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 Infl ammatory disease and uveitis Clinic at the university of California, San Francisco.
nataLie aFshari, mD, FaCs, is professor of oph-thalmology 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 ophthal-mology 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 Communica-tions, 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 A CONTINUING MEDICAL EDUCATION PUBLICATION DECEMBER 2014 • ISSUE 52 CME CONTINU
ING MEDICAL EDUCA
TION
TOPICS
IN
Ocular
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 medica-tions can infl uence 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 effi cacy, 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 inac-tive ingredients more evident than in the clinical experience of performance
dif-ferences between proprietary vs. generic drugs. As is well known, bioequivalence of active ingredients is the principal requirement for developing and mar-keting 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. Th ere 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 man-date exists for clinical proof of safety and effi cacy 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 diff er from the original branded ver-sion 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 diff erent drug delivery vehicles if doing so translates into economic savings for them or patients.
Th e tradeoff , however, can be sub-stantial. For example, one branded formulation of topical prednisolone ac-etate 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 concentra-tions of active ingredient, and dosing instructions are identical, the amount of drug delivered to the ocular surface, and hence effi cacy, may diff er. In clinical
see insiDe for:
current strategies for Managing ocular adenovirus infection
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:
• Th e widespread “off -label” use of topical ophthalmic anti-biotics 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.
• Th e escalating levels of multi-drug resistance in common ocular pathogens.1
• Th e emergence and increasing prevalence of once-atypical infections that may require diagnostic and treatment techniques relatively unfamiliar to comprehensive oph-thalmologists.2
• Th e introduction of new and potentially more effi cacious and/or safe ophthalmic antiinfectives.3
• Th e introduction of new and potentially more accurate diagnostic techniques for ophthalmic infections.4 • Widespread discussion over the effi cacy and safety of novel
or alternative delivery techniques and vehicles for prophy-lactic ophthalmic antibiotics (including but not limited to intracameral injection and topical mucoadhesives).5,6 • Increased understanding of the infl ammatory damage
caused by ocular infections and the best ways to prevent/ alleviate infl ammation 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 antiinfec-tive 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. 2008 Jun;145(6):951 -8. 2. Gower EW, Keay LJ, Oechsler RA, et al. Trends in fungal
keratitis in the United States, 2001 to 2007. Ophthalmol-ogy. 2010 Dec;117(12):2263-7.
3. Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Virgan 0.15%) in the treatment of herpes simplex keratitis. Cornea. 1997;16:393-9.
4. Sambursky R, Tauber S, Schirra F, et al. Th e RPS adeno detector for diagnosing adenoviral conjunctivitis. Oph-thalmology. 2006;113(10):1758-64.
5. Akpek EK, Vittitow J, Verhoeven RS, et al. Ocular surface distribution and pharmacokinetics of a novel ophthalmic 1% azithromycin formulation. J Ocul Pharmacol Th er. 2009;25:433-9.
6. Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of postop-erative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identifi cation of risk factors. J Cataract Refract Surg. 2007;33(6):978-88.
oFF-LaBeL use statement Th is work discusses off
-label 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). Th e University of Florida College of Medicine designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Th ere 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 Offi ce PO Box 100233, Gainesville, FL 32610-0233 phone: 352-733-0064 fax: 352-733-0007 Or you can take the test online at http://cme.ufl .edu/ocular System requirements for this activity are: For PC users: Win-dows® 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 2014. Ap-proved for a period of 12 months.
aCCreDitation statement Th is activity has been planned and implemented in accordance with the Es-sential 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. Th e University of Florida College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
CreDit DesiGnation statement Th e 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 Infl ammatory Disease and Uveitis Clinic at the University of California, San Fran-cisco. She states that in the past 12 months, she has not had a fi nancial 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 fi nancial 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 Uni-versity, 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 Pharmaceu-ticals, 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 Th omas 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 Phar-maceuticals, Allergan, Bausch & Lomb, EyeGate Research, Imprimis Pharma, Isis Pharmaceuticals, Kala Pharmaceuti-cals, Lacrisciences, NiCox, Omeros, Pfi zer, Santen, and Shire. Shachar Tauber, MD, is a corneal and refractive surgeon and director of ophthalmic research at Mercy Medical Center, Springfi eld, 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. Th e 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 sup-ported by an unrestricted educational grant from Bausch + Lomb, Inc.
topics in ocular antiinfectives, issue 52
practice, anecdotal accounts abound of patients experiencing fl are-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 ophthal-mic aminoglycosides, such as tobramy-cin and gentamytobramy-cin, 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 combi-nation agents are available—including branded formulations of tobramycin with dexamethasone and tobramycin with loteprednol etabonate—that off er distinct advantages over generic aminoglycoside/ corticosteroid combinations. Th e branded ophthalmic combination of tobramycin 0.3%/dexamethasone 0.05%, for ex-ample, has a viscosity agent (xanthan gum) in the vehicle, which endows it with greater ocular surface viscosity than its generic competitors. Th e viscosity agent enabled developers to reduce the concen-tration of corticosteroid in the prepara-tion 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 lotepre-dnol 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 cor-ticosteroids.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. Increas-ing formulation viscosity reduces dosIncreas-ing
of medication use for untested indica-tions, we have to regard it in earnest. However, it is also important to judge potential risks in the context of the ben-efi t off ered by the intervention as well as in the context of our own body of clini-cal 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 fl ap. Th is practice is not recommended until more objective data is available.
relevance to other surgery types
A LASIK flap is inherently un-stable; 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 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 eff ectiveness by providing more con-sistent drug distribution on the ocular surface over time. Furthermore, taking fewer doses per day can lower potential drug-related toxicity, as well as adverse eff ects 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 signifi cant advance over tradi-tionally prescribed trifl uridine solution in the treatment of herpetic keratoconjunc-tivitis for many reasons. First the superior bioavailability aff orded by gel formulation markedly reduces dosing frequency. Sec-ondly, the medication does not require refrigeration. Th ird 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
thi-merisol in trifl uridine preparations is the most toxic preservative still marketed today, while ganciclovir gel utilizes a low 0.0075% concentration of BAK (benzal-konium chloride). In fact, trifl uridine is the only medication currently available in the United States with this preservative.
Advanced formulations may also contain lower concentrations of preserva-tives, 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 for-mulations contain the same concentration of main ingredient and are both labeled for dosing four times daily, in my experi-ence the gel formulation can be used less frequently without compromising effi cacy.
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 antiinfl am-matory agent ketorolac tromethamine and various nonpreserved artifi cial 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: azithro-mycin 1% and besifl oxacin ophthalmic suspension 0.6%.14-16 In the case of the
azithromycin formulation, this vehicle allows for just once-daily dosing, fol-lowing 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 Clini-cal Committees issued a safety alert around perisurgical and intraoperative use of topical ocular formulations that contain advanced vehicles.17 Th e
com-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-infl ammatory agents on the bare stroma before re-positioning of the LASIK fl ap. Th e PRK cases involved the placement of these agents on a bare stromal bed under a ban-dage contact lens. A consistent feature of these adverse events was placement of agents with advanced vehicles immedi-ately prior to or during LASIK or PRK surgeries. Problems with such agents fol-lowing 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 infl uence safety, tolerability, effi cacy, 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 2013.
➤ Postoperative use of these agents has not been reported to increase risk for adverse events.
fl ap 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. Further-more, 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 heal-ing interface. As a second example, the biggest wound in all of ophthalmologic surgery—the full-thickness corneal transplant wound—is stabilized by su-tures; in my view, there is no reason or clinical evidence to believe that trans-plant wound healing is compromised by appropriate use of high-viscosity topical agents. I have personally per-formed thousands of successful and uncomplicated surgeries, including cataract extractions, full thickness corneal transplants, endothelial kerato-plasties, 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 infl uence on drug effi cacy, tolerability,
toxicity and patient experience. In-creasing 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 specifi c circumstances until objective randomized clinical trials better char-acterize these potential risks.
John D. Sheppard, MD, is president of Virginia Eye Consultants and professor of ophthalmology, micro-biology, and molecular biology at Eastern Virginia Medical School in Norfolk. He is also ophthalmology residency program research director, clinical director for the Th omas 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 Phar-maceuticals, Allergan, Bausch & Lomb, EyeGate Research, Imprimis Pharma, Isis Pharmaceuticals, Kala Pharmaceuticals, Lacrisciences, NiCox, Omeros, Pfi zer, 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;4:243-51. 2. O’Brien TP. Besifl oxacin ophthalmic
sus-pension, 0.6%: a novel topical fl uoroquino-lone for bacterial conjunctivitis. Adv Th er. 2012;29:473-90.
3. FDA website: FDA ensures equivalence of generic drugs. Available at: http://www.fda. gov/Drugs/EmergencyPreparedness/Bioter-rorismandDrugPreparedness/ucm134444. htm. Accessed on September 8, 2014.
4. Review of Ophthalmology. Topical ophthal-mic generics: they’re back. Available at: http:// www.revophth.com/content/d/features/ i/1203/c/22694/ Accessed September 9, 2014. 5. Roberts CW, Nelson PL. Comparative analy-sis of prednisolone acetate suspensions. J Ocul
Pharmacol Th er. 2007;23:182-7.
6. Scoper SV, Kabat AG, Owen GR, et al. Ocular distribution, bactericidal activity and settling characteristics of TobraDex ST ophthalmic suspension compared with TobraDex oph-thalmic suspension. Adv Th er. 2008;25:77-88. 7. Comstock TL, Holland EJ. Loteprednol and
tobramycin in combination: a review of their impact on current treatment regimens. Expert
Opin Pharmacother. 2010:11:843-50.
8. Budai L, Hajdu M, Budai M, et al. Gels and liposomes in optimized ocular drug delivery: studies on ciprofl oxacin formulations. Int J
Pharmaceutics. 2007;343-34-40.
9. Zhu H, Chauhan A. Eff ect of viscosity on tear drainage and ocular residence time. Optom Vis
Sci. 2008;85(8):715-25.
10. Chou TY, Hong BY. Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effectiveness, toler-ability, safety, and future applications. Th er
Clin Risk Manag. 2014;10:665-81.
11. Lotemax gel [prescribing information]. Tampa, FL: Bausch and Lomb; 2013. 12. Lotemax suspension [prescribing
informa-tion]. Tampa, FL: Bausch and Lomb; 2013. 13. Acuvail [prescribing information]. Irvine, CA:
Allergan; 2012.
14. Insite website. Durasite compound advantage. Available at: http://www.insitevision.com/ durasite. Accessed September 9, 2014. 15. Azasite [prescribing information].
White-house Station, NJ. Merck & Co, Inc.; 2012. 16. Besivance [prescribing information]. Tampa,
FL: Bausch and Lomb; 2012.
17. ASCRS issues medication alert for LASIK and PRK. Available at: http://bmctoday.net/ crstoday/2013/03/article.asp?f=ascrs-issues-medication-alert-for-lasik-and-prk. Accessed August, 19, 2014.
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 signifi cant proportion—possibly the majority—of acute infectious
conjunc-tivitis cases.1,2 Th ere 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 pha-ryngoconjunctival 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
re-markably 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
Th ese viruses’ diversity and trans-missibility—combined with the chal-lenges of accurate clinical diagnosis— have made adenovirus conjunctivitis
therapies diffi cult to develop and deploy. But as an in-offi ce 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 improv-ing; and therapies that speed symptom resolution and shorten the period of infectivity are under investigation.2,7
importance of Diagnostic accuracy
Th e prompt and accurate diagnosis of ocular adenovirus infection can be important for the patient, the treatment team, and the unsuspecting individu-als who will come in contact with the patient. Although adenovirus conjuncti-vitis is most often self-limiting, patients fi nd 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 bacte-rial isn’t easy. The etiology of acute conjunctivitis is typically determined from clinical signs and symptoms, many of which are nonspecifi c. Th e overlap-ping appearances of allergic, bacterial, and viral conjunctivitides challenge diagnosis even among corneal/external disease experts.8,9
Confi rming the diagnosis of adeno-virus infection has a number of benefi ts. It rules out other, potentially vision-threatening diagnoses, such as ocular herpes, uveitis, or acute angle closure glaucoma. And a correct diagnosis in-forms treatment: limiting, for example, the ineff ective (and costly) use of topical antibiotics. Finally, a clear diagnosis of adenovirus infection enables clinical staff to take appropriate measures to pro-tect themselves and subsequent patients.
ocular adenovirus: morbidity
Ocular adenovirus infections can be associated with signifi cant pain and discomfort, photophobia, and the devel-opment of pseudomembranes, subcon-junctival hemorrhages, or subepithelial infi ltrates. Th ese infi ltrates, the result of immune reaction, can increase
pho-tophobia, reduce visual acuity, and last for weeks or months, with the potential to fl are up years after initial onset.
Scarring of the conjunctiva, cornea, eyelids, and, more rarely, the lacrimal duct can also occur as a result of adeno-virus infection; and consequent sym-blepharon or persistent corneal epithelial defect can leave a wake of long-lasting dry eye symptoms.2
Differential Diagnosis
I often speak to pediatricians and ur-gent 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.
Th e clinical characteristics of adeno-virus 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 fi rst eye aff ected) may also be present.
Ultimately, however, redness, dis-charge, 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-offi ce testing
This makes the availability of a rapid test with 93% sensitivity and 98% specifi city 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 lim-ited to the ophthalmology clinic—it is useful in all of the primary care settings from which we receive red eye referrals.
Th e 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
nooks, crannies, and extra equipment. Staff should be trained to fl ag acute (es-pecially 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.
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 signifi cant diagnostic challenge, a quick, in-offi ce 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 infi ltrates, 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-n-dichlorodimethyltaurine may be an effective agent for the treatment of ocular adenovirus infection.
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 artifi cial 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 re-turn to work or school.
The designated red-eye isolation room must be equipped with a disin-fectant able to meet the challenge posed by the hardy adenovirus, such as 10% bleach, 70% ethyl alcohol, or glutaral-dehyde (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 set-ting is ideal.
We have been involved in teaching the clinics in our network and com-munity 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 infec-tion 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 obliga-tions. Patients and practice staff alike should be made to appreciate that, while adenovirus infection is typically not life or visionthreatening, it is signifi
-cantly debilitating while it lasts and is a legitimate public safety concern.
treatment Challenge
An eff ective 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 infl ammatory sequelae such as corneal infi ltrates. But developing an antiviral with activity against the many and often genetically divergent serotypes of these hardy viruses has been challenging: Hu-man 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 anti-herpetic agents.4
Beyond the diffi cultly of engineering a suitable agent, the necessary clini-cal 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 at-tractive to pharmaceutical companies. Still, some promising therapies are under investigation.
Povidone iodine and/or Corticosteroid
Th e disinfectant povidone iodine has been studied and used in the treatment of infectious conjunctivitis. In vitro work suggests that dilute po-vidone iodine is eff ective 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 eff ective for viral conjunctivitis.12
Studies of 2% and 5% povidone iodine in adults with EKC have been con-ducted and are ongoing (clinicaltrials. gov NCT01179412).
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 dexa-methasone (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 4.13 In six of these eyes, adenovirus
detected by quantitative polymerase chain reaction was signifi cantly reduced by day 5. Larger, randomized studies examining the eff ect of diff erent con-centrations of each agent are warranted.
Corticosteroids have the advantage of off ering some relief from symptoms and infl ammation in adenovirus con-junctivitis, 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 off er to my patients, is ganciclovir ophthalmic gel 0.15%, an antiviral indicated for the treatment of herpetic keratitis. (Th is 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 infec-tion.14-16
My personal experience using gan-ciclovir gel to treat ocular adenovirus infection has been very positive (albeit this is only anecdotal evidence). Resolu-tion of symptoms and signs often occurs in 3 to 5 days with treatment, vs. 7 to 10 days on artifi cial tears alone. Unlike povidone iodine, ganciclovir gel is com-fortable 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 topi-cal cyclosporine (in varying concentra-tions from 0.05% to 2%) for the
treat-ment of adenovirus keratoconjunctivitis, with some positive fi ndings of symptom relief in the acute phase and reduction of subepithelial infi ltrates and associated vision loss in patients who responded poorly to corticosteroid therapy.17,18
Considering the risks associated with corticosteroid use in adenovirus kera-toconjunctivitis, cyclosporine represents a potentially useful adjunct, and I have had good experience with it.
In a rabbit model of ocular ad-enovirus infection, the use of topical cyclosporine (2% or 0.5%) signifi cantly reduced the development of subepi-thelial infiltrates, but increased and prolonged viral shedding.19 Although it
is not certain whether initiation of cyclo-sporine therapy during the acute phase of adenovirus infection has a preventive eff ect with regard to the development of subepithelial infi ltrates in humans, my anecdotal experience in this application has been positive, and the side eff ect profi le of cyclosporine is favorable.
our regimen
Until recently, the typical care for patients with adenovirus conjunctivitis included, in addition to hygiene and isolation, chilled artifi cial tears, cold compresses, and perhaps an antihista-mine 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 infi ltrates—I empathize with these patients, and I am motivated to give them any relief I can.
I off er ganciclovir gel 0.15%, dosed fi ve times daily, and cyclosporine 0.05%, dosed four times daily, to all my patients with confi rmed adenovirus infection. Th e key challenge with these off -label uses is cost and lack of insurance cover-age; but when the option is presented as having the potential advantages of symptom relief, reduced infectiv-ity, 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 leu-kocytes to kill pathogens and have been found eff ective against a broad range of viruses, bacteria, and fungi.
Th e drug N-N-dichlorodimethyl-taurine (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 NCT00901693) of 81 ocular adenovirus patients.21 And
even at high concentrations, this drug is not cytotoxic. Its further study and
development will be watched eagerly. In addition to the promise of these investigational treatments, I am encour-aged to see the more widespread adop-tion of in-offi ce testing for adenovirus conjunctivitis. Noting the impact this test is already having in our multi-center 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 non-infected patients.
Shachar Tauber, MD, is a corneal and refractive surgeon and director of ophthalmic research at Mercy Medical Center, Springfi eld, MO. He is a consultant for Allergan and Bausch + Lomb. Managing editor Jen-nifer Zweibel assisted in the preparation of this article. REFERENCES
1. Sambursky RP, Fram N, Cohen EJ. Th e preva-lence of adenoviral conjunctivitis at the Wills Eye Hospital Emergency Room. Optometry. 2007;78:236-9.
2. O’Brien TP, Jeng BH, McDonald M, et al. Acute conjunctivitis: truth and misconcep-tions. Curr Med Res Opin. 2009;25(8):1953-61. 3. Russell KL, Broderick MP, Franklin SE, et al.
Transmission dynamics and prospective envi-ronmental sampling of adenovirus in a military recruit setting. J Infect Dis. 2006;194:877-85. 4. Kinchington PR, Romanowski EG, Gordon
YJ. Prospects for adenovirus antivirals. J
An-timicrob Chemother. 2005;55:424-9.
5. Kowalski RP, Romanowski EG, Waikhom B, et al. Th e survival of adenovirus in multidose bottles of topical fl uorescein. Am J Ophthalmol. 1998;126:835-6.
6. 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):1419-24.
7. Kaufman HE. Adenovirus advances: new di-agnostic and therapeutic advances. Curr Opin
Ophthalmol. 2011;22:290-3.
8. Cheung D, Bremner J, Chan JTK. Epidemic keratoconjunctivitis—do outbreaks have to be epidemic? Eye. 2003;17:356-63.
9. 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;84:968-72.
10. Sambursky R, Trattler W, Tauber S, et al. Sensitivity and specifi city of the AdenoPlus Test for diagnosing adenoviral conjunctivitis.
JAMA Ophthalmol. 2013;131(1):17-22.
11. Monnerat N, Bossart W, Th iel MA. Povidone-iodine for treatment of adenoviral conjunctivi-tis: an in vitro study. Klin Monbl Augenheilkd.
2006;223(5):349-52.
12. 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):681-8.
13. Pelletier JS, Stewart K, Trattler W, et al. Combination povidone-iodine 0.4%/dexa-methasone 0.1% ophthalmic suspension in the treatment of adenoviral conjunctivitis. Adv
Th er. 2009;26(8):776-83.
14. Huang J, Kadonosono K, Uchio E. Anti-adenoviral effects of ganciclovir in types inducing keratoconjunctivitis by quantitative polymerase chain reaction methods. Clin
Ophthalmol. 2014;8:315-20.
15. Tabbara KF. Ganciclovir eff ects in adenoviral keratoconjunctivitis. Poster B253. Association for Research in Vision and Ophthalmology. Fort Lauderdale, FL; 2001.
16. 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):100-4.
17. Hillenkamp J, Reinhard T, Ross RS. Topical treatment of acute adenoviral keratoconjuncti-vitis with 0.2% cidofovir and 1% cyclosporine.
Arch Ophthalmol. 2001;119:1487-91.
18. Okumus S, Coskun E, Tatar MG, et al. Cyclo-sporine a 0.05% eye drops for the treatment of subepithelial infi ltrates after epidemic kerato-conjunctivitis. BMC Ophthalmol. 2012;12:42. 19. 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):86-91.
20. Nagl M, Larcher C, Gottardi W. Activity of N-chlorotaurine against herpes simplex and adenoviruses. Antiviral Res. 1998;38:25-30. 21. 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;92:470-8.
examination answer sheet
Topics in ocular anTiinfecTives, issue 52evaluation:
1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding
11. Extent to which the activity met the identified: Objective 1: 1 2 3 4 5 Objective 2: 1 2 3 4 5 Objective 3: 1 2 3 4 5 12. Rate the overall effectiveness of how the activity: Related to my practice: 1 2 3 4 5 Will influence how I practice: 1 2 3 4 5 Will help me improve patient care: 1 2 3 4 5 Stimulated my intellectual curiosity: 1 2 3 4 5 Overall quality of material: 1 2 3 4 5 Overall met my expectations: 1 2 3 4 5 Avoided commercial bias/influence: 1 2 3 4 5 13. Will the information presented cause you to make
any changes in your practice? Yes No 14. If yes, please describe: __________________________ ________________________________________________ 15. How committed are you to making these changes?
1 2 3 4 5
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________________________________________________________________ FIRSt NAmE lASt NAmE dEGREE ________________________________________________________________ ORGANIzAtION/INStItutE ________________________________________________________________ AddRESS lINE 1 ________________________________________________________________ AddRESS lINE 2 ________________________________________________________________
CItY StAtE zIP
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PHONE FAx
This CmE activity is jointly sponsored by the
univer-sity of Florida and Candeo Clinical/Science Com-munications, llC, and supported by an unrestricted educational grant from Bausch + lomb, Inc. mail to: university of Florida CmE Office, PO Box 100233,
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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, 2015.
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 ansWers:
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 http://cme.ufl.edu/ocular.
examination Questions
Topics in ocular anTiinfecTives, issue 52 1. Which of the followingis 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
