Traditionally, antibiotics and the ocular surface have rarely occupied the same clinical space. However, significant advances in our understanding of the properties of antibiotics combined with a broader understanding of the ocular surface have underscored the increasingly important role these drugs can play in managing ocular surface disorders and restoring ocular surface health.
To better comprehend the role of antibiotics in ocular surface management, we need to assemble a number of discrete pieces much as we would piece together a jigsaw puzzle.
In this article, we’ll take a closer look into these areas:
• The ocular surface and its dynamics.
• Effects of modern antibiotics on ocular surface function and health.
• Target tissues and drug effects.
• Infectious and non-infectious conditions.
• Antibiotic, anti-inflammatory and disease modifying drug properties.
• Treatment route—topical vs. oral and drug delivery systems.
The Complexities of the Ocular Surface
For most of us, our perception of the ocular surface and tear film derives from our student days (and may actually be decades old). We must realize that, over time, these foundational concepts have changed, and they have changed rapidly. The first real discussion of dry eye and surface disease can be traced back to Henrik Sjögren in 1933, and the first published perspective of the envisioned complexity of tear film layer was described in 1946 by Eugene Wolff.1,2
Admittedly, it is easier visualize Wolff’s concept and treat the tear film as having three distinct layers while viewing dry eye and ocular surface disease as a deviation in one or more of those components. Modern thinking, however, combines a more holistic perspective with recognition of the active and reactive nature of the ocular environment.
Today’s understanding is that the tear layer consists of myriad elements, but rather than existing as discrete components, they naturally combine into an exquisitely complex microenvironment. This environment is centrally and locally controlled, and it reflects balance and interaction rather than independent and isolated behavior. For example, the role of mucins in surfacing the tear and assisting in its adherence to the ocular surface has long been recognized. We now also understand that mucins mix with the aqueous component to create a complex viscoelastic structure. Additionally, mucins interface with the lipid contained in meibomian secretions to aid in cohesiveness of the tear layer and ocular surface complex. Not long ago, the lipid layer was considered almost exclusively an evaporative barrier, but now, we realize that it has numerous other functions.
Even before this broad view of the tear layer and ocular surface fully emerged, a seminal paper by Tseng and Tsubota revolutionized the clinical perspective of the ocular surface and tear layer.3 Their vision of ocular surface health described a complex harmonization of elements, in which dysfunction reflected a breakdown in one or more of the subsystems that maintain ocular surface integrity.
Current thinking suggests that disruption to any of these complex subsystems, either functional or physical, will lead to a progressive downward spiral of ocular surface disease and tear dysfunction. For that reason, it is critically important to sustain normal function of all of these elements and surrounding tissue.
The Function of Antibiotics
The origins of antibiotics can be traced back to the fortuitous blunder that led Alexander Fleming to discover penicillin and the brilliant work of bacteriologist Gerhard Domagk, who won the Nobel prize for his discovery of sulfa drugs. Despite their incredibly important germ-fighting ability, it has long been realized that antibiotic compounds possess other properties as well. While these are often overlooked, they are nonetheless important.
Tetracycline class drugs are often prescribed for non-antibiotic activity.4 Their ability to modulate inflammation is well known—inhibition of proteolysis, angiogenesis, apoptosis, metal chelation as well as anticollagenolytic activity has been investigated. As a class, these drugs have been increasingly used to manage a variety of disorders, including rosacea and other dermatologic disease, neutrophilic diseases, sarcoidosis, aortic aneurysm, cancer metastasis, periodontitis and autoimmune disorders—such as rheumatoid arthritis and scleroderma.
In the eye, tetracycline, minocycline and doxycycline are frequently utilized to manage meibomian gland dysfunction and anterior blepharitis. The actions of doxycycline include reduction of staphylococcal overpopulation of the lids and a variety of local and secondary ocular surface anti-inflammatory effects.
Inhibition of matrix metalloproteinase (MMP) activity and IL-1 synthesis as well as reduced neutrophil chemotaxis decrease surface disruption and promote healing.5 Anticollagenolytic effects reduce scarring and deformation of the lids and advance wound healing. Modifying effects on meibum production, saturation and free fatty acid levels also has significant therapeutic value for lid and ocular surface management. Clinically, tetracycline class drugs such as doxycycline have been shown to speed wound healing and can help manage chronic punctate keratitis regardless of etiology.6
More recently, macrolide class antibiotics have also been found to have antibiotic and nonantibiotic properties that aid in both oral and topical forms, in treating meibomian gland dysfunction.7,8
Management of Lid and Ocular Surface Disease
Anterior and posterior blepharitis are among the most common conditions affecting the eye. Both conditions often combine infectious and inflammatory components.
The presence of high populations of staphylococcal bacteria and staphylococcal exotoxins are associated with increased inflammation, which, in turn, may lead to focal or diffuse punctate keratitis, infiltrative keratitis, phlyctenular keratoconjunctivitis and progressive corneal vascularization.9
So, managing staphylococcal overpopulation of the lid surfaces is critical in controlling lid disease and its sequelae.
While first-line treatment involves warm compresses and lid massage to help mobilize and remove stagnant meibum, topical and oral medications may be necessary to control the disease. Topical agents deliver high concentrations to affected tissues, present substantially less risk of side effects and are less likely to promote growth of resistant organisms due to sublethal concentrations.
Typical flora on the lids include Staphylococcus epidermidis and S. aureus, Propionibacterium acnes and Corynebacterium sp.10 Antibiotic therapy has historically been aimed at reducing overpopulation of native flora while eliminating or reducing pathogenic organisms.
A variety of antibiotic ointments with good gram-positive coverage have traditionally been prescribed in conjunction with warm compress and lid massage therapy. Examples of such ointments include polysporin, bacitracin and erythromycin.
But, one shortcoming of ointments—especially in adults—is difficulty in removing residue and blurry vision. These effects can be especially annoying for contact lens wearers. To minimize these issues, application of topical antibiotic drops to the lid margins using a Q-tip or fingertip is often preferred. Chronic long-term use of antibiotics is somewhat controversial; however, ongoing periodic application every few weeks may be necessary in some patients to limit bacterial overgrowth of the lids.11
Inflammation is also part of the natural history of anterior blepharitis, and, to an even greater extent, posterior blepharitis and meibomian gland dysfunction. As meibomian gland dysfunction persists and becomes chronic, progressive damage to the meibomian glands occurs. The abnormal meibum produced becomes stagnant and rife with saturated rancid free fatty acids. These fatty acids, along with bacterial overpopulation and the toxins and enzymes the organisms produce, can perpetuate and exacerbate lid disease. As the disease continues to worsen, eyelids thicken, telangiectatic vessels appear on the lid margins, and scarring eventually leads to permanent dropout of the meibomian glands.
With progression, the conjunctiva becomes increasingly inflamed, and corneal surface disruption may result. This can be secondary to meibomian gland disease or directly due to tear dysfunction and subsequent dry eye. A variety of other conditions can also cause or contribute to ocular surface disease; these include infectious keratitis, ocular cicatricial pemphigoid, Stevens-Johnson syndrome and alkali burns. Regardless of etiology, inflammation plays a significant role.
Because inflammation is a key element in ocular surface disease, a variety of strategies have been employed to control it. Most commonly, combination antibiotic-anti-inflammatory ointments and suspensions have been prescribed more for their anti-inflammatory properties than their anti-infective coverage. Examples include Maxitrol (neomycin and polymyxin B sulfates and dexamethasone, Alcon), Blephamide (prednisolone/sulfacetamide, Allergan), Tobradex (dexamethasone/tobramycin, Alcon) and Zylet (loteprednol/tobramycin, Bausch + Lomb). Here as well, ointments can be problematic due to blurring and persistent residue.
Tobramycin-based Tobradex is the most prescribed and combines tobramycin and the potent steroid dexamethasone. Although loteprednol-based products are reported to posses a superior side effect profile, the relatively short-term use of these agents and apparent clinical superiority weigh in favor of dexamethasone-based combination agents for managing blepharitis.12 A newer formulation of Tobradex that adds a controlled delivery vehicle may be even more effective than the original formulation.13
It is important to note that all steroid-containing agents should be utilized for controlled periods and that patients must be educated regarding possible long-term effects, such as intraocular pressure elevation, cataract and interference with wound healing.
While topical steroid medications are a mainstay of managing some of these surface disorders, they have a significant downside as described previously. For that reason, the anti-inflammatory properties of antibiotics have attracted growing attention. It is important not to confuse antibiotic and anti-inflammatory properties. Both are important and may exhibit synergistic behavior, but these properties are independent of each other. For example, when treating blepharitis, the antibacterial properties of the tetracycline and macrolide drug classes help check staphylococcal overpopulation even at low doses, but their secondary and possibly more important benefit lies in their anti-inflammatory properties.14
Clinically, oral antibiotics, including tetracycline, doxycycline and (to a lesser extent) minocycline, are usually prescribed for chronic, recalcitrant lid disease. Minocycline is less frequently used due to its comparatively higher rates of side effects, which includes an association with autoimmune diseases like lupus.
Typical dosing for tetracycline ranges from 250mg to 500mg q.d. or usually b.i.d. Doxycycline is the most commonly prescribed drug of this class for ocular use. It is available in doses ranging from 20mg Periostat (doxycycline hyclate, Collagenex Pharmaceuticals) to 100mg. Many clinicians recommend starting with 50mg to 100mg b.i.d. for up to a month and then continuing a maintenance dose as low as 20mg q.d., depending on the severity and persistence of the disease.
Possible benefits of long-term oral therapy must be weighed against potential risks. Among them, an increased risk of breast cancer in females undergoing long-term antibiotic therapy has been reported.15 Considering that long-term use of tetracycline class antibiotics has been advocated, possible risk to benefit has to be weighed carefully. Also, these drugs must not be taken with Coumadin (Warfarin, Bristol-Myers Squibb) as the interaction may enhance blood thinning potential.
Perhaps the newest development in the antibiotic management of blepharitis and meibomian gland dysfunction is AzaSite (Azithromycin ophthalmic 1%, Inspire Pharmaceuticals). Azithromycin is a macrolide class agent and one of the most frequently prescribed systemic antibiotics. Zithromax tablets come in 250mg and 500mg doses. The Z-Pak is a package of six 250mg tablets taken b.i.d. the first day, then q.d. Other oral and IV forms are available.
AzaSite has been available in the United States since 2007. Although it was initially approved and marketed for the treatment of bacterial conjunctivitis, the drug’s utility in treating blepharitis was quickly recognized.8 Azasite is formulated using a unique gel-forming delivery system DuraSite, which when combined with a long drug half life permits a favorable dosing regimen and effectively concentrates high levels of the antibiotic within lid and conjunctival tissue. DuraSite helps minimize penetration into deeper tissues, minimizing systemic absorption and increasing drug concentration within target tissues.
The antibacterial activity of Azasite is broad-spectrum, with particular effectiveness against gram-positive species typical of lid flora. However, its anti-inflammatory activity has drawn as much, if not more attention than its antibacterial efficacy.16,17 Recent research has shown that Azasite has significant positive effect on meibomian gland secretions and function, improving patient symptom grades and extending tear film break-up time.18
Because Azasite is currently approved only for bacterial conjunctivitis, dosing instructions are optimized for that indication. Better-targeted alternatives may include topical application directly to the lids using a finger or Q-tip. As with other topical agents, application following warm compresses and massage is recommended. But, unlike many ointments or suspensions, Azasite is well tolerated and does not cause significant visual disturbance. Twice daily dosing is acceptable to most patients and is continued for up to a month, followed by daily or alternate day application immediately prior to sleep. In some ways, particularly in the context of blepharitis and meibomian gland dysfunction, Azasite can be viewed as the topical equivalent of oral tetracycline class drugs, but without significant adverse effects.
The Big Picture
It has become increasingly evident that the ocular surface and its support systems are far more complex than we could possibly have imagined just a few years ago. Despite this complexity and redundant protective mechanisms, the delicate balance that maintains ocular surface health can be quite fragile. The intersection of antimicrobial and anti-inflammatory therapy is an exciting area for the knowledgeable clinician. When properly used, antibiotic medications can be an effective means of managing a variety of ocular surface disorders.
Dr. Epstein is a well-known author and lecturer with special interest in anterior segment diseases. He is a contributing editor for Review of Optometry and chief medical editor of Optometric Physician. His consulting and advisory relationships include Alcon Labs and Inspire Pharmaceuticals.
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