. Upon close examination the patient will often have tiny marginal infiltrates, and there is likely to be more inflammation than infection. IMPORTANT SAFETY INFORMATION ZYLET is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infections of the eye and fungal diseases of ocular structures. Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, and defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. Use of corticosteroids may result in posterior subcapsular cataract formation. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where appropriate, fluorescein staining. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infections. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. Employment of corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and exacerbate the severity of many viral infections of the eye (including herpes simplex). Fungal infections of the cornea are particularly prone to develop coincidentally with long-term, local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, and burning and stinging upon instillation. 9

10 In the absence of anti-inflammatory treatment, the condition will improve slowly at best. These cases often warrant a switch from the originally prescribed antibiotic to a combination product, with an effective anti-inflammatory drug and a different antimicrobial. Other times, we will see referred patients who have not yet been treated; they often turn out to have blepharokeratoconjunctivitis, but the referring clinician failed to see the very small marginal infiltrates that are essential to making that diagnosis. Other cases of blepharitis that get referred to us are in preoperative patients those going in for cataract surgery or, more often, for glaucoma filtering surgery. Bloomenstein I often have cases of blepharoconjunctivitis referred to me because of a diagnostic uncertainty. In such cases I always start by examining the lids, and more often than not I find a blepharitis component. For those situations in which the ocular surface, and especially the cornea, is affected by the inflammatory and infectious process going on in the lid, I think a combination drop is indicated and can be very effective. BRUCE E. ONOFREY, OD, RPH, FAAO Onofrey I think the smartest doctors are not necessarily those with the highest IQs, but those with the longest differential diagnosis lists. In addition to a long differential diagnosis list, doctors also need multiple treatment plans. Treatment must be staged, as we ve discussed, and individualized. And I ll reiterate what I began by saying: inflammatory ocular surface disease is more complex than many think. It is often multifactorial. And it takes time to treat it effectively. The most valuable thing a practitioner can do is gather information and use that to individualize therapy. Smick A theme running through our discussion is the complex and often confounding nature of blepharitis in its various presentations. We have discussed the importance of a careful lid margin exam, and have outlined several concrete steps we can take to recognize and intervene in early-stage cases of anterior and posterior blepharitis. These conditions have inflammatory and infectious components that respond well to treatment. In addition to the eyelid hygiene and warm compresses that have long been the mainstays of blepharitis treatment, we now recognize a multitude of pharmacologic treatment options. One of these is treatment with a combination anti-inflammatory/ antibiotic combination agent to address both critical components of the disease. Among these, ZYLET (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) stands out for both its safety profile and its efficacy. REFERENCES 1. Lemp MA, Nichols KK. Blepharitis in the United States 2009: A survey-based perspective on prevalence and treatment. Ocul Surf. 2009;7(2):S Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012;31: Hom MM, Kwan JT. Prevalence of dry eye sub-types and severity of evaporative dry eye using objective tests. Poster presented at the Association for Research in Vision and Ophthalmology Meeting; May 5-9, 2013; Seattle, WA. 4. Blackie CA, Korb DR, Knop E, Bedi R, Knop N, Holland EJ. Nonobvious obstructive meibomian gland dysfunction. Cornea. 2010;29: Viso E, Rodriguez-Ares MT, Abelenda D, Oubina B, Gude F. Prevalence of asymptomatic and symptomatic meibomian gland dysfunction in the general population of Spain. Invest Ophthalmol Vis Sci. 2012;53: Tomlinson A, Bron AJ, Korb DR, et al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci. 2011;52(4): Paugh JR, Kwan J, Nguyen AL, Senchyna M, Christensen M, Meadows DL. Preliminary analysis of a meibomian gland dysfunction-specific symptom questionnaire. Poster presented at the Association for Research in Vision and Ophthalmology Meeting; May 6-9, 2012; Fort Lauderdale, FL. 8. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2): White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis. Curr Med Res Opin. 2008;24(1): Adebayo A, Parikh JG, McCormick SA, Shah MK, Huerto RS, Yu G, Milman T. Shifting trends in in vitro antibiotic susceptibilities for common bacterial conjunctival isolates in the last decade at the New York Eye and Ear Infirmary. Graefes Arch Clin Exp Ophthalmol. 2011;249(1): Dougherty JM, McCulley JP. Comparative bacteriology of chronic blepharitis. Br J Ophthalmol. 1984;68(8): Comstock TL, Holland EJ. Loteprednol and tobramycin in combination: a review of their impact on current treatment regimens. Expert Opin Pharmacother. 2010:11(5): Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: Nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145: Pavesio CE, DeCory HH. Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol. 2008;92: Chen M, Gong L, Sun X, et al. A multicenter, randomized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with blepharokeratoconjunctivitis. Curr Med Res Opin. 2012;28(3): Dart JK, Radford CF, Minassian D, Verma S, Stapleton F. Risk factors for microbial keratitis with contemporary contact lenses: a case-control study.. Ophthalmology. 2008;115: Arita R, Itoh K, Inoue K, Kuchiba A, Yamaguchi T, Amano S. Contact lens wear is associated with decrease of meibomian glands. Ophthalmology. 2009;116: ZYLET is a trademark of Bausch & Lomb Incorporated or its affiliates Bausch & Lomb Incorporated. ZYL.0062.USA.18 10

11 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension) safely and effectively. See full prescribing information for ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%). Zylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% Initial U.S. Approval: INDICATIONS AND USAGE Zylet is a topical anti-infective and steroid combination for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. (1) DOSAGE AND ADMINISTRATION Apply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. (2.1) DOSAGE FORMS AND STRENGTHS Zylet contains 5 mg/ml loteprednol etabonate and 3 mg/ml tobramycin. (3) CONTRAINDICATIONS Zylet, as with other steroid anti-infective ophthalmic combination drugs, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. (4.1) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing 2.2 Prescription Guideline 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 4.1 Nonbacterial Etiology 5 WARNINGS AND PRECAUTIONS 5.1 Intraocular Pressure (IOP) Increase 5.2 Cataracts 5.3 Delayed Healing 5.4 Bacterial Infections 5.5 Viral Infections 5.6 Fungal Infections 5.7 Aminoglycoside Hypersensitivity FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Zylet is a topical anti-infective and corticosteroid combination for steroidresponsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies. The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye WARNINGS AND PRECAUTIONS Intraocular pressure (IOP)-Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored. (5.1) Cataracts-Use of corticosteroids may result in posterior subcapsular cataract formation. (5.2) Delayed healing The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of a magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. (5.3) Bacterial infections Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infection. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be reevaluated. (5.4) Viral infections Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). (5.5) Fungal infections Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. (5.6) ADVERSE REACTIONS Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burning and stinging upon instillation. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC, at or FDA at FDA-1088 or See 17 for PATIENT COUNSELING INFORMATION. Revised: 08/ ADVERSE REACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. The particular anti-infective drug in this product (tobramycin) is active against the following common bacterial eye pathogens: Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae, and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing Apply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. During the initial 24 to 48 hours, the dosing may be increased, to every one to two hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely. 11

12 2.2 Prescription Guideline Not more than 20 ml should be prescribed initially and the prescription should not be refilled without further evaluation [see Warnings and Precautions (5.3)]. 3 DOSAGE FORMS AND STRENGTHS Zylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% contains 5 mg/ml loteprednol etabonate and 3 mg/ml tobramycin. 4 CONTRAINDICATIONS 4.1 Nonbacterial Etiology Zylet, as with other steroid anti-infective ophthalmic combination drugs, is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. 5 WARNINGS AND PRECAUTIONS 5.1 Intraocular Pressure (IOP) Increase Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. 5.2 Cataracts Use of corticosteroids may result in posterior subcapsular cataract formation. 5.3 Delayed Healing The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where appropriate, fluorescein staining. 5.4 Bacterial Infections Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. 5.5 Viral Infections Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). 5.6 Fungal Infections Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal cultures should be taken when appropriate. 5.7 Aminoglycoside Hypersensitivity Sensitivity to topically applied aminoglycosides may occur in some patients. If hypersensitivity develops with this product, discontinue use and institute appropriate therapy. 6 ADVERSE REACTIONS Adverse reactions have occurred with steroid/anti-infective combination drugs which can be attributed to the steroid component, the anti-infective component, or the combination. Zylet: In a 42-day safety study comparing Zylet to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate keratitis (approximately 15%). Increased intraocular pressure was reported in 10% (Zylet) and 4% (placebo) of subjects. Nine percent (9%) of Zylet subjects reported burning and stinging upon instillation. Ocular reactions reported with an incidence less than 4% include vision disorders, discharge, itching, lacrimation disorder, photophobia, corneal deposits, ocular discomfort, eyelid disorder, and other unspecified eye disorders. The incidence of non-ocular reactions reported in approximately 14% of subjects was headache; all other non-ocular reactions had an incidence of less than 5%. Loteprednol etabonate ophthalmic suspension 0.2% - 0.5%: Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. In a summation of controlled, randomized studies of individuals treated for 28 days or longer with loteprednol etabonate, the incidence of significant elevation of intraocular pressure ( 10 mm Hg) was 2% (15/901) among patients receiving loteprednol etabonate, 7% (11/164) among patients receiving 1% prednisolone acetate and 0.5% (3/583) among patients receiving placebo. Tobramycin ophthalmic solution 0.3%: The most frequent adverse reactions to topical tobramycin are hypersensitivity and localized ocular toxicity, including lid itching and swelling and conjunctival erythema. These reactions occur in less than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. Secondary Infection: The development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used. Secondary bacterial ocular infection following suppression of host responses also occurs. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects: Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb fixtures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at 5 mg/kg/day doses, and cleft palate and umbilical hernia at 50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with 50 mg/kg/day). Treatment of rats at 0.5 mg/kg/day (6 times the maximum daily clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of 5 mg/kg/day. Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival and retarded development in the offspring during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period. Reproductive studies have been performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally and have revealed no evidence of impaired fertility or harm to the fetus. There are no adequate and wellcontrolled studies in pregnant women. Zylet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids that appear in human milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when Zylet is administered to a nursing woman. 8.4 Pediatric Use Two trials were conducted to evaluate the safety and efficacy of Zylet (loteprednol etabonate and tobramycin ophthalmic suspension) in pediatric subjects age zero to six years; one was in subjects with lid inflammation and the other was in subjects with blepharoconjunctivitis. In the lid inflammation trial, Zylet with warm compresses did not demonstrate efficacy compared to vehicle with warm compresses. Patients received warm compress lid treatment plus Zylet or vehicle for 14 days. The majority of patients in both treatment groups showed reduced lid inflammation. In the blepharoconjunctivitis trial, Zylet did not demonstrate efficacy compared to vehicle, loteprednol etabonate ophthalmic suspension, or tobramycin ophthalmic solution. There was no difference between treatment groups in mean change from baseline blepharoconjunctivitis score at Day 15. There were no differences in safety assessments between the treatment groups in either trial. 12