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A Supplement to

22nd EDITION

Randall Thomas, OD, MPH Patrick Vollmer, OD

The Clinical Guide to Dr. Melton Ophthalmic[

[ Dr. Thomas Drugs

Dispense as writ ten — no substit utions. Refills: unlimit ed.

May 15, 2018 Dr. Vollmer

Peer-to-peer advice to help boost your prescribing prowess.

Supported by an unrestricted grant from Bausch + Lomb

001_dg0518_fc.indd 3 5/11/18 10:52 AM FROM THE AUTHORS

DEAR OPTOMETRIC COLLEAGUES: Supported by an Welcome to the 2018 edition of our annual Clinical Guide to Ophthalmic unrestricted grant from Drugs. Herein, we provide updates on our collective clinical experiences and Bausch + Lomb heavily season them with pertinent excerpts from the literature. This guide is intended to bring solid, scientifically accurate and clinically relevant information to our optometric colleagues. If you want to understand CONTENTS how the three of us treat, and what factors led us to develop these methods, you’ll find it explained here. The methods and opinions represented are our own. We recognize that other doctors may use alternative approaches. That First-year Impressions ...... 3 is true in all of health care. But this three-doctor writing team has logged over 75 combined years of clinical optometry, and we bring that ‘real-world’ spirit to the discussions that follow. Know that, above all, we are doctors who are genuinely concerned for our patients’ well-being and who endeavor to Care ...... 6 provide them the best of care, and we write from that perspective. The two topics of greatest interest and need for most physicians right now are glaucoma and dry . We have devoted considerable Off-Label Prescribing ...... 19 energy to thoroughly and comprehensively discuss them within these pages. Both are making the headlines these days. In dry eye, the role of omega-3 supplementation—long considered a staple of therapy in dry eye disease—has Dry Eye Therapy ...... 22 been challenged by a major study showing no benefit. We will cover this more completely in our dry eye chapter. The situation is more positive in glaucoma. We’re always excited to have new and improved approaches to reduce . Vyzulta Use ...... 30 (latanoprostene bunod ophthalmic solution 0.024%) was approved in November 2017, and the following month, rho-kinase inhibitor Rhopressa (netarsudil ophthalmic solution 0.02%) was approved. These new medicines Nonsteroidal Drugs ...... 37 complement our glaucoma armamentarium. A third new product of note derives from the glaucoma world but has found a new indication. Lumify ( tartrate ophthalmic solution Allergy Drugs ...... 38 0.025%), a redness reliever OTC eye drop that works on the venule tissues through a totally different mechanism of action, is now available, and should completely eclipse the old tetrahydrozaline-containing drops. We are grateful that Bausch + Lomb and Review of Optometry have Antiviral Therapy ...... 43 partnered with us for more than two decades to produce this important resource, as we endeavor to bring our profession the most up-to-date clinical information available to enhance patient care. Antibiotic Agents...... 48

With best wishes,

Randall K. Thomas, Ron Melton, Patrick M. Vollmer, OD, MPH, FAAO OD, FAAO OD, FAAO

Disclosure: Drs. Melton and Thomas are consultants to, but have no financial interests in, the following companies: Bausch + Lomb/Valeant and Icare. A PEER-REVIEWED Dr. Vollmer has no financial interests in any company. SUPPLEMENT

Note: The authors present unapproved and “off-label” uses of specific drugs in this guide.

002_dg0518_Intro.indd 2 5/10/18 11:04 AM FIRST-YEAR IMPRESSIONS

FIRST-YEAR IMPRESSIONS

We newcomers y rookie year in practice I choose not to refer theses cases out, has been fascinating, terri- not because I am overly confident (I lost inherit a world fying and exhilarating, all some sleep at night initially) but because of opportunity at the same time. I believe the patients came to me specifically to Mthis effect holds even truer help them. Additionally, to do good, for if you are a solo practitioner, as I am. Af- is a surgical discipline. None of the cases ter officially being in private practice a above warrant surgical procedures, nor our patients and little more than a year, I realize I do not did ophthalmology have any more access have all (or even most) of the answers. to the medicines used to treat the cases our profession. But I can speak from experience about listed above (even the compounded anti- what I have learned so far about growing biotics used to treat Pseudomonas). Let’s use it. an eye care practice and moving forward If you want to build up your name By Patrick Vollmer, OD, FAAO in a competitive environment. Here is my (and your services are within the associ- advice: ated scope of practice), you simply need • Stop referring your patients out. to care for these patients yourself. Aside from some posterior pathology and • Embrace . I prescribe surgeries, I have topical or oral steroids on a daily basis. only referred out one I can confidently say that their short- case to ophthalmology lived side effects (particularly with at the time of this writ- Lotemax) are negligible compared to the ing. Examples of cases enormous benefits they can provide to that I have not referred your patients. out include: Pseudo- Not only should you fully embrace monas infection, other your ability to prescribe these agents, peripheral and central you also should prescribe them aggres- corneal ulcers, corneal sively early on in the inflammatory pro- lacerations, herpes sim- cess. Tentatively prescribing steroids at plex , multiple suboptimal dosages will not bring your herpes zoster ophthal- patient disease resolution. Out of all the micus cases with severe cases I have treated, I have yet to have anterior chamber reac- one patient not drastically improve while tions, preseptal celluli- on corticosteroids. tis, an eye swollen com- • Befriend your urgent care centers. No pletely shut by bullous secret here—urgent care hates “treat- impetigo (misdiagnosed ing” eye-related emergencies. When the as shingles by the PCP), prescribed antibiotics failed to make Dr Vollmer examines a patient during his first year in thermal and chemical patients’ ocular inflammation better private practice. burns, and many more. (antibiotics do absolutely nothing for

REVIEW OF OPTOMETRY MAY 15, 2018 3

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ADVICE TO NEW GRADS • Develop relationships with urgent care centers, Advice for new optometric graduates could fill a text- pharmacy-based quick-care centers and primary care book, but it also can be succinct; we opt for the latter. physicians. These centers and PCPs have extremely • Buy used equipment, and slowly upgrade to state-of- limited knowledge of eye and vision problems, and the-art as finances prudently allow. would be relieved to have someone willing to help • Do all you reasonably can to keep your overhead low. them. Set up a time to take these colleagues to • Get help and advice on all topics and concerns— lunch, and carry business cards that make you easily don’t go it alone! Don’t be afraid to ask other suc- accessible. Many health care providers do not real- cessful professionals (even outside of eye care) their ize the scope of practice and wealth of knowledge advice. Their success was for a reason. Model them— optometrists have. And always send a succinct letter then improvise. documenting your findings and appreciation for any • Regarding the nightmare of insurance, every ophthal- referrals. mology office has a resident authority in this area. • Assuming you have a sound skill set, use your deep Choose an excellent ophthalmologist to work with courage to step up to the plate. Your professional for surgical referrals, and in reciprocal benefit, obtain growth will astound you. help from their insurance expert. Also, be aware that • The first time we do anything, there is a level of there are billing/insurance third-party companies uncertainty, uneasiness and anxiety. When treating a available, many compatible with your EHR. condition for which some of these emotions or con- • You are well trained and your basic clinical knowl- cerns arise within you, simply get the patient’s con- edge is at a peak. Use this asset to keep and care for tact number and let them know you will be calling any and all patients who present to your office. Refer them in a day or two to check on them. A personal out with great restraint. Never in your life will you phone call to a patient makes them realize how com- have a greater opportunity to solidify your clinical passionate and caring you are. skills than during your first few years in practice. • You are not a salesperson; you are a doctor. Put your • Remember, referring out carries a high potential for whole heart into what is absolutely best for your patient loss at a time when you are working to grow patients, and the revenue will follow. your practice. You have the same access to drugs • Of the big instruments/equipment (beyond the that other doctors do. Your patient came to you for basics), you will need to acquire the following, in this help. Give it to them. order: • Chat with (in person or by phone) older, benevolent 1. Pachymeter optometrists in your area to get their advice about 2. Humphrey visual field unit any and every aspect of your business. But choose 3. High-quality optical coherence tomography your advisors wisely. Tread carefully! device • Let your patients know you truly care about them. 4. Icare tonometer Rigorously adhere to the Golden Rule; such behavior 5. Retinal camera will always be appreciated and rewarded. 6. Slit-lamp camera • Be available to your patients. When a patient calls 7. Meibography unit your office, you should have a number where you (or 8. LipiFlow a colleague with whom you have developed a co- These are but a few of many practice management sharing of call responsibilities) can be reached. This is pearls that can be enormously helpful to a willing practi- paramount. tioner. Ponder these and their potential merit thoroughly, • Dress for success. Wear nice, professional clothing, and have the determination and courage to pursue them and a sharp, white lab coat that bears your name. Be based on your interests and the character of the practice proud to be an OD! you hope to build.

inflammation), those cases would don’t get nervous around these folks. available and remind them of all the wind up in my office several days Medical/nursing/PA schools instruct services you provide. later. their candidates to refer to ophthal- • Always send a follow-up letter. Now, after months of frequent- mology. To make matters worse, a If another provider refers to you, all ing their clinics, many urgent care very low percentage of all these cases they care about is that you treated/ eye cases now are referred directly to ever require surgery, essentially over- addressed the referred issue. If you my practice without any initial treat- burdening our surgical colleagues don’t send a succinct, brief follow- ment at all. and delaying patient care. up letter (don’t send the entire EHR • Befriend MDs and other health- While many primary providers are exam), the referrer has no way to care providers. To be perfectly hon- certainly well-versed in the physiol- document that you did anything est, I was met with some initial re- ogy of numerous organs, the eye is at all. This leaves no motivation to sistance here. That being said, please just not one of them. Make yourself have referrals sent your way in the

4 REVIEW OF OPTOMETRY MAY 15, 2018

0003_dg0518_firstyear03_dg0518_firstyear NEW.inddNEW.indd 4 55/10/18/10/18 11:0611:06 AMAM future. By the way, many EHRs al- • Don’t recommend a product or out in the community to introduce ready have such templates available. service a patient doesn’t need. While yourself, rather than fretting over • Remind your patients of all the the financial aspects of consumer- when you will see your next appoint- medical services you offer. Devote ism are beneficial, no one wants to ment. I often (unfortunately) com- 20 seconds at the end of each patient be upsold on something that won’t pare myself to my other colleagues encounter to letting them know you benefit them. Talk with your patients who see more than 30 patients a day, treat myriad ocular emergencies. to figure out what is most conducive although many of those individuals • Be available to your patients to serving their needs. Patients will have been in practice for decades and around the clock. I’m not sure that tell you that they appreciate this, and have established patient bases. strictly being available during busi- are much more likely to trust your Control what you can control, ness hours represents the best of advice in the future, and recommend and your practice will prosper. If you patient care. Everyone knows most family members and friends. can commit to doing your best for all conditions and emergencies happen • Be patient. I think that this is the your patients, perhaps you’ll look after business hours! If your patient single most important piece of advice back fondly on the days when you can’t find a way to contact you, their I can give a new graduate. Some days still got a short break for lunch. DG care could be significantly delayed. you will be slow. Don’t let these lulls Develop a way to be reached at any in patient care get you down! Spend Patrick Vollmer, OD, is owner of time. this time reading journals or getting a practice in Shelby, NC.

EVOLVING TECHNOLOGY Plaquenil patients are overdosed.1 TO AID YOUR PRACTICE Two somewhat competing approaches to calculating ■ ePA solutions help streamline prior authorizations appropriate dose exist:1 for providers. • Calculating ideal body weight (IBW): assumes that Electronic prior authorization (ePA) is the automated HCQ is stored mostly in lean tissue process of exchanging patient health and medication • Using actual body weight (ABW): assumes that information, enabling health care providers to initiate PA the drug is distributed evenly in muscle, skin and requests after a rejection at the pharmacy or prospec- fat tively in their e-prescribing workflow. In an effort to solve the dilemma, a team of Services such as CoverMyMeds and PARx Solutions Massachusetts Eye and Ear ophthalmologists developed partner with electronic health records (EHRs), health care a free smartphone app—DoseChecker—that blends the providers, payers and pharmacies to initiate, transmit and two approaches. The app became available in the App track the status of PA requests within the clinical work- Store in September 2017. Users enter the patient’s height flow, helping patients to more quickly receive the medica- and weight, and the app calculates the proper HCQ dose. tions they need for therapy. However, the app deviated from current American For example, health care providers can initiate and Academy of Ophthalmology (AAO) screening recom- manage ePA requests using CoverMyMeds in an online mendations for calculating optimal daily dosage, which is 2 portal or at the point of prescribing through one of the leading to a software revision in progress. The AAO now recommends that all patients using HCQ keep daily dos- 500-plus EHR vendors integrated with the company’s age less than 5mg/kg actual body weight—not ideal body technology. Health care providers can receive electronic weight. Older recommendations once advised calculating determinations, often within minutes, and create renewals dosage as 6.5mg/kg ideal body weight, but that conclu- from previously submitted requests. sion was based on 50-year-old studies about HCQ and In addition, PARx says its streamlined, user-friendly, full fat-using animals, according to an article in the April 2018 service approach is free to prescribers, combines web- issue of EyeNet.3 based technology and personalized support, and uses a When the revised app is available, it is expected to be universal approach across all health plans. endorsed by the AAO to simplify the calculation of daily

HCQ dose and schedule of tablets needed to provide a ■ App for calculating Plaquenil dosing proper weekly dose.3 undergoes revisions. Hydroxychloroquine (HCQ) (HCR) is a poten- 1. Perlman EM, Greenberg PB, Browning D, et al. Solving the hydroxychloro- quine dosing dilemma with a smartphone app. JAMA Ophthalmol. 2018 Feb tially blinding disease. Once HCR is detected, the disease 1;136(2):218-9. often continues to progress, even when the medication 2. Murray JJ, Lee MS. Re: Marmor et al.: American Academy of Ophthalmology Statement: Recommendations on screening for chloroquine and hydroxychloro- is stopped. As such, primary prevention by appropriate quine retinopathy (2016 Revision). (Ophthalmology 2016;123:1386-1394). Oph- dosing of HCQ (brand name Plaquenil) is the best way to thalmology. 2017 Mar;124(3):e28-e29. 3. Mott M. New app to tackle hydroxychloroquine dosing dilemma. EyeNet. minimize the risk of HCR. Studies show that about half of 2018;22(4): 19.

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DON’T LOSE SIGHT OF GLAUCOMA

Screening laucoma seldom progresses THE quickly, so take the time to While ancillary testing in glaucoma make a careful diagnosis should always workups can be helpful, remember and thoughtful decisions be on the that glaucoma is a disease of the optic Gregarding therapy prior to nerve. radar of an treatment. Diagnosis and management The typical head is of glaucoma should be a welcomed op- slightly oval and more vertically orient- attentive portunity in our offices and clinics, ed. Within the disc lies the optic cup, a where referral should be exceedingly paler, central depression devoid of any optometric rare.1-3 ganglion cell axons with visibility of Let’s start with some best practices the lamina cribrosa. physician. and reminders for a proper diagnostic The tissue that lies between the cup With a glaucoma evaluation. and the edges of the disc is referred to • Carefully observe the optic nerve as the neuroretinal rim. Subtle changes multitude of head. This is the foundation for the rest to the rim can result in significant of the glaucoma workup. Many times changes in a patient’s visual field, so diagnostic and glaucomatous will be carefully scrutinize this tissue. missed because a “normal” intraocular Remember that the size of the therapeutic pressure (IOP) lured the clinician into disc and the cup are typically closely tools at our complacency. However, low-tension related; a larger disc will usually have a glaucoma can be found in a sizable mi- larger cup. disposal, nority of patients, so analyze the optic nerve with close attention to the neuro- patient retinal rim tissue. • Perform tonometry (and at different referral should times of the day). While the prevalence be a rarity. of glaucoma increases with higher IOP, absolute diagnosis should almost never be made from a single pressure reading alone. It is good practice to get at least three different readings, with at least one reading in the early morning, given the circadian variability of IOP. This optic nerve head, while Large-scale population studies have considerably cupped, honors the ISNT determined that the mean IOP is around rule, and therefore is highly likely 15.5mm Hg. Two standard deviations physiologic cupping. on either side of this value approximate

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006_dg0518_Glaucoma.indd 6 5/10/18 3:46 PM TOPICAL GLAUCOMA DRUGS BRAND NAME GENERIC NAME MANUFACTURER CONCENTRATION BOTTLE SIZE Beta Blockers Betagan levobunolol hydrochloride Allergan and generic 0.25% 5ml, 10ml 0.5% 5ml, 10ml, 15ml Betimol hemihydrate Akorn 0.25% 5ml 0.5% 5ml, 10ml, 15ml Betoptic-S hydrochloride Novartis 0.25% 5ml, 10ml, 15ml Istalol timolol maleate Bausch + Lomb 0.5% 2.5ml, 5ml Timoptic timolol maleate Bausch Health 0.25% 5ml, 10ml, 15ml and generic 0.5% 5ml, 10ml, 15ml Timoptic (preservative-free) timolol maleate Bausch Health 0.25% unit-dose 0.5% unit-dose Timoptic-XE timolol maleate Bausch Health 0.25% 2.5ml, 5ml and generic 0.5% 2.5ml, 5ml

Prostaglandin Analogs bimatoprost generic 0.03% 2.5ml, 5ml, 7.5ml Lumigan bimatoprost Allergan 0.01% 2.5ml, 5ml, 7.5ml Travatan Z Novartis 0.004% 2.5ml, 5ml Travoprost travoprost generic 0.004% 2.5ml, 5ml Vyzulta latanoprostene bunod Bausch + Lomb 0.024% 5ml Xalatan Pfizer, + generic 0.005% 2.5ml Zioptan tafluprost Akorn 0.0015% unit-dose

Alpha Agonists Alphagan P brimonidine Allergan 0.1%, 0.15% 5ml, 10ml, 15ml Brimonidine brimonidine generic 0.15%, 0.2% 5ml, 10ml, 15ml

Carbonic Anhydrase Inhibitors Azopt suspension Novartis 1% 5ml, 10ml, 15ml Trusopt Merck and generic 2% 5ml, 10ml

Combination Glaucoma Medications Combigan brimonidine/timolol Allergan 0.2%/0.5% 5ml, 10ml Cosopt dorzolamide/timolol Akorn and generic 2%/0.5% 5ml, 10ml Cosopt PF dorzolamide/timolol Akorn 2%/0.5% unit-dose Simbrinza brinzolamide/brimonidine Novartis 1%/0.2% 8ml suspension Rho Kinase Inhibitors Rhopressa netarsudil Aerie Pharmaceuticals 0.02% 2.5ml

Author’s Note: Be advised that this is not an exhaustive list of the topical beta blockers. Several less commonly used drugs have been omitted for space.

a normal range to be between 10mm • Check central corneal thick- all optometrists would simply mea- Hg and 21mm Hg. ness. Having a pachymeter readily sure the central corneal thickness Traditionally, IOP had been available is crucial to establishing (CCT) in these pseudo-ocular hyper- thought to peak in the early morn- a true IOP. We regularly see refer- tensives (with semi-annual follow- ing hours, but research has revealed rals for a glaucoma evaluation in ups), it would be an immense service that IOP is highest during the sleep patients who have an IOP in the to patients and our profession. cycle. Normal diurnal variation mid-to-upper 20s, with 0.2 or 0.3 According to the Ocular Hyper- is less than 3mm Hg; fluctuations central cups and corneal thicknesses tensive Treatment Study (OHTS), greater than 6mm Hg necessitate a of 620µm to 640µm. These patients CCT has a major effect on IOP read- more attentive and closer follow-up. commonly have a normal workup. If ings. Without a pachymeter, IOP is

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FROM THE LITERATURE THE POSNER-SCHLOSSMAN SYNDROME This unilateral ocular condition—characterized by recurrent, acute attacks of mild, non-granulomatous, anterior and raised IOP—can result in chron- NEW PERSPECTIVES ic secondary glaucoma.1 Look for: ON TARGET IOP • Anterior uveitis accompanied by markedly elevated IOP (generally “Meta-analysis shows mean IOP 40mm Hg to 50mm Hg) reduction with prostaglandin • Results from recurrent cytomegalovirus infection in the anterior cham- analogues ranges from 28-33%. ber Slightly smaller IOP reduction • Incidence in primarily middle-age male population (although not exclu- is typically achieved with beta- sively) blockers whereas alpha-agonists Standard treatment includes topical steroids and ocular hypertensive medi- and carbonic anhydrase inhibi- cines. The syndrome is an uncommon cause of glaucomatous neuropathy. tors will usually reduce IOP by 15-20%.”1 1. Megaw R, Agarwal PK. Posner-Schlossman Syndrome. Surv of Ophthalmol 2017;62(3):277-85.

1. Clement CI, Bhartiya S, Shaarawy T. New perspectives on target intraocular pressure. Surv Ophthalmol. 2014 Nov- Dec;59(6):615-26. optic neuropathy, which needs to be inferior tissues are usually the thick- factored into risk assessment. est, followed by superior rim tissues, • Evaluate the neuroretinal rim. then nasal rim, with the temporal relatively meaningless. Remember the ISNT rule? It goes rim being the thinnest. This is not a Keep in mind that a physiological- like this: inferior > superior > nasal bulletproof concept, but it is a good ly thin appears to be an inde- > temporal. Let’s refresh: general guide. pendent risk factor for glaucomatous In a normal optic nerve head, the Even with much larger cup-to-

FROM THE LITERATURE subjects leads to a significant reduction of neuro- retinal parameters and may explain a large propor- AGING ALONE CAN EXACERBATE tion of the deterioration observed in patients with PROGRESSION IN GLAUCOMA PATIENTS treated glaucoma. Furthermore, both cross-section- It stands to reason that natural quantitative loss of optic al and longitudinal studies of healthy subjects show nerve fibers over time can contribute to glaucomatous patterns of regional loss similar to those in patients optic neuropathy. An article in Ophthalmology (December with glaucoma, suggesting that age-related region- 2015) gives important insights into the impact of natural al susceptibility may be accelerated in glaucoma. aging on visual field compromise in the setting of glau- Because several previous longitudinal studies of coma progression, per these excerpts:1 structural progression of glaucoma lacked a control • “Age-related loss of neuroretinal parameters may population, the observed changes were attributed explain a large proportion of the deterioration to glaucoma, perhaps overestimating the rate of observed in treated patients with glaucoma and change in treated glaucoma. Therefore, without an should be carefully considered in estimating rates understanding of the significant normal age-related of changes.” changes, there could be errors in rate estimates • “Because there is accumulating evidence that aging and the diagnostic accuracy of glaucoma-related in otherwise healthy subjects also results in statisti- progression.” cally significant change, often with patterns resem- Thankfully, there are many metrics and parameters to bling those in glaucoma, the clinical assessment of guide us in clinical decision making beyond the visual glaucomatous progression can be challenging.” field. However, this article serves to make us more • “The effect of IOP variability on ONH parameters is analytical in evaluating changes in the visual fields. probably related to changes in laminar position and Remember, in order to establish true progression, we prelaminar tissue compression.” would have to do three or four fields about every six to • “Because mean deviation (MD) is age adjusted, it 12 months. This is why it’s so challenging and minimally is likely that the absence of normal aging effects productive to micromanage the visual field component with this parameter allows better estimates of glau- of the comprehensive glaucoma assessment. coma-related damage than with the neuroretinal parameters.” 1. Vianna JR, Danthurebandara VM, Sharpe GP, et. al. Importance of normal aging in estimating the rate of glaucomatous neuroretinal rim and retinal • “Our findings indicate that aging in healthy control nerve fiber layer loss. Ophthalmology. 2015;122(12):2392-8.

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0006_dg0518_Glaucoma.indd06_dg0518_Glaucoma.indd 8 55/10/18/10/18 3:463:46 PMPM TIMOLOL EYE DROPS FOR MIGRAINE HEADACHE? CENTRAL CORNEAL Acute migraine headaches may be reduced in intensity or THICKNESS stopped altogether with eye drops. While the In a large study using manometric daily use of beta-blocker pills has been proven effective in methods to record intraocular preventing chronic migraine headaches, they have been pressure, 44% of normal-tension unsuccessful in treating acute, sudden-onset migraines. glaucoma patients would have Beta-blocker eye drops, however, are absorbed more been reclassified as having prima- quickly than pills by tear duct drainage onto the nasal ry open-angle glaucoma (POAG), mucosa, achieving therapeutic plasma levels “within min- while 35% of patients diagnosed utes.”1 with would have been reclassified as normal 1. Migliazzo CV, Hagan JC. Beta-blocker eyedrops for treatment of acute after CCT was taken into account.1 migraine. Missouri Medicine. 2014;111(4):283-8. To a statistically significant degree, researchers have deter- mined that African-Americans FROM THE LITERATURE tend to have thinner CCT measurements than Asians, Caucasians and Hispanics. This CUP-TO-DISC ASYMMETRY IN GLAUCOMA leads to a considerable underesti- A study in the August 2017 Ophthalmology described the prevalence of verti- mation of true IOP.2 cal cup-to-disc ratio (vCDR) asymmetry in US adults and assessed the utility Importantly, CCT is a predictor of vCDR asymmetry in the glaucoma diagnosis.1 The researchers concluded: of the extent of glaucomatous • vCDR asymmetry was predictive of prevalent glaucoma, although the damage in patients.3 positive predictive value remained low even at high degrees of asym- metry. 1. Ehlers N, Bramsen T, Sperling S. Applanation tonometry and central corneal thickness. Acta • vCDR asymmetry should initiate a more comprehensive glaucoma Ophthalmol (Copenh.) 1975;53:34-43. workup, especially in individuals with additional risk factors, but it is not 2. Shimmyo M, Ross AJ, Moy A, et al. Intraocu- appropriate as a screening metric for glaucoma. lar pressure, Goldmann applanation tension, corneal thickness, and corneal curvature in Caucasians, Asians, Hispanics, and African 1. Qiu M, Boland MV, Ramulu PY. Cup-to-disc ratio asymmetry in U.S. adults: Prevalence and Americans. Am J Ophthalmol. 2003;136:603-13. association with glaucoma in the 2005-2008 national health and nutrition examination survey. Ophthalmology. 2017 Aug;124(8):1229-36. 3. Herndon LW, Weizer JS, Stinnett SS. Central corneal thickness as a risk factor for ad- vanced glaucoma damage. Arch Ophthalmol. 2004;122:17-21. disc ratios, the focal rim tissue larger cup-to-disc ratios. can be healthy and well-perfused • Look at the patient’s history. with no pathology present. Ero- Glaucoma tends to run in fami- siblings to also seek an optometric sion of rim tissue, if found, is usu- lies. When we see patients who glaucoma evaluation. Such screen- ally seen at the inferotemporal have glaucoma or who are labeled ings have been shown to yield addi- (macular vulnerability zone) or as high-risk glaucoma suspects, we tional diagnoses. supero temporal areas. This is sec- always ask about siblings, as they • Check blood pressure in-office. ondary to the relatively sparse glial can have a higher risk of developing Carefully assess the patient’s sys- tissue support in this area. Remem- glaucoma that increases with age. temic conditions, especially hyper- ber, larger optic nerves will have We urge our patients to encourage tension. Particularly in low-tension

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FROM THE 24-2 OR 10-2: LITERATURE WHICH IS BETTER? Researchers studied the asso- STUDY COMPARES FIRST-LINE MEDICATIONS FOR ciation between quality of life PRIMARY OPEN-ANGLE GLAUCOMA (QOL) and visual function as This article in Ophthalmology (January 2016) definitively confirms what clini- measured by 24-2 and 10-2 VFs cians have witnessed over the last decade: All the prostaglandins work simi- in patients with primary open- larly.1 Some quotes from this article provide unique insights: angle glaucoma.1 They also tested • “The objective of this article is to assess the comparative effectiveness of the hypothesis that patients with first-line medical treatments for lowering IOP in patients with POAG or ocular vision-related QOL disproportion- hypertension through a systematic review and network meta-analysis and to ate to their 24-2 VF status may provide relative rankings of these treatments. By using a systematic review exhibit 10-2 damage overlooked and network meta-analysis, we estimated the pairwise comparative effective- by the 24-2 test.1 Here are some ness of 14 first-line IOP-lowering drugs used in patients with POAG or ocular of the findings: hypertension.” • 50% of all ganglion cells were • “Drugs in the prostaglandin class were more efficacious than drugs in within 8 degrees of fixation. other classes, although the within-class differences were generally small. • 90% of the visual cortex Bimatoprost 0.01% is no more effective than latanoprost or travoprost in low- involved 10 degrees of the ering IOP at three months. Brimonidine lowered IOP more than apraclonidine; central VF. and unoprostone and betaxolol lowered IOP the least.” • 24-2 did not sufficiently sam- • “In conclusion, we found that all active first-line drugs are effective com- ple the central VF. pared with placebo and that prostaglandins were more efficacious in lowering • Using only 24-2VF “may IOP at three months than beta-blockers, alpha-agonists, or carbonic anhy- underestimate the extent, drase. Bimatoprost, latanoprost and travoprost are among the most effica- location, and implication of cious drugs, although the within-class differences were small and may not be VF loss.” clinically meaningful. All factors, including side effects, patient preferences • Macular damage can occur and cost, should be considered in selecting a drug for a given patient.” early in glaucoma in the This final statement is a clinically practical admonishment. A key factor the macular vulnerability zone authors failed to mention is frequency of administration. While cost is a pre- (MVZ) . eminent factor, ease of use is similarly so. We find topical timolol to be cheap, • Macular glaucoma as mea- simple and safe (in non-asthmatic patients), which is why we often start there sured by the 10-2 VF was “a in select patients. It is most definitely our go-to second-line drug when target strong, frequently unmea- IOP is not achieved with a prostaglandin. Now, with the availability of Vyzulta sured, explanatory variable in (Bausch + Lomb), we anticipate using it first line since studies show IOP vision-related quality of life.” reductions of 7mm Hg to 9mm Hg and outperformance of latanoprost.2,3 1. Blumberg DM, De Moraes CG1, Prager AJ, 1. Tianjing Li, Lindsley K, Rouse B, et al. Comparative effectiveness of first-line medications for et al. Association between undetected 10-2 primary open-angle glaucoma. Ophthalmology. 2016;123(1):129-40. visual field damage and vision-related aual- 2. Prescribing Information: Vyzulta (latanoprostene bunod ophthalmic solution) 0.024%, for topical ity of life in patients with glaucoma. JAMA ophthalmic use. Available at: http://www.bausch.com/Portals/69/-/m/BL/United%20States/US- Ophthalmol. 2017 Jul 1;135(7):742-7. Files/Package%20Inserts/Pharma/vyzulta-prescribing-information.pdf?ver=2017-12-19-122554-107 (last accessed April 24, 2018). 3. Weinreb RN, Ong T, Scassellati Sforzolini B, et al. A randomised, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open standing of low-tension glaucoma. angle glaucoma: The VOYAGER study. Br J Ophthalmol. 2015;99:6:738-45. Many of these patients have blood pressures that are too low, which glaucoma patients, blood pressure tively new knowledge and asking can often explain glaucoma progres- medicines taken in the evening or them to consider having patients sion, despite achievement of target at bedtime can pathologically lower take blood pressure medicines in the IOP. Small, forearm-worn (radial) nocturnal blood pressure, which can mornings. devices for measuring blood pres- accelerate glaucomatous progres- Measuring systemic blood pres- sure are inexpensive and easy to use sion by decreasing optic nerve head sure can accomplish two goals: by ancillary personnel, and can be perfusion.4 We find ourselves fre- screening for uncontrolled (or of enormous value to patient health quently sending letters to primary under-controlled) systemic hyper- and glaucoma assessment. care physicians explaining this rela- tension and fine-tuning our under- In another unique group of

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0006_dg0518_Glaucoma.indd06_dg0518_Glaucoma.indd 1100 55/10/18/10/18 3:523:52 PMPM KNOW YOUR TYPE OF GLAUCOMA ways, the more information you col- lect, the more confident you can be Type Intraocular Pressure Optic Nerve in your decisions as you follow the Primary Open Angle Elevated Glaucomatous disease over time. Glaucoma • Perform perimetry (repeat, if any doubt). Ultimately, glaucoma Ocular Hypertension Elevated Normal is a disease that affects the visual Normal Pressure Glaucoma Normal/Low Glaucomatous field. Humphrey VF 24-2 SITA Fast testing remains our assessment of Normal Pressure Glaucoma Normal/Low Suspicious choice. One test result, especially Suspects in a naïve-to-VF test patient, can be The definition of glaucoma has evolved. Once thought to be exclusively a confusing unless it is either normal disease of high intraocular pressure, we now know that glaucomatous optic or it is abnormal but corresponds to neuropathy can occur in 25% to 40% of patients with normal IOPs. Don’t let a the optic nerve head assessment. The normal IOP distract you from careful nerve head observation and potentially problem is that many initial (and delayed treatment. some subsequent) VF results are “noisy” and fruitless. Remember that central VF loss patients, many asthmatics can use cell layers. While in no way is optical can occur early in glaucoma. Where a topical beta-blocker successfully. coherence tomography (OCT) abso- a 24-2 VF has only four central test However, we never prescribe one lutely diagnostic, the added benefits points, a 10-2 VF has 44 central before soliciting the primary care of such testing can be immensely points. While routine 10-2 testing physician for clearance and written helpful in tracking glaucoma pro- is not considered practical, strongly documentation attesting to such. gression. In addition to standard consider it when one or two central (As an aside, we also find ourselves RNFL scans and a quick ganglion defects are seen on the 24-2 VF. communicating more often with cell layer evaluation, analysis of the Once a repeatable visual field rheumatologists, since many of these macula can potentially give the clini- defect is present, following the pa- specialists have a proclivity to over- cian additional information. tient over time is best done with se- dose patients taking hydroxycholo- The latest literature suggests that rial VFs. Nerve fiber layer analyzers roquine. Sending a copy of the EMR very early glaucomatous damage can are more helpful in staging risk or is an extremely poor substitute for a involve the macula, specifically the helping to detect early glaucoma, brief letter.) inferotemporal portion of the gan- whereas serial VFs are optimal for • Analyze the retinal nerve fiber glion cell layers, referred to as the following patients with established layer (RNFL) and macular ganglion macular vulnerability zone. As al- VF defects.

OUR PERSPECTIVE ON CORNEAL HYSTERESIS • “A large correlation study found that corneal hys- A number of researchers have tried to determine whether teresis is influenced by age, corneal thickness, and corneal hysteresis (CH)— a biomechanical property relat- IOP.3 This presents a problem for measuring and ing to the eye’s ability to absorb and respond to pres- interpreting a result, because so many different fac- sure—is an independent risk factor for glaucoma. Some tors interact.” studies have determined that low CH is associated with • “I remain unconvinced at this time that hysteresis is optic nerve and visual field damage in glaucoma, and risk of value in the management of glaucoma.” of structural and functional glaucoma progression. One While glaucoma specialists continue to study the potential recent study supports the association as a risk factor for of this technology, we personally have found our tried- developing glaucoma, but the authors note that it was and-true methods amply sufficient for assessing ocular 1 likely not a factor in therapeutic decision-making. pressure. We are of the same mind as the author of a 2016 Glaucoma Today article, who wrote at the time that he 1. Susanna CN, Diniz-Filho A, Daga FB, et al. A prospective longitudinal was unconvinced that CH was a valuable measurement study to investigate corneal hysteresis as a risk factors for predicting development of glaucoma. An L Ophthalmol. 2018. Mar;187:148-152. for managing glaucoma.2 He noted the following: 2. Elsenberg D. What Is the Real IOP? Glaucoma Today. 2016 July/Au- • “A cornea has several features that might alter hys- gust. Available at: http://glaucomatoday.com/2016/08/what-is-the-real- teresis such as hydration status, thickness, curvature, iop/ (last accessed March 30, 2018). and IOP. The shape of the force-time curve of the air 3. Carbonaro F, Hysi PG, Fahy SJ, et al. Optic disc planimetry, corneal hysteresis, central corneal thickness, and intraocular pressure as risk fac- puff could also change the hysteresis results.”2 tors for glaucoma. Am J Ophthalmol. 2014;157(2):441-446.

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FROM THE USING THE MACULA TO LITERATURE ANALYZE GLAUCOMA Don’t assume that glaucoma is a NEWS ON HOME TONOMETRY disease that affects only periph- A study in the October 2017 JAMA Ophthalmology of 100 eral vision, and pass up the oppor- patients with glaucoma or ocular hypertension found the tunity to analyze the patient’s majority could perform self-tonometry successfully and ganglion cell layer and RNFL 1 would be happy to do so in the future: The study found: scans. Research has shown that • “Up to 75% of individuals have peak IOP outside of this sensitive area, specifically the office hours.” inferior/temporal ganglion cells • “…73% [of patients] could perform self-tonometry using a rebound of the macula, is highly vulnerable tonometer and obtain IOP measurements within 5mm Hg of a clinician. to early glaucomatous damage. Self-tonometry was judged easy and comfortable by most patients; most were happy to perform self-tonometry in the future.” Macular fibers enter the inferior • “A total of 56 of 79 successful or partially successful patients (71%) felt part of the optic disc, resulting in self-tonometry was easy, with 73 of 79 (92%) reporting self-tonometry to a superior “comma defect” on a be comfortable, and a similar number happy to perform self-tonometry in 10-2 VF.1 the future.” For glaucoma patients com- plaining of “hazy vision,” or with 1. Pronin S, Brown L, Megaw R, et al. Measurement of intraocular pressure by patients with glau- central defects on a 24-2 VF, coma. JAMA Ophthalmol. 2017;135(10):1030-16. strongly consider ganglion cell analysis along with a 10-2 VF. • Look at the angle. When per- Most patients with pigment dis- 1. Hood, DC et. al. Glaucomatous damage of forming , use a four- persion syndrome or pseudoexfolia- the macula. Prog Retin Eye Res. 2013:32C mirror . After administering an tion are at higher risk for increased 1-21. anesthetic drop, this procedure can intraocular pressure due to clogging be done relatively quickly. While the of the trabecular meshwork by bio- Pseudoexfoliation can be missed non-contact Van Herick assessment logic debris. Screening for pigment if the is not pharmacologically is helpful, it may not be as sensitive dispersion can be accomplished by dilated, as deposits on the face of the or specific as gonioscopy. This tech- careful examination of the corneal lens may be obscured. Qualifying nique is especially important in mod- endothelium and retroillumination and quantifying such debris in the erate to high hyperopia if progressive of the non-dilated to look for ra- angle is vital, especially in the setting nuclear sclerotic cataract is further dial (or splotchy) iris transillumina- of increasing IOP. narrowing the iridocorneal angle. tion defects. It is also important to annotate the pigmentation of the angle tissues when contemplating laser trabecu- FROM THE loplasty. Pigment absorbs the laser LITERATURE energy to enable a positive therapeu- tic response. If little or no pigmenta- OCT IN STRUCTURAL DIAGNOSIS tion can be found in the trabecular A November 2016 study in AJO investigated the role of spectral-domain opti- meshwork tissues, the patient likely 1 cal coherence tomography (SD-OCT) in the structural diagnosis of glaucoma. won’t experience a useful therapeutic The researchers wrote: response from the procedure. On the • “Evaluation of structural changes is the initial, fundamental step in glau- other hand, heavily pigmented angles coma diagnosis. Structural changes serve as the primary sign of glau- tend to result in decreased IOP low- coma likelihood; they provide the basis of initial glaucoma diagnostic ering effects. Gonioscopy should be indication as to whether patients will undergo further examination or performed to rule out causes such as treatment.” angle recession or neovascularization. • “In reality, clinicians exercise discretion in accepting OCT results or not • Consider trabeculoplasty ear- based on their impressions gained from clinical examinations. Thus, the lier. Laser trabeculoplasty is more diagnostic role of OCT should be examined within the context of the effective in phakic than in pseudo- process of clinical decision making.” phakic . We typically repeat go- 1. Kim KE, Oh S, Jeoung JW, et al. Spectral-domain optical coherence tomography in manifest glau- nioscopy every five years or sooner coma: its additive role in structural diagnosis. Am J Ophthalmol. 2016 Nov;171:18-26. with unexplained increasing IOP.

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006_dg0518_Glaucoma.indd 12 5/10/18 3:53 PM FROM THE have different thresholds and phi- LITERATURE losophies but, by and large, there is no rush to treat because glaucoma RISK FACTORS FOR RAPID PROGRESSION OF POAG is usually a slowly progressive neu- ropathy. This study in the August 2017 AJO aimed to determine the intraocular and systemic risk factor differences between rapid and non-rapid glaucoma pro- The decision to treat requires gressors.1 It determined: much care, contemplation and com- • “Cardiovascular disease is an important risk factor for rapid glaucoma prehensive assessment. Also, don’t disease progression irrespective of IOP control.” forget that we are not treating a • “…worse baseline mean deviation (MD), higher baseline IOP, more condition or disease; we are treat- frequent ocular antihypertensive medication changes, and number of ing a person, so involving patients IOP-lowering medicines were also robust predictors for rapid progres- in the decision-making process is sion in our cohort. Although other risk factors including lower CCT, PXF, appropriate. Also remember: This disc hemorrhages and hypotension were more common in the rapid publication is a drug guide, not a progression cohort, they did not have a significant effect in predicting textbook. We assume a significant disease progression.” level of knowledge on the part of the reader. There can be exceptions to 1. Chan TCW, Bala C, Siu A, et al. Risk factors for rapid glaucoma disease progression. Am J Oph- thalmol. 2017 Aug;180:151-7. everything said herein, and every pa- tient has to be cared for in a highly individualized manner. To summarize the diagnostic eval- in the setting of low-tension glau- Let’s now look at glaucoma medi- uation: coma. By doing all these things, you cations we have in our armamen- (1) Carefully study the optic nerve will reduce the chance of missing tarium. with -enabled ophthalmos- glaucoma. copy. FIRST-LINE THERAPY (2) Note the IOP. THERAPEUTIC With few exceptions, a prostaglan- (3) Check CCT. PERSPECTIVES din or timolol remain the frontrun- Beyond these three maneuvers, Currently, lowering IOP is the only ners in treating patients with glau- take a careful family history, obtain proven treatment for glaucoma. coma. RNFL measurements and baseline Knowing when to initiate therapy Since its initial release in 1996, VFs, and perform gonioscopy. Last- is the Holy Grail of patient manage- latanoprost (Xalatan) paved the ly, check blood pressure, especially ment. Equally competent doctors way for prostaglandins as first-line

FROM THE LITERATURE

PROGRESSION AND FREQUENCY OF TESTING Research published in the June 2017 Ophthalmology described the time required to detect statistically significant progression of different rates of VF loss using standard automated perimetry when considering different frequencies of testing.1 The authors indicated: • “Standard automated perimetry (SAP) remains the most important clinical tool for detecting progressive damage.” • It is essential to obtain two reliable tests within a short time frame at base- line. • “Confirming the presence of progressive loss through repeated testing is rec- ommended to reduce the probability of incorrectly diagnosing progression.” • “The initiation or intensification of glaucoma treatment, or even its mere diagnosis, can have a negative impact on an individual.” • It is important to obtain semi-annual testing within the first year of follow-up. When in doubt, repeat the field. • Tailor your care with each patient.

1. Wu Z, Saunders LJ, Daga FB, et al. Frequency of testing to detect visual field progression derived using a longitudinal cohort of glaucoma patients. Ophthal- mology. 2017 Jun;124(6):786-92.

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NO SINGLE VF DIAGNOSES Do not make the mistake of relying on a single VF to diagnose glaucoma. Depending on the level of patient risk, do your due diligence to repeat the fields in a few weeks to months, looking for defect repeatability. Also, remember that glauco- matous VF defects are most commonly arcuate and nasal in shape. Patients can have irregularities in their fields that are not glaucomatous and, depending upon the pattern, may or may not necessitate other routes of investigation. Once a diagnosis of glaucoma is firmly established, initiation of drop therapy is the next step. Note: never make a change in medical therapy based on the results of a single visual field test, as it is established that repeating VF testing three to four times is necessary before one can confirm true progression of a VF.

therapy to treat glaucoma. Prosta- difference in morning vs. evening in- clude iris color darkening, increased glandins lower intraocular pressure stillation of a prostaglandin is some- pigmentation, hypertrichosis by elevating the presence of extracel- where in the vicinity of 1mm Hg, and conjunctival hyperemia. Anoth- lular metalloproteinases that break so good adherence in the morning er side effect, superior eyelid sulcus down the collagen matrix, thereby is much preferred to poorer adher- deepening, can be dramatic in some enhancing uveoscleral outflow of ence in the evening. Additionally, patients. aqueous. This class of drugs com- prostaglandins’ long duration of ac- Prostaglandins can be contrain- monly reduces baseline pressures by tion can be seen for up to 72 hours, dicated in patients with a history of 25% to 33%. which is convenient in less compli- uveitis, herpes simplex and Prostaglandins also have an ex- ant patients. (due to the slight increased risk of cellent diurnal effect. However, the Side effects, while minimal, in- ).

TOP LEFT: Since the inferior and superior neural tissues have the least robust glial tissue support, they are most prone to sustain loss. Here the loss of neuroretinal rim is manifested as clinical “notching,” a hallmark observation in many glaucoma patients.

MIDDLE LEFT: This optic nerve sustained severe loss of neural tissue, thus showing a C/D ratio of 0.8.

BOTTOM LEFT: Side effect of prostaglandins include periorbital fat atrophy that gives rise to marked deepening of the superior lid sul- cus, which can result in and enophthal- mos; beyond the obvious cosmetic concerns, such altered lid/orbital anatomy can make applanation tonometry challenging.

TOP RIGHT: This optic nerve head was judged to be 0.1 by a previous doctor, but a careful look will show a very thinned neuroretinal rim in a shallow cup. Note also the peripapillary atrophy.

BOTTOM RIGHT: Because this patient’s IOP was 16mm Hg, we surmise the prior eye doctor failed to carefully study the optic nerve head. Note the pronounced infe- rior erosion of the neuroretinal rim, which manifested as a superior hemispheric visual field defect.

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006_dg0518_Glaucoma.indd 14 5/10/18 3:53 PM ASSESSING THE NARROW ANGLE1 • “Often, at cocktail parties, glaucoma specialists get together and say, ‘What’s wrong with the general ophthalmologists? They’re missing a lot of angle clo- sure.’ And I usually say, ‘Well, what’s wrong with us that we haven’t been teaching them FROM THE gonioscopy?’” LITERATURE • “…there are a lot of cases that come from optometry where RISK FACTORS FOR ANGLE CLOSURE they have been referred for A study in the September/October 2017 Survey of Ophthalmology revealed high pressure, and no assess- that reasons why and how people develop acute angle-closure closure glau- ments of the angle were per- coma are still not well-elucidated.1 The researchers illuminated that: formed.” • “Narrow anterior chamber angle, advanced age, female gender, and • Always “do gonioscopy in a Asian ethnic background are considered risk factors for acute primary completely darkened room angle closure.” […]. There should be no light • “…acute angle closure eventually develops in only a relatively small pro- through the pupil.” portion of anatomically predisposed eyes.” • “It remains difficult to predict and prevent acute angle closure attacks.” 1. Asrani SG, et al. MD Roundtable: Expert Tips for Assessing the Narrow Angle. Eye Net, 2015. January. 1. Zhang X, Liu Y, Wang W, et al. Why does acute primary angle closure happen? Potential risk fac- tors for acute primary angle closure. Surv Ophthalmol. 2017 Sep - Oct;62(5):635-47.

Generic latanoprost is a common- QUOTABLE ly prescribed glaucoma drop, and for many patients, it may be the best ini- tial option because of cost. However, “PRIMARY OPEN-ANGLE GLAUCOMA (POAG) IS A CHRONIC, choosing the right medicine is highly PROGRESSIVE OPTIC NEUROPATHY IN ADULTS IN WHICH THERE complicated due to diverse and ever- changing marketing promotion. In IS A CHARACTERISTIC ACQUIRED ATROPHY OF THE OPTIC some situations, a brand-name-pro- NERVE AND LOSS OF RETINAL GANGLION CELLS AND THEIR tected product can be less expensive, AXONS.”1 especially with a coupon.

As well, different insurance com- 1. American Academy of Ophthalmology. Preferred Practice Pattern. Primary Open-Angle Glaucoma. panies have different drug formular- 2016. www.aaojournal.org/article/S0161-6420(15)01276-2/pdf (last accessed March 30, 2018). ies. To help you navigate this dynam- ic landscape, turn to the GoodRx, fensive as commonly touted. In fact, dine, Zioptan has to be stored under Micromedex and UpToDate web we have found that the 0.01% for- refrigeration at the pharmacy. sites to help you in your decision- mulation with the higher BAK con- Timolol, a non-selective beta- making. centration has better corneal pen- blocker, lowers IOP by decreasing In our patients, the 0.01% for- etration. aqueous humor production. It was mulation of Lumigan (bimatoprost, That said, for patients sensitive the first topical beta-blocker to be Allergan) is much better tolerated to BAK, Travatan Z (travoprost, used as an ocular hypotensive for with less hyperemia than the 0.03% Novartis) is preserved with SofZia. glaucoma in the United States, and (which is generically available), yet And for those rare individuals who for decades was considered the gold there is four times as much benzal- truly need a preservative-free option, standard by which all other glauco- konium chloride (BAK) in the lesser- Zioptan (tafluprost, Akorn) nicely ma drops were compared. Timolol concentrated formula. We feel that meets this need. The main downside typically lowers pressures 25% from this suggests that BAK is not as of- is that, like latanoprost and trifluri- baseline.

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A VICTORY FOR VYZULTA under refrigeration until dispensed to the patient. The first new glaucoma medication in quite some time, Approved for once-daily use (in the evening) and latanoprostene bunod ophthalmic solution, 0.024% recommended for people over age 16, Vyzulta’s main (LBN) was FDA approved in November 2017, more side effect is conjunctival hyperemia (about 6%). It is than 20 years after Xalatan made its debut in 1996. preserved with 0.02% BAK (just like latanoprost) and LBN is the first IOP-lowering agent with a novel dual comes in a 7.5mL bottle filled to 5mL volume. mechanism of action. Once in the eye, resident ester- Since it is established that every millimeter reduc- ases cleave the molecule into latanoprost acid and tion in IOP significantly decreases the risk of glaucoma butanediol mononitrate, which is further metabolized, progression, we perceive using this new medicine in at yielding nitric oxide that appears least four clinical situations: to relax the smooth muscles of the 1. First line in an attempt to drive IOP as trabecular meshwork. This outcome low as possible. enhances aqueous outflow. The IOP- 2. Patients in whom target IOP is nearly lowering effects were up to 7mm Hg achieved with any of the older generation 1 to 9mm Hg. prostaglandins. We could easily add a beta- In a 28-day trial head-to-head trial blocker once daily, but this would require (VOYAGER) against latanoprost, LBN the acquisition of another topical preserved demonstrated superior diurnal reduc- eye drop that might not be necessary. tions in IOP from baseline.2 Four con- 3. Certainly, if the patient has asthma or is centrations of LBN (0.006%, 0.012%, a beta-blocker nonresponder, Vyzulta might 0.024% and 0.040%) were compared achieve target IOP. with Xalatan. All demonstrated a higher IOP reduction than Xalatan, 4. When a prostaglandin and a beta- with the high concentrations of LBN blocker come close but do not achieve (0.024% and 0.040%) showing the target IOP, replacing the prostaglandin with greatest IOP reduction from baseline. Vyzulta might meet treatment goals. Because the two higher concentra- We are pleased to have a new, dual- tions of LBN ended up having similar clinical efficacy mechanism, single-molecule drug available that can (probably due to receptor saturation), the 0.024% help us achieve further IOP reduction and provide dose was selected for further clinical evaluation. In the optic nerve protection, as well as potentially delay the study, Vyzulta led to an additional IOP reduction of need to add a second or third drug. 1.2mm Hg.2 1. Prescribing Information: Vyzulta (latanoprostene bunod ophthal- Vyzulta is a prostaglandin analog indicated for the mic solution) 0.024%, for topical ophthalmic use. Available at: http:// reduction of IOP in patients with open-angle glaucoma www.bausch.com/Portals/69/-/m/BL/United%20States/USFiles/ Package%20Inserts/Pharma/vyzulta-prescribing-information. or ocular hypertension. Note that it is not indicated for pdf?ver=2017-12-19-122554-107 (last accessed April 24, 2018). “elevated” IOP, thus acknowledging that many patients 2. Weinreb RN, Ong T, Scassellati Sforzolini B, et al. A randomised, have normal pressure glaucoma or are glaucoma sus- controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: The pects. Like latanoprost, the drop is stored long-term VOYAGER study. Br J Ophthalmol. 2015;99:6:738-45.

Unlike the dosing of prostaglan- cost is a well-recognized reason for therapy (assuming no contraindica- dins, it is important to dose this patient noncompliance. For patients tions). If a second drug was needed, drop in the morning. Remember, who need a preservative-free beta- we would have the patient instill beta-blockers act on the sympathet- blocker, Timoptic (Bausch + Lomb) one drop of the beta-blocker in the ic nervous system, which is greatly in ocudose (a unit-dose container) is affected eye in the morning, and one downregulated during our sleeping available, though not generically. drop of the prostaglandin in the eve- hours. There is no proven benefit of ning. This combined therapy usually dosing this drop in the evening or ADJUNCTIVE THERAPY achieves target IOP. more than once a day. If we prescribe a prostaglandin for If the beta-blocker is contraindi- Perhaps the greatest asset of ge- initial therapy, and it works well but cated (e.g., in a patient with asth- neric timolol is its cost—under $10 doesn’t achieve the proposed target ma), our next preferred drop is the for a 5mL bottle—so you likely range of IOP reduction, we would alpha-2 selective adrenergic agonist won’t find a better price point on consider switching to Vyzulta before 0.2% brimonidine. While 1% apra- the market. This is important, as adding a beta-blocker as adjunctive clonidine demonstrates a more rapid

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006_dg0518_Glaucoma.indd 16 5/10/18 3:54 PM EVERY MILLIMETER COUNTS While on alpha-2 adrenergic ago- nists, patients may experience an in- • “…the risk reduction could be about 19% per mm Hg, confirming results from creased prevalence of dry mouth and the EMGT [Early Manifest Glaucoma Trial] and Canadian Glaucoma Study, and nose, so potential adverse side effects showing that IOP reduction is highly effective, and that every mm Hg of pressure should be brought to the patient’s at- counts… These results […] should also serve as a stimulus to the pharmaceutical tention before starting treatment. industry to continue development of new and even more potent drugs.” Carbonic anhydrase inhibitors Heijl A. Glaucoma treatment: by the highest level of evidence. Lancet. 2015 Apr 4;385(9975):1264-6. (CAIs) reduce IOP by reducing aque- • “Patients treated in the EMGT had half of the progression risk of control ous production by up to 2mm Hg to patients. The magnitude of initial IOP reduction was a major factor influencing 3mm Hg when used as monotherapy, outcome. Progression was also increased with higher baseline IOP, exfoliation, and an additional 15% when used in bilateral disease, worse mean deviation, and older age, as well as frequent combination with a prostaglandin or disc hemorrhages during follow-up. Each higher (or lower) millimeter of mer- beta-blocker, we have found. CAIs cury of IOP on follow-up was associated with an approximate 10% increased have to be used twice daily. So we (or decreased) risk of progression.” feel that such factors limit their clini- Leske MC, Heijl A, Hussein M, et al. Factors for Glaucoma Progression and the Effect of the Treatment. Arch cal usefulness. Ophthalmol. 2003 Jan;121(1):48-56. The most common side effects • “…elevated IOP is a strong risk factor for glaucoma progression, with the HR with CAIs are mild burning and a [hazard ratio] increasing by 11% for every 1mm Hg of higher IOP.” lingering metallic taste after instilla- Bengtsson B, Leske MC, Hyman L, et. al. Fluctuation of intraocular pressure and glaucoma pro- tion. Although CAIs have a sulfa side gression in the early manifest glaucoma trial. Ophthalmology. 2007 Feb;114(2):205-9. chain, we have observed little or no cross-reactivity in people who are al- decrease in IOP, the drop is reserved use. Alternatively, the therapy can be lergic to sulfonamide antimicrobials for short-term adjunctive use due to a prescribed as brand-name Alphagan since the molecular structures differ slight propensity to cause redness and P (0.1% brimonidine, Allergan) with greatly. Be aware that topical CAIs tachyphylaxis when used longer than Purite as the preservative to decrease may hinder endothelial function in one month. Alpha-2 adrenergic ago- chances for adverse effects; however, patients with endothelial compro- nists exert their effects by decreasing this route is considerably more ex- mise, so take caution in using these aqueous humor production and in- pensive. eye drops in this setting. creasing uveoscleral outflow. The av- erage IOP reduction is around 26%.5 NEW GLAUCOMA CLASS OF DRUG One drop is instilled within 20 to The trabecular meshwork is finally getting some over- 30 minutes after waking, followed by a second drop of brimonidine due attention. A new class of drugs known as rho kinase between 4pm and 5pm in the after- (ROCK) inhibitors is focused on enhancing conventional noon. Though FDA-approved dosing outflow. for the medication is TID, off-label Netarsudil ophthalmic solution 0.02%, marketed under use of brimonidine BID as an ad- the brand name Rhopressa (Aerie Pharmaceuticals), was junctive therapy tends to work well FDA approved in December 2017 for lowering elevated for about eight hours, and does very IOP in patients with open-angle glaucoma or ocular little during the sleep cycle; thus, late hypertension. The solution is to be used once daily. afternoon instillation provides maxi- Findings from a Phase II trial comparing netarsudil to mum therapeutic benefit. latanoprost revealed that IOP reductions were similar, In our experience, the addition of and in all enrolled patients netarsudil was 1mm Hg less 1 0.2% brimonidine has two main lim- effective than latanoprost. The most frequently reported itations. First, the drop is dosed BID adverse event with netarsudil was conjunctival/ocular 1 as adjunctive therapy—the patient hyperemia, with an incidence of about 52%. will now be instilling a total of three These rho kinase inhibitors represent a new class of IOP-lowering agents to drops in the affected eye, per day. help many glaucoma patients try to achieve target IOP. As of the time of pub- The second is the possibility of ocu- lishing, we have not yet had access to Rhopressa to be able to assess its utility in lar surface allergic disease. We have clinical patient care. found a type IV conjunctival hyper- 1. Bacharach J, Dubiner HB, Levy B, et al. Double-masked, randomized, dose-response study sensitivity response in about 30% of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. of patients after six to 12 months of 2015;122(2):302-307.

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SYSTEMIC MEDICINE AND IOP widely available for under $10. Be Understanding associations between systemic medication use and IOP may help mindful that we have found that us manage glaucoma patients being treated for systemic comorbidities, a recent prostaglandins generally reduce in- study suggested.1 A few highlights included that: traocular pressure by about 30%, • “Participants taking systemic beta-blockers had lower IOPs.” If a glaucoma whereas nonselective beta-blockers reduce IOP by about 25%. That’s patient or suspect stops their systemic beta-blocker, reassess their IOP. a separation of only about 1mm Hg • “Multiple longitudinal studies show no increased risk of POAG for persons to 3mm Hg. Do not lose sight of the with diabetes.” fact that beta-blockers remain an ex- • “IOP alone is a poor tool for identifying whether an individual has glauco- cellent choice for reducing IOP. ma.” Glaucoma diagnosis “requires a careful assessment of all relevant risk Initial therapeutic interventions factors, an expert examination of the optic disc, and an assessment of the generally are not complicated. How- visual field.” ever, if the patient is a prostaglandin 1. Foster PJ, Khawaja AP. (Invited Commentary) The association of systemic medication and disease nonresponder or has active asthma, with intraocular pressure. JAMA Ophthalmol. 2017;135(3):203-4. establishing a therapeutic plan be- comes more like a chess game, in- This drug class is available as a employing a more expensive combi- volving considerable thought and solution (generic dorzolamide) and nation drug might not be necessary. trials until target IOP is achieved. a suspension (Azopt [brinzolamide, Cosopt is unique in that it is ge- Glaucoma should be readily em- Novartis]). Only Azopt and Sim- nerically available as a bottled prod- braced by more optometric offices and brinza (Novartis) are glaucoma sus- uct and also as a brand-name-pro- clinics. While the disease remains a pensions, which have to be shaken tected, preservative-free unit-dose leading cause of blindness worldwide, before instillation. product. The carbonic anhydrase blindness from glaucoma in developed inhibitors, which reduce IOP about countries is relatively uncommon. COMBINATION DROPS 15% by suppressing aqueous pro- Optimal care necessitates appropriate Many glaucoma patients are treated duction, are approved as TID-dosed ancillary testing when needed, treat- with multiple drops during the du- products (similar to brimonidine), ment initiation when indicated and a ration of their disease. Three com- yet they are mainly used twice daily close observation of the optic nerves at bination drops are on the market: in general clinical care. Dorzolamide follow-up visits to prevent vision loss. Cosopt (0.5% timolol with 0.2% is an ophthalmic solution (original As medical practitioners of the eye, it dorzolamide, Akorn), Combigan brand name Trusopt) and brinzol- seems appropriate that we should be (0.5% timolol with 0.2% brimoni- amide is an ophthalmic suspension first-line providers for the majority of dine, Allergan) and Simbrinza (0.2% (original brand name Azopt). glaucoma patients. DG brimonidine with 1% brinzolamide When we need to prescribe one, 1. Tham Y-C, Li X, Wong TY, et al. Global prevalence suspension). we dose the medication twice dai- of glaucoma and projections of glaucoma burden Simbrinza—the only suspension ly—in early morning and about through 2040. Ophthalmology. Nov 2014;121(11): combination drug available to treat eight hours later (as with brimoni- 2081–90. 2. U.S. Department of Health and Human Services glaucoma—must be shaken before dine), since effectiveness wanes after Health Resources and Services Administration Bu- use. Unlike the other combination about eight hours. reau of Health Professions October 2006. Physi- cian Supply glaucoma drops, Simbrinza does and Demand: Projections to 2020. Available at: not contain a beta-blocker. So, for FINAL THOUGHTS https://bhw.hrsa.gov/sites/default/files/bhw/ nchwa/projections/physician2020projections.pdf an asthmatic patient or one who We typically initiate glaucoma ther- (last accessed March 29, 2018). is nonresponsive to beta-blockers, apy with a prostaglandin, and add 3. U.S. Department of Health and Human Services Health Resources and Services Administration Bu- Simbrinza might be an ideal add-on timolol 0.25% or 0.5% once daily reau of Health Professions December 2008. The to a prostaglandin drug, once trials (in the morning) if target IOP is Physician Workforce: Projections and Research into Current of brinzolamide and brimonidine are not reached with the prostaglandin Issues Affecting Supply and Demand. Available found to be efficacious. alone. at: https://bhw.hrsa.gov/sites/default/files/bhw/ nchwa/projections/physiciansupplyissues.pdf If first-line therapy with a prosta- Glaucoma therapy with a beta- (last accessed March 29, 2018). glandin just misses target IOP, it is blocker is often reserved until we 4. De Moraes CG. NTG: The Nocturnal Blood Pres- possible that switching to Vyzulta, need a 5mm Hg to 6mm Hg re- sure Factor. Rev Ophthalmol. 2014;24(2):54-57. 5. Mishra D, Sinha BP, Kumar MS, et al. Comparing or adding once-daily timolol, generic duction in IOP or when we believe the efficacy of latanoprost (0.005%), bimatoprost dorzolamide or generic brimonidine that cost is a factor in patient com- (0.03%), travoprost (0.004%), and timolol (0.5%) in the treatment of primary open angle glaucoma. alone might get the IOP to target, so pliance. A 5ml bottle of timolol is Korean J Ophthalmol. 2014 Oct;28(5):399–407.

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ON THE RECORD ABOUT ‘OFF-LABEL’ THERAPY

The FDA hat does “off-label” The early-generation fluoroquinolones really mean? The an- were approved to treat and indication swer: little or noth- keratitis. The fourth-generation fluoro- is only a ing. Allow us to ex- quinolones and the bi-halogenated qui- Wplain. nolone besifloxacin are FDA-approved starting point It is outrageously expensive to get only for treatment of conjunctivitis, but drugs approved for their true therapeutic are commonly and effectively used “off- for a drug’s intent, and the idea is to get the drug to label” to treat bacterial keratitis. market as quickly and as inexpensively as Years ago, a drug known as Vexol (ri- career, and possible. So, pharma companies choose mexolone, Novartis) was the only topi- often a poor the easiest path to approval—not nec- cal steroid FDA-approved for postop- essarily the one that best showcases the erative care, but it never gained intended one at that. drug’s capabilities. Once approved, doc- traction. Interestingly, Pred Forte (pred- tors can and do find other uses and we, nisolone acetate 1%, Allergan), which is We doctors collectively, determine its proper role in widely used for this purpose, does not the therapeutic toolbox. have a specific indication for postopera- determine the It is indeed a game—a very high-stakes tive care. proper use of game—but it should not be this way. Lotemax suspension (loteprednol eta- “Conjunctivitis” and “postoperative bonate 0.5%, Bausch + Lomb) has a any drug based care” are two common targets for a new litany of anti-inflammatory indications; drug approval purely because they are the however, the newer drug delivery system on the scientific easiest to get through, even though these for loteprednol, known as Lotemax gel, conditions may have nothing to do with is only FDA approved for postoperative literature. the true clinical intent for the new drug. care, as this was simply the easiest path to Here are a few examples corroborat- approval; however, it’s the exact same ing this candid perspective. molecule.

QUOTABLE

“We recall seeing a pediatrician a few years ago with acute epidemic . She was miserable and in full- panic mode. We explained to her that the Betadine treatment we would recommend was off-label. She laughed and said, ‘Ninety percent of what I do is off-label; let’s get on with it!’”

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Both alpha-agonists and topical over the years for this very carbonic anhydrase inhibitors are purpose. We recall seeing a FDA-approved for three-times-a-day pediatrician a few years ago administration, yet they are most with acute epidemic kera- commonly used twice daily, which is toconjunctivitis. She was an off-label use albeit reasonable and miserable and in full-panic efficacious for most patients. mode. We explained to her Oracea (doxycycline, Galderma that the Betadine treatment Laboratories) is a relatively new we would recommend was prescription drug containing 30mg off-label. She laughed and of standard doxycycline and 10mg said, “Ninety percent of of time-released doxycycline. This what I do is off-label; let’s is the only FDA-approved drug to get on with it!” This exem- treat rosacea. Regular doxycycline is plifies the clinical virtue of not specifically labeled for rosacea. off-label drug use. By the Betadine being administered to a patient. These drugs are clinical equivalents, way, she was much better at but the brand-name, on-label drug her two-day follow-up visit, and was twice daily instead of the FDA-ap- is very expensive, while standard extremely appreciative of our help. proved TID. doxycycline is relatively inexpensive. It should now be abundantly • Using a fourth-generation fluo- So, treating rosacea with evident that off-label use of many roquinolone or the bi-halogenated regular doxycycline is off-label; yet medicines can render a significant besifloxacin to treat a over the decades we have used it ad therapeutic benefit to many patients. when these medicines are only FDA- infinitum for this very purpose, as do As stressed above, such off-label approved to treat bacterial conjunc- legions of dermatologists. use needs to be underpinned by a tivitis. Topamax (topiramate, Janssen scientific rationale, preferably dis- • Using Pred Forte in postopera- Pharmaceuticals) has indications for cussed in the professional literature tive care, when it is not FDA-ap- the treatment of seizure disorders and should demonstrate an expected proved for such. and the prevention of migraine head- clinical outcome. • Using Lotemax gel or ointment aches, yet it is heavily used to treat to treat dry eye disease, when its obesity, bipolar disorder and some PRUDENT AND EFFECTIVE FDA-approved indication is for post- forms of eating disorders, among OFF-LABEL USE operative care. The literature consis- others. Here are examples of intelligent, ra- tently endorses a corticosteroid in There is no FDA-approved drug tional and patient-centric off-label the short term to treat dry eye dis- for the treatment of acute adenovi- uses of medications in eye care: ease, yet such is not FDA approved. ral infection, yet, based on sound • Using an alpha-adrenergic re- • Using Alrex to treat dry eye dis- scientific rationale, we have suc- ceptor blocker, such as brimonidine ease when its only FDA-approved in- cessfully used off-label Betadine 0.1%, 0.15% or 0.2%, or a topical dication is for treating ocular allergy. 5% (povidone-iodine ophthalmic carbonic anhydrase inhibitor, such • Betadine 5% sterile ophthalmic solution, Novartis) numerous times as dorzolamide or brinzolamide, prep solution is intended to be used to sterilize the ocular surface prior to sur- gery or intravitreal in- jection. However, its off-label use to treat epidemic keratocon- junctivitis is the only effective approach to quickly and inexpen- sively quell this viru- lent adenoviral afflic- tion. Betadine for this purpose is especially

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019_dg0518_offlabel.indd 20 5/10/18 4:15 PM THE GREATEST OFF-LABEL STORY EVER TOLD The year was 2005. Genentech was prepping a new drug called Lucentis that looked to revolutionize treatment of the wet form of age-related (AMD) the following year. This would be the first time that eye doctors could bring back some vision that patients had lost to AMD. Everyone knew it would be a blockbuster. But then... Bascom Palmer specialist Philip Rosenfeld, MD, published a study showing that the same company’s drug Avastin, commonly used for the intra- venous cancer therapy, could be reformulated into an intravitreal dose and (Top) This male patient presented with used for AMD, with results comparable to Lucentis.1 At a fraction of the cost: classic EKC. (Bottom) Following our about $50 vs. $2,000. Lucentis did just fine in the marketplace—some MDs do Betadine protocol, his condition was prefer the on-label, factory-fresh Lucentis instead of working with a compound- immensely improved in just three days. ing pharmacy to obtain Avastin for ocular use. But Avastin was the revolution within the revolution. A recent retrospective review of Medicare payments for anti-VEGF therapy ing off-label use of medical products, in eye care documents the savings attributable to Avastin from 2008 to 2015 stating in part: “Physician-directed 2 at $17.3 billion. That figure represents a $13.8 billion savings to Medicare and applications, also known as ‘off-label a $3.5 billion savings to patients, the article states. But the real number is even uses,’ are an integral component of greater. “This amount underestimated the actual cost-savings to Medicare pro- the art and science of medical prac- viders since approximately 30% of Medicare-eligible recipients received care tice, particularly for specialty physi- within Medicare Advantage plans and were not included in this analysis,” says cians.”1 the article. Also, since anti-VEGF drugs are used to treat more than just AMD, The Alliance of Specialty Medicine and Avastin has been used in eye care for 13 years while this study only looked maintains that a specialty physician at the years 2005 to 2013, surely the savings are even higher than the already may prescribe or administer any le- eye-popping number of $17 billion. gally marketed product for an off-la- Now, think of who had to allow this. Retina subspecialist MDs, a very conser- bel use within the authorized practice vative group of clinicians, had to be comfortable with the idea of going outside of medicine where the physician ex- the FDA system. Medicare had to allow this as a reimbursable expense. And in ercises appropriate medical judgment one high profile case, the Veterans Administration even condoned the use of and it is in the best interests of the Avastin, knowing how much money this could save, which they could then put patient. to better use for America’s vets. It says further that specialty physi- Yes, it was a little risky, since it was an injectable drug. An outbreak of endo- cians are limited as to what we can phthalmitis due to poor sterilization methods at one compounding pharmacy say in educational settings because did cause serious infections in a small number of patients. But the vast majority of regulations surrounding teaching of patients treated with Avastin have been well served by their doctor’s deci- on off-label medicines, and that we sion to do so. must educate our colleagues the best Keep that story in mind the next time you reach for your Rx pad. we can within forums that allow us to discuss off-label usage. 1. Rosenfeld, PJ, Moshfeghi, AA, Puliafito, CA. Optical coherence tomography findings after an Our take: Within the guidelines intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331–335. and perspectives set forth above, 2. Rosenfeld PJ, Windsor MA, Feuer WJ, et al. Estimating Medicare and patient savings from the use we simply want our optometric of bevacizumab for the treatment of exudative age-related macular degeneration. Am J Ophthalmol [ePub ahead of print.] colleagues to feel completely com- fortable doing what is best to serve patients with FDA-approved medi- effective when the keratoconjunctivi- be hampered by bureaucratic guide- cines using the most effective drugs tis is caught in the early, actively rep- lines; rather, rely on community stan- available. DG licative phase. dards of care based on scientific rigor. The bottom line: follow the peer- 1. Physician-Directed Applications: A Position WHAT THE EXPERTS SAY Statement of the Alliance of Specialty Medicine. reviewed literature; use sound, ratio- Available at: www.specialtydocs.org/files/ nal, patient-centered judgment—and The Alliance of Specialty Medicine Alliance_Off-label_Statement_5.2.14.pdf (last get on with it. Don’t allow yourself to released a position statement regard- accessed February 27, 2017).

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A SYSTEMATIC APPROACH TO DRY EYE DISEASE

A wealth or many decades after dry eye was first named in the 1950s, of hands- the focus of diagnosis and treat- ment remained on the aqueous on clinical Fcomponent of the tears pro- duced by the lacrimal glands. This initial- experience ly made sense because dry eye was first and the latest identified in a group of Sjögren’s patients. However, as far back as 1977, McCulley wisdom from and Sciallis published findings of dry eye in a group with no evidence of lacrimal Note that this patient has a scant lacrimal the literature dysfunction.1 These patients presented lake volume. are changing with reduced tear film breakup time, su- perficial punctate keratitis, symptoms of one squeezed out the meibomian gland the way we dryness and stagnated meibomian secre- contents, the tear film normalized and tions. McCulley and Sciallis named this patient symptoms improved significant- think about, condition meibomian dysfunction. ly. Despite this study and the hundreds Their discovery is what we now know that followed, all of which repeatedly and treat, this as meibomian gland dysfunction (MGD). evidenced that healthy meibomian gland all-too-common McCulley and Sciallis also showed that if physiology was critical to the health of the ocular surface, it took until 2011 for condition. the scientific community to conclude that MGD was the leading cause of dry eye.2 Today, we use meibography to stage the degree of meibomian gland atrophy and make a critical diagnostic assess- ment. We believe the diagnostic tools LipiView and LipiScan—a combination system from TearScience, now part of Johnson & Johnson Vision—represents the pinnacle of managing and preventing dry eye disease secondary to MGD. In ad- dition, the company’s Meibomian Gland Evaluator can help assess gland secretions Corneal break up with fluorescein dye is during a slit lamp exam and its LipiFlow useful in quantifying the expression of tear device aids in restoring function to ob- film integrity. structed glands. Though TearScience has led the charge

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022_dg0518_Dry eye.indd 22 5/11/18 9:37 AM PERSPECTIVE ON DRY EYE TESTING We share the sentiments expressed in this editorial piece from 2017 about diagnostic approaches to dry eye.1 While it may not come from the peer- reviewed literature, its practical insights ring true to our ears, as busy clinicians who feel comfortable diagnosing dry eye without the need for additional testing. • “None of the currently available methods for testing—Schirmer’s, validated questionnaires, tear osmolarity, tear breakup time, Sjö, MMP-9—are Clogged meibomian gland orifices definitive.” restrict lipid secretion and lead to • “Having a numeric value to attach to dry eye became less useful when the evaporative dry eye. generated number did not support the patient’s experience or exam.” • “It was challenging trying to explain treatment plans to my patients in part based on numbers that did not make sense.” • “…reimbursements for dry eye testing, which admittedly can vary wildly in developing technology for MGD, between insurance plans and geographic regions, were regularly less than other methods of assessing gland the cost of the test.” structure are available. Some topog- • “In the end, I base my treatment decisions on the patients’ symptoms and raphers have meibography capabili- on a thorough slit lamp exam with staining.” ties, and a white light transillumina- • “The best use of our patients’ resources is to give them an accurate diag- tor is available if you do not have nosis and a treatment that will make a noticeable difference in their dry access to imaging technology. And, eye disease.” of course, since many patients pres- • “There is no value in spending money on a battery of tests that tell ent to us at an advanced, symptom- patients what they (and you) likely already know—that they have dry atic level of ocular surface disease, eyes—instead of on something that could help them mitigate or cure the precorneal tear film breakup time problem.” and vital dye staining further quan- • “My patients are happier because they are using their money to address tify the extent of tissue compromise. the problem, not just test it to death.” Unsurprisingly, we have found The bottom line is this: When the tear film and fail to protect the that about 90% of dry eye is related ocular surface from exposure to desiccating stress, a cascade of events is to MGD, and that up to 70% of our triggered. If the exposure to desiccating stress becomes chronic, the ocular clinical population has MGD. We hy- surface commonly exhibits signs and symptoms of dry eye. These are vari- pothesize that the following reasons able and frequently manifest independently, especially in the earlier stages of are why MGD is so prevalent: poor dry eye disease. Short-term management may involve lipid tear supplements blink function due to unrelenting use and suppression of inflammation with loteprednol, but long-term rehabilita- of digital technology, poor dietary tion requires that the eyelid function (primarily and including meibomian gland hygiene and behaviors that actively function) and patient behavior be optimized to reduce exposure to desiccating stress the tear film, e.g., stress. wear, cataract and refractive sur- geries, and chronic use of preserved 1. Toyos M. Dry Eye: Emphasis on treatment, not testing. Ocular Surgery News. 2017; Feb 25. topical eye drops. Fortunately, life- style and blinking patterns can be ad- Engaging these diverse approaches surface and then work back up the dressed with education. For patients can be highly variable, depending on continuum of interventions. who wear contact lenses, need to un- the decade of patient presentation as The key to patient care is to un- dergo surgery or use preserved topi- well as the degree of disease severity. derstand the pathophysiology of dry cal medications daily, the meibomian The rationale behind this three- eye disease so that appropriate steps glands can be routinely assessed and tiered approach is that we find that can be taken, either concurrently or treated as needed. most patients present when their dry sequentially, to care for the patient. eye disease has advanced to the de- Let’s take a closer look at these TREATING DRY EYE: gree that several of these staged in- staged interventions. AS EASY AS 1-2-3 terventions may be required to help There are three somewhat fluid re-establish comfort and enhanced PRIMARY INTERVENTIONS stages of intervention we can use to quality of life. Oftentimes, we, as Start with these, as they tend to be prevent the escalation of dry eye dis- clinicians, are forced to engage in the easiest, cheapest and most broad- ease, each discussed in detail below. tertiary care first to quiet the ocular ly applicable.

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COMMONLY USED LIPID-BASED ARTIFICIAL TEARS

Brand Name Manufacturer Lipid Lubricants Preservative Refresh Optive Allergan castor oil carboxymethylcellulose, glycerin, Purite (stabilized oxychloro Advanced polysorbate 80 complex) Refresh Optive Allergan castor oil carboxymethylcellulose, glycerin, none Advanced polysorbate 80 Preservative Free Retaine MGD OcuSoft glycerol light mineral oil, mineral oil none Soothe XP Bausch + Lomb light mineral oil, polysorbate 80 polyquaternium-1 mineral oil Systane Balance Alcon mineral oil propylene glycol polyquaternium-1

Blink function. Educating patients dinner and bedtime, as this about the importance of blinking is simple maneuver helps many critical and easy to accomplish. Apps individuals. We recommend are available that teach proper blink- the orbicularis squeeze for ing exercises, and we encourage our five seconds, with a brief dry eye patients to avail themselves break before repeating the of these. For example, Donald Korb cycle for a full minute. One Blink Training can be downloaded respected colleague shared for free from iTunes or Google Play. anecdotally that having pa- We also proactively share this educa- tients set hourly alarms on tion with patients at risk of meibo- their smartphone or smart- mian gland disease (e.g., computer watch during the work day users, contact lens wearers, patients to remind them to stop and using preserved topical medications do blink exercises is as effec- daily and those preparing for cata- tive as using an app. ract and refractive surgeries). Oral supplementation. While the has been little Level 1 evidence to sol- Our guidance is for patients to eye care community has historically idly support this intervention. Now, perform these blinking exercises four espoused omega-3 supplementation with the publication of the DREAM times daily—at breakfast, lunch, to help with dry eye disease, there Study, published in the April 13

FROM THE LITERATURE have more than $2 billion in annual sales in the United States?” JAMA PERSPECTIVE ON RESTASIS • “Clinicians typically do not learn about new products An interesting editorial was published in the January 2018 from regulatory documents; they learn from commercially issue of the Journal of the American Medical Association – sponsored, promotional efforts, such as detailing visits and Internal Medicine about Restasis (cyclosporine ophthalmic events where food and beverages are provided.” emulsion, 0.05%, Allergan).1 The following are excerpts Every drug has the ability to help some people, and we from the paper written by the Dartmouth Institute for have patients who have indeed been helped with Restasis; Health Policy and Clinical Practice-based authors: we have plenty more for whom no help was obtained. • In addition to a court battle over efforts to halt generic The three drugs in common use to treat ocular surface versions of Restasis, “the more fundamental question has inflammation are Lotemax, Restasis and Xiidra. One of received little attention: Does Restasis work? Restasis is not these drugs much more robustly reduces inflamma- approved in the European Union, Australia or New Zealand, tion than the others. The scientific literature consistently where in 2001, registration applications were ‘withdrawn endorses the short-term use of a steroid to address the prior to approval due to insufficient evidence of efficacy.’ inflammation associated with dry eye disease. Our own Although Canada approved Restasis, its national technol- clinical experiences match what the science tells us, which ogy assessment unit, unconvinced of meaningful benefit, is why we favor the use of loteprednol for most cases. recommended Canada not pay for it.” 1. Schwartz LM, Woloshin S. A clear-eyed view of restasis and chronic dry eye dis- • “Given the scant evidence of efficacy, why does Restasis ease. JAMA Intern Med. 2018;178(2):181-2.

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022_dg0518_Dry eye.indd 24 5/11/18 9:37 AM online edition of the New England acid considered to be neutral with Journey of Medicine, we have (for respect to inflammation control. LIPIFLOW TREATMENT FOR better or worse) authoritative Level 1 And, though the study olive oil had a CONTACT LENS WEARERS Thermal pulsation of the eyelids science showing little or no evidence small amount of alpha-linolenic acid could be a major benefit to thou- of a clinically meaningful effect of (ALA), a plant-based omega-3, the sands of patients struggling with 3,000mg of a triglyceride-based fish total dose was 30mg, while our rec- contact lens comfort. A study 3 oil. ommended omega-3 dosage of EPA in Clinical Ophthalmology found However, since the study’s recent and DHA for patients is 3,000mg, that a single LipiFlow treatment publication, a number of prominent or about 1,000 times that delivered extended contact lens wearing ophthalmologists specializing in dry by the placebo. Furthermore, ALA time by four hours, with the ben- eye, some of whom have lead re- conversion to EPA and DHA is not efit lasting for an average of three search showing the benefits of ome- known to be efficient. months.1 ga-3 supplementation, have raised Dry eye experts have also pointed concerns about the methodology of out that both groups in the study had 1. Blackie CA, Coleman CA, Nichols KK, et al. A sin- gle vectored thermal pulsation treatment for meibo- the study and the choice of a poten- statistically significant improvements mian gland dysfunction increases mean comfortable contact lens wearing time by approximately 4 hours tially active placebo. in OSDI symptom scores, which per day. Clin Ophthalmol. 2018;12:169-183. They have noted, among other is- somewhat contradicts early press re- sues, that the manufacturer of the ac- ports indicating that the study found tive dry eye therapy was not disclosed omega-3 supplementation failed to vanced meibomian gland disease, es- in the study, that study participants yield a beneficial response. pecially when accompanied by rosa- were permitted to use a wide variety Whether we are at the end of an cea blepharitis, a four-month course of dry eye therapies concurrently and era in which such supplementary in- of oral doxycycline can help jump- change therapies during the study, tervention has a significant role in start the clinical response. and that it’s not known whether re- the care of patients with dry eye dis- It is important to instruct patients esterified forms of omega-3 thera- ease remains to be seen. We would to take doxycycline with food, pref- pies were used, which like to see another study erably at breakfast or lunch, as some many dry eye experts have replicating these findings people develop gastroesophageal re- pointed out is essential for before we would be fully flux with this therapy, which can re- maximum absorption and comfortable abandoning sult in erosive esophagitis when they bioavailability. a therapeutic intervention lie down. (This is why we try to avoid Critics have also ex- that for many years has evening dosing of doxycycline.) After pressed reservations that appeared to work. A dis- three to four months of doxycycline the controls received ol- cussion of the report can therapy, enduring periodic use of ive oil with fish essence, be read on our website: warm soaks hopefully will maintain which are known anti- www.eyeupdate.com. an enhanced lipid layer. inflammatories and which Moving on to orally Screen usage recommendations. may have included an ac- administered doxycycline, Excessive screen use, either by choice tive ingredient, given the at 50mg per day for three or necessity, has become a way of improvements observed to four months, this drug life. Thus, educating patients on the in controls. Yet, we were has been shown to en- impact of digital media use is essen- able to uncover that the hance meibomian gland tial. When patients understand why olive oil was 68% oleic function. Thus, for those an activity isn’t healthy, they are acid, an omega-9 fatty patients with more ad- more apt to engage in behaviors to

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A NEW TREATMENT FOR CHRONIC It is widely known that millions of people purchase over-the-counter “get the red out” eye drops every year. Most of these purchases are made by individuals suffering from dry eyes, chronic allergy, blepharitis and/ or exposure to smoke (e.g., tobacco, marijuana). Though tetrahydrozaline-containing eye drops have been shown to whiten eyes, they must be used chronically, which typically leads to the development of protracted and rebound hyperemia. Now, a newly approved venule-based vascular constrictor should quickly replace tetrahydroza- line over time. This over-the-counter drop, Lumify (brimonidine tartrate ophthalmic solution 0.025%, Bausch + Lomb), is a revolutionary agent that quickly “whitens” eyes, with effects lasting several hours and without reports of rebound hyperemia. This low-dose brimonidine is a 0.025% solu- tion with approximately a 10-fold dilution of 0.2% brimonidine. Our impression is that people with idiopathic, untreated or undertreated secondary chronic redness might use Lumify once daily in the Here, in just 20 seconds, this patient’s eyes appear whiter. morning, primarily on the days when their eyes are noticeably red. Since the drop, which could be used again in the afternoon or evening if needed, is not by prescription, it is our job to make patients aware of this newer-generation, more effective and longer-lasting topical vasocon- strictor. We would never recommend such a medication as first-line therapy since redness is a secondary result of a primary problem such as dry eyes. Always try to remedy any primary conditions first, and, if other rational therapies do not relieve the redness, Lumify should be called in to handle the job.

mitigate the negative effects. We pro- be beneficial to en- actively tell our intensive screen us- hance meibomian ers to consciously and purposefully gland function. Pa- look up and away from the screen tients frequently tell every few minutes and to blink sev- us that their eyes feel eral times. better following such Avoiding desiccating stress. En- use. The limiting fac- courage patients to minimize expo- tor is that patients sure to ceiling fans, forced air drafts rarely make time to from home or car heating and air- use warm soaks con- conditioning systems. Patients can sistently. also minimize low-humidity environ- Moisture-preserv- ments by using a humidifier when- ing eyewear. Dry ever possible. eye does not exist in Moisture-preserving eyeglasses can be a helpful 100% humidity, so Application of warm soaks. Ap- intervention for highly symptomatic dry eye disease. plying warm soaks using a clean anything one can do washcloth, uncooked white rice in to increase the ambi- a stocking (warmed in the micro- ent humidity of the ocular surface is the years and offer us another meth- wave) or a commercially available a step in the right direction. Moisture odology to preserve, protect and en- device such as a Bruder mask, can “goggles” have vastly improved over hance ocular surface health.

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022_dg0518_Dry eye.indd 26 5/11/18 10:48 AM While they might not make much of a fashion statement, they are much more visually acceptable now than they were years ago. Ziena Eyewear and 7eye by Panoptx feature contem- porary, moisture-preserving eyeglass designs on their websites for your re- view and analysis.

SECONDARY INTERVENTIONS Options in this class tend to be more focused on addressing a specific com- ponent of dry eye pathogenesis, such as reduced tear volume or meibo- mian gland obstruction. To debride the lower lid margin, we gently wipe a golf club spud repeatedly across Lipid-based artificial tears and the margin to remove debris. lubricating ointments. Since a healthy lipid layer is critical in most all cases of dry eye disease, we start nearly all of our patients on a lip- • “The favorable tolerability pro- rapidly returns to body temperature, id-based artificial tear. We gener- file and efficacy of lipid-based ther- negating the effect. ally recommend either Soothe XP apies in improving both signs and The gold standard for perform- (Bausch + Lomb) or Systane Balance symptoms of dry eye make them a ing this highly therapeutic maneu- (Alcon), as both drugs were invented promising therapeutic option in the ver is the LipiFlow, which heats the by Donald Korb, OD, a world-rec- management of DED.” meibomian glands from the tarsal ognized expert in the area of MGD. Meibomian gland expression. conjunctival side (as opposed to the When we need a preservative-free Physical/mechanical evacuation of epidermal side) of the eyelid, while product, we recommend OcuSoft’s the meibomian glands is essential. protecting the cornea. LipiFlow is Retaine MGD. Patients are gener- This can be done effectively only cleared by the FDA for the safe and ally encouraged to use artificial tears in the office. Perform manual glan- effective direct treatment of meibo- at least four times a day, although dular expression the old-fashioned mian gland disease by addressing patients rarely use them as often as way, using the Mastrota Meibomian obstruction. recommended. Paddle (OcuSoft), the butt end of Another unique aspect of the de- A study published in the Journal a pair of jewelers’ forceps or even vice is that during the 12 minutes of of Pharmacology and Therapeutics a cotton swab to enable adequate highly specific heating, a compressive reported the following:4 trans-eyelid pressure. function simultaneously mechani- • “Lipid based therapies […] are If expression is attempted by cally expresses the glandular con- an attractive alternative to water- pressing on the lids with the as tents. As a result, the newly formed based artificial tears because they a backstop, sufficient pressure can- meibum mimics natural physiology, more closely mimic the composition not be applied and the IOP might resulting in a healthier lipid layer and of the tear film. Lipid-based thera- become pathologically high. Some enhanced tear film function. Another pies not only relieve patient symp- advocate for heating the lids prior device, the MiBo ThermoFlo (MiBo toms immediately after topical ad- to expressing the glands, possibly Medical Group), delivers emissive ministration, but may also directly to make the expression process a heat to the meibomian glands. improve the lipid tear film structure little easier. However, there are two Debridement of lower lid margins. and thickness component in ocu- limitations to this process: the mei- It is well-established that meibomian lar surface disease, resulting in en- bomian glands cannot be adequately gland obstruction is a weak link in hanced tear film stability.” heated from the outside since the the chain of lipid production, excre- • “Oil-in-water emulsions reduce meibomian glands reside in the pos- tion and incorporation into the tear the signs and symptoms of all types terior portion of the eyelids, and the film. Thus, anything that enhances of dry eye, but are particularly rec- highly vascularized nature of the tis- this process is virtuous. One effec- ommended for lipid-deficient dry sue in this area means that, once the tive and simple procedure that can be eye patients.” heat source is removed, the tissue performed at the slit lamp is to take a

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golf club spud and gently scrape back and forth, four or five times, along the top of the lower eyelids. We do this at each follow-up visit. The procedure helps to open/de- obstruct the meibomian gland ori- fices and smooth the surface of the lower eyelids—particularly if there is any debris on the mucocutaneous border—and enhance the backward flow of meibum into the tear film. A topical anesthetic is not necessary for this effective 15-second procedure, which currently has no CPT code. This patient’s lid, imaged with meibography technology, displays severe meibomian Since meibomian gland expression gland dysfunction. devices are not yet ubiquitous due to cost, many clinicians will need to per- form in-office expression, enhanced “pulse-dose” Lotemax QID for a and only 1.9% of patients had re- by pre-expression warm soaks. week, once or twice a year, should currence. No serious complications Consider intranasal stimulation. there be any breakthrough symp- (such as IOP elevation or cataract With this new approach, a handheld tom recurrence. A smaller subset formation) were encountered during intranasally inserted device uses elec- of patients may require once-daily the entire follow-up period.” trical impulses to stimulate the tri- Lotemax on an ongoing basis. Furthermore: “A recent retro- geminal nerve and tear production. As patient-centric doctors, we al- spective safety study, listing 77 This procedure may be helpful to se- ways attempt to use the least amount published studies, concluded that lect patients, but as of press time, we of cost-valued medicine possible to topical treatment with loteprednol had no clinical experience with this meet the care needs of our patients. etabonate has minimal effect on IOP technique. We have found that Lotemax gel when used in treatment of a wide drops are vastly less expensive than range of ocular surface and intraoc- TERTIARY INTERVENTIONS any of the BID prescription “dry ular inflammatory disorders, includ- These options will be among the eye” drops and have far superior ing ocular allergy, DED, anterior most effective in reducing dry eye anti-inflammatory properties. uveitis, penetrating keratoplasty, symptoms and may require greater One of the key benefits of short- endothelial keratoplasty, and post- skill by the clinician to perform. term pulse-dosing of a topical cor- operative pain and inflammation Topical anti-inflammatory drops. ticosteroid is its ability to induce following ocular surgery.” As previously mentioned, untreated long-term cessation of DED. As an What more could a clinician ask MGD invariably leads to a cascade example, the TFOS DEWS II Man- for? of events resulting in ocular surface agement and Therapy Report re- Punctal plugs. Once loteprednol inflammation. The most efficacious, ported the following:5 has been used for at least two weeks, and least expensive, intervention to “Fifty-three patients with Sjögren the bulk of ocular surface inflamma- suppress ocular surface inflamma- syndrome were treated with topical tion usually has been suppressed. At tion is through the use of a topical nonpreserved 1% methylpredniso- this juncture, consideration of punc- corticosteroid. lone four times a day for two weeks, tal occlusion is quite reasonable. It Because the ester-based steroid and then re-evaluated and tapered is important to use a steroid first, as loteprednol has become our drug off the medication until they demon- the “plug first and steroid second” of choice in such settings, we pre- strated no corneal fluorescein stain- treatment regimen could actually scribe Lotemax gel-drops QID for ing or symptoms. Most patients were worsen symptoms by further con- two weeks, then BID for two more in a disease-free state for a relatively centrating proinflammatory cyto- weeks. Our clinical experience long period (57 weeks) after the first kines in the already hyperosmotic reveals that the inflammatory com- pulse therapy, and eleven individu- tear film. ponent of dry eye disease is con- als (21%) experienced recurrence of Autologous serum. The concept trolled within about four weeks for either symptoms or signs. After the of using a patient’s blood-derived most patients. second pulse therapy, a disease-free serum for topical drop application A subset of patients may need to period of 72 weeks was observed is not new. While a somewhat cum-

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022_dg0518_Dry eye.indd 28 5/11/18 9:38 AM bersome process, use of autologous WHY SYMPTOMS AND SIGNS DON’T ALWAYS AGREE serum is a reasonable approach for Why is there discordance between symptoms and signs in patients with dry patients suboptimally helped with eye disease? other more common interventions. • There is “growing evidence that part of the dry eye population may show The drops may need to be used QID signs of dysfunctional somatosensory pathways, indicating neuropathic ocular for many weeks; however, they are pain.” not to be used as simple monother- • Patients with chronic pain syndromes (CPSs) had 30% greater symptoms apy. Autologous serum drops are than signs. Important CPSs are irritable bowel syndrome, fibromyalgia, chronic best used to supplement more com- pelvic pain and osteoarthritis. prehensive care. • Many patients with itchy eyes also have dry eyes. “Patients with atopy or Lacrisert. These dissolvable pel- allergy have a sensitized ocular surface because of inflammatory processes lets of hydroxypropyl cellulose can influencing corneal nerves, which can lead to symptoms of dry eye even when provide a time-released supplemen- the homeostasis of the ocular surface is minimally compromised.” tal enhancement to the tear volume.

Because of their somewhat challeng- Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ. Predictors of discordance between symptoms ing insertion and cost, they are not and signs in dry eye disease. Ophthalmology. 2017 Mar;124(3):280-286. used first-line, but some of our pa- tients have been helped by Lacrisert more than any other intervention. PRIORITIZE THE Most dry eye patients are suc- Go to www.lacrisert.com for more MEIBOMIAN GLANDS cessfully managed using a variety details on this prescription hydra- Because there are so many dry pa- of primary, secondary and tertiary tion device. tients out there, there’s no one interventions. The key is to focus Amniotic membrane devices. template that works for everyone. on meibomian gland function en- These devices can be remarkably However, if patients consistently hancement, since many tertiary care beneficial for non-healing epithelial use omega-3 supplements and lipid- maneuvers can be preempted or de- defects, including recalcitrant SPK. based artificial tears, and periodi- creased in frequency. It takes some practice to insert the cally apply effective warm soaks to Symptomatic eye disease is epi- devices, requiring a technique simi- the eyelids, most will do quite well. demic and will only become more lar to large-diameter contact lenses. The response to these therapeutic prevalent in our screen-addicted Amniotic membranes dissolve over approaches is greatly enhanced if world. It’s our duty to arm ourselves several days to a couple of weeks, LipiFlow treatments are done ini- with the knowledge, instrumenta- and can play a beneficial role in re- tially and repeated every year or so tion and drug therapies to meet this solving stubborn SPK. as needed. clinical challenge. Scleral rigid contact lenses. While A portion of dry eye patients Lastly, remember to assess each these lenses have a learning curve to will have breakthrough of initial patient as an individual, since no algorithm can uniformly meet the QUOTABLE needs of everyone. Bottom line: if we can adequately enhance meibomian gland function, we may not have to “MOST DRY EYE PATIENTS ARE SUCCESSFULLY MANAGED wait until patients present with dry USING A VARIETY OF PRIMARY, SECONDARY AND TERTIARY eye discomfort to intervene. DG INTERVENTIONS. THE KEY IS TO FOCUS ON MEIBOMIAN 1. McCulley JP, Sciallis GF. Meibomian keratoconjuncti- vitis. Am J Ophthalmol. 1977;84(6):788-93. GLAND FUNCTION ENHANCEMENT, SINCE MANY TERTIARY 2. Schaumberg DA, Nichols JJ, Papas EB, et al. The in- ternational workshop on meibomian gland dysfunction: CARE MANEUVERS CAN BE PREEMPTED OR DECREASED IN Report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol FREQUENCY.” Vis Sci. 2011 Mar; 52(4):1994-2005. 3. Dry Eye Assessment and Management Study Re- search Group. n-3 Fatty Acid Supplementation for the properly fit, they can be a lifesaver, symptoms from time to time. This Treatment of Dry Eye Disease. N Engl J Med. 2018; Apr as many patients have been helped by is when we employ pulse-dosing 13. [Epub ahead of print]. 4. Garrigue JS, Amrane M, Faure MO, et al. Relevance these devices when other approaches of Lotemax gel-drops QID for one of lipid-based products in the management of dry eye have failed. As such, we encourage week—a highly effective, safe and disease. J Ocul Pharmacol Ther. 2017 Nov;33(9):647-61. all ODs to become adept at provid- inexpensive approach to providing 5. Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. The Ocular Surface. ing care with these lenses. symptomatic relief. 2017;15(3):575-628.

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HARNESS THE POWER OF CORTICOSTEROIDS

Prudent use of The eye is vulnerable to damage from intraocular and ocular surface inflammation. these versatile, Untreated, inflammation may lead to temporary, or even permanent, vision loss. Steroids suppress cellular infiltration, collagen deposition, fibroblast proliferation and FDA-approved scar formation. They stabilize cell membranes and block phospholipase A2—a critical initial step in the inflammatory cascade of the arachidonic acid pathway. drugs to Topical corticosteroids derive from two different molecular classes: ketones and esters. Ketone-based steroids (e.g., dexamethasone, prednisolone, fluorometholone) bring ocular have a higher propensity over time for unwanted side effects compared with ester- inflammation based steroids (e.g., loteprednol). Our bodies have limited means to actively degrade the ketone molecules, whereas esters are rapidly broken down by innate physiologi- under control cal esterases into inert substances shortly after providing effective anti-inflammatory action. Loteprednol has been shown to greatly lower the risk for increased intraocular continues to be pressure, with no reports of cataract formation. For either category, the risks associated with short-term topical use are minimal. constrained by Remember: Suppressing ocular inflammation early in the disease process substan- tially decreases the potential for tissue damage. Uncontrolled intraocular inflammation unwarranted carries far more risks than appropriate steroid therapy. apprehension. Here’s our he next time you encounter an ing various presentations of conjunctivitis acute red eye, consider the fol- (viral, allergic, nonspecific or bacterial) tried and true lowing statistic: Up to 80% of can be maddening. And bolstered by the conjunctivitis cases are viral knowledge that conjunctivitis is usually approach. Tin nature.1 Ocular infections self-limiting and the notion that antibiot- cause secondary conjunctival inflamma- ics are safe due to their limited side effects, tion. Doctors who solely prescribe antibi- antibiotics continue to be erroneously pre- otics for acute red eyes are not keeping up scribed by wary physicians. with widespread research that refutes this Unfortunately, this mindset can delay antiquated practice. Antibiotics treat bac- best practice patterns and do more harm terial infections. Prescribing them for viral than good, as inflammation does not go infections not only contributes to a greater into clinical remission with antibiotics antibiotic resistance profile for the patient, alone. Thus, in the setting of acute red it also provides no benefit to the majority eyes, we strongly advocate for the aggres- of patients with acute red eyes. sive use of topical ophthalmic steroids, The irrational hesitation to prescribe either as monotherapy or in combination corticosteroids may stem from clinical with an antibiotic. At the same time, make uncertainty on the part of the prescriber. sure to rule out herpetic etiology—the For the inexperienced clinician, segregat- main contraindication to topical steroids.

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0030_dg0518_Corticosteroids.indd30_dg0518_Corticosteroids.indd 3030 55/11/18/11/18 9:429:42 AMAM PAVLOV’S “RED EYE” UPDATE ON Ivan Pavlov is iconic in clinical Thankfully, fungal keratitis is a rare occurrence in temperate climates.1 psychology for his theory on clas- However, we need to be at the ready when patients present with this dread- sical conditioning, demonstrated ful condition. Most eye doctors ask the cornea subspecialist to care for these by presenting a stimulus (food) patients, but all eye doctors need to know the most up-to-date medicines to to a dog and eliciting a predict- address such clinical challenges. It is well-known that (Natacyn, able response (salivation). Let’s Novartis) has been the gold standard for treatment of fungal keratitis for translate this model to our clinics: decades.2 Some individuals speculated whether the newer voriconazole might The next time a familiar stimulus supersede the efficacy of natamycin; however, recent studies have firmly con- (acute red eye) ends up in your cluded that natamycin continues to be the drug of choice for treating most all chair, take your initial evaluation cases of fungal infection.2 (inflammation to be treated with 1. Nielsen E, Heegaard S, Prause JU, et al. Fungal Keratitis – Improving Diagnostics by Confocal a corticosteroid or antibiotic/ Microscopy. Case Rep Ophthalmol. 2013 Sep-Dec 4(3):303–10. steroid combination), and instead 2. Austin A, Lietman T, Rose-Nussbaumer J. Update on the Management of Infectious Keratitis. of trying to establish the necessity Ophthalmology. 2017 Nov;124(11):1678-89. of a corticosteroid, present the reasons not to use one. This will enhance good patient care. If all of eye care would collec- tively adapt the mindset whereby a common presentation elicits a warranted therapeutic approach, it would condition our thought patterns to how acute conjunctivi- tis should be treated and exercise best practices in the process. Fusarium corneal ulcer. Note the feathery edges in a minimally injected eye.

To be clear, improper use of ste- uncertainty of diagnosis. To explain, are exceedingly rare. roids (and contact lenses) can have it’s possible, for example, to have an When prescribing steroids, the unwanted and damaging results for Acanthamoeba or fungal keratitis initial dosage must be sufficiently your patient. While there are plenty that is difficult to diagnose, especially frequent to achieve symptomatic re- of indications for the use of topical in the early stages. The use of a ste- lief and expedite remission. In our steroids, there is only one contrain- roid—even a combination antibiotic/ practices, we suppress inflammation dication: epithelial herpetic infection. steroid—could cause the condition to by “hammering” it with corticoste- There is also only one precaution: worsen; however, such presentations roids out of the gate. This approach TOPICAL CORTICOSTEROID DRUGS BRAND NAME GENERIC NAME MANUFACTURER PREPARATION BOTTLE/TUBE Maximum Strength Steroids Durezol difluprednate 0.05% Alcon emulsion 5ml Lotemax gel loteprednol etabonate 0.5% Bausch + Lomb gel drops 5g Lotemax ointment loteprednol etabonate 0.5% Bausch + Lomb ointment 3.5g Pred Forte prednisolone acetate 1% Allergan and generic suspension 5ml, 10ml, 15ml generic prednisolone prednisolone sodium generic solution 5ml, 10ml, 15ml sodium phosphate phosphate 1% Maxidex dexamethasone 0.1% Novartis suspension 5ml Vexol rimexolone 1% Novartis suspension 5ml, 10ml

Moderate and Lesser Strength Steroids Alrex loteprednol etabonate 0.2% Bausch + Lomb suspension 5ml, 10ml Flarex fluorometholone acetate 0.1% Novartis suspension 5ml, 10ml FML fluorometholone alcohol 0.1% Allergan and generic suspension 5ml, 10ml, 15ml FML ointment fluorometholone alcohol 0.1% Allergan ointment 3.5g Pred Mild prednisolone acetate 0.12% Allergan suspension 5ml, 10ml

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shouldn’t dampen your willingness to OBSERVATIONS ON WHY ANTIBIOTICS treat with topical steroids, having the ARE OVERPRESCRIBED patient return to you in a timely man- During our many years in clinical eye care practice, we have identified the fol- ner will illuminate ineffective treat- lowing reasons why many doctors overprescribe antibiotic agents: ments or misdiagnosed conditions. 1. Many eye care providers neglect to stay abreast of current research and, When you elect to see the patient back consequently, get stuck in habitual practices and become therapeuti- sooner rather than later, you position cally complacent. yourself to confirm your diagnosis or 2. Clinically differentiating between different types of conjunctivitis can be alter treatment if necessary. If you are challenging. This leads providers to prescribe antibiotics “just in case” truly concerned, call the patient in a there is an underlying infection. couple of days to check on the ther- 3. The patient perception that antibiotics are a harmless cure-all for their apy’s progress. Patients love having ailments leads many patients to frequently request prescriptions “to be their doctors call to check on them. safe.” To improve patient satisfaction and address potentially relentless As one example, let’s say you see a requests, providers submit to these unfounded petitions. patient with typical lesions that could be Thygeson’s superficial punctate QUOTABLE keratopathy or herpetic eye disease. Since most red eyes are inflammatory in nature, we are inclined to initiate “Most cases of acute conjunctivitis are nonbacterial therapy with a steroid. in origin, and even among those with a bacterial However, in the uncertainty of a diagnosis, we would tell the patient cause, antibiotics have only a modest benefit in something like this: “This medicine reducing symptom duration. The complications should help your eye get better quick- of acute conjunctivitis are so rare that there is no ly; however, at this time the diagnosis of your condition is not completely evidence from systematic reviews that antibiotics clear, and there is a chance your eye reduce rates of complications.”1 could worsen on this medicine. It is important that you let me see you 1. Keen M, Thompson M. Treatment of Acute conjunctivitis in the United States and evidence of antibiotic again in a couple of days. I will be overuse: isolated issue or a systematic problem? Ophthalmology. 2017 Aug;124(8):1096-8. glad to work you in anytime.” As previously mentioned, this caring conversation is crucial for optimal quickly controls the inflammatory doctor-patient trust. This, in turn, re- patient care and rapport. cascade, after which an appropriate duces the likelihood of patients seek- All of this falls under the heading tapering schedule (if necessary) can be ing unwarranted second opinions that of “patient management” and is far executed. delay care. more than just disease management. In all cases of disease manage- Trying to manage the disease without ment, proper follow-up is paramount. NEED FOR FOLLOW-UP managing the patient will often result Education of patients and open dis- Acute conjunctivitis rarely presents in frustration for both the doctor and cussions minimize patient miscon- in textbook fashion. More often than patient. (This not only applies to cor- ceptions and concerns about a given not, the eye will just show signs of ticosteroid treatment, but to the treat- condition or therapy, and strengthen nonspecific inflammation. While this ment of any eye condition.)

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030_dg0518_Corticosteroids.indd 32 5/11/18 9:43 AM recognition as a popular postopera- DUREZOL: UNIFORMITY FOR ALL tive drug. Clinically, we prefer it over Steroid molecules are lipophilic in nature. Their inability to dissolve in solu- Pred Forte for several reasons: We tions makes the majority of corticosteroids on the market available only in have found it to be more effective, it suspension form. But ophthalmic suspensions separate over time, causing the active ingredients to settle at the bottom. To ensure homogenous distribution, does not need to be shaken prior to patients must vigorously shake the bottle prior to instillation. Otherwise, the instillation and it does not need to be patient risks subtherapeutic dosing, rendering less than desirable outcomes dosed as often as Pred Forte, thereby despite full compliance with drops. increasing patient compliance. Even when the bottle is shaken as directed, the particles still have a ten- Durezol’s glucocorticoid binding dency to agglomerate, especially as the particle size of the drug increases. affinity for the active metabolite dif- This causes dosage inconsistencies, and potential frustrations from the doctor luprednate was found to be 56 times and the patient. stronger than prednisolone.2 A de- In 2008, the FDA approved difluprednate ophthalmic emulsion 0.05% to rivative of prednisolone, the drug’s treat inflammation and pain associated with ocular surgery. The drop was for- structural modifications to have a mulated as a stable oil-in-water emulsion, giving optimum dose consistency, stronger binding affinity and a more while eliminating the need for shaking. In clinical trials, the drop showed ther- consistent potency compared with its apeutic dose consistency far surpassing generic prednisolone acetate suspen- counterpart. sion 1% and branded prednisolone acetate suspension 1% in cataract surgery.1 As a general rule, the more power- Durezol’s excellent drug uniformity and decreased dosing suggests ful the drug, the more potential for increased compliance and more predictable results vs. other steroids in its adverse side effects. Durezol is no ex- class. ception, as it can be associated with 1. Donnenfeld ED, Holland EJ, Solomon KD, et al. A multicenter randomized controlled fellow eye elevated IOP. Thus, standard of care trial of pulse-dosed difluprednate 0.05% versus prednisolone acetate 1% in cataract surgery. Am J Ophthalmol. 2011 Oct;152(4):609-617.e1. practices must be engaged, with fre- quent follow-ups to monitor the con- of topical corticosteroids, and is dition and check IOP. looked upon favorably when moder- Pred Forte. While not as clini- ate to severe inflammation needs to be cally effective as Durezol, predniso- rapidly suppressed. Durezol is com- lone acetate 1% possesses impressive pounded as an emulsion and does not anti-inflammatory efficacy. Its wide- need to be shaken before use. spread use in ocular inflammatory The drug has a long history of use conditions is most notably embraced in the setting of severe or non-resolv- postoperatively as well as in anterior ing iritis, and more recently is gaining uveitis cases. Remind your patients to This patient has a classic case of bacterial conjunctivitis as evidenced by KEEP IT LOCAL WITH LOTEMAX the mucopurulent discharge and A number of years ago, researchers examined the clinical efficacy of lotepre- moderately inflamed . dnol etabonate 0.5% in rabbit .1 After instillation, the researchers assessed tissue structures in the eye. The cornea was found to have the high- MAXIMUM EFFICACY est ratio of metabolite to loteprednol etabonate 0.5%, followed by a much STEROIDS lesser concentration in subsequent tissues posteriorly. Strikingly, the aqueous Don’t let ocular inflammation linger humor concentration of the drug was 100 times lower than the concentration by hesitantly prescribing topical ste- found in the cornea. roids. Corticosteroids must be dosed By keeping high levels of the drug out of the aqueous humor, the trabecular early and often, with an appropriate meshwork was less affected, and the propensity to increase IOP was consider- tapering schedule when needed. ably less than other topical steroids. Clinically, we have found the two Of equal significance, when the drug was absorbed systemically, it was rap- most efficacious topical ophthalmic idly excreted through bile and urine. steroids in the last several years to The prompt de-esterification of Lotemax gel and its ability to be expelled be Durezol emulsion (difluprednate promptly with any systemic absorption should make the prescribing doctor 0.05%, Novartis) and Pred Forte confident in applying its use in patient care. (prednisolone acetate 1%, Allergan). Durezol. Introduced in 2008, Du- 1. Druzgala P, Wu WM, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res. 1991 Oct;10(10):933-7. rezol is often used as the heavyweight

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LOTEMAX GEL VS. LOTEMAX OINTMENT Patients, practitioners and pharmacists may mix up these two medicines, so let’s set the record straight. • Lotemax gel. Though called a gel, this comes in a dropper bottle, like a solution. However, inside the bottle it is indeed a highly viscous, semisolid gel formulation. But, through a process called adaptive viscosity, it becomes a liquid when squeezed out of the dropper. And upon instillation in the eye (no shaking is necessary), the formulation loses its gel struc- ture altogether as the polycarbophil polymer interacts with the electrolytes in tears. Still, the drop is rather thick upon Inflammatory resulting from instillation and will cause a moment of initial blur until the moderate to severe anterior uveitis. gel fully converts into a liquid. We advise patients to allow the drop to spread out on the ocular surface for four to five seconds before blinking, so that the initial blink does not dis- Bausch + Lomb). An ester-based place the drop onto the eyelid. steroid, its propensity to raise IOP Because of the nature of this unique gel, the steroid does not settle out of is substantially less than its ketone- the vehicle, so it does not require shaking. (It is best to tip the bottle back based counterparts. and forth once to make sure the drug enters the tip of the dropper prior to Lotemax is highly lipophilic—10 instillation, but no actual shaking is necessary.) Also, unlike suspensions, this times greater than dexamethasone— 1 delivery system provides a perfectly uniform dose at every instillation. thereby increasing its efficacy and 2 • Lotemax ointment. This preparation comes in a 3.5g tube and contains penetration across cell membranes. inactive ingredients of white petrolatum and mineral oil. Because it is an Additionally, loteprednol etaboate ester-based corticosteroid and also because it is a preservative-free prepa- 0.5% undergoes rapid de-esterifica- ration, it may provide a safety advantage over fluorometholone ointment. tion to an inactive metabolite after Lotemax ointment is indicated for the treatment of postoperative inflamma- exerting its effect, minimizing the tion and pain, but is also applicable in many other cases in which an ointment is useful for suppression of inflammation. risks of drug toxicity while maintain- ing good clinical efficacy.

1. Marlowe ZT, Davio SR. Dose uniformity Lotemax gel is a non-settling eye of loteprednol etabonate ophthalmic drop that does not require shaking gel (0.5%) compared with branded and generic prednisolone acetate ophthal- before instillation. Though labeled as mic suspension (1%). Clin Ophthalmol. 2014;8:23-9. a gel, it becomes a viscous liquid once 2. Comstock TL, Paterno MR, Singh A, on the ocular surface (see “Lotemax et al. Safety and efficacy of loteprednol Gel vs. Lotemax Ointment”). etabonate ophthalmic ointment 0.5% for the treatment of inflammation and pain fol- We commonly prefer Lotemax gel lowing cataract surgery. Clin Ophthalmol. 2011;5:177-86. as an off-label treatment in many of our dry eye patients, and also use it to treat many other chronic, recur- vigorously shake the bottle before in- phosphate 1% solution (original rent, inflammatory conditions such stillation because the drop is a suspen- brand name Inflamase Forte) and ge- as stromal , sion. neric prednisolone acetate 1%. Dexa- Thygeson’s SPK, uveitis, inflamed Some pharmacists will dispense ge- methasone, either in solution or sus- neric prednisolone acetate, even when pension form, is also in this category. you have indicated “dispense as writ- Of note, we have found that generic ten.” Although less expensive, the ge- prednisolone sodium phosphate 1% nerics are considerably less effective.3 solution does not penetrate trans- When maximum efficacy is required, corneally as effectively as the acetate Durezol is our drug of choice. moiety, but has the advantage of not requiring shaking. HIGH EFFICACY STEROIDS Lotemax gel. Perhaps one of the Next in clinical efficacy are Lotemax most commonly used drugs among gel (loteprednol 0.5%, Bausch + the corticosteroid class is lotepred- Inflamed . Lomb), generic prednisolone sodium nol etabonate 0.5% (Lotemax gel,

34 REVIEW OF OPTOMETRY MAY 15, 2018

030_dg0518_Corticosteroids.indd 34 5/11/18 9:43 AM roid daily to maintain control over their condition. TIPS FOR TAPERING While older ketone-based steroids have been used Ever had a challenge tapering a patient off a topical for long-term therapy in the past, we would recommend corticosteroid? Steroids are wonderful for short-term ester-based loteprednol 0.5% gel off-label once daily for therapy, but carry intrinsic risks when used long-term. these protracted dosing schedules. (The ketone-based Here are a couple of thoughts: steroids seem to work well in this You can usually get the patient low-dose approach, yet it stands down to three or two times a to reason that loteprednol, being day, or even once daily before a an ester-based steroid, is prefer- relapse occurs. If a relapse does happen, you have to increase the able because of its enhanced safety dosage frequency again and try a profile.) longer, slower taper. Though Lotemax gel can seem In addition, try adding a ccost prohibitive for patients with- topical NSAID such as Prolensa oout drug coverage, most eligible (bromfenac, Bausch + Lomb) ccommercially insured patients pay or Ilevro (nepafenac ophthal- nno more than a $25 co-pay for mic suspension, Novartis) once ttheirh first prescription through the daily, or generic diclofenac or AAccess Program, and eligible refills ketorolac QID as you begin the next step-down of at Walgreens and other participat- the corticosteroid. This may offer enough supplemental ing independent pharmacies. Discounted pricing is also anti-inflammatory support to enable the continuation of available for eligible uninsured patients, according to the steroid taper. Or, try the oral NSAID route: Celebrex Bausch + Lomb’s website. (celecoxib, Pfizer) 100mg per day for a few weeks. As well, Novartis offers various coupons for Durezol There are instances when long-term steroid use is (difluprednate). And when there is no getting around indicated. Some patients who have had corneal trans- cost issues for the patient, generic FML (fluorometho- plants, stromal immune corneal disease, chronic uveitis lone 0.1%, Allergan) is another option. In addition, or recalcitrant dry eye disease may be kept on low-dose consulting www.goodrx.com can turn up the best local steroids for life. Some patients require one drop of ste- prices.

pinguecula, pterygia and many other lution—not a suspension—and does MODERATE EFFICACY inflammatory conditions. not need to be shaken before instil- STEROIDS While we have found that the drug lation. It remains an excellent choice The two most common topical ste- is not quite as efficacious as pred- for older patients with arthropathies roids in this category are fluorometh- nisolone and Durezol, its ester-based that make shaking a bottle challeng- olone 0.1% suspension and Alrex sus- derivatives correlate to fewer un- ing. It’s also well-suited for soft con- pension (loteprednol 0.2%, Bausch + wanted side effects (e.g., subcapsular tact lens wearers because it won’t Lomb), both of which must be shaken , elevated IOP). precipitate on the lens to the extent prior to instillation. In Phase III studies, for instance, of suspension drops. Fluorometholone 0.1%. There are only two out of 409 patients on Prednisolone acetate 1%. Generic two derivatives of fluorometholone Lotemax gel had an increase in IOP prednisolone acetate suspension is 0.1% suspension: alcohol (FML, greater than 10mm Hg after 18 days relatively inexpensive, and a reason- Allergan; and generic) and acetate of treatment.4 When used for post- able choice for mild to moderate (Flarex, Novartis; and generic). The operative cataract surgery inflamma- acute inflammatory conditions—but acetate moiety gives the fluorometho- tion, loteprednol 0.5% suspension not preferred in the setting of ad- lone molecules some additional anti- was shown to be as effective as pred- vanced iritis and . Make inflammatory effectiveness over the nisolone acetate, with less effect on sure that you indicate “brand name alcohol moiety.6 IOP.5 necessary” when prescribing for clin- Fluorometholone alcohol is avail- Prednisolone sodium phosphate ical situations that are potentially vi- able generically, so it is relatively in- 1%. Although generic, this drug re- sion threatening. expensive. While fluorometholone mains a viable option when an in- Rather than battle with the phar- has less likelihood of raising IOP than expensive, potent steroid is needed. macy or insurance company, we rec- other ketone steroids, we are not near- Unlike many of the other topical ste- ommend prescribing Durezol to by- ly as comfortable using it long-term as roids, the drop is prepared as a so- pass such bureaucratic hassles. we are using ester-based loteprednol.

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Since the lowest effective dose works well for periocular dermati- should be used in all cases, FML Forte tis conditions. Triamcinolone 0.1% (fluorometholone 0.25% ophthal- cream, which became generic many mic suspension) is not recommended years ago, has been our favorite because the 0.1% concentration rep- medication to treat contact blepharo- resents the top of the dose response dermatitis. It comes in 15g and 30g curve—meaning that 0.25% is no tubes, each costing about $10 in most more efficacious than 0.1%. markets. We have treated hundreds Alrex. An ester-based corticoste- of periocular contact dermatitis pa- roid, Alrex is an excellent off-label This slit-lamp view shows dense anterior tients with this drug with consistent, treatment option in cases when a stromal inflitration of leukocytes with superb, clinical outcomes. patient needs long-term therapy. We minimal epithelial breakdown. Such Be sure to tell the patient that the often use Alrex in our patients with findings, in our experience, always statement “Not for Ophthalmic Use” allergic eye disease when clinical signs indicate an inflammatory process is on the side of the tube, but that the of conjunctival injection, chemosis or meriting antibiotic/steroid therapy. medication is perfectly fine to use as eyelid swelling accompany itching. In prescribed. We explain to patients such cases, Alrex (or even Lotemax that triamcinolone is frequently used gel) will best help subdue the patient’s Lotemax ointment. The only by retina subspecialists for FDA- condition. We typically dose Alrex (or available ester-based steroid oint- approved injection into the eye, so if Lotemax gel) QID for one week, then ment, Lotemax ophthalmic ointment some of the triamcinolone cream gets BID for one month. (loteprednol 0.5%, Bausch + Lomb), into patients’ eyes, it’s nothing to be Beyond awareness of the various is indicated for postoperative inflam- concerned about. Doctors should be delivery systems (suspensions, solu- mation and pain, but has many ben- cautioned to use this approach only tions, emulsions, gels and ointments), eficial off-label clinical applications. for short-term relief, as long-term knowing the clinical efficacy of these Some examples are dry eye, allergy, use can result in skin atrophy and, in drugs is important. corneal transplant protection, bleph- some cases, elevated IOP (which we aritis, giant papillary conjunctivitis, have never seen). STEROID OINTMENTS chronic uveitis, stromal immune her- Corticosteroids are the most es- The ophthalmic ointments enjoy a petic keratitis, Thygeson’s SPK, recur- sential and highly prescribed drugs wide array of clinical indications. rent corneal erosion, augmentation of in the treatment of ocular inflamma- Three corticosteroid medicines that steroid eye drop therapy in acute ad- tion of any stripe. Their widespread merit frequent clinical use are: vanced uveitis or episcleritis, contact clinical usage confirms that ocular dermatitis and other inflammatory inflammation is the most common RELATIVE CLINICAL conditions. Lotemax ointment is ide- clinical manifestation seen in eye EFFICACY OF TOPICAL ally suited for patients who complain care. It is imperative that all doctors STEROIDS of how sandy and gritty their eyes feel of optometry embrace this reality Here, based on our clinical expe- upon awakening. and become comfortable using these rience and the comparative in- FML ointment. Used similarly to essential drugs in order to effectively formation we have available, we Lotemax ointment, FML ophthalmic care for patients with inflammatory rate the relative efficacy of the ointment (fluorometholone 0.1%, Al- eye disease. DG topical steroids, starting with lergan; and generic) is indicated for 1. Azari AA, Barney NP. Conjunctivitis: A systematic the most efficacious: inflammation of the palpebral and review of diagnosis and treatment. JAMA. 2013 Oct 23;310(16):1721-9. • Difluprednate 0.05% bulbar conjunctiva, cornea, anterior 2. Donnenfeld ED. Difluprednate for the prevention segment of the globe as well as the off- of ocular inflammation postsurgery: an update. Clin • Prednisolone acetate 1% Ophthalmol. 2011;5:811-6. label uses mentioned earlier. The only 3. Roberts CW, Nelson PL. Comparative analysis of • Loteprednol 0.5% prednisolone acetate suspensions. J Ocul Pharma- minor difference is to keep a closer col Ther. 2007 Apr;23(2):182-7. • Rimexolone 1% 4. FDA Center for Drug Evaluation and Re- watch for steroid-related adverse ef- search. Deputy Division Director Review for • Fluorometholone acetate 0.1% NDA 202-872. 2012 Sep 27. Available at: fects since it is a ketone formulation. www.accessdata.fda.gov/drugsatfda_docs/ Triamcinolone 0.1% cream. This nda/2012/202872Orig1s000MedR.pdf (last ac- • Dexamethasone 0.1% cessed March 21, 2018). • Fluorometholone alcohol 0.1% is a dermatological preparation that 5. Lane SS, Holland EJ. Loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for the treatment of inflammation after cataract surgery. J • Loteprednol 0.2% Cataract Refract Surg. 2013 Feb;39(2):168-73. • Prednisolone 0.125% 6. Leibowitz HM, Hyndiuk RA, Lindsey C, Rosenthal AL. Fluorometholone acetate: clinical evaluation in the treatment of external ocular inflammation. Ann • Hydrocortisone 1% Ophthalmol. 1984 Dec;16(12):1110-5.

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030_dg0518_Corticosteroids.indd 36 5/11/18 9:44 AM NONSTEROIDAL DRUGS

NSAIDs: PARAMETERS FOR BEST PRACTICES When used opical nonsteroidal anti-in- 0.07%, Bausch + Lomb). FDA-approved flammatory drugs (NSAIDs), for post-op inflammation and pain, the judiciously, a employed sparingly in the clini- drugs are dosed QD.4,5 cal setting, are mainly approved Ilevro, a prodrug, is highly permeable to nonsteroidal in to treat pain and inflammation the cornea and rapidly hydrolyzed to am- T 4,5 concert with a associated with cataract surgery, although fenac in the aqueous. Prolensa, structur- some off-label uses exist. Additional thera- ally similar to amfenac, contains a bromine corticosteroid py can be used to maintain dur- atom, making it highly lipophilic, which in- ing cataract surgery and decrease pain in creases corneal penetration and duration of can arrest photorefractive keratectomy patients.1,2 action.6 Since NSAIDs are fundamentally acidic, Prolensa is buffered to a pH of 8.3 postoperative INDICATIONS for added comfort with instillation.6 Amfe- cystoid NSAIDs primarily ameliorate pain on nac is a potent inhibitor of COX-1/COX-2 the ocular surface. When used together, isoenzymes.6 Once-a-day dosing is also an macular edema NSAIDs and corticosteroids have beneficial option due to the increased nepafenac con- therapeutic effects on postoperative cystoid centration from 0.1% to 0.3%. formation. macular edema (CME) formation. Gener- Other NSAIDs include: Acular LS (ke- ally, topical NSAIDs are prescribed in com- torolac tromethamine ophthalmic solu- bination with maximal-efficacy steroids to tion 0.4%, Allergan), Acuvail (ketorolac treat postoperative CME. tromethamine ophthalmic solution 0.45%, Dosing ranges from QD to QID, and Allergan), Bromsite (bromfenac ophthal- recommended dosing limits should be fol- mic solution 0.075%, Sun Pharma) and lowed to minimize side effects. It may also Voltaren (diclofenac sodium topical gel be prudent to comanage surgical patients 1%, Endo Pharmaceuticals). with cataract surgeons. Duration of use As with all medical therapy, the availabil- should be limited to two weeks with the ex- ity of once-daily dosing increases patient ception of CME cases, for which we’ll pre- compliance, and the right formulations are scribe one month of a topical NSAID with key to ensuring appropriate concentrations a potent steroid. Note that chronic use of with each instillation. DG NSAIDs can retard corneal epithelial 1. Schalnus R. Topical nonsteroidal anti-inflammatory thera- healing, and lead to, in very rare cas- py in ophthalmology. Ophthalmologica. 2003;217(2):89-98. 3 2. Eslampoor A, Ehsaei A, Abrishami M. Effect of topical es, corneal melting and perforation. diclofenac on postoperative photorefractive keratectomy pain: a randomized, controlled trial. Clin Exp Ophthalmol. 2014 Dec;42(9):810-4. MORE RECENT DRUGS 3. Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melt- ing associated with use of topical nonsteroidal anti-in- Newer to the topical NSAID space flammatory drugs after ocular surgery. Arch Ophthalmol. 2000;118(8):1129-32. are Ilevro (nepafenac ophthalmic sus- 4. Alcon. Ilevro package insert. Ft. Worth, TX, 2013. pension 0.3%, Novartis) and Prolen- 5. Bausch + Lomb. Prolensa package insert. Tampa, FL, 2013. 6. Ahuja M, Dhake AS, Sharma SK, Majumdar DK. Topical ocu- sa (brom fenac ophthalmic solution lar delivery of NSAIDs. The AAPS Journal. 2008;10(2):229-41.

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DON’T OVERLOOK OCULAR ALLERGIES

This common atients with ocular allergies make up a large portion of condition clinical encounters in daily responds practice. Nearly one-third of Pthe population is affected by well to allergic disease, with an estimated 40% to 80% of individuals manifesting ocu- therapy. Start lar involvement.1 And yet, allergic eye disease is often misdiagnosed as aller- symptom gic rhinitis or sinusitis, since the condi- tions frequently coexist, according to the suppresion American Academy of Allergy, Asthma right away and Immunology. As a result, sinus in- This is a classic presentation of acute allergic flammation is routinely diagnosed, treat- conjunctivitis. Note the bulbar conjunctival and let ed and managed, while ocular allergies chemosis which is pathognomonic for a local are not. hypersensitivity reaction. resolution As in all cases of an allergic response, exposure to an allergen prompts the im- guide your mune system to overreact and produce that cause the symptoms of allergy and decisions, but immunoglobulin E (IgE) antibodies that cascade of local inflammation—a pro- bind to mast cells. Ongoing exposure cess known as mast cell degranulation. don’t miss leads to the release of chemical mediators Allergic eye disease, an IgE-mediated coexisting IDENTIFYING COMMON TRIGGERS dry eye. The two most prevalent allergens—pollen and animal dander—cycle throughout varying seasons. In the spring, grass and tree pollen aeroallergens are most common; in the fall, ragweed is more predominant. Meanwhile, indoor pets can be the cause of allergic eye disease year-round. The symptoms of ocular allergy are usually itching, redness and tearing. Without itch- ing, the patient likely does not have allergic eye disease. Allergists suggest that patients suffering from chronic and cyclical signs and symptoms caused by allergic disease should be tested to identify the offender.1 Treatment is found through medicine, environment control (avoidance) or allergy injections/sublingual drops. The next time your patient presents with a long-standing history of repeatable allergic patterns, consider the role of an allergist to further assist your management.

1. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 100 3 Supp (2008):S1-148.

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038_dg0518_Allergy.indd 38 5/11/18 1:20 PM “Do Your Eyes Itch or Burn?” • Itching: If the patient tells you that itching is the pri- mary concern, determine if it’s an isolated symptom or if it’s associated with paral- lel signs of inflammation, and then treat accordingly. Remember: Symptoms Only: Use an antihistamine/mast cell sta- bilizer Symptoms and Signs: Use a steroid such as Lotemax, Alrex or FML. • Burning: If the main symp- tom is burning, a full dry Determine signs and symptoms by first asking, “Do your eyes burn or itch?” eye workup is in order for your patient. Also be sure to consider dry eye as the foun- therapeutic options are essentially predominant symptom, therapy is dational condition, and treat the same, perennial allergic con- directed toward one of two paths, accordingly. junctivitis follows a more indolent discussed below. Of course, nothing in the course, often requiring more atten- rulebook states that a patient SYMPTOMS ONLY can’t have both of these symp- tive and persistent care by the at- toms concomitantly. Due to tending doctor. If the anterior segment exam shows the prevalence of dry eye Itching is the definitive hallmark minimal or unremarkable signs of across all ages, recognize and of ocular allergy. Patients should (e.g., conjunc- also treat this disease whether be asked: “Is itching or burning tival chemosis, conjunctival injec- or not it is affiliated with aller- your main symptom?” Typically, tion, eyelid edema and/or papillae), gic eye disease. their response can isolate your next treatment with a combination anti- step. If your patient is unable to histamine/mast cell stabilizer is the response and type I hypersensitivity decide which symptom distresses ideal clinical choice. To date, there reaction, presents in various forms, them the most, treatment with an are six drugs in this class to choose from a persistent itch to a poten- ester-based steroid drop typically from: tially sight-threatening corneal ulcer solves both complaints. Preferred • Alcaftadine (Lastacaft, Aller- (vernal keratoconjunctivitis). For options include Alrex (loteprednol gan) seasonal allergic conjunctivitis, the etabonate 0.2%, Bausch + Lomb) • Azelastine (Optivar, Meda Phar- treatment protocols are straightfor- and Lotemax (loteprednol etabonate maceuticals; generic available) ward: antihistamines/mast cell stabi- 0.5%, Bausch + Lomb). • Bepotastine (Bepreve, Bausch + lizers or corticosteroids. Though the If patients report itching as their Lomb)

FROM THE LITERATURE attributed to climate changes, pollu- confirming the importance of early tion, increased pollen and a height- therapeutic intervention. ened immunological sensitivity in AN UPDATE ON 1. Worldwide variation in prevalence of symptoms PREVALENCE response to environmental changes, of asthma, allergic rhinoconjunctivitis, and atopic 2 eczema: ISAAC. The International Study of Asth- According to the published find- among other factors. About 40% ma and Allergies in Childhood (ISAAC) Steering of patients who suffer from allergies Committee. Lancet. 1998 Apr;351(9111):1225-32. ings from a series of studies con- 2. D’Amato G, Holgate ST, Pawankar R, et al. ducted by the International Study of reportedly experience some form of Meteorological conditions, climate change, new emerging factors, and asthma and related Asthma and Allergies in Childhood ocular symptomology (itching, che- allergic disorders. A statement of the World (ISAAC) starting two decades ago, mosis, redness).3 Allergy Organization. World Allergy Organ J. 2015; 8(1):1-52. allergic conjunctivitis has shown Of equal significance are the doc- 3. Singh K, Axelrod S, Bielory L. The epidemiol- a worldwide trend in increasing umented negative impacts of ocular ogy of ocular and nasal allergy in the United States, 1988-1994. World Allergy Organ J. prevalence.1 This upsurge has been allergies on patient quality of life, 2015;8(1):25.

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038_dg0518_Allergy.indd 39 5/11/18 1:21 PM ALLERGY DRUGS

OLOPATADINE: HISTORICAL GOLD STANDARD OF ALLERGY TREATMENT The first dual-action antihistamine/mast cell stabilizer to transform ocular allergy therapy was olopatadine 0.1% (Patanol, Novartis). In 1996, the FDA approved Patanol for the treatment of signs and symptoms of allergic conjunctivitis. The drug is highly selective for the H1 receptor, and has been shown in studies to possess anti-inflammatory properties, as well the ability to inhibit the release of leukotrienes, cytokines and adhesion molecules.1 Olopatadine 0.1% was the first topical drop for allergic conjunctivitis approved for BID dosing, far surpassing the second-generation antihistamines, which, in their time, had advanced to QID. In 2010, olopatadine 0.2% (Pataday) became available with comparable efficacy and improved patient satisfaction for relief of ocular symptoms for up to 18 hours. Five years later, olopatadine 0.7% (Pazeo) made its market debut with effi- cacy surpassing 24-hour ocular itching relief while maintaining a similar safety profile to lesser concentrations that came before it.

1. Ackerman S, Smith LM, Gomes PJ, et al. Ocular itch associated with allergic conjunctivitis: latest evidence and clinical management. Ther Adv Chronic Dis. 2016 Jan; 7(1): 52–67.

all of the antihistamine subtype 1 receptor blockers nicely suppress ocular itching. As well, all are dosed initially BID (except Pazeo, Pataday and Lastacaft, which are dosed QD). After two weeks of BID therapy, consider reducing instillation to QD for maintenance dosing. Remember, as with any treatment, the lowest ef- fective dose is always desired. In our experience, once the inflammation

KEEP Some people rub their itchy eyelids to the point of epidermal abrasion. Topically IN MIND applied Lotemax, FML or triamcinolone ointment could have prevented this. Now an antibiotic/steroid ointment is needed to restore tissue health. WHEN THE ITCHY EYE IS ALSO DRY Most patients with allergic con- • Epinastine (Elestat, Allergan; generic 0.1% olopatadine junctivitis also suffer from dry generic available) • Cetirizine (Zerviate, Nicox/ eye and hyperemia, even if the • Ketotifen (Zaditor, Alcon; many Akorn) dryness has not elicited symp- generics available. This drop is Of these, all are rated pregnancy toms of burning. Specifically, OTC.) category C except for Lastacaft, the likelihood of allergic con- • Olopatadine—branded (Pazeo/ which is pregnancy category B. Not- junctivitis patients also having Pataday/Patanol, Novartis) and withstanding other fine differences, dry eye is more than twice that of patients without symptoms of itch, and the chance of these patients also experiencing red- ness is more than seven times that of patients with non-itchy eyes.1 These results suggest that some symptomatic patients concomitantly have features of allergic conjunctivitis and .

1. Hom MM, Nguyen AL, Bielory L. Allergic conjunctivitis and dry eye syndrome. Ann Al- lergy Asthma Immunol. 2012 Mar;108(3):163-6.

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038_dg0518_Allergy.indd 40 5/11/18 1:21 PM TOPICAL ANTIHISTAMINE DOSING: is brought under control, less phar- IT TAKES TWO TO TANGO? maceutical intervention is needed to maintain suppression of symptoms. Forget about prescribing pure mast cell stabilizing drugs, according to Mark Then again, some patients still re- Abelson, MD, a world-renowned ocular allergist at Harvard Medical School. Dr. Abelson told us that pure mast cell stabilizing drugs have little clinical use, quire a second additional drop later as their lag period and mandatory chronic dosing severely limits their clinical in the afternoon. applicability. Rather, topical combination antihistamine/mast cell stabilizers Perhaps the best news for the con- give patients nearly instantaneous relief due to the rapid onset of action; also sumer was the loss of patent protec- compelling is their affordability. Dr. Abelson explained that antihistamine/mast tion for Zaditor (Novartis). Since cell stabilizer drugs actually do a better job of stabilizing mast cell membranes 2007, ketotifen has been available than a pure mast cell stabilizer. generically and over the counter. In The cost of an OTC topical combination antihistamine/mast cell stabilizer addition to Zaditor, several brand drop is similar to a pure mast cell stabilizer. Remind your patients that tran- name OTC ketotifen preparations sient burning and stinging upon instillation is common. are available, including Alaway For patients who have symptomatic disease, one drop in the morning may (Bausch + Lomb), Refresh Eye Itch suffice for lasting improvement throughout the day. However, a subset of Relief (Allergan) and others. All patients may need to instill a second drop later in the afternoon. Which is cor- come in 5ml bottles, except for Al- rect? In the end, either is appropriate, as care of the symptomatic patient is a away and TheraTears Eye Itch Re- tailored, rather than a one-size-fits-all, approach. lief (Akorn), which come in 10ml In your patients with severe allergy expression, therapy is slightly more bottles. involved. In addition to an antihistamine/mast cell stabilizer BID, consider an When a prescription medication ester-based corticosteroid such as Alrex (loteprednol 0.2%, Bausch + Lomb) is preferable, 5ml bottles of Alrex or off-label use of Lotemax gel (loteprednol 0.5%, Bausch + Lomb) QID ini- and Bepreve are only $10 copays tially along with cold compresses. for the first Rx and refills through Once the inflammation has settled down, the steroid may be discontinued, the Bausch + Lomb Access program usually within two weeks, and the patient can remain on the antihistamine/ at Walgreens and other participat- mast cell stabilizer once or twice daily as needed. ing independent pharmacies during

OCULAR ALLERGY MEDICINES BRAND NAME GENERIC NAME MANUFACTURER PEDIATRIC USE BOTTLE SIZE(S) DOSING Acute Care Products Acular LS ketorolac tromethamine 0.4% Allergan and generic 3 yrs 5ml, 10ml QID Alaway (OTC) ketotifen fumarate 0.035% Bausch + Lomb 3 yrs 10ml BID Alrex loteprednol etabonate 0.2% Bausch + Lomb 12 yrs 5ml, 10ml QID Bepreve bepotastine besilate 1.5% Bausch + Lomb 2 yrs 5ml, 10ml BID Elestat epinastine HCl 0.05% Allergan and generic 3 yrs 5ml BID Emadine emedastine difumarate 0.05% Novartis and generic 3 yrs 5ml QID Lastacaft alcaftadine 0.25% Allergan and generic 2 yrs 3ml QD Optivar azelastine hydrochloride 0.05% Meda and generic 3 yrs 6ml BID Pataday olopatadine hydrochloride 0.2% Novartis 3 yrs 2.5ml QD Patanol olopatadine hydrochloride 0.1% Novartis and generic 3 yrs 5ml BID Pazeo olopatadine hydrochloride 0.7% Novartis 2 yrs 2.5ml QD Zaditor (OTC) ketotifen fumarate 0.035% Novartis and generic 3 yrs 5ml BID

Chronic Care Products Alocril nedocromil sodium 2% Allergan and generic 3 yrs 5ml BID Alomide lodoxamide tromethamine 0.1% Alcon 2 yrs 10ml QID Crolom cromolyn sodium 4% Bausch + Lomb 4 yrs 10ml QID and generic

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AN OUNCE OF PREVENTION… Frequency of instillation is tai- Avoidance is one of the best ways to prevent common eye allergies. Other lored to the severity of the patient’s tips from the Asthma and Allergy Foundation of America include: signs and symptoms. Typically, we • Don’t touch or rub the eye(s). prescribe a steroid drop Q2H for • Wash hands often with soap and water. two days, then QID for one week, • Use a vacuum with a HEPA filter to reduce exposure to allergens. followed by BID for one more week. • Wash bed linens and pillowcases in hot water and detergent to reduce Once the signs of allergic eye disease allergens. are subdued, consider switching your • Use allergen covers (encasements) for pillows, comforters, duvets and patient to an antihistamine/mast cell mattresses, and consider using them for box springs. stabilizer for ongoing symptomatic • Keep pets out of the bedroom to reduce pet dander allergen in bedding. regulation. • Wear sunglasses and a wide-brimmed hat to help keep pollen from getting into the eyes. AN EQUAL-OPPORTUNITY • Close windows during high-pollen and mold seasons. Run the air condi- DISEASE tioner in the car and at home, and consider using a HEPA filter. While once considered to be a “dis- ease of affluence,” allergic conjunc- Eye Allergies (Allergic Conjunctivitis). Asthma and Allergy Foundation of America. Available at: www.aafa.org/page/eye-allergy-conjunctivitis.aspx. Accessed March 12, 2018. tivitis is now clearly recognized around the world, with increasing prevalence in countries with sus- allergy season (between February 15 inflammation early to avoid poten- tained growth and developing ur- and June 15, and August 1 through tial late complications. ban populations.2 Doctors should October 31); they are only $15 co- In individuals presenting with bear in mind that, while the disease pays for the first Rx and refills filled symptoms of allergy along with clas- is not life-threatening, the persistent outside of the program’s participat- sic anterior segment findings, a topi- symptoms experienced by those who ing pharmacies during allergy sea- cal, ester-based corticosteroid is a suffer from ocular allergies can have son. Also consider consulting www. wonderful option. We recommend a profound impact on productivity goodrx.com to find the best avail- Alrex or off-label use of Lotemax gel and quality of life. able price in your area. (loteprednol 0.5%, Bausch + Lomb). Remember, allergy is an expres- Additionally, the generic, ketone- sion of inflammation. In addition to SYMPTOMS AND SIGNS based corticosteroid FML ophthal- the therapeutic strategies listed above, Whenever possible, therapy for ocu- mic suspension (fluorometholone don’t forget to discuss with patients lar allergies should be prophylactic. 0.1%, Allergan; and generic) is a via- palliative options such as daily cold Therefore, in the setting of allergic ble therapy, although we have found compresses. Telling your patients to conjunctivitis, initiate therapy early it has a higher propensity to increase place their allergy drops in the refrig- in the process, make sure it is suffi- IOP compared with its ester-based erator until it’s time to instill the drop cient to suppress the patient’s signs loteprednol counterparts. (Also of can add additional relief. DG and symptoms, and have the patient interest, FML, though generic, is of- 1. Kari O, Saari KM. Diagnostics and new develop- continue for long enough to prevent ten more expensive than the varying ments in the treatment of ocular allergies. Curr conversion into a chronic disease. concentrations of loteprednol once Allergy Asthma Rep. 2012;Jun;12(3):232-9. 2. Gomes PJ. Trends in prevalence and treatment The basis of treating any allergic eye a Bausch + Lomb coupon has been of ocular allergy. Curr Opin Allergy Clin Immunol. disease remains the same: quell the applied). 2014 Oct;14(5):451-6.

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VANQUISH THE VIRUS

Early he herpes virus can manifest in a wide range of ocular condi- recognition tions, from a mild vesicular lid and lesion to an aggressive retini- Ttis. Clinicians should be aware appropriate that the virus can affect every ocular tis- sue and treat the patient accordingly. therapy are HERPES SIMPLEX crucial to The herpes simplex virus (HSV), char- acterized by its ability to remain latent maintaining in the nervous system, can impact indi- Primary herpes simplex blepharodermatitis. the integrity viduals of all ages. By adulthood, almost all of the population has herpes simplex of the ocular antibodies, with the majority of people have between two to five relapses in their having had exposure by age five. HSV, lives; an additional 11% will experience tissues when a DNA virus largely spread by close per- between six and 15 relapses.2 sonal contact, is primarily broken down A reactivation from the ophthal- treating into two types: herpes simplex I (oral/ mic branch of the trigeminal ganglion patients with facial/ocular) and herpes simplex II (geni- may result in HSK. In those who ex- tal); HSV can also cross-infect between hibit relapsing HSK, the three pri- viral eye type 1 and type 2.1 mary presentations of keratitis—epi- In the setting of periocular skin dis- thelial, stromal and endothelial—can diseases. ease, the patient may have confined pro- occur in isolation, combination or dromal symptoms such as mild pain, tin- succession. gling, itching or burning before the lesion With HSK, the patient will often pres- potentially progresses to the following ent with unilateral injection and a mild, stages: macule, papule, vesicle, encrusta- watery discharge. It is imperative to re- tion and healing (without scarring). Only member that, early on, corneal lesions after skin lesions are encrusted is the pri- may not present in their classic dendrite mary disease no longer contagious. formation. When caught at the start of It is well known that herpes simplex dis- the infection process, HSK may appear ease tends to recur. With a prevalence of merely as a superficial punctate keratitis 150 per 100,000 people in western coun- secondary to dry eye. However, these pri- tries, patients have a 1% global lifetime marily coarse punctate lesions form uni- risk of developing herpes simplex keratitis laterally (with the exception of children (HSK). Furthermore, 40% of patients will with atopic disease who may get bilateral

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OTHER FACES OF HSV EXPRESSION people are the target We all are familiar with the typical clinical manifestations population. Unlike healthy of primary herpes simplex expression, but there are two gladiatorum patients, ecze- other presentations to recognize: herpes gladiatorum ma herpeticum patients and eczema herpeticum. While both are dermatologic in usually have some degree nature and share a similar clinical presentation, unique dif- of immune system com- ferences exist between them. promise, and so feel unwell with possible swollen HERPES GLADIATORUM Eczema herpeticum. This form is seen almost exclusively in high school or lymph nodes. college wrestlers. The athlete develops a spontaneous Because of the potential primary infection, engages for more severe disease with herpeticum, we prescribe in wrestling activity and the zoster dosage of acyclovir 800mg, five times daily; transmits the virus via vig- valacyclovir 1,000mg, three times daily or famciclovir orous skin-to-skin contact. 500mg, three times daily for a course of 10 to 14 days. Note that while spontane- Remember that these oral antiviral drugs are quite safe, ous primary HSV expression and only moderate to severe renal disease requires a is generally unilateral, this reduced dosage. condition (as well as eczema Fortunately, these patients usually present to primary herpeticum) can be much care physicians or dermatologists initially, but eye doc- Herpes gladitorum as seen more diffusely dispersed. A in the typical male wrestler. patient history is critical to tors are often consulted with findings of any periocular diagnosis, and both primary involvement. With these forms of herpes simplex derma- and gladiatorum forms are treated either with acyclovir tological disease, the globe is rarely involved. Typically, 400mg, five times a day for seven to 10 days; valacyclovir only a premium-quality artificial tear would be needed for 500mg, three times a day for seven to 10 days; or fam- ocular involvement, as oral antiviral drugs treat the full ciclovir 250mg, three times a day for seven to 10 days. spectrum of the disease manifestation. Because of the easier dosing schedule of valacyclovir and Only on occasions in which secondary, concurrent or famciclovir (TID), we generally prescribe one of these two bacterial infection (mostly Staphylococcus aureus, but drugs. Check with www.goodrx.com to find where this occasionally Streptococcus pyogenes) is suspected or medicine is the least expensive in your area. determined would a topical non-ophthalmic antibiotic ointment (mupirocin, brand name Bactroban) or systemic ECZEMA HERPETICUM This is somewhat of an opportunistic infection, in that it antibiotic (cephalexin, brand name Keflex) be warranted. is almost always seen in patients with eczema, a subset All of these herpetic disease processes respond well to of atopic disease. As with gladiatorum, it has a rather dis- oral antivirals, and patients usually heal well. Our role as seminated expression that does not respect laterality. The eye physicians is to assess the ocular tissues and inform face and neck are most commonly involved, and younger the initial treating doctor about the eye and eyelid tissues.

disease though remaining immuno- ity that often leads to neurotrophic HERPES ZOSTER VIRUS competent), are more commonly dry eye, delayed epithelial healing and The varicella virus (chickenpox) is found centrally and will not respond persistent inflammation even when the initial or primary infection of to dry eye therapy alone.3 the disease is not in an active stage. the herpes zoster virus (HSV) disease In patients who develop HSK, ap- process. Herpes zoster, better known proximately 15% will develop se- Year 2 Year 5 Year 7 as “shingles” to the general public, is vere complications.4 With those who Risk of HSK 22% 40% 67% the reactivation of the varicella virus have epithelial keratitis, moderate Relapse2 and is seen most commonly in the pain is the most expressed symptom, sixth to seventh decades of life. When in contrast with the other two vari- Clinical pearl: Limbal dendrites an individual is initially exposed to ants—stromal and endothelial—in are typically more recalcitrant to chickenpox, the virus becomes latent which varying degrees of vision loss treatment than central ones because in the sensory ganglion of the trigemi- will be present. Approximately 11% the immunological armamentarium nal nerve. If the disease is reactivated, of patients will have a final VA below (antibodies and leukocytes) is abun- the virus will travel down the neural 20/200.2 Other complications of HSK dantly present in the limbal micro- pathways to its respective afferent can include a loss of corneal sensitiv- vasculature.5 peripheral nerves and dermatome (an

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043_dg0518_Antiviral.indd 44 5/11/18 1:35 PM area of skin that is mainly supplied by a single spinal nerve). A shingles outbreak is always uni- lateral, and will not cross the midline of the patient, thus making it one of the most recognizable disease pro- cesses in medicine. The recurrence of the zoster virus is rather low—less than 6%—as additional outbreaks could lead to the patient to become immunocompromised.6 Up to 30% of patients will devel- op a herpes zoster outbreak in their lifetimes. The prevalence of HZV is Herpes simplex epithelial keratitis without (left) and with (right) cobalt blue well-documented to have increased filter. Since the location of this presentation involves the visual axis, vision will be over the past decade.7 Each year, temporarily compromised. nearly one million Americans devel- op shingles—with the face being the nerve that innervates corneal is available in topical and oral second most common site of infec- and intraocular tissues), the eye form; now let’s look at our op- tious development, after the trunk.8 is, too. With the first branch tions. Fortunately, due to the advent of the innervating the structures of childhood Varivax vaccine (live vari- the eye, it is easy to see why TOPICAL THERAPY cella virus, Merck), which came to nearly every ocular tissue Ocular HSV keratitis re- market in 1995, generations of peo- can be affected by a viral sponds well to either Zir- ple will never have shingles because reactivation. gan (ganciclovir gel 0.15%, they will never contract chickenpox. Ocular involvement of Bausch + Lomb) or Viroptic This, however, is a double-edged HZO presents as an inflam- (trifluridine 1%, Pfizer and sword. Prior to the Varivax vaccine, matory keratitis, uveitis, generic). If the disease is con- children with chickenpox in various conjunctivitis or a combi- fined to the epithelium, never stages of contagion came into con- nation of all three. Uveitic treat with topical steroids, as tact with adults during the course of involvement manifests as inflamma- that can enhance viral replication daily living, boosting the adult popu- tory cells in the anterior chamber, that could progress to a potentially lation’s immunity against the varicel- corneal involvement as stromal sight-threatening geographic ulcer. la zoster virus. Since Varivax, such inflammation and conjunctival in- Ganciclovir 0.15% (preserved immune-stimulation has diminished volvement as unilateral injection, with benzalkonium chloride) is a each year. Thus, we face another 30 to varying degrees. An elevated in- more advanced option than trifluri- to 50 years of increasing occurrence traocular pressure may occur if the dine 1%, allowing for less frequent of shingles in those underexposed trabecular meshwork is inflamed. dosing, in turn decreasing risk of patients who have not had sufficient Should the IOP be sufficiently el- toxicity. Patients should instill one exposure to boost their immunity evated, a temporary reduction can drop into the affected eye five times against it. As such, clinicians need to be accomplished with a topical beta- daily until the corneal ulcer heals, be ready to competently care for this blocker such as timolol and/or the then one drop three times daily for expanding population. alpha-adrenergic agonist brimoni- a week. Remember that ganciclovir Herpes zoster ophthalmicus (HZO) dine, for a few days. Conjunctival is available as a gel only. Dosed ap- is present in up to 25% of all zos- injection will accompany these sce- propriately, most HSK cases resolve ter outbreaks, and occurs when the narios to some degree. over the course of two weeks or less. virus affects the first branch of the Treatment for ocular involvement For patients with ocular involve- trigeminal nerve (V1, or ment in the setting of HZO, the ophthalmic branch).9 A the strategy is quite differ- long-held clinical belief has ent. Typically, an aggressive been that, if the tip of the approach with nose is involved (Hutchin- and topical steroids is de- son’s sign, indicating in- ployed. We prescribe hom- volvement of the nasociliary 5% BID to QID,

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Herpes Simplex Herpes Zoster Acyclovir 400mg 5x/day Acyclovir 800mg 5x/day for 7 to 10 days for 7 to 10 days Valacyclovir 500mg TID Valacyclovir 1,000mg TID for 7 to 10 days for 7 to 10 days Famciclovir 250mg TID Famciclovir 500mg TID for 7 to 10 days for 7 to 10 days

ORAL THERAPY The three aforementioned oral an- When shingles presents as an uncom- tivirals are generic. Acyclovir tends plicated skin disease accompanied by to be less expensive than valacyclovir Classic image of acute herpes simplex pain, erythema and vesicular expres- or famciclovir, but is dosed five times epithelial keratitis. sion, we recommend an oral antiviral a day. As a quick rule of thumb, the for seven to 10 days. We find three dosage of the antiviral drug is halved such medications equivalent in their to treat simplex disease. along with Durezol (difluprednate therapeutic effectiveness (dosed spe- Remember that antiviral medica- 0.05%, Novartis) every one to two cifically for zoster disease): tions are most efficacious during the hours for a few days until the inflam- • Acyclovir 800mg five times daily early, replicative phase of the infec- mation is well controlled. Only then • Valacyclovir 1,000mg three tion (initial 72 hours). This does not is tapering initiated. times daily mean that after three days, the op- Recurrent flare-ups may require • Famciclovir 500mg three times portunity for medical intervention maintenance therapy as a prophylac- daily has passed, just that there is decreas- tic measure. Once the inflammation Interestingly, some research ad- ing clinical efficacy with each day is brought fully under control with vocates the use of famciclovir over of delayed care. With more virulent Durezol, we switch the topical steroid acyclovir and its prodrug valacyclo- expressions, especially in older indi- to Lotemax gel. The sequence would vir in adults >65 years of age with or viduals, concurrent therapy with oral be something like this: TID for one without reduced renal function. This prednisone (usually 40mg to 60mg/ month, BID for two to four months is due to findings that valacyclovir day for a week) can be valuable in and then once daily for several more and acyclovir carry an increased risk decreasing pain and inflammation, months. The goal is to find the mini- of central nervous system adverse and may dampen the expression of mum therapeutic dosing to achieve reactions (agitation, confusion, en- post-herpetic neuralgia. the desired result. cephalopathy) and acute renal fail- Oral antivirals are extremely safe It should be noted that some phar- ure compared with famciclovir.10,11 and effective. Their only Achilles’ macies in certain locations don’t al- Moreover, in lactose-intolerant pa- heel is that they are metabolized ways stock topical antivirals, so oral tients, valacyclovir is preferred. In by the kidneys. Thus, if a patient therapy can be an equally effective, children, the oral suspension form of has clinically significant renal dis- and less expensive, approach. acyclovir is a prudent option. ease, the antiviral dosage must be

TOPICAL THERAPY FOR HERPES SIMPLEX/ZOSTER BRAND NAME GENERIC NAME MANUFACTURER PEDIATRIC USE PREPARATIONS DOSING Viroptic trifluridine 1% Pfizer 6+ solution 8x/day Zirgan ganciclovir 0.15% Bausch + Lomb 2+ gel 5x/day

ORAL THERAPY FOR HERPES SIMPLEX BRAND NAME GENERIC NAME MANUFACTURER PEDIATRIC USE HSV DOSE HZV DOSE Zovirax acyclovir GlaxoSmithKline Adjusted dose for 400mg 5x/day 800mg 5x/ infants day Valtrex valacyclovir GlaxoSmithKline Adjusted dose for 500mg TID 1,000mg TID infants Famvir famciclovir Novartis Adjusted dose for 250mg TID 500mg TID infants

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043_dg0518_Antiviral.indd 46 5/11/18 1:36 PM best treatment options and prophy- effect. We do know that a single laxis against HSV keratitis—looked 500mg dose of valacyclovir is equiv- at more than 700 patients with vari- alent to 400mg of acyclovir BID for ous manifestations of ocular HSV long-term suppression therapy when infection.12 needed. The study concluded that: • The placebo group had a 32% SHINGLES OUTLOOK cumulative probability of ocular LOOKS BRIGHT— HSV recurrence during the first 12 EVENTUALLY months. With the advent of the childhood • Epithelial disease alone did not Varivax vaccine, generations of make future recurrences more likely, people will never have shingles, as but stromal disease definitely did. they never contracted chicken pox. • With regards to patients who This leaves a sizable majority of the had epithelial dendrites, oral acyclo- adult population underexposed to A patient exhibiting HZO. Note the vir did not reduce the rate of stromal the virus, diminishing their immuni- first division, trigeminal distribution, disease. ty and increasing the prevalence of dermatological vesicles, the edema • Oral acyclovir did not improve the disease for the next several de- to the upper eye lid and the mild outcomes in stromal keratitis cases, cades. It is critical that this popula- ocular inflammation. Treatment would nor did it prevent stromal involve- tion is swiftly and effectively treated include an oral antiviral and a topical ment. when it arises in our offices and corticosteroid. Oral prednisone (40mg) • Stromal disease was best man- clinics. DG for a week could also be considered aged with topical steroids, which did 1. Waggoner-Fountain LA, Grossman LB. Herpes depending upon the pain level of the not increase the rate of recurrence. simplex virus. Pediatr Rev. 2004 Mar;25(3):86-93. patient. As revealed in the Acyclovir Pre- 2. Reynaud C, Rousseau A, Kaswin G, et al. Persis- vention Trial, oral acyclovir 400mg tent impairment of quality of life in patients with herpes simplex keratitis. Ophthalmology. 2016; dosed BID for one year resulted in Nov. 15. [Epub ahead of print]. reduced. A phone consultation with a 45% decrease in the chance of 3. Souza PM, Holland EJ, Huang AJ. Bilateral her- petic keratoconjunctivitis. Ophthalmology 2003 the patient’s primary care physician, recurrence for all forms of ocular Mar;110(3):493-6 nephrologist or pharmacist is of ut- involvement. However, the effect 4. Darougar S, Wishart MS, and Viswalingam ND. Epidemiological and clinical features of primary most importance in determining op- was stopped upon discontinuation herpes simplex virus ocular infection. Br J Ophthal- timum dosages in the setting of renal of the drug.13 This research points mol. 1985 Jan;69(1):2-6. 5. Dua HS, Gomes JA, Singh A. Corneal epi- disease. to the importance of potential life- thelial wound healing. Br J Ophthalmol. 1994 time treatment with oral acyclovir in May;78(5):401-8. THE HERPETIC EYE patients who have two or more out- 6. Tseng HF, Chi M, Smith N, et al. Herpes zoster vaccine and the incidence of recurrent herpes zos- DISEASE STUDY breaks in a year, or a recurrent dis- ter in an immunocompetent elderly population. J Originally undertaken to evaluate ciform keratitis. Newer data show a Infect Dis. 2012 Jul;206(2):190-6. 7. Kawai K, Gebremeskel BG, Acosta CJ. Systemat- the usefulness of oral acyclovir in parallel effect with a single 500mg ic review of incidence and complications of herpes stromal HSV disease, the Herpetic dose of valacyclovir. zoster: towards a global perspective. BMJ Open. 2014 Jun 10;4(6):e004833. Eye Disease Study (HEDS)—which While acyclovir was used in the 8. Harpaz R, Ortega-Sanchez IR, Seward JF; Advi- consisted of five randomized, place- HEDS, it is our belief that the oth- sory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). bo-controlled trials to determine the er antivirals would have a similar Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Prac- tices (ACIP). 9. Catron T, Hern HG. Herpes Zoster Ophthalmicus. West J Emerg Med. 2008 Aug;9(3):174-6. 10. Asahi T, Tsutsui M, Wakasugi M, et al. Valacy- clovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol. 2009;16:457-60. 11. Adair JC, Gold M, Bond RE. Acyclovir neurotox- icity: Clinical experience and review of the litera- ture. South Med J. 1994;87:1227-31. 12. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral acy- clovir for herpes simplex stromal keratitis. Ophthal- mology. 1994 Dec;101(12):1871-82. 13. Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med. 1998 Jul;339(5):300-6.

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SMART SELECTION OF ANTIBIOTIC AGENTS

Both the egarded as one of the greatest always results from some expression discoveries in medicine, anti- of inflammation. These inflammatory topical and biotics have been used since conditions require corticosteroids, not the 1940s to treat millions antibiotics, yet time and time again, cli- oral forms Rof patients with infections nicians will prescribe an antibiotic drug should be used worldwide. However, antibiotics are, that does not improve the patient’s con- in a sense, victims of their own success: dition. judiciously dosing has become widespread and over- Let’s take a more in-depth look at this prescribed over time. As a result, some class of medicines. There are many anti- to avoid bacteria are now resistant to antibiotics biotics; however, only a few enjoy—or that were once highly effective. should enjoy—widespread use. perpetuating According to a report from the Cen- antibiotic ters for Disease Control and Prevention, BACITRACIN antibiotic resistance causes two mil- Available since 1948, bacitracin is resistance. Here lion bacterial and fungal illnesses, and only available in ointment form, and is 23,000 deaths, yearly.1 It also results in strictly a gram-positive antibiotic often are strategies an annual increase in direct health care employed in the clinical setting of staph- costs of $20 billion, plus $35 billion in ylococcal blepharitis. After warm com- to choose the lost productivity.1 Though most studies presses and lid scrubs, bacitracin can be right medicine on antibiotic resistance have focused on applied to the lid margins at night before systemic antibiotics, researchers have be- the patient goes to bed for four to six and dose it gun to look at resistance to topical oph- days. However, since tissue inflamma- thalmic antibiotics. tion invariably accompanies staphylo- correctly. Given this growing epidemic of antibi- coccal blepharitis, we more frequently otic resistance across medical disciplines, have our patients apply an antibiotic- researchers are under increasing pressure steroid combination ointment such as from the clinical world to seek out po- generic Maxitrol (dexamethasone/neo- tential new drugs to treat infections. mycin/polymyxin B) here. For true bacterial corneal infections, a RED EYES ARE broad-spectrum antibiotic is always pre- RARELY INFECTIOUS ferred. In such cases, we dose Besivance We have found that acute red eyes un- (besifloxacin ophthalmic suspension, commonly derive from bacterial infec- Bausch + Lomb) by day with Polysporin tion. The presence of mucopurulent dis- ophthalmic ointment at bedtime (baci- charge with acute red eyes is often the tracin/polymyxin B), as the polymyxin result of a bacterial infection. Lacking B is bactericidal against gram-negative “discharge,” the acute red eye almost pathogens.

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0048_dg0518_Antibiotics.indd48_dg0518_Antibiotics.indd 4488 55/11/18/11/18 12:5012:50 PMPM TOPICAL ANTIBIOTIC DRUGS BRAND NAME GENERIC NAME MANUFACTURER PREPARATION PEDIATRIC USE BOTTLE/TUBE Fluoroquinolones Besivance besifloxacin 0.6% Bausch + Lomb suspension > 1 yr. 5ml Ciloxan ciprofloxacin 0.3% Novartis and generic sol./oint. > 1 yr./ > 2 yrs. 5ml, 10ml/3.5g Moxeza moxifloxacin 0.5% Novartis solution > 4 mos. 3ml Ocuflox ofloxacin 0.3% Allergan and generic solution > 1 yr. 5ml, 10ml Vigamox moxifloxacin 0.5% Novartis solution > 1 yr. 3ml Zymaxid gatifloxacin 0.5% Allergan and generic solution > 1 yr. 2.5ml

Aminoglycosides Tobrex tobramycin 0.3% Novartis and generic sol./oint. > 2 mos. 5ml/3.5g Garamycin gentamicin 0.3% Perrigo and generic sol./oint. N/A 5ml/3.5g

Polymyxin B Combinations Polytrim polymyxin B/trimethoprim Allergan and generic solution > 2 mos. 10ml Polysporin polymyxin B/bacitracin generic ointment N/A 3.5g Neosporin polymyxin B/neomycin/ generic solution N/A 10ml gramicidin polymyxin B/neomycin/ generic ointment N/A 3.5g bacitracin

Other Antibiotics AzaSite azithromycin 1% Akorn solution > 1 yr. 2.5ml Ilotycin erythromycin 0.5% Perrigo and generic ointment > 2 mos. 3.5g Bacitracin bacitracin 500u/g Perrigo ointment N/A 3.5g

THE AMINOGLYCOSIDES: A somewhat atypical peripheral GENTAMICIN, NEOMYCIN circumlimbal sterile leukocytic infiltrate AND TOBRAMYCIN from 2 o’clock to 5 o’clock, which only The aminoglycosides historically were minimally stains—a classic finding in all a go-to drug for optometrists. How- expressions of sterile anterior stromal ever, they have taken a back seat with infiltrates. An antibiotic/steroid such as the advent of fluoroquinolones. To- Zylet is an excellent treatment. day, some clinicians may be reluctant to prescribe the aminoglycosides due to their potential to cause a type IV positive agent can extend the total hypersensitivity reaction. Neomycin antibiotic coverage achieved. is broad-spectrum, but does not cover Polytrim. Originally marketed by Pseudomonas, which is why it is al- Allergan and now generically avail- ways packaged with polymyxin B or able, Polytrim (polymyxin B/trim- an antibiotic effective against gram- ethoprim) is an effective combina- negative organisms. In our experi- tion antibiotic available in solution ence, type IV delayed hypersensitivity form. Polymyxin B is active only dermatoconjunctivokeratitis reactions against gram-negative bacteria. Tri- are exceedingly rare when the neomy- methoprim is broad-spectrum against cin combination is used for no more many gram-positive and some gram- than a week. negative bacteria, and works by in- terfering with the folic acid pathway. POLYMYXIN B COMBINATIONS Note that trimethoprim itself is not a Combination drugs that pair poly- sulfa drug, although it also inhibits myxin B with a complementary gram- the production of bacterial folic acid.

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CUT THE PILL—AND THE COST—IN HALF The cost of brand name and generic drugs is continually changing, and clinicians are con- stantly faced with dynamic and ever-changing pricing structures. Regarding doxycycline, we have Polytrim (trimethoprim/polymyxin how efficacious compounded vanco- found in several instances that B), tobramycin or Besivance (Bausch mycin is, and would expect similar the 100mg units are cheaper + Lomb), depending on the nature and in-vivo performance with Besivance. than the 50mg units. To be more severity of the infectious condition, as As a suspension, this thick eye cost-effective for the patient, we these options are much less prone to drop must be shaken prior to each will occasionally prescribe 100mg cause any type of allergic reaction. use. The patient also must refrain doxycycline monohydrate tablets from blinking for several seconds af- that can be split in half. Of course, THE FLUOROQUINOLONES ter instillation to allow the drop to following all theses ever-changing The options in this class have some spread out across, and remain on, price structures can be daunting. notable differences. the ocular surface. When properly Besifloxacin. Besivance, a unique, instilled, Besivance has been shown In reality, though, it’s not used very dual-halogenated fluoroquinolone, to maintain very high concentrations often in clinical practice because new is the only topical ophthalmic antibi- on the ocular surface, with minimal studies have found it to be suboptimal otic that comes as a suspension. As systemic exposure. against methicillin-resistant staphy- with all fluoroquinolones, Besivance An Ophthalmology and Therapy loccal epidermis species. provides activity against DNA gyrase study finds: “Large randomized, con- Polysporin. This drug, which com- and topoisomerase IV. Its broad- trolled clinical trials have established bines polymyxin B with bacitracin, spectrum coverage combats gram- the efficacy and safety of besifloxa- is available generically but only as positive, gram-negative (including cin administered three times daily for an ophthalmic ointment. The pair- Pseudomonas) and anaerobic organ- five days for the treatment of acute ing of polymyxin B’s gram-negative isms, as well as methicillin-resistant bacterial conjunctivitis in both adults and bacitracin’s gram-positive action Staphylococcus aureus (MRSA) and and children, with high rates of clini- makes this an excellent, nontoxic, methicillin-resistant Staphylococ- cal resolution (up to more than 70% broad-spectrum antibiotic. cus epidermidis (MRSE). The latest by day five) and bacterial eradication The drug is often used in pediatric research (i.e., the ARMOR study) (more than 90% by day five), and a eye care, and instilled along the lids has demonstrated in vitro that besi- low incidence of adverse effects.”3 and lashes, where body temperature floxacin and vancomycin share very For severe infectious processes

melts the ointment and allows ad- low MIC90 levels against the common such as microbial keratitis, we dose equate ocular surface application of gram-positive ocular pathogens.2 Besivance hourly (while awake) for the drug. This approach obviously This is important in that we know one to three days, then taper the dose can be applied to patients of all ages. to every two hours for a few more In cases of bacterial keratitis or a days, then to four times a day for a severe bacterial conjunctivitis, Poly- few more days. Depending upon the sporin ointment can be especially use- severity and character of the infec- ful at night for sustained antibacterial tious process, we may adjunctively coverage. prescribe Polysporin or Neosporin Neosporin. This triple-antibiotic of ointment at bedtime. Practically neomycin, bacitracin and polymyxin speaking, Besivance is a white vis- B is conveniently available generi- cous drop that can bother some pa- cally as an ophthalmic ointment and tients, so patients should be advised solution (the solution contains grami- of its consistency. cidin, not bacitracin). We rarely use An infected, tender LUL of four Ciprofloxacin. Ciloxan, a sec- Neosporin in eye drop form due to days’ duration. Cephalexin (Keflex) ond-generation fluoroquinolone, re- the aforementioned potential type IV 500mg BID was prescribed along with mains a drug of choice against the hypersensitivity reaction in some pa- aggressive use of warm soaks. gram-negative Pseudomonas species, tients. Alternatively, we prefer generic and remains close in efficacy to the

50 REVIEW OF OPTOMETRY MAY 15, 2018

048_dg0518_Antibiotics.indd 50 5/11/18 12:51 PM as two double-strength tablets BID for one week, which is the standard, commonly prescribed dosage. If the patient is truly allergic to penicillin and sulfa, consider oral doxycycline 100mg BID for one week, or the oral fluoroquinolone le- vofloxacin 500mg once daily for one week. For perspective, the risk of a cross-sensitivity reaction of a cepha- losporin in a patient truly allergic to penicillin is about 0.1%—but why fourth-generation fluoroquinolones. deolum) to long-term or maintenance ever take the miniscule risk? Just pre- Note that generic forms of the drug therapy (for meibomian gland disease scribe an alternative class. can be less expensive for the patient. and rosacea blepharitis). As well, the extremely rare occur- Moxifloxacin. Two popular For an acute internal hordeola, we rence of tendonitis or tendon rupture fourth-generation fluoroquinolones— prefer the first-generation cephalo- associated with oral fluoroquinolone topical moxifloxacin 0.5% available sporin, cephalexin (Keflex), at 500mg use makes this class our last option. as Moxeza (Novartis) and Vigamox BID for one week. If the condition is Occasionally, we encounter pa- (Novartis)—function similarly. Of severe and/or the patient is large in tients who need antibiotic treatment clinical note, Vigamox and Moxeza size, 500mg QID for one week may for chronic care conditions such as are the only preservative-free oph- be indicated. This predominantly meibomian gland disease or rosacea thalmic fluoroquinolone antibiotics, gram-positive antibiotic, along with blepharitis. We prescribe doxycycline thus minimizing the potential for a warm soaks, has been shown to at 50mg daily for three to six months. toxic or allergic response (although improve acute hordeola in about a The dichotomous nature of doxycy- such is exceedingly rare). Patients week. We may also prescribe generic cline (anti-infective at high dosage should be informed that the drop has Maxitrol ointment at night to the lid and anti-inflammatory at low dos- a slight yellow color, to avoid the margins to use after warm compress- age) requires customized dosing. misconception that it has gone bad. es and lid scrubs. This will be covered Though doxycycline hyclate and Ofloxacin. A second-generation in the combination drug section. doxycycline monohydrate are well- fluoroquinolone, ofloxacin is rarely Patients tend to have allergies to tolerated, the monohydrate form ap- used. However, because the drug is antibiotics more than other classes of pears to be a bit better tolerated. DG generic, it remains a reasonable, inex- drugs. Always take a careful medical 1. Centers for Disease Control and Prevention. An- pensive option for bacterial conjunc- history to avoid the risk of an allergic tibiotic Resistance Threats in the United States, tivitis. It is also available as brand- reaction. If a patient has had a true 2013. Available at: https://www.cdc.gov/drugre- sistance/threat-report-2013/ (last accessed March name Ocuflox (Allergan). anaphylactic reaction to penicillin or 14, 2018). Gatifloxacin. A fairly effective penicillin-like drugs such as cephalo- 2. Asbell PA, Sanfilippo CM, Pillar CM, et al. Anti- biotic resistance among ocular pathogens in the fourth-generation fluoroquinolone, sporins, we opt for Levaquin (500mg United States: Five-Year results from the antibiotic resistance monitoring in ocular microorganisms Zymaxid is FDA-approved to treat QD) or doxycycline (200mg QD), or (ARMOR) surveillance study. JAMA Ophthalmol. bacterial conjunctivitis. While useful Bactrim DS or Septra DS (both com- 2015 Dec;133(12):1445-54. 3. Mah FS, Sanfilippo CM. Besifloxacin: Efficacy and and generically available, fourth-gen- mon brand names of trimethoprim safety in treatment and prevention of ocular bacte- eration fluoroquinolones are exhib- with sulfamethoxazole) prescribed rial infections. Ophthalmol Ther. 2016 Jun; 5(1):1-20. iting increasing bacterial resistance.

SYSTEMIC AGENTS Oral antibiotics remain wonderful options when used judiciously in patient care. Their clinical indica- tions are vast, and can be used in short-term therapy (such as for internal hor-

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