TOPICS. Does Formulation Matter? Formulation and Potential adverse events

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1 A CONTINUING MEDICAL EDUCATION PUBLICATION CME CONTINUING MEDICAL EDUCATION DECEMBER 2014 ISSUE 52 INOcular TOPICS Antiinfectives Does Formulation Matter? Formulation and Potential adverse events John D. Sheppard, MD Advanced formulations of topical ocular medications reduce dosing frequency and improve consistency of drug delivery to the ocular surface. But do thicker agents compromise postsurgical healing? Selecting antibiotics and other medications for perisurgical use goes beyond choosing the most appropriate active molecule. So called inactive ingredients in topical ocular medications can influence nearly every aspect of drug performance, including safety, tolerability, dosing, product quality, and overall patient experience. 1 In addition, inactive ingredients can have a direct bearing on drug efficacy, as drug action depends upon the duration and reliability of active ingredient delivery to tissues. 2 how Generics Cut Corners Nowhere is the importance of inactive ingredients more evident than in the clinical experience of performance differences between proprietary vs. generic drugs. As is well known, bioequivalence of active ingredients is the principal requirement for developing and marketing generic drugs that will compete with a proprietary formulation with an expiring patent. Inactive ingredients, on the other hand, are not subject to the same level of FDA scrutiny. There is no requirement that inactive ingredients be the same as in the original drug, so long as the generic compound can be shown to be stable in its new formulation. Furthermore, no government mandate exists for clinical proof of safety and efficacy of generic formulations; the highly empirical expectation is that they will perform similarly to the branded version. 3 Inactive ingredients may vary from one formulation to the next and differ from the original branded version of the drug. 4 Manufacturers of generic formulations are well aware that prescribers, pharmacists, and patients rarely consider inactive ingredients or preservative content, giving the generic manufacturers an opportunity to select different drug delivery vehicles if doing so translates into economic savings for them or patients. The tradeoff, however, can be substantial. For example, one branded formulation of topical prednisolone acetate 1% contains smaller, more uniform suspension particles providing more reliable drug delivery compared with some generic formulations of the same drug, which use larger, more variably sized suspension particles. 5 Although branded and generic topical ocular products contain similar concentrations of active ingredient, and dosing instructions are identical, the amount of drug delivered to the ocular surface, and hence efficacy, may differ. In clinical see inside for: current strategies for Managing ocular adenovirus infection by Shachar Tauber, MD target audience this educational activity is intended for ophthalmologists and ophthalmologists in residency or fellowship training. LearninG objectives upon completion of this activity, participants will be able to: 1. describe the ways in which generic drugs can differ from their branded predecessor and discuss possible clinical consequences of those differences. 2. State the advantages and potential downsides of high viscosity agents used to prolong the on-eye residence time of topical ophthalmic drugs. 3. Articulate a protocol for isolating, diagnosing, and managing patients with ocular adenovirus infection. EdItORS nisha acharya, md, ms, is associate professor and director of the Ocular Inflammatory disease and uveitis Clinic at the university of California, San Francisco. natalie afshari, md, FaCs, is professor of ophthalmology and chief of cornea and refractive surgery at Shiley Eye Center, university of California San diego. marguerite B. mcdonald, md, FaCs, is clinical professor of ophthalmology at New York university, New York, and adjunct clinical professor of ophthalmology at tulane university School of medicine, New Orleans, louisiana. Topics in Ocular Antiinfectives is jointly sponsored by Candeo Clinical/Science Communications, llc, and the university of Florida College of medicine. this publication is administered by an independent editorial board and supported by an unrestricted educational grant from Bausch + lomb, Inc. Copyright 2014 Candeo Clinical/Science Communications, llc. All rights reserved. Neither the university of Florida nor Candeo Clinical/Science Communications, llc, assume any responsibility for injury or damage to persons or property arising from the use of information or ideas contained in this publication. COuRSE director anup KuBaL, md university of Florida Gainesville, Fl, usa Supported by an unrestricted educational Topics in grant ocular from antiinfectives Bausch + Lomb, Inc. 1

2 practice, anecdotal accounts abound of patients experiencing flare-ups of ocular surface inflammation when they are deliberately switched by a pharmacist usually unbeknownst to the prescribing clinician from branded to generic prednisolone acetate. Likewise, switching from branded to generic within any drug class antiinfective, antiinflammatory, or combination agent may interfere with therapeutic success and/or patient tolerability due to variations unrelated to the active ingredient. For example, generic formulations of topical ophthalmic aminoglycosides, such as tobramycin and gentamycin, may have fewer ph-stabilizing and surface-soothing components in the vehicle, making them less comfortable to patients. Combination agents Several proprietary formulations of aminoglycoside/corticosteroid combination agents are available including branded formulations of tobramycin with dexamethasone and tobramycin with loteprednol etabonate that offer distinct advantages over generic aminoglycoside/ corticosteroid combinations. The branded ophthalmic combination of tobramycin 0.3%/dexamethasone 0.05%, for example, has a viscosity agent (xanthan gum) in the vehicle, which endows it with greater ocular surface viscosity than its generic competitors. The viscosity agent enabled developers to reduce the concentration of corticosteroid in the preparation while increasing antibiotic levels in tears, thereby increasing bactericidal action on the cornea and conjunctiva. 6 Another antibiotic/corticosteroid combination, the branded drug that combines tobramycin 0.3% with loteprednol etabonate 0.5%, has no currently available generic substitute. However, that fact doesn t preclude attempts at substitution with other tobramycin/ corticosteroid combination agents, even though loteprednol is associated with a lower risk of intraocular pressure elevation compared to many other corticosteroids. 7 Generic substitutions for this drug must involve changing a main ingredient, which can reduce safety. Formulations trends A longer dosing interval is a valued feature and a major trend in both topical and systemic drug development. Increasing formulation viscosity reduces dosing topics in ocular antiinfectives, issue 52 statement of need Ophthalmologists face numerous challenges in optimizing their competencies and clinical practices in the realm of preventing, diagnosing, and treating ocular infections and their sequelae; these challenges include: The widespread off-label use of topical ophthalmic antibiotics to prevent and treat serious and sight-threatening infections given the reality that the most widely used topical antibiotics in ophthalmology have FDA approvals restricted to bacterial conjunctivitis. The escalating levels of multi-drug resistance in common ocular pathogens. 1 The emergence and increasing prevalence of once-atypical infections that may require diagnostic and treatment techniques relatively unfamiliar to comprehensive ophthalmologists. 2 The introduction of new and potentially more efficacious and/or safe ophthalmic antiinfectives. 3 The introduction of new and potentially more accurate diagnostic techniques for ophthalmic infections. 4 Widespread discussion over the efficacy and safety of novel or alternative delivery techniques and vehicles for prophylactic ophthalmic antibiotics (including but not limited to intracameral injection and topical mucoadhesives). 5,6 Increased understanding of the inflammatory damage caused by ocular infections and the best ways to prevent/ alleviate inflammation without fueling the growth of pathogenic organisms. Given the continually evolving challenges described above, Topics in Ocular Antiinfectives aims to help ophthalmologists update outdated competencies and narrow gaps between actual and optimal clinical practices. As an ongoing resource, this series will support evidence-based and rational antiinfective choices across a range of ophthalmic clinical situations. references 1. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol Jun;145(6): Gower EW, Keay LJ, Oechsler RA, et al. Trends in fungal keratitis in the United States, 2001 to Ophthalmology Dec;117(12): Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Virgan 0.15%) in the treatment of herpes simplex keratitis. Cornea. 1997;16: Sambursky R, Tauber S, Schirra F, et al. The RPS adeno detector for diagnosing adenoviral conjunctivitis. Ophthalmology. 2006;113(10): Akpek EK, Vittitow J, Verhoeven RS, et al. Ocular surface distribution and pharmacokinetics of a novel ophthalmic 1% azithromycin formulation. J Ocul Pharmacol Ther. 2009;25: Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33(6): off-label use statement This work discusses offlabel uses of antiinfective medications. GeneraL information This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Bausch + Lomb, Inc. Directions: Select one answer to each question in the exam (questions 1 10) and in the evaluation (questions 11 16). The University of Florida College of Medicine designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit. There is no fee to participate in this activity. In order to receive CME credit, participants should read the report, and then take the posttest. A score of 80% is required to qualify for CME credit. Estimated time to complete the activity is 60 minutes. On completion, tear out or photocopy the answer sheet and send it to: University of Florida CME Office PO Box , Gainesville, FL phone: fax: Or you can take the test online at System requirements for this activity are: For PC users: Windows 2000, XP, 2003 Server, or Vista; Internet Explorer 6.0 or newer, or Mozilla Firefox 2.0 or newer ( JavaScript and Java enabled). For Mac users: Mac OS X 10.4 (Tiger ) or newer; Safari 3.0 or newer, Mozilla Firefox 2.0 or newer; ( JavaScript and Java enabled). Internet connection required: Cable modem, DSL, or better. Date of original release December Approved for a period of 12 months. accreditation statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Florida College of Medicine and Candeo Clinical/Science Communications, LLC. The University of Florida College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. CreDit DesiGnation statement The University of Florida College of Medicine designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. FaCuLtY and DisCLosure statements Nisha Acharya, MD, MS (Faculty Advisor), is associate professor and director of the Ocular Inflammatory Disease and Uveitis Clinic at the University of California, San Francisco. She states that in the past 12 months, she has not had a financial relationship with any commercial organization that produces, markets, re-sells, or distributes healthcare goods or services consumed by or used on patients. Natalie Afshari MD, FACS (Faculty Advisor), is professor of ophthalmology and chief of cornea and refractive surgery at Shiley Eye Center, University of California San Diego. She states that in the past 12 months, she has not had a financial relationship with any commercial organization that produces, markets, re-sells, or distributes healthcare goods or services consumed by or used on patients. Marguerite B. McDonald, MD, FACS (Faculty Advisor), is a clinical professor of ophthalmology at New York University, New York, NY, and an adjunct clinical professor of ophthalmology at Tulane University School of Medicine, New Orleans, LA. She states that in the past 12 months she has been a consultant for Abbott Medical Optics, Alcon Laboratories, Allergan, Bausch + Lomb, Fera Pharmaceuticals, Focus Laboratories, OcuSoft, TearLab, and Topcon. John D. Sheppard, MD, is president of Virginia Eye Consultants and professor of ophthalmology, microbiology, and molecular biology at Eastern Virginia Medical School in Norfolk. He is also ophthalmology residency program research director, clinical director for the Thomas Lee Center for Ocular Pharmacology and medical director of Lions Eye Bank of Eastern Virginia. Dr. Sheppard is or has recently been an advisor to and/or speaker for Alcon, Aldexa Pharmaceuticals, Allergan, Bausch & Lomb, EyeGate Research, Imprimis Pharma, Isis Pharmaceuticals, Kala Pharmaceuticals, Lacrisciences, NiCox, Omeros, Pfizer, Santen, and Shire. Shachar Tauber, MD, is a corneal and refractive surgeon and director of ophthalmic research at Mercy Medical Center, Springfield, MO. He is a consultant for Allergan and Bausch + Lomb. DisCLaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and professional development. The information presented in this activity is not meant to serve as a guideline for patient care. Procedures, medications, and other courses of diagnosis and treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients conditions and possible contraindications or dangers in use, applicable manufacturer s product information, and comparison with recommendations of other authorities. CommerCiaL supporters This activity is supported by an unrestricted educational grant from Bausch + Lomb, Inc. 2 Topics in ocular antiinfectives

3 frequency by prolonging contact time of the active ingredient on the ocular surface. Longer ocular surface residence not only improves convenience and compliance by reducing the number of doses needed per day but also improves effectiveness by providing more consistent drug distribution on the ocular surface over time. Furthermore, taking fewer doses per day can lower potential drug-related toxicity, as well as adverse effects associated with preservatives or other inactive medication components. One strategy for prolonging drug contact time on the ocular surface is to use more viscous gel vehicles in place of more rapidly eliminated aqueous solutions or suspensions. 8,9 Topical ganciclovir gel 0.15% is a significant advance over traditionally prescribed trifluridine solution in the treatment of herpetic keratoconjunctivitis for many reasons. First the superior bioavailability afforded by gel formulation markedly reduces dosing frequency. Secondly, the medication does not require refrigeration. Third the more selective mechanism of action and reduced surface toxicity associated with the principal ingredient, ganciclovir is less irritating to epithelial cells already compromised by herpetic infection. 10 Finally, the thimerisol in trifluridine preparations is the most toxic preservative still marketed today, while ganciclovir gel utilizes a low % concentration of BAK (benzalkonium chloride). In fact, trifluridine is the only medication currently available in the United States with this preservative. Advanced formulations may also contain lower concentrations of preservatives, a factor that reduces ocular surface toxicity. For example, the corticosteroid agent loteprednol etabonate ophthalmic gel 0.5% is formulated with 0.003% benzalkonium chloride, a fraction of the concentration in the previous suspension formulation of the same drug (0.01%). 11,12 Even though the gel and suspension formulations contain the same concentration of main ingredient and are both labeled for dosing four times daily, in my experience the gel formulation can be used less frequently without compromising efficacy. unit-dose Formulations Another growing trend involves packaging ophthalmic medications in unit-dose aliquots without preservatives, as has been done with one formulation of the topical nonsteroidal antiinflammatory agent ketorolac tromethamine and various nonpreserved artificial tear preparations. 13 Reducing preservative content in topical ophthalmic agents should improve tolerability and ocular surface safety for patients. 4 As noted, high viscosity sustained delivery systems can prolong ocular surface residence time of the active agent. 8 One such sustained-delivery macromolecular system is a proprietary combination of polycarbophil, edetate disodium, and sodium chloride that is a component in an increasing number of ophthalmic agents, including two ocular antibiotic formulations: azithromycin 1% and besifloxacin ophthalmic suspension 0.6% In the case of the azithromycin formulation, this vehicle allows for just once-daily dosing, following twice-daily induction. 15 safety alert regarding advanced Formulations But these viscous formulations may have a downside. In 2013, the ASCRS Cornea and Refractive Surgery Clinical Committees issued a safety alert around perisurgical and intraoperative use of topical ocular formulations that contain advanced vehicles. 17 Th e c o m - mittee cited case reports of adverse events flap slippage and/or diffuse lamellar keratitis following LASIK and impaired epithelial healing following PRK that were thought to be related to viscous topical agents. In the LASIK cases, the problem seemed related to placement of advanced vehicle antibiotic and anti-inflammatory agents on the bare stroma before repositioning of the LASIK flap. The PRK cases involved the placement of these agents on a bare stromal bed under a bandage contact lens. A consistent feature of these adverse events was placement of agents with advanced vehicles immediately prior to or during LASIK or PRK surgeries. Problems with such agents following surgery have not been reported. As with any formal alert regarding rare but potentially serious consequences core concepts inactive ingredients in topical ocular medications can influence safety, tolerability, efficacy, and bioavailability. although they have the same concentration of active agent, generic drugs may be formulated differently from their proprietary precursors. Gels and sustained release delivery vehicles prolong ocular surface residence of the active agent and may improve drug potency. reports of adverse events related to topical agents with advanced formulations used immediately preoperatively or intraoperatively in patients undergoing LasiK or PrK resulted in an alert from the ascrs in Postoperative use of these agents has not been reported to increase risk for adverse events. of medication use for untested indications, we have to regard it in earnest. However, it is also important to judge potential risks in the context of the benefit offered by the intervention as well as in the context of our own body of clinical experience. We should recognize that placing any agent in the interface of a surgical wound may alter tissue adhesion, wound edge juxtaposition, and overall healing dynamics. I share the committee s concern for placing sustained release agents under a LASIK flap. This practice is not recommended until more objective data is available. relevance to other surgery types A LASIK flap is inherently unstable; it has a wide interface that, until reepithelialization, relies on an osmotic pressure gradient to remain in place. Minimal manipulation can disrupt this critical anatomical re-approximation. The ASCRS committee s cautionary words regarding perisurgical use of viscous topical agents under a LASIK Topics in ocular antiinfectives 3

4 flap should not however, in my view, be extrapolated to other forms of surgical wounds that are more stable. By contrast, the cataract wound, which is small and fashioned at the limbus, has very good stability. Furthermore, wound-edge approximation can be rendered even stronger by hydration. Topical medications used in a typical cataract surgery case can be thought of as guarding the entry point to the wound rather than as covering an actively healing interface. As a second example, the biggest wound in all of ophthalmologic surgery the full-thickness corneal transplant wound is stabilized by sutures; in my view, there is no reason or clinical evidence to believe that transplant wound healing is compromised by appropriate use of high-viscosity topical agents. I have personally performed thousands of successful and uncomplicated surgeries, including cataract extractions, full thickness corneal transplants, endothelial keratoplasties, lamellar keratectomies, ocular surface reconstructions, and pterygium excisions with conjunctival autografts utilizing adjunctive topical agents with modern viscous vehicles. Conclusion Inactive ingredients in topical ocular drug formulations can exert a major influence on drug efficacy, tolerability, toxicity and patient experience. Increasing drug viscosity improves drug pharmacokinetics and thereby patient compliance. However, reports of issues with perisurgical use of these agents underscore a need for caution in some specific circumstances until objective randomized clinical trials better characterize these potential risks. John D. Sheppard, MD, is president of Virginia Eye Consultants and professor of ophthalmology, microbiology, and molecular biology at Eastern Virginia Medical School in Norfolk. He is also ophthalmology residency program research director, clinical director for the Thomas Lee Center for Ocular Pharmacology and medical director of Lions Eye Bank of Eastern Virginia. Dr. Sheppard is or has recently been an advisor to and/or speaker for Alcon, Aldexa Pharmaceuticals, Allergan, Bausch & Lomb, EyeGate Research, Imprimis Pharma, Isis Pharmaceuticals, Kala Pharmaceuticals, Lacrisciences, NiCox, Omeros, Pfizer, Santen, and Shire. Medical writer Noelle Lake, MD, assisted with the preparation of this article. REFERENCES 1. Januleviciene I, Siaudvytyte L, Barsauskaite R. Ophthalmic drug delivery in glaucoma-a review. Pharmaceutics. 2012;4: O Brien TP. Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. A d v Th e r. 2012;29: FDA website: FDA ensures equivalence of generic drugs. Available at: gov/drugs/emergencypreparedness/bioterrorismanddrugpreparedness/ucm htm. Accessed on September 8, Review of Ophthalmology. Topical ophthalmic generics: they re back. Available at: i/1203/c/22694/ Accessed September 9, Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther 2007;23: Scoper SV, Kabat AG, Owen GR, et al. Ocular distribution, bactericidal activity and settling characteristics of TobraDex ST ophthalmic suspension compared with TobraDex ophthalmic suspension. A d vth e r.2008;25: Comstock TL, Holland EJ. Loteprednol and tobramycin in combination: a review of their impact on current treatment regimens. Expert Opin Pharmacother. 2010:11: Budai L, Hajdu M, Budai M, et al. Gels and liposomes in optimized ocular drug delivery: studies on ciprofloxacin formulations. Int J Pharmaceutics. 2007; Zhu H, Chauhan A. Effect of viscosity on tear drainage and ocular residence time. Optom Vis Sci. 2008;85(8): Chou TY, Hong BY. Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, tolerability, safety, and future applications. Th e r Clin Risk Manag. 2014;10: Lotemax gel [prescribing information]. Tampa, FL: Bausch and Lomb; Lotemax suspension [prescribing information]. Tampa, FL: Bausch and Lomb; Acuvail [prescribing information]. Irvine, CA: Allergan; Insite website. Durasite compound advantage. Available at: durasite. Accessed September 9, Azasite [prescribing information]. Whitehouse Station, NJ. Merck & Co, Inc.; Besivance [prescribing information]. Tampa, FL: Bausch and Lomb; ASCRS issues medication alert for LASIK and PRK. Available at: crstoday/2013/03/article.asp?f=ascrs-issuesmedication-alert-for-lasik-and-prk. Accessed August, 19, current strategies for Managing ocular adenovirus infection Shachar Tauber, MD Ocular adenovirus infection can cause signif icant discomfort and loss of productivity. There are, however, a number of promising new approaches to diagnosis and management of the condition. Adenoviruses are responsible for a significant proportion possibly the majority of acute infectious conjunctivitis cases. 1,2 There is a long list of infectious adenovirus serotypes, and this diversity of serotypes is mirrored in the range of ophthalmic presentations, which run the gamut from relatively mild follicular conjunctivitis, to pharyngoconjunctival fever, to epidemic keratoconjunctivitis (EKC), the most severe and most contagious form. With so many adenovirus serotypes, the prevalence of antibody to any given one is low and so the level of immunity is limited. 3,4 Adenoviruses are also remarkably hardy and can survive in a desiccated state on hard surfaces for over a month. 5 Common disinfectants like 70% isopropyl alcohol or 3% hydrogen peroxide may not completely inactivate highly contagious serotypes on hard surfaces and ophthalmic instruments. 6 These viruses diversity and transmissibility combined with the challenges of accurate clinical diagnosis have made adenovirus conjunctivitis 4 Topics in ocular antiinfectives

5 therapies difficult to develop and deploy. But as an in-office adenovirus test gains traction in eyecare clinics and primary care settings (where the majority of acute red eyes present fi rst), diagnosis and infection control processes are improving; and therapies that speed symptom resolution and shorten the period of infectivity are under investigation. 2,7 importance of Diagnostic accuracy The prompt and accurate diagnosis of ocular adenovirus infection can be important for the patient, the treatment team, and the unsuspecting individuals who will come in contact with the patient. Although adenovirus conjunctivitis is most often self-limiting, patients find even mild cases unpleasant; and the need to limit human contact while contagious can significantly disrupt their routines. But determining whether any given case of conjunctivitis is viral or bacterial isn t easy. The etiology of acute conjunctivitis is typically determined from clinical signs and symptoms, many of which are nonspecific. The overlapping appearances of allergic, bacterial, and viral conjunctivitides challenge diagnosis even among corneal/external disease experts. 8,9 Confirming the diagnosis of adenovirus infection has a number of benefits. It rules out other, potentially visionthreatening diagnoses, such as ocular herpes, uveitis, or acute angle closure glaucoma. And a correct diagnosis informs treatment: limiting, for example, the ineffective (and costly) use of topical antibiotics. Finally, a clear diagnosis of adenovirus infection enables clinical staff to take appropriate measures to protect themselves and subsequent patients. ocular adenovirus: morbidity Ocular adenovirus infections can be associated with significant pain and discomfort, photophobia, and the development of pseudomembranes, subconjunctival hemorrhages, or subepithelial infiltrates. These infiltrates, the result of immune reaction, can increase photophobia, reduce visual acuity, and last for weeks or months, with the potential to flare up years after initial onset. Scarring of the conjunctiva, cornea, eyelids, and, more rarely, the lacrimal duct can also occur as a result of adenovirus infection; and consequent symblepharon or persistent corneal epithelial defect can leave a wake of long-lasting dry eye symptoms. 2 Differential Diagnosis I often speak to pediatricians and urgent and primary care physicians about the diagnosis and management of the acute red eye. In these talks I emphasize the importance of asking about severe pain or vision loss to rule out serious, vision-threatening conditions like angle closure glaucoma or uveitis. The clinical characteristics of adenovirus conjunctivitis include unilateral or bilateral hyperemia, serous discharge, and a follicular response visible on the inferior tarsal conjunctiva. Eyelid edema and swelling of the preauricular lymph node (particularly on the side of the first eye affected) may also be present. Ultimately, however, redness, discharge, burning and itching, and even follicles and lymphadenopathy, are signs that can occur in conjunctivitis of bacterial, herpes virus, or allergic origin. Misdiagnosis of acute conjunctivitis, particularly in its early stages, occurs frequently and can be responsible for unnecessary prescriptions and/or lost productivity. 2 in-office testing This makes the availability of a rapid test with 93% sensitivity and 98% specificity for the presence of ocular adenovirus antigen in tears a true boon. 10 My colleagues and I were involved in the original multicenter clinical studies to evaluate this test, but its value is not limited to the ophthalmology clinic it is useful in all of the primary care settings from which we receive red eye referrals. The test functions best as part of a rigorous protocol in which all staff participate. Ideally, the practice can set aside an isolation room relatively free of core concepts accurate and timely diagnosis of ocular adenovirus infection is important for affected patients and their families, as well as for healthcare practices and the community at large. Because the acute red eye poses a significant diagnostic challenge, a quick, in-office test for ocular adenovirus infection makes diagnosis more straightforward and allows for better management. whether in a primary care, urgent care, or eyecare setting, the adenovirus test should be part of a rigorous protocol that includes patient isolation and thorough disinfection of surfaces. adenovirus conjunctivitis is most often self-limited, but corneal infiltrates, conjunctival scarring, and other sequelae can develop and affect patients for long periods. agents that may be used off-label for shortening the course and reducing the symptoms of adenoviral infection include ganciclovir gel 0.15%, dilute povidone iodine (alone or in combination with corticosteroid), and cyclosporine 0.05%. if approved, n-ndichlorodimethyltaurine may be an effective agent for the treatment of ocular adenovirus infection. nooks, crannies, and extra equipment. Staff should be trained to flag acute (especially a bilateral) red eye patients, and a technician should be made responsible for isolating each such patient, taking vitals, and administering the adenovirus test. After 10 minutes, the clinician can review the result and instruct and treat the patient accordingly. Topics in ocular antiinfectives 5

6 If the adenovirus test is positive, the patient should remain in the isolation room, with any necessary paperwork brought in, given treatment options (at the very least, preservative-free artificial tears for comfort), and instructed about the urgent need for infection control. If the test is negative and the presentation suggests a bacterial infection, the patient can be prescribed a broad-spectrum topical antibiotic and permitted to return to work or school. The designated red-eye isolation room must be equipped with a disinfectant able to meet the challenge posed by the hardy adenovirus, such as 10% bleach, 70% ethyl alcohol, or glutaraldehyde (2.4% or 2.65%); there should be a sign on the door to indicate when the room is contaminated or being cleaned. 6 Employing disposable tonometer tips and other single-use devices in this setting is ideal. We have been involved in teaching the clinics in our network and community how to deal with the acute red eye and have asked them to perform the adenovirus test prior to referring a red eye patient to us. By administering the test and taking appropriate infection control precautions, these clinics help limit the spread of contagion and reduce the burden of cost from misdiagnosis. I would encourage any multicenter group or referral network to implement a similar plan. infection Control Guidance Patients with an ocular adenovirus infection may feel concerned and even guilty about unwittingly contaminating their family, coworkers, or members of their community. So clear instruction about how to protect others from infection is critical; and the most important step in that is strict hand washing. We tell patients that as long as there is discharge from their eyes, they are contagious and they should plan ahead for childcare, work, and other obligations. Patients and practice staff alike should be made to appreciate that, while adenovirus infection is typically not life- or vision-threatening, it is significantly debilitating while it lasts and is a legitimate public safety concern. treatment Challenge An effective treatment for ocular adenovirus infection has long been sought. Ideally, the treatment would decrease associated redness, tearing, and photophobia, shorten the period of infectivity, and reduce the potential for inflammatory sequelae such as corneal infiltrates. But developing an antiviral with activity against the many and often genetically divergent serotypes of these hardy viruses has been challenging: Human adenoviruses often do not survive in animal models, and adenoviruses do not encode the nucleotide-modifying enzymes (such as thymidine kinase) that activate current ophthalmic antiherpetic agents. 4 Beyond the difficultly of engineering a suitable agent, the necessary clinical studies are challenging to conduct and slow to enroll; and the return on investment for a treatment to manage a self-limiting condition may not be attractive to pharmaceutical companies. Still, some promising therapies are under investigation. Povidone iodine and/or Corticosteroid The disinfectant povidone iodine has been studied and used in the treatment of infectious conjunctivitis. In vitro work suggests that dilute povidone iodine is effective against free adenovirus particles in tears but not against virus within infected cells. 11 In a study of 459 children with infectious conjunctivitis, 1.25% povidone iodine administered four times daily was found comparable to antibiotic therapy in eyes with bacterial conjunctivitis, but it was not effective for viral conjunctivitis. 12 Studies of 2% and 5% povidone iodine in adults with EKC have been conducted and are ongoing (clinicaltrials. gov NCT ). While povidone iodine is safe, it is extremely uncomfortable for patients. Preliminary research combining lower concentrations (0.4%) of this potent antiseptic with the corticosteroid dexamethasone (0.1%) shows some promise. In one small pilot study of adenovirus conjunctivitis, eight out of nine eyes enrolled showed clinical resolution of conjunctival injection and discharge by day In six of these eyes, adenovirus detected by quantitative polymerase chain reaction was significantly reduced by day 5. Larger, randomized studies examining the effect of different concentrations of each agent are warranted. Corticosteroids have the advantage of offering some relief from symptoms and inflammation in adenovirus conjunctivitis, but their use is controversial (they may prolong adenovirus shedding) and underscores the critical importance of a reliable adenovirus diagnosis, as corticosteroids can exacerbate herpetic or certain bacterial infections. 7 Ganciclovir A promising option, and one I offer to my patients, is ganciclovir ophthalmic gel 0.15%, an antiviral indicated for the treatment of herpetic keratitis. (This use of ganciclovir gel is off label in the US.) Ganciclovir has been shown to inhibit certain adenovirus serotypes (including those commonly associated with EKC) in cell culture; and small studies and case reports indicate that ganciclovir gel may improve symptoms and shorten the course of ocular adenovirus infection My personal experience using ganciclovir gel to treat ocular adenovirus infection has been very positive (albeit this is only anecdotal evidence). Resolution of symptoms and signs often occurs in 3 to 5 days with treatment, vs. 7 to 10 days on artificial tears alone. Unlike povidone iodine, ganciclovir gel is comfortable for patients. It is still uncertain to what degree the period of infectivity is reduced, but it is possible that we may be able to send patients back to school and work sooner than we can now. Cyclosporine Several studies have looked at topical cyclosporine (in varying concentrations from 0.05% to 2%) for the treat- 6 Topics in ocular antiinfectives

7 ment of adenovirus keratoconjunctivitis, with some positive findings of symptom relief in the acute phase and reduction of subepithelial infiltrates and associated vision loss in patients who responded poorly to corticosteroid therapy. 17,18 Considering the risks associated with corticosteroid use in adenovirus keratoconjunctivitis, cyclosporine represents a potentially useful adjunct, and I have had good experience with it. In a rabbit model of ocular adenovirus infection, the use of topical cyclosporine (2% or 0.5%) significantly reduced the development of subepithelial infiltrates, but increased and prolonged viral shedding. 19 Although it is not certain whether initiation of cyclosporine therapy during the acute phase of adenovirus infection has a preventive effect with regard to the development of subepithelial infiltrates in humans, my anecdotal experience in this application has been positive, and the side effect profile of cyclosporine is favorable. our regimen Until recently, the typical care for patients with adenovirus conjunctivitis included, in addition to hygiene and isolation, chilled artificial tears, cold compresses, and perhaps an antihistamine or mast-cell stabilizing drop to decongest the eye. Having experienced ocular adenovirus twice myself one case of which was EKC that progressed to subepithelial infiltrates I empathize with these patients, and I am motivated to give them any relief I can. I offer ganciclovir gel 0.15%, dosed five times daily, and cyclosporine 0.05%, dosed four times daily, to all my patients with confirmed adenovirus infection. The key challenge with these off-label uses is cost and lack of insurance coverage; but when the option is presented as having the potential advantages of symptom relief, reduced infectivity, and reduced chance of long-term corneal sequelae, many patients accept this regimen. For those who do not, the standard regimen, including instruction to call us in the event of vision changes or sudden pain, is typically adequate. Looking ahead One agent from a novel class of drugs, the chlorotaurines, is currently showing great promise in the treatment of adenovirus ocular infection. 20,21 Th e chlorotaurines mimic an oxidizing mechanism employed by human leukocytes to kill pathogens and have been found effective against a broad range of viruses, bacteria, and fungi. The drug N-N-dichlorodimethyltaurine (auriclosene) has been shown to inhibit extracellular adenovirus in vitro, and was shown superior to its vehicle in a randomized, double-masked clinical trial (clinicaltrials.gov NCT ) of 81 ocular adenovirus patients. 21 And even at high concentrations, this drug is not cytotoxic. Its further study and REFERENCES 1. Sambursky RP, Fram N, Cohen EJ. The prevalence of adenoviral conjunctivitis at the Wills Eye Hospital Emergency Room. Optometry. 2007;78: O Brien TP, Jeng BH, McDonald M, et al. Acute conjunctivitis: truth and misconceptions. Curr Med Res Opin. 2009;25(8): Russell KL, Broderick MP, Franklin SE, et al. Transmission dynamics and prospective environmental sampling of adenovirus in a military recruit setting. J Infect Dis. 2006;194: Kinchington PR, Romanowski EG, Gordon YJ. Prospects for adenovirus antivirals. J Antimicrob Chemother. 2005;55: Kowalski RP, Romanowski EG, Waikhom B, et al. The survival of adenovirus in multidose bottles of topical fluorescein. Am J Ophthalmol. 1998;126: Rutala WA, Peacock JE, Gergen MF, et al. Efficacy of hospital germicides against adenovirus 8, a common cause of epidemic keratoconjunctivitis in health care facilities. Antimicrob Agents Chemother. 2006;50(4): Kaufman HE. Adenovirus advances: new diagnostic and therapeutic advances. Curr Opin Ophthalmol. 2011;22: Cheung D, Bremner J, Chan JTK. Epidemic keratoconjunctivitis do outbreaks have to be epidemic? Eye. 2003;17: Uchio E, Takeuchi S, Itoh N, et al. Clinical and epidemiological feature of acute follicular conjunctivitis with special reference to that caused by herpes simplex virus type 1. Br J Ophthalmol. 2000;84: Sambursky R, Trattler W, Tauber S, et al. Sensitivity and specificity of the AdenoPlus Test for diagnosing adenoviral conjunctivitis. JAMA Ophthalmol. 2013;131(1): Monnerat N, Bossart W, Thiel MA. Povidoneiodine for treatment of adenoviral conjunctivitis: an in vitro study. Klin Monbl Augenheilkd. development will be watched eagerly. In addition to the promise of these investigational treatments, I am encouraged to see the more widespread adoption of in-office testing for adenovirus conjunctivitis. Noting the impact this test is already having in our multicenter group, I predict that primary care physicians and large employers will increasingly be motivated to deploy this test to limit both costly outbreaks and unnecessary absence from work by noninfected patients. Shachar Tauber, MD, is a corneal and refractive surgeon and director of ophthalmic research at Mercy Medical Center, Springfield, MO. He is a consultant for Allergan and Bausch + Lomb. Managing editor Jennifer Zweibel assisted in the preparation of this article. 2006;223(5): Isenberg SJ, Apt L, Valenton M, et al. A controlled trial of povidone-iodine to treat infectious conjunctivitis in children. Am J Ophthalmol. 2002;134(5): Pelletier JS, Stewart K, Trattler W, et al. Combination povidone-iodine 0.4%/dexamethasone 0.1% ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv Th e r. 2009;26(8): Huang J, Kadonosono K, Uchio E. Antiadenoviral effects of ganciclovir in types inducing keratoconjunctivitis by quantitative polymerase chain reaction methods. Clin Ophthalmol. 2014;8: Tabbara KF. Ganciclovir effects in adenoviral keratoconjunctivitis. Poster B253. Association for Research in Vision and Ophthalmology. Fort Lauderdale, FL; Affeldt J, Gadaria-Rathod N, Fernandez KB, et al. Ganciclovir in the treatment of ophthalmic viral infections case reports. US Ophthalmic Review. 2012;5(2): Hillenkamp J, Reinhard T, Ross RS. Topical treatment of acute adenoviral keratoconjunctivitis with 0.2% cidofovir and 1% cyclosporine. Arch Ophthalmol. 2001;119: Okumus S, Coskun E, Tatar MG, et al. Cyclosporine a 0.05% eye drops for the treatment of subepithelial infiltrates after epidemic keratoconjunctivitis. BMC Ophthalmol. 2012;12: Romanowski EG, Pless P, Yates KA, et al. Topical cyclosporine a inhibits subepithelial immune infi ltrates but also promotes viral shedding in experimental adenovirus models. Cornea. 2005;24(1): Nagl M, Larcher C, Gottardi W. Activity of N-chlorotaurine against herpes simplex and adenoviruses. Antiviral Res. 1998;38: Yoon J, Jekle A, Najafi R, et al. Virucidal mechanism of action of NVC-422, a novel antimicrobial for the treatment of adenoviral conjunctivitis. Antiviral Res. 2011;92: Topics in ocular antiinfectives 7

8 examination Questions Topics in Ocular Antiinfectives, Issue 52 This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted educational grant from Bausch + Lomb, Inc. Directions: Select the one best answer to each question in the exam (Questions 1 10) and in the evaluation (Questions 11 16) below by circling one letter for each answer. Participants must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University of Florida College of Medicine designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit. There is no fee to participate in this activity. You can take the test online at 1. Which of the following is a significant trend in the formulation of topical ophthalmic medications? A. Use of suspensions in place of solutions B. Use of solutions in place of suspensions C. Use of high viscosity polymeric vehicles to increase residence time D. All of the above 2. In comparing generic vs. branded drugs, which of the following aspects of the overall formulation must be bioequivalent? A. The active agent B. ph buffering agents C. The inactive ingredients D. Preservative 3. Which of the following is NOT a significant part of a protocol for controlling the spread ocular adenovirus infection in a healthcare practice? A. A dedicated isolation room B. 70% isopropyl alcohol wipes C. Staff training to identify a potentially infectious red eye D. In-office adenovirus test 4. The 2013 ASCRS alert regarding the use of topical medications with advanced vehicles was based, in part, upon which of the following? A. Case reports of postoperative Acanthamoeba infections associated with the use of preservative-free topical antibiotics B. Animal studies that showed corneal toxicity associated with polymeric lubricating agents C. Reports of LASIK flap issues when these drugs had been placed under the flap D. Reports of LASIK flap slippage with postoperative antimicrobial prophylaxis 5. Which of the following is NOT true of generic medications? A. They typically cost less than the branded version B. They need not have the same inactive ingredients as the branded version C. Generics require identical but smaller clinical trials than the branded original D. Differences between the generic and branded versions may cause patients to react differently 6. Povidone iodine: A. Inhibits adenovirus replication within infected cells B. Is too expensive for use in cases of adenovirus ocular infection C. Is soothing but ineffective against adenovirus D. Is effective against free adenovirus in tears 7. Which of the following is LEAST likely to be affected by inactive ingredients contained in topical ocular medications? A. Ocular surface residence time B. Drug store availability C. Tolerability D. Safety 8. The clinical characteristics of adenovirus conjunctivitis include all of the following EXCEPT: A. Serous discharge B. Severe eye pain and vision loss C. Hyperemia D. Follicular response on the inferior tarsal conjunctiva 9. In ocular adenovirus infection, topical corticosteroids may: A. Prolong virus shedding B. Increase the risk of corneal melting C. Exacerbate symptoms D. All of the above 10. Which of the following is a suitable disinfectant for use in adenovirus contamination? A. 70% isopropyl alcohol B. 3% hydrogen peroxide C. 10% bleach D. All of the above examination Answer Sheet Topics in Ocular Antiinfectives, Issue 52 This CME activity is jointly sponsored by the University of Florida and Candeo Clinical/Science Communications, LLC, and supported by an unrestricted educational grant from Bausch + Lomb, Inc. Mail to: University of Florida CME Office, PO Box , Gainesville, FL Directions: Select the one best answer for each question in the exam above (Questions 1 10). Participants must score at least 80% on the questions and complete the entire Evaluation (Questions 11 16) to receive CME credit. CME exam expires November 30, ANSWERS: 1. A B C D 2. A B C d 3. A B C D 4. A B C D 6. A B C D 7. A B C d 8. A B C D 9. A B C D evaluation: 1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding 11. Extent to which the activity met the identified: Objective 1: Objective 2: Objective 3: Rate the overall effectiveness of how the activity: Related to my practice: Will influence how I practice: Will help me improve patient care: Stimulated my intellectual curiosity: Overall quality of material: Overall met my expectations: Avoided commercial bias/influence: Will the information presented cause you to make any changes in your practice? Yes No 14. If yes, please describe: If you wish to receive credit for this activity, please fill in the following information. Retain a copy for your records. Please print clearly First NamE last name degree organization/institute Address line 1 Address line 2 CitY State Zip PHONE Fax 15. How committed are you to making these changes? A B C D 10. A B C D 16. Are future activities on this topic important to you? 8 Topics in ocular antiinfectives Yes No address