Probably the greatest challenge in treating patients with ocular itching is separating dry eyes (which can have a mild itchy component) from allergy (which can occasionally present with some burning). The differential diagnosis becomes rather clear in most all cases when the clinical findings are reflected against the subjective complaints. A sizable minority of patients have mild itching as an expression of opportunistic allergy resulting from primary precorneal tear film dysfunction, commonly called dry eyes. For these patients, simply addressing their dry eyes will eliminate secondary allergy expression. Always bear in mind that dysfunctions of the precorneal tear film represent the most common treatable eye condition in North America.
There are only two noteworthy allergy updates since last year. Allergan has reformulated Acular 0.5% (ketorolac tromethamine) and now offers a more patient-friendly 0.4% solution, marketed as Acular LS. Allergan has also thrown its hat into the ring of the already crowded "antihistamine-mast cell stabilizer" market with Elestat (epinastine HCl 0.05%) ophthalmic solution. These drugs are discussed in more detail later in this chapter.
Managing patients with symptomatic, seasonal allergic conjunctivitis is a routine part of optometric practice. Following is a practical/clinical look at this class of drugs.
Most all of the allergy drugs work well in managing seasonal allergic conjunctivitis. More and more, it comes down to determining which is the least expensive medicine, since there can be up to a $25-per-bottle difference among these medications.
Conventional wisdom holds that if it itches, it's allergy. As simple as it sounds, this truth is borne out in clinical reality. However, it remains highly virtuous to attempt to discover the inciting cause, or circumstances that lead to allergy expression. Furthermore, are the patient's complaints of itching primary, or secondary to precorneal tear film dysfunction? Keep in mind, a poorly functioning tear film can set the stage for allergy expression by failing to properly dilute and wash away environmental allergens.
Since dry eye syndrome is the most common eye disease, it often plays a complicating adjunctive role in many, if not most all, ocular surface maladies. The acknowledgement of this clinical reality comes center stage when the patient presents with a chief complaint of "itching and burning." With this history, the astute clinician must perform a decisive slit lamp examination. The issue at hand is, "Does this patient have mainly dry eyes (burning) with secondary allergic (itching) expression, or perhaps a somewhat equal affliction of both?"
Whichever the case, it is the good doctor who makes an exquisite diagnosis prior to determining a management plan. Many, if not most all, of these mixed histories (i.e., itching/burning) are opportunist expression of dry eyes. Appropriately frequent instillation of a premium quality artificial tear will make most of these patients asymptomatic.
Now, let's move into absolute allergy—the patient with itchy eyes. It is well known that allergic conjunctivitis can present as an isolated clinical entity, or as a component of allergic rhinitis and/or allergic sinusitis. The patient's history can fairly easily paint the picture. Obviously, if the allergic expression is limited to the eye, management is clear cut. Extraocular tissue involvement may dictate the need for an intranasal corticosteroid spray, or a systemic antihistamine in addition to the eye drop therapy.
A quick look at pathophysiology shows the mast cells to be the cellular machinery that makes allergy happen. Initial exposure to an allergen sensitizes mast cell membranes via immunoglobin E (IgE). Subsequent exposure to this allergen causes these mast cell-affixed IgE molecules to react so as to cause destabilization and degranulation of the mast cells. Mast cells contain thousands of microvacuoles which contain many chemical mediators of allergy, most notably histamine. These chemical mediators in turn react with other cell membrane receptors, which result in clinical disease. Histamine stimulates both type 1 and type 2 receptors; the first subserves itch and partial vasodilation, the latter only vasodilation. Antihistamine medicines block the histamine type 1 receptors, stopping itch more so than vasodilation. Type 2 receptor blockers, such as ranitidine (Zantac) and cimetidine (Tagamet), are not used in combating allergy since blocking the H1 receptors seems to sufficiently quell the allergic cascade in the eye.
It should be evident that if mast cell membranes can be prevented from degranulating, itch would not occur. This is indeed clinical reality. However, the problem is, when the patient in your examination room is complaining of itching, the horse is already out of the barn—mast cells have degranulated. Such acute itching must be treated with an appropriate acute care drug, such as an antihistamine, antihistamine/mast cell stabilizer or steroid. The duration of such therapy depends upon the unique circumstances of each patient presentation. For example, is this a first time event, or a chronic, recurrent problem? Is the causative agent known? How intense are the symptoms? Is the allergic expression localized to the eye/eyelids, or is there concurrent sinusitis and/or rhinitis? If the allergy expression is localized to the eye and is a new occurrence of mild to moderate severity, then any antihistamine or antihistamine/mast cell stabilizing drug, or topical steroid would be an excellent choice. If the itching is more severe, we would choose a steroid, such as Alrex or Lotemax, and instruct the patient on the proper use of cold compresses. If there is also non-ocular allergic expression, we would consider prescribing an oral antihistamine, such as Claritin or Zyrtec.
If the patient tells us this episode of itching is a flare-up of long term, chronic, recurrent allergic disease, employ the above-mentioned acute therapy for five to ten days, then prescribe one of the newer mast cell stabilizers, such as Alamast or Alocril, used for months at a time if the history dictates. All of these non-steroidal products are incredibly safe, so long-term use is no problem. We generally use Alrex or Lotemax up to a couple of months comfortably, but prefer a mast cell stabilizer for protracted therapy.
You might ask, "Why not use an antihistamine mast cell stabilizing drug instead of a pure mast cell stabilizer for long term care?" This would likely do fine, but think about it—if the mast cells are being pharmacologically stabilized, is there a need for an antihistamine? The logic follows that it would have little or no clinical role. Furthermore, it is our clinical judgment that a pure mast cell stabilizer is more effective at stabilizing mast cell membranes than antihistamine drugs that have some mast cell stabilizing properties.
One final note about itch: Keep in mind the less common causes of allergy, such as atopic and vernal disease. These are more severe and long term afflictions that must be treated with a balance of potent steroids and mast cell stabilizers. Numerous, excellent reference texts detail the management of these uncommon conditions.
Let's look at the different classes of allergy drugs, as well as each individual product, according to two main categories: acute and chronic.
|Pearls for Ocular Allergy
Acute Care Drugs
First, discourage patients from using OTC anti-allergy drugs, the kind that include vasoconstrictors. At least one study has found that vasoconstrictors, alone or combined with antihistamines, can cause acute and chronic inflammatory conjunctivitis, which usually takes several weeks to resolve upon discontinuation of the drug.1 The authors state, "although previous experience suggests that vasoconstrictors never or rarely incite conjunctival hyperemia, the 50 cases in this series clearly demonstrate that ophthalmic decongestants containing phenylephrine, naphazoline, or tetrahydrozoline can cause rebound dilation of conjunctival vessels."
A careful history in patients with chronic conjunctivitis has often revealed the etiology of the problem in the long term use of these products containing vasoconstrictors. Furthermore, it has long been known that topical ophthalmic antihistamines themselves can, paradoxically, cause allergic reactions and ocular irritation. Thus, encouraging patients, either passively or actively, to use OTC anti-allergy preparations may not be in their best interest since they may continue to self-medicate for a long time. We much prefer to write a prescription for a drug in which we have scientific and clinical knowledge of effectiveness and for which we, not the patient, have control over drug exposure duration.
There are eight products that nicely meet the clinical challenge of acute allergic suppression:
Acular LS is generally used four times daily for a week or two, then two to three times daily thereafter as needed for itching. Symptomatic relief is usually achieved in an hour or so. Ketorolac tromethamine is also available in a preservative-free, unit-dose system, which is mainly used in post-operative refractive surgery management. Unit-dose delivery systems are always more expensive, so it would be the exceedingly rare patient who would merit this preservative-free formulation for allergy therapy.
Alrex (loteprednol etabonate 0.2%) ophthalmic suspension is approved for the treatment of ocular allergy. Its more potent partner, Lotemax (loteprednol etabonate 0.5%), is approved to treat more advanced ocular and postoperative inflammatory conditions. (A comprehensive discussion of loteprednol etabonate is found in the corticosteroid section.)
Other than HMS (Allergan), which was marketed many years ago, Alrex is the first topical corticosteroid to be FDA-approved for the treatment of ocular allergy. Because of the uniqueness of this "site-specific" steroid, the active drug resides at the target tissue long enough to render a therapeutic effect, but rarely long enough to cause secondary rises in IOP and, presumably, posterior subcapsular cataracts. A review of the literature shows this to be a safe and effective therapy for allergic conjunctivitis. It is to be used four times a day as needed to control itching.
Alrex, a corticosteroid, has the unique advantage of being able to suppress the entire inflammatory cascade which addresses all the signs and symptoms of the allergic response. Conjunctival vascular involvement in allergic eye disease can range from subclinical to marked. While Alrex can be used in all cases of allergic conjunctivitis, it is particularly effective when there isconsiderable conjunctival inflammation. As a suspension, it needs to be shaken prior to instillation.
Emadine (emedastine difumarate 0.05%) ophthalmic solution is virtually identical to levocabastine. Emadine is a topical antihistamine approved for temporary relief of the signs and symptoms of allergic conjunctivitis. It is to be used four times a day as needed and, like all antihistamines, is safe and effective.
Livostin (levocabastine 0.05%), a potent histamine type 1 (H1) receptor blocker, has gained great popularity and is an effective suppressor of itching. As a topical antihistamine, it competes with histamine for the H1 receptor binding site. If these H1 receptors are preemptively bound by an antihistamine, then histamine is denied the opportunity to produce or propagate allergic expression. It is generally prescribed just like emedastine: q.i.d. for a week or two, then one to three times per day thereafter as needed for itching. Since it is a suspension, shaking is required.
Patanol (olopatadine hydrochloride) is a topical antihistamine with some mast cell stabilizing properties. It is available in two concentrations; 0.1% for b.i.d. use, and 0.2% for once-daily use. Notice how increased concentration tends to prolong the pharmacologic effect. Of practical note, we have observed that many patients using any of these wonderful antihistamine/mast cell stabilizers can remain comfortable using them once daily after a week or two of b.i.d. use. Currently, however, Patanol 0.2% is the only antihistamine/mast cell stabilizer FDA-approved for once-daily use.
Highly successful drugs in the ophthalmic market rarely remain without competition. Patanol's awesome dominance of the allergy market caught the attention of Novartis Ophthalmics, Bausch & Lomb and Allergan. They have developed three excellent products which stand side by side with Patanol. Novartis Ophthalmics brought Zaditor (ketotifen fumarate 0.025%) ophthalmic solution to market in 1999, Bausch & Lomb launched Optivar (azelastine hydrochloride 0.05%) ophthalmic solution in 2000, and Allergan received approval to market Elestat (epinastine hydrochloride 0.05%) ophthalmic solution in 2004. Like Patanol, they are all antihistamine/mast cell stabilizing medicines, which are highly effective at b.i.d. dosing, and are approved for use in pediatric and adult patients. While each of these four products are touted to have small advantages over their competitors, the main difference we have discovered is the cost of these drugs. Check with pharmacies in your community to get a feel for drug costs. Interestingly, Optivar comes in a 3ml and 6ml bottle sizes. Since these four drugs are all used b.i.d., they pretty much eclipse Acular LS, Livostin, Emadine, the cromolyn sodiums, and Alomide, since these are generally prescribed for use q.i.d.
It is well known that contact lens wearers are disproportionately bothered by allergy. This begs the question of safety and efficacy of using Patanol, Zaditor, Optivar or Elestat with contact lenses. No problem. Just to be conservative, have the patient instill the morning drop a few minutes prior to insertion; the afternoon drop can go right on top of the contact lens.
To quell hyperacute allergic reactions, use potent topical corticosteroids (Lotemax, Inflamase Forte, Vexol, fluorometholone acetate 0.1%, or prednisolone acetate 1%) every hour or two for a day or two. In these more marked expressions, cold compresses can be immensely helpful in restoring calm.
Once you've neutralized the marked inflammatory response using one of the potent corticosteroids, then, if indicated, switch to an appropriate anti-allergy medication to continue to suppress any chronic expression of disease.
Chronic Care Drugs
Chronic allergic eye disease is the less prevalent subset of allergy expression. This category of drugs is exclusively represented by agents that can stabilize mast cell membranes. Keep in mind, however, that all of these medicines can give some degree of acute symptomatic relief by virtue of their dilution and washing away of allergens resident in the precorneal tear film.
Since mast cell stabilizing drugs have little or no direct anti-histaminic nor anti-inflammatory properties, they are poorly suited to address acute allergic disease. However, these are excellent drugs for long-term preventive and maintenance therapy. They are well suited for multiple-week therapy for patients afflicted with allergies at known times (e.g., "every March and April") or when anticipating exposure to known allergens (visiting a home with cats).
Mast cell stabilizers, when used appropriately, can virtually eliminate the outbreak of allergic reactions. These drugs work by inhibiting the degranulation of mast cells, preventing them from releasing histamine and other allergy mediators. They are completely safe medications that can be used for weeks or months without any significant side effects. Since they are preserved, there is a low risk of toxicity, especially in patients with compromised tear function.
|Chronic Care Ocular Allergy Drugs
The "newer" products, Alamast and Alocril, are indicated for treating or preventing itch associated with allergic conjunctivitis, whereas the "older" mast cell stabilizers are only indicated for treating vernal disease. In reality, all of these products have the same mechanism of action and are efficacious against the entire spectrum of allergic expression. Ophthalmologist Mark B. Abelson, arguably the world's foremost authority on allergic eye disease, made the following observation in Review of Ophthalmology a few of years ago: "Alamast x showed ongoing effectiveness in what became the longest clinical trial in this pharmaceutical segment to date, 21 weeks. Also, though the medication is for q.i.d. dosing, it appears most likely that, after a loading period at q.i.d., Alamast can be reduced to b.i.d. dosing without a loss of effect. In addition, many patients on Alamast experienced a total prevention of itching, suggesting that the agent will become the mast cell stabilizer of choice."2
All of these drugs are excellent and generally perform well. It should be noted that Alocril has a slight yellow color. This is the nature of the formulation and should be explained to patients so they won't think it's "gone bad." Although Alocril is recommended as b.i.d. therapy, its identical counterpart in Canada suggests it can be increased to q.i.d. with advanced disease.
Stress to patients that mast cell stabilizers must be used regularly throughout their "at risk" season. They only perform properly when mast cell membranes remain stabilized. Giant papillary conjunctivitis (GPC) is routinely treated with a mast cell stabilizing agent. Such therapy is generally adjunctive to some of the following traditional therapeutic maneuvers: switching to disposable lenses; decreasing contact lens wearing time; enhancing daily lens hygiene; and using artificial tears with lens wear. When indicated in GPC, we prescribe a mast cell stabilizing drug q.i.d. for a month, then b.i.d. for a month or longer if indicated.
The question is always asked, "Can you use these drugs with soft contact lenses?" With disposable and GP lenses, no problem. These can be used with soft contact lenses replaced at least monthly, or GPs. Because of long-term potential toxicity from solution preservatives with conventional soft lenses, we try to limit use of topical ophthalmic medicines with annual replacement lenses. With yearly replaced conventional soft lenses, we have never had problems using these drugs as follows: one drop a few minutes before lens insertion, one drop at midday, and one drop in the evening after lens removal.
While there are other topical eye drops available to treat ocular allergy, we recommend one of the drugs discussed in this section. But, lastly, don't forget the benefit of cold compresses for acute flare-ups, or oral adjunctive therapy (e.g. Claritin, steroid nasal sprays, etc.) when indicated.
In summary, there are now eight excellent acute care, and five excellent chronic care allergy products. They all work well when used properly by the patient.
While these drugs are less commonly used by eye doctors, there are times when oral therapy nicely augments topical therapy. These are for patients who most commonly have allergic conjunctivitis concurrently with allergic sinusitis and/or allergic rhinitis. They can occasionally be helpful in treating eyelid myokymia (lid twitch) should a topical antihistamine fail to break the orbicularis fasciculation.
There are two main categories of oral antihistamines: OTC and prescription. The two most common OTCs are diphenhydramine (e.g., Benadryl) and chlorpheniramine (e.g., Chlor-Trimeton).
Now that Claritin has gone OTC, almost all drug plans disallow prescription antihistamines unless the doctor feels (and requests in writing) that a specific brand is required for an individual patient. It may be that corticosteroid nasal sprays (of which there are several) give greater relief from allergic rhinitis without the many potential side effects of oral antihistamines.
There are also several prescription antihistamines which are minimally sedating although dryness-inducing. For safety and effectiveness, only four are recommended: Claritin (loratadine) 10mg q.d., Clarinex (desloratadine) 5mg q.d., Zyrtec (cetirizine) 5mg and 10mg, and Allegra (fexofenadine) 60mg b.i.d. or 180 mg q.d. n
1. Ciprandi G, Cosentino C, Milanese M, Tosca MA. Rapid anti-inflammatory action of azelastine eyedrops for ongoing allergic reactions. Ann Allergy Asthma Immunol 2003 Apr;90(4):434-8.
2. Abelson M. 2000 Year in Review: Pharmaceuticals—Anti-allergics. Rev Opthalmol 2000 Nov:7(11):57-58.
Topical corticosteroids remain the cornerstone of ocular anti-inflammatory therapy.
Next to refractive error and dry eye, inflammatory conditions represent the most common clinical challenges. It is imperative that optometrists become familiar with the various topical steroids, and become competent and comfortable in their clinical use.
It's also critical that clinicians overcome the myths that surround the use of steroids, most notably that they pose a great risk of elevated intraocular pressure. Studies show that significant ocular hypertension is unlikely to occur before three to five weeks of prolonged topical steroid use even in known "steroid-responders," yet most cases of ocular inflammation are resolved well within this time frame.
Topical steroids are safe and effective agents that are useful in treating a host of ocular inflammatory conditions. Indeed, far more harm has come from withholding steroids than has occurred from their use. The risks associated with short-term use are minimal, yet the therapeutic benefits are significant. The addition of loteprednol etabonate has further widened the window of safety in topical therapy.
Selecting the Proper Drug
There are a number of topical steroids available, and making the proper selection may be confusing.
We recommend that you streamline your choices to a handful of safe and effective agents, and tailor your selection to the severity of the case.
As predicted last year, we have indeed been blitzed with a promotional overdose of "fourth generation" antibiotics. We wonder if the discovery of penicillin was as highly touted! These new antibiotics do, however, perform beautifully, just like their predecessors.
As with any of the fluoroquinolones, the key to a clinical cure of bacterial infection is to reach and maintain a high inhibitory concentration at the infection site. This is accomplished by frequent dosing, and we truly doubt it makes any difference which of the fluoroquinolones you choose to use. To wit, it would be interesting to see the change (or lack thereof) in the incidence of postoperative infection with the widespread use of these newer antibiotics.
A very nice article looked at the antibiotic susceptibility patterns of coagulase-negative staphylococcus bacteria.1 It found that the greatest sensitivities were "to vancomycin, the aminoglycosides (except neomycin), and levofloxacin." Unfortunately, moxifloxacin, gatifloxacin, and 1.5% levofloxacin were not available at the time this study was initiated; undoubtedly, these three would have performed at least as well. When this study looked at a multi-resistant bacteria, the aminoglycosides outperformed even the fluoroquinolones, and were 95% as effective as vancomycin, the gold standard in treating gram-positive pathogens.
Another article discussing in vitro antibacterial activity—which compared gatifloxacin and moxifloxacin with levofloxacin, ciprofloxacin and ofloxacin against isolates of bacteria known to cause corneal infection—reported that "for most keratitis isolates, there were no susceptibility differences among the five fluoroquinolones."2 The authors also say, "Minor differences in minimal inhibitory concentrations among fluoroquinolones may be less important clinically, however, as long as effective antibiotic tissue concentrations remain high." This is best accomplished via frequent dosing schedules with higher concentrations of fluoroquinolone. The authors go on the state, "the actual clinical efficacy of the newer fluoroquinolones remains to be defined by the results of clinical trials for the treatment of bacterial keratitis and conjunctivitis." The salient points from these two recent articles nicely summarize the key elements of the topical fluoroquinolones.
Bear in mind that all the ophthalmic fluoroquinolones have systemic counterparts. These orally administered drugs have been more rigorously studied and have been in clinical use longer than their ophthalmic offspring. Whatever these drugs do systemically, they do even better when they are topically applied. Since the efficacy of the fluoroquinolones is largely concentration-dependent, and we can place enormously greater drug per unit volume on the ocular surface than a can a pill distributed throughout the entire body, it is usually a simple task to kill ocular bacterial pathogens.
Although our sources were unable to get us the exact numbers for 2004, they conveyed that (as of June 2004) the percent national market share of oral fluoroquinolones in first quarter 2004 was very similar to the same period a year previously, no more than 2 percentage points higher or lower. Their popularity rank was in the same order: levofloxacin, ciprofloxacin, moxifloxacin, gatifloxacin, ofloxacin. Two conclusions that can be drawn from this are that the "real" doctors just don't get it, or the eye doctors are being very heavily marketed. The nice thing is, all of the fluoroquinolones work well when used properly. Pick one and go for it!
The two most hyped ophthalmic fluoroquinolones are moxifloxacin (Vigamox, Alcon) and gatifloxacin (Zymar, Allergan). Of these two fine drugs, we generally prefer moxifloxacin for three reasons: its 0.5% concentration, its pH of 6.8, and it is self-preserved. Gatifloxacin is 0.3%, has a pH of 6.0, and contains BAK as a preservative.
The Bottom Line on Fluoroquinolone Frequency
When using any ophthalmic fluoroquinolone, use it aggressively (q1-2 hours) for two to three days for moderate to severe conjunctivitis.
For true bacterial keratitis (not sterile infiltrate!), use a fluoroquinolone every 15 to 30 minutes for several hours to saturate the corneal tissues, then hourly for as many days as it takes to quiet the tissues (usually three to four days). Have these patients concurrently use Polysporin ointment for coverage during the sleep cycle.
Once the infection is under control, decrease the frequency of instillation from hourly to q2 hours for three to four more days, then q.i.d. for three to six additional days.
Never drop below q.i.d. unless you want to purposefully create resistance. It is protracted sub-bactericidal drug levels that set the stage for resistance development.
Aminoglycosides are less expensive than fluoroquinolones and are effective for most "garden variety" cases of bacterial conjunctivitis, making them our drug of choice for treating most acute bacterial infections.
There are two notable aminoglycosides: gentamicin and tobramycin. Because tobramycin ophthalmic solution is available in generic form and is slightly more effective while slightly less toxic than gentamicin, we invariably prescribe tobramycin when we need an aminoglycoside. The third aminoglycoside, neomycin, is not available as a stand-alone drug, but is found in certain combination drugs such as Neosporin, Maxitrol, etc.
Aminoglycosides work by inhibiting protein synthesis. They're most effective against gram-negative bacteria, especially Pseudomonas species, but are also effective against most gram-positive bacteria.
Though aminoglycoside toxicity is legendary—clinical signs include epithelial breakdown (SPK), injection in the inferior cul-de-sac, and a weepy erythema and edema of the eyelid tissues—these responses are usually not serious and mostly occur after the drug is used in excess of a week or two. In our years of clinical practice, we have never seen such an occurrence. For short-term use, these drugs are excellent cost-effective choices for killing bacterial ocular pathogens. Rarely are they used long enough to produce any significant side effects, unless the patient is pre-sensitized.
Tobramycin and gentamicin are available in solution (0.3%) and ointment (0.3%) form, but generally should not be used beyond one week because of their toxic potential. Being aminoglycosides, they can cause allergic reactions similar to those seen with neomycin, but are less likely to do so. When bactericidal therapy is needed in ointment form, Polysporin is our choice.
Erythromycin, which is only available in ophthalmic ointment form, is our drug of choice for pressure patching corneal abrasions and for nocturnal antibiosis/lubrication. It is gentle on the cornea and provides good antibacterial prophylaxis. It is a wonderful drug that is available generically and is used extensively in primary eye care of the external eye tissues.
Erythromycin, which is bacteriostatic, works by inhibiting protein synthesis. The topical form of this drug is effective against many gram-positive and some gram-negative organisms. If used over several days, staphylococcal resistance may develop. The drug is only available as a 0.5% ointment. For these reasons erythromycin is not a drug of choice for active therapy, but is an excellent prophylactic and supportive antibiotic.
Erythromycin is commonly used in labor and delivery suites as a second-line therapy to tetracycline ophthalmic ointment for neonatal prophylaxis against Neisseria, Treponemia and Chlamydia ocular inoculation during birth process. Topical erythromycin is commonly known by the brand name Ilotycin by Dista, and from Bausch & Lomb as an 0.125 oz. conventional ophthalmic tube and a 1gm unit-dose tube. Erythromycin ophthalmic ointment is widely available from numerous other generic manufacturers.
The Research Literature on Fluoroquinolones
"Resistance is more likely to arise after exposure of a bacterial subpopulation to repeated rounds of sub-lethal doses of fluoroquinolone."
"All three of the newer fluoroquinolones possess characteristics that are conducive to maximizing the tissue concentration relative to the MIC, and thus have a lower theoretical likelihood of encouraging the development of resistance, assuming the fluoroquinolone is properly used and dosed.
"[Gatifloxacin and moxifloxacin] are still susceptible to resistance due to one or more mutations in other genes (a not infrequent event) or due to a double mutation in both topoisomerase II (DNA gyrase) and topoisomerase IV (a highly improbable event)."
"Newer fluoroquinolones such as levofloxacin and in particular the 8-methoxyfluoroquinolones gatifloxacin and moxifloxacin offer the opportunity to help address [declining efficacy of older fluoroquinolones] in two ways. First, their enhanced activity against Gram-positive pathogens increases the probability that the strains resistant to an older fluoroquinolone will be susceptible to one of the newer fluoroquinolones. Second, they are less prone to encouraging the development of resistance on a number of fronts, primarily because of their higher activity against gram-positive pathogens, but also for other reasons (higher concentration in the case of levofloxacin; resistance to single-step topoisomerase mutations in the case of gatifloxacin and moxifloxacin). Primary use of newer fluoroquinolones in preference to initial use of older fluoroquinolones offers a potential strategy for helping to forestall the development of resistance, but this approach must be coupled with the overall strategy of avoiding indiscriminate use and ensuring proper dosing of these antimicrobials.
Bacitracin ophthalmic ointment is our drug of choice for treating bacterial blepharitis. The drug, which breaks down cell walls, works well against staphylococcal bacteria, the main bacterial cause of blepharitis and the most common ocular pathogen. If there is clinically significant lid margin inflammation concurrent with the staph. blepharitis, then a one-week course of TobraDex is better initial medical therapy.
Its effectiveness and minimal toxicity would make bacitracin a drug of choice for treating gram-positive infections, except that it is only available as an ophthalmic ointment. Even so, bacitracin can sometimes be very difficult to find, so we tend to prescribe Polysporin (the polymyxin B is just inertly "along for the ride").
Also keep in mind that the mainstay of therapy for blepharitis is meticulous long-term eyelid hygiene. But a short course of bacitracin in chronic staphylococcal blepharitis would augment the hygienic maneuvers and hasten the recovery process. Its singular practical use, in our opinion, is in these select cases of moderate to severe staphylococcal blepharitis. It is available from Bausch & Lomb and other generic manufacturers.
Polymyxin B Combinations
Many drugs are relatively "broad-spectrum" yet do not adequately cover Pseudomonas and other gram-negative species. As bacitracin is effective against gram positive organisms, polymyxin B is a potent killer of gram negative bacteria, including Pseudomonas. Resistance, toxicity and allergic reactions are rare. It works by destroying the cell membrane's structural and functional integrity, resulting in cell death. For this reason, polymyxin B is commonly found in the following combination products.
• Polytrim ophthalmic solution (Allergan). Trimethoprim, a diaminopyrimidine, achieves bacteriostasis by interfering with folic acid synthesis. Specifically, it interrupts the synthesis of tetrahydrofolic acid, the metabolically usable form of folic acid. Trimethoprim is active against most common gram-positive and gram-negative ocular pathogens, except Pseudomonas species.
Trimethoprim sulfate (0.1%) with polymyxin B is marketed as Polytrim ophthalmic solution by Allergan, and available generically. This combination product is an excellent antibiotic for treating bacterial conjunctivitis in children and adults. Untoward side effects are very rare. It is clinically effective against most common ocular pathogens, and is minimally toxic to the eye. It has a high clinical efficacy against Haemophilus influenzae and Streptococcus pneumoniae, the most common causes of bacterial eye infections in children, making it our drug of choice in these cases. To wit, pediatricians are the largest prescribers of Polytrim.
It isn't available in ointment form, and may not be suitable for smaller children in whom drop instillation is physically impossible or crying washes out the drops. In those cases, you could substitute Polysporin or Ciloxan ophthalmic ointment; both have good coverage against Haemophilus and Streptococcus species.
Interestingly, it has been reported that "H. influenzae type-B is now nearly non-existent as a pathogen in childhood epiglottis, meningitis, buccal cellulitis, and otitis."4 This may well be valid for conjunctivitis as well. It does appear that most infections tend to be strep and staph. Therefore, good coverage against gram-positive organisms is essential.
The recommended frequency of administration is one drop every three hours (q3h) while awake. This is a bit more frequent than the more common four times-a-day schedule. As with most other anti-bacterial agents, treatment should continue for a full week.
• Polysporin (Monarch Pharmaceuticals). This is an excellent broad-spectrum antibiotic combination that enjoys widespread use in eye care. The combination of bacitracin and polymyxin B is excellent for two reasons:
1. It is highly efficacious against most of the common ocular pathogens, both gram positive and gram negative.
2. It is relatively non-toxic to global epithelial tissues. It can play a role in any bacterial infectious process, but it is only available in ointment form, which limits its practical use.
We discourage use of ointments in adults for daytime therapy because it is not very patient-friendly. But if there is an indication for using an effective antibiotic at nighttime to get around-the-clock antibacterial coverage, certainly Polysporin (or Ciloxan) would be an excellent choice. In the event of a "dirty" corneal abrasion, such as a scratch by a dirty piece of metal, then it might be preferable to use Polysporin (or Ciloxan) instead of erythromycin. However, these are relatively rare occurrences.
Doctors can prescribe this drug safely in most bacterial infections. In blepharitis therapy, since polymyxin B is non-toxic, Polysporin can be substituted for bacitracin should the pharmacy not have bacitracin. Ciloxan ointment could also be used for infectious blepharitis.
• Neosporin (Monarch Pharmaceuticals). Bacitracin (or gramicidin) with polymyxin B and neomycin is available as Neosporin as a solution and an ointment. In the solution, gramicidin replaces bacitracin, since bacitracin is unstable in water. In terms of activity, gramicidin is virtually identical to bacitracin but more water-soluble.
The addition of neomycin, an aminoglycoside, kills a broad spectrum of bacteria by inhibiting protein synthesis. It's effective against most gram-positive and gram-negative bacteria, with the notable exception of Pseudomonas.
We rarely use it, however, because of the possibility of neomycin reactions, although they are uncommon. About 5% of all patients will experience a delayed, type IV hypersensitivity reaction to neomycin. If the patient has not been exposed to the drug before, the reaction can occur after several days of therapy. If the patient has been previously sensitized, the reaction can happen more quickly, usually within 12 to 72 hours.
If such a classic neomycin hypersensitivity were to occur, you will usually see erythema and mild edema of the eyelids, conjunctival injection, and possibly superficial punctate keratitis. The reaction usually is most pronounced in the inferonasal region of the eye because gravity and blink mechanics carry the drug there. The primary therapy is to discontinue the drug.
The reaction typically resolves on its own within a few days. Consider recommending cold compresses and/or a topical steroid ointment such as FML, or a combination ophthalmic ointment containing 10% sodium sulfacetamide and either 0.2 or 0.25% prednisolone (Blephamide, Isopto-cetapred) or 0.5% prednisolone (Metimyd or Vasocidin), applied to the inflamed tissues once or twice during the day and then at bedtime. The antibacterial agent plays no role here; the only way to obtain low concentrations of prednisolone in ointment form is in such combination products.
Triamcinolone 0.1% dermatological cream has become our favorite for treating all expressions of delayed (Type IV) hypersensitivity contact dermatitis.
Because newer antibiotics are now available that are less toxic and equally or superiorly efficacious, there is little reason to use products containing neomycin. Clinicians have other options that work just as well without the unnecessary risk of annoying neomycin side effects.
Pearls to Remember When Treating Infections
Collectively, the herpes viruses and adenoviruses are the etiologic agents for legions of viral infections annually. We have excellent antiherpes virus therapy, yet no specific medicine to kill the adenoviruses, which cause epidemic keratoconjunctivitis (EKC) and pharyngoconjunctival fever (PCF). The herpes viruses cause herpes simplex epithelial keratitis, herpes zoster infections, acute retinal necrosis, Epstein-Barr infections, herpetic genital diseases, and other disease processes.
Adenoviral infections are some of the most common external eye infections. In children, these are generally accompanied by a mild sore throat and low-grade fever, thus the descriptive name, pharyngoconjunctival fever. These infections present in adults as hemorrhagic conjunctivitis with an acute, painful red eye and, most notably, an ipsilateral, palpable preauricular lymphadenopathy.
While we eagerly await the development of topical ophthalmic anti-adenoviral drugs, we are able to utilize (off-label) Betadine 5% Ophthalmic Prep Solution to meet the needs of our patients with moderate-to-severe disease. When indicated, we proceed as:
Meanwhile, there are approximately 50,000 new cases of herpes simplex epithelial keratitis in the United States each year. For the most part, herpetic infections are relatively easy to diagnose and treat with a variety of antiviral drugs.
About 20 percent of patients have concurrent or delayed stromal inflammatory keratitis. This is where the immune system responds to deposited viral antigenic particles during or following epithelial infection. This can be tedious to treat, and can occasionally be left alone to pathophysiologically slowly burn itself out. Otherwise, steroids are judiciously used (concurrently with antiviral therapy until the steroid dose frequency is reduced to once daily; usually 4 to 6 weeks) over many months to years to suppress the immune response.
Recurrence of HSK is problematic. Recurrence rates are approximately 10 percent per year for five years. Recurrent infectious or stromal inflammatory disease is seen in 40-60 percent of patients between 5 and 20 years. A major report of the Herpes Eye Disease Study Group was published in the July 30, 1998 New England Journal of Medicine. That study has shed important new light on how we can positively influence recurrent herpetic disease. The key finding is very straightforward: acyclovir 400mg bid can reduce the recurrent rate of herpetic eye disease by about 50 percent! Less straightforward is which patients merit such therapeutic intervention. Patients with high rates of recurrence, especially of stromal inflammatory disease, appear to benefit the most. Therapy was done for 12 months. There was no rebound in the recurrence rate six months after cessation of therapy. This is important information, and gives us sound guidance in improving the quality of life in this subset of patients. We are now keeping many of these "high risk" patients on low dose oral antiviral therapy for 2 or 3 years without any problems.
Varicella zoster infection, or shingles, most commonly affects the first division of the trigeminal nerve, giving the classic presentation of herpes zoster ophthalmicus. All expressions of varicella zoster infection are essentially treated the same. Any one of these regimens is generally effective; however, their maximum clinical benefit is achieved when therapy is initiated within the first 72 hours of the onset of signs and/or symptoms. The three available oral antivirals are:
These drugs were initially designed to treat herpes zoster (i.e., varicella zoster) and therefore the standard, usual dosage recommendations are for zoster disease. However, these oral medicines are highly effective against herpes simplex disease, both dermatologic (skin vesicles) and corneal epithelial keratitis. Since the herpes simplex viruses are roughly twice as easy to kill, the dosages of these oral antivirals are used half-zoster-strength as shown above.
While it is true that epithelial herpetic disease can be treated with these oral antivirals, such is not standard of care. Topical Viroptic (trifluridine) remains the usual therapy for HSV epithelial keratitis.
For herpes zoster ophthalmicus or herpes zoster dermatitis near the eye without global involvement, use Zovirax, Famvir or Valtrex po for seven days. The globe itself is involved only about half of the time when the ophthalmic (1st) division of the 5th cranial nerve is involved. Globe involvement, which usually manifests as an inflammatory keratitis and/or anterior uveitis, can be concurrent with the dermatological disease or can be delayed weeks or months. In either case, aggressively use a highly efficacious topical ophthalmic steroid to suppress the inflammation and preserve tissue integrity.Topical Antivirals
Have patients frequently instill preservative-free artificial tears to help promote corneal healing, especially if there is suboptimal tear function or significant SPK along with the epithelial herpetic lesions. Viroptic is approved for use in patients 6 years and older.
Vira-A died June 7, 2001 when its sole manufacturer, Monarch Pharmaceuticals, pulled the plug. This is no great loss since between the two of us, in all our combined years of clinical practice, have prescribed it on five occasions. Actually, its absence may improve quality of care since we had heard of doctors prescribing trifluridine drops by day, and vidarabine ointment at night when treating epithelial herpes simplex keratitis; this is an unnecessary overkill and represents overly expensive care. When treating HSV epithelial keratitis, all that is needed is topical trifluridine drops, as explained above. Now, for you obsessive/compulsive over-treaters out there, you will need to replace Vira-A with oral acyclovir at 400mg 5 times a day!
The two legitimate occasions where Vira-A was used was as substitute therapy were when the patient was trifluridine-allergic, and in children for whom drop instillation was problematic and/or crying rapidly washed away the drops. The oral antivirals are very safe in children when dosed according to their age and weight. Acyclovir is commercially available in a ____mg liquid for pediatric use.
Commonly known by the brand name Zovirax and available generically, acyclovir is effective in treating both herpes simplex and herpes zoster. The drug is non-toxic due to its unique mechanism of action; viral thymidine kinase activates the drug, so non-infected cells remain unaffected. The only notable side effect is mild nausea.
The recommended treatment for HSV keratitis is 400mg five times per day for one week if topical therapy is impractical for some rare reason. While such oral therapy works well, topical Viroptic is the standard of care in the U.S. A 5% dermatologic ointment of acyclovir is available to treat genital HSV infection.
Since oral therapy is effective in both dermatological and ophthalmic disease, how does one treat patients with both eyelid vesicular disease and keratitis? The answer is simple. Use oral ACV since it nicely addresses viral replication in both tissues. We have seen the rare patient whose keratitis did not succumb to oral dosing, and in those cases had to use trifluridine concurrently. This is yet another example where optimum care requires individualized therapy.
Valacyclovir (Valtrex) is a pro-drug of acyclovir. Because it is a pro-drug, it has enhanced bioavailability and a longer half-life than the parent compound, acyclovir. Due to the enhanced pharmacodynamics, valacyclovir is used three times a day rather than the five times a day of acyclovir. Valtrex seems to be less expensive than its equally efficacious competitor, Famvir, making it generally preferred when treating herpetic disease. However, generic acyclovir will be the least expensive of the three oral antivirals, although it must be used 5 times a day, as opposed to only 3 times a day for the two newer drugs.
Famciclovir (Famvir) has the same mechanisms of action as acyclovir. It is a pro-drug of penciclovir and is a functional equivalent to acyclovir and valacyclovir. It has a relatively long intracellular half-life of seven to 10 hours. The main advantage of famciclovir is that it is used only three times a day (instead of the five times a day dosage of acyclovir), and it has been shown to decrease the duration and severity of post-herpetic neuralgia. It is active against herpes simplex and varicella. It can be taken without regard to meals, and is metabolized by the kidneys. This is true for all the oral antivirals, therefore, in patients with kidney disease, consultation with the patient's kidney doctor or a pharmacist is mandatory to prescribe the proper dosage in the setting of compromised renal function.
In summary, we have an excellent topical medicine and three very equivalent choices of oral anti-herpetic drugs. All of these medications are safe, effective, and provide us with excellent tools to rapidly normalize infected tissues.