PAAO September 2014 vol.13-3

VISION THE PAN-AMERICAN JOURNAL OF OPHTHALMOLOGY

Editorial

ISSN 2219-4665 September 2014, Vol. 13(3)

Dantas PEC

Section Editor Editorial Allan R. Slomovic and Alejandro Lichtinger

Trust the Evidence, Not Your Instincts: Evidence-Based Clinical and Surgical Guidelines for the Anterior Segment.

Richard L. Abbott

What is the best treatment approach for severe blepharitis?

Paramdeep Mand and Mark J. Mannis

Management of acute bacterial keratitis: fortified antibiotics or fluoquinolones?

Ana Luisa Hofling-Lima and Francisco Bandeira e Silva

Management of fungal keratitis: Topical or systemic therapy?

Darlene Miller and Eduardo Alfonso

What is the best therapeutic scheme for Acanthamoeba keratitis?

Denise de Freitas and Fabio RS Carvalho

Evidence-based treatment of epithelial, stromal and endothelial herpetic keratitis Enrique Graue Hernández and Eduardo Arenas

Management of ocular surface tumors: excision vs topical treatment Sotiria Palioura, Anat Galor & Carol L. Karp

Management of acute and chronic ocular allergy M. Cristina Nishiwaki-Dantas

Prevention and management of corneal graft rejection Alejandro Lichtinger

CORNEA SPECIAL ISSUE

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EDITORIAL Indexed

Editorial Vision Pan-America is also listed at the collection of the National Library of Medicine Catalog under the serial #101553235

Membership, Associations and Editorial Guidelines

Aims and scope: Vision Pan-America (printed version ISSN 2219-4665, electronic version ISSN 2219-4673), the official publication of the Pan-American Association of Ophthalmology, is a quarterly fully peer reviewed scientific publication that publishes original research in Ophthalmology, including review articles on ophthalmic diseases and surgical techniques, clinical scientific studies, basic investigation, case reports, brief communications and letters to the editor in four languages: Spanish, English, Portuguese and French. In addition, the journal publishes critical reviews of new texts in ophthalmology deemed to be of importance to the Pan-American practitioner.

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Paulo E.C. Dantas, MD Editor-in-Chief

One year ago, during the XXX Pan-American Congress of Ophthalmology in Rio de Janeiro, we conducted, together with Dr. Richard L. Abbott, a well attended symposium on evidence-based clinical and surgical guidelines to the anterior segment diseases. In this symposium, we requested to the invited speakers that all presentations were based on good scientific studies, avoiding anedoctal information, hence the symposium main titlte: Trust the evidence; not your instincts!

It was a tremendous success with a lot of people asking for the syllabus or any kind of written information with the symposium content.

That’s why, under the regency of our corneal and external disease section coordinator, Prof. Allan Slomovic, and Dr. Alejandro Lichtinger, member of the Editorial Review Board, we invited an exceptional panel of corneal and external disease specialists to present an evidence-based approach to the treatment of specific anterior segment conditions.

The result is an impressive collection of evidence-based data that will bring strengh to our clinical decisions.

Once again, Vision Pan-America, The PanAmerican Journal of Ophthalmology is pleased to offer to our readers, one special issue with the “crème de la crème” on important topics of a subespecilaity.

Another exceptional must keep special issue!

Paulo E.C. Dantas, MD Editor-in-Chief.

Vision Pan-America, The Pan-American Journal of Ophthalmology pauloecdantas@uol.com.br pauloecdantas@me.com

Editorial from the Corneal and External Disease Section Editor Allan R. Slomovic MSc, FRCSC and Alejandro Lichtinger MD

Recent advances and discoveries in the field of Cornea and External ocular diseases are having a major impact on patient treatment and outcomes. The goal of this special edition of Vision Pan-America is to provide evidencebased clinical and surgical guidelines to the management of anterior segment diseases.

In this special edition of VPA, we have put together an international panel of corneal experts to provide an impactful, updated evidencebased review of the management of common ocular diseases that both the comprehensive ophthalmologist and the cornea subspecialist deal with on a regular basis. Left untreated or inappropriately managed, these corneal and anterior segment diseases can have serious sight threatening complications. The approach taken in each chapter will be to provide evidencebased guidance in the decision-making process to allow the reader to combine critical thinking with the use of the best available scientific evidence and information with the end goal of providing optimal clinical care to our patients.

In addition to thanking all the authors for their time and effort, I would like to thank Dr Paulo E.C. Dantas, editor-in-chief of Vision PanAmerica, for his tremendous editorial help in putting this special Cornea edition together and for his support and guidance.

We sincerely hope that the evidence-based clinical and surgical guidelines presented in this issue will allow the reader to incorporate evidence-based clinical guidelines in their practices and combine this with their own clinical experience with the end goal of providing optimal care for our patients.

Allan R. Slomovic MSc, FRCSC Corneal and External Disease VPA Section Editor Marta and Owen Boris Endowed Chair in Cornea and Stem Cell Research Associate Professor of Ophthalmology, University of Toronto Research Director of the Cornea Service President of the Canadian Ophthalmological Society Alejandro Lichtinger MD VPA Editorial Review Board Member Instituto de Ciencias Oftalmológicas, Hospital Ángeles Lomas Cornea, Cataract and Refractive Surgery

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Introduction Richard L. Abbott, MD Trust the Evidence, Not Your Instincts: Evidence-Based Clinical and Surgical Guidelines to the Anterior Segment Diseases.

Richard L. Abbott, MD Thomas W. Boyden Health Sciences Clinical Professor Department of Ophthalmology, University of California San Francisco Research Associate, Francis I. Proctor Foundation Corresponding Address: Department of Ophthalmology, University of California San Francisco 10 Koret Way K-301 San Francisco, California 94143 USA

The global peer reviewed literature in Ophthalmology is immense and presents a daunting task to the practitioner trying to stay up to date with the latest information for patient care. The emergence and use of clinical practice guidelines as a tool for improving the quality of care for patients is international. By reading and incorporating the recommendations from evidencebased clinical practice guidelines, created by panels of experts who systematically review the literature and extract evidence-based recommendations, the clinician can remain up to date and current in the care of their patients. The term “Evidence-Based” implies that the recommendation has been created using an unbiased and transparent process of systematically reviewing, appraising, and incorporating the best clinical research findings of the highest value to aid in the delivery of optimum clinical care to patients.1 The Institute of Medicine defines clinical practice guidelines as “…Statements that include recommendations, intended to optimize patient care, that are informed by a systematic review of evidence and an assessment for the benefits and harms for alternative care options”.2 Simply put, guidelines 66

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provide a way to support effective clinical practice.3 They are created for populations of patients and not necessarily for one specific individual, and combine both the best research evidence with clinical expertise and opinion, as well as patient values.

For a clinical practice guideline to be effective, the practitioner must be aware of its existence, in agreement with its recommendations, willing to adopt the recommendation into practice, and adhere to the guideline recommendation for a majority of patients. Barriers to guideline implementation include lack of reimbursement, lack of time, lack of skills to perform the recommendation, and a belief that the recommendation will not change the outcome for the patient.4 Often we are taught to do something one way and unless there is a compelling reason to change, we typically follow the path of least resistance and continue in our old ways. Many times it is a matter of culture, custom or habit that keeps us from changing.

Evidence-based clinical guidelines are likely to be followed if they are relatively simple, flexible, rigorous, and have the basic tenet to improve patient care and ultimately patient outcome.5 If guidelines fail to

contain an element of flexibility, they may discourage clinicians from tailoring treatment or care to the individual needs of specific patients. Studies of the economic impact of guidelines generally confirm that there is a cost saving to standardizing portions of clinical practice.

The key-defining attribute of clinical guidelines is their foundation in research evidence (6). Each clinical guideline generally has two parts: a synthesis of the clinical studies analyzed on the topic and a set of recommendations based on the evidence discussed.

The recommendations are categorized from the strongest recommendation (level 1 evidence) to the weakest recommendation (level 3 evidence).

Deviation from recommendations with level 1 evidence is rarely recommended; however, departure from a level 3 recommendation may be done frequently, especially since culture, practice patterns, and resources may be highly variable in different clinical settings.

The charge to the authors participating in this special Cornea Edition of Vision Pan-America was to carefully review the current evidence in the peer reviewed literature and present recommendations on diagnosis and management for a specific condition or disease entity.

Although, a full systematic review of the literature for the topic assigned was not necessarily completed by each author, the focus of each chapter is to illustrate what level of evidence exists for each recommendation discussed, and how this recommendation could then be applied to any given patient.

The goal of this special Cornea Edition of Vision Pan-America is to assist the reader in evaluating and summarizing the current evidence in the peer reviewed literature and then help direct them to doing

the right thing, at the right time, and doing it well for their patients.

Although the information presented in the journal is not a formal clinical guideline, it provides a pathway for the reader to recognize the importance of using evidencebased recommendations to improve the quality of care for our patients.

In summary, the key to successfully using evidencebased clinical guidelines and recommendations in our clinical practices is to combine the information we learn from the literature with our clinical experience and professional intuition, as well as taking into count patient preferences. It is important to note that the “evidence-base” in the literature changes continually and the necessity to keep up to date and to modify our decision making process is a fundamental principle in practicing high quality medicine. I encourage future Symposia to follow this format by encouraging its speakers to present the best and latest evidence-based information on a specific topic to the audience and combining this information with the expertise and clinical experience of each speaker.

REFERENCES 1.

2.

3.

4.

5.

6.

Watters, WC. 2008. Defining Evidence-Based Clinical Practice Guideline. American Academy of Orthopedic Surgeons. http://www. aaos.org/news/aaosnow/jul08/ research2.asp) Consensus Report, Institute of Medicine, Clinical Practice Guidelines We Can Trust. March 23, 2011 http//www.iom.edu/reports/2011/ Clinical-Practice-Guidelines-We-CanTrust.aspx).

Field, G. and Lohr, K. 1990. Clinical Practice Guidelines: Directions for a New Program. National Academy Press, Washington DC Cabana M. 1998. The American Journal of Managed Care. Vol 4, No 12, S741-748.

Flores G. et al. 2000. Pediatricians’ Attitudes, Beliefs, and Practices regarding Clinical Practice Guideline: A National Survey. Pediatrics: 105:496-501.

Duff, et al. Clinical Guidelines: an introduction to their development and implementation. Journal of Advanced Nursing 23 (5), 887-895.

Mand P, Mannis MJ. Treatment of severe blepharitis.

What is the best treatment approach for severe blepharitis?

Paramdeep Mand, MD1, Mark J. Mannis, MD, FACS2

Corresponding author:

1. Clinical Fellow, Cornea, External Disease, and Refractive Surgery, UC Davis Eye Center, University of California, Davis

Mark J. Mannis, MD, FACS Department of Ophthalmology & VIsion Science UC Davis Eye Center 4860 Y St, Suite 2400 Sacramento, CA 95817 E-mail: mjmannis@ucdavis.edu

2. Professor and Chair, Department of Ophthalmology & VIsion Science, UC Davis Eye Center Funding: None Proprietary/financial interest: None

Abstract

Blepharitis is one of the most common disorders encountered in ophthalmology.

Despite this, it can often be overlooked and misdiagnosed. Blepharitis can manifest as anterior and/or posterior disease. The form of blepharitis can be determined based on patient symptoms or clinical presentation. An appropriate treatment plan can be made once the form of blepharitis is elucidated. Three key strategies should be addressed in the treatment of blepharitis: (1) management of symptoms, (2) control of any inflammation that is present to prevent long-term damage, and (3) prevention of recurrence. This review focuses on the treatment of this disease as well as suggestions for treating the most severe cases while keeping these goals in mind.

Key words: Blepharitis; clinical management; eye disorders

Relevant evidence-based information

Although multiple classification schemes have been introduced over the last century, there has not been a uniformly accepted classification scheme. Elsching is credited for first describing the condition in 1908.3 Thygeson established the first major classification scheme in 1946. He defined the disorder as a chronic inflammation of the lid border and described the disease in two general categories: squamous and ulcerative.4 McCulley provided a much more complex classification, splitting blepharitis into 6 categories.5 Recently, the American Academy of Ophthalmology’s Preferred Practice Patterns have offered a more simplified classification of blepharitis, splitting it into anterior blepharitis, posterior blepharitis, and a combination of the two.6 Anterior blepharitis includes such entities as seborrheic or staphylococcal disease. Posterior blepharitis

refers to meibomian gland dysfunction.

The type of blepharitis can occasionally be determined based on patient symptoms. For example, symptoms of early morning irritation or eyelid sticking are more typical for anterior blepharitis, whereas symptoms that worsen as the day progresses suggest posterior disease.

However, there is often overlap, and it can be difficult to determine the etiology based on symptoms alone. Patients often complain of redness, irritation, burning, tearing, itching, eyelash crusting, blurring or fluctuating vision, photophobia and contact lens intolerance. They may describe a history of multiple styes and/ or chalazia. Other factors, such as rosacea or atopy, can contribute to the diagnosis as well.

The clinical presentation of anterior blepharitis usually signals the underlying cause. Staphylococcal anterior blepharitis is more common in young to middle-aged women.7 It is often associated with the presence of “scurf” or collarettes at the eyelid margin and on lashes as well as madarosis and trichiasis. In more severe cases, other findings associated with staphylococcal hypersensitivity, such as perilimbal infiltrates and corneal neovascularization, can be found.

In contrast, seborrheic disease tends to affect an older population without a predilection for gender.8 These patients will exhibit erythematous and flaking skin around the eyelids and eyebrows with oil hypersecretion on the skin and seborrheic hypertrophy.

Other causes, such as rosacea and Demodex infestation, must also be considered as treatment strategies may vary.

Posterior blepharitis and meibomian gland disease can be acquired or secondary.9 However, the clinical presentation will often be similar. Patients may present with internal horedola or chalazia. The meibomian gland orifices can be obstructed with epithelial debris or may express turbid secretions with pressure.

In the most advanced form, meibomian secretions can be difficult to express due to a paste-like consistency. Chronic disease will lead to telangiectasia of the eyelid margin with cicatricial changes resulting in an irregular lid margin and misdirection of the meibomian gland orifices. It is also important to note that recurrent or irregular appearing chalazia can be a harbinger for malignancy. While this is rare, these lesions should be biopsied to rule out potential sebaceous cell carcinoma.10 Once the type of blepharitis has been categorized, it is possible to target the specific pathophysiology with the appropriate treatment.

Treatment goals will vary based on the clinical presentation, but three key strategies should be addressed: (1) management of symptoms, (2) control of any inflammation that is present to prevent long-term damage, and (3) prevention of recurrence.

Results Treatment of anterior blepharitis

The basis of the treatment of blepharitis is improving the local environment of the eyelids. Therefore, one of the first interventions that should be undertaken is patient education and effective lid hygiene, including warm compresses and lid scrubs.

Warm compresses liquefy debris and oils, making it easier to remove them with lid scrubs. Compresses should be performed at least twice daily early in the disease course and can be performed daily or once every few days once symptoms are controlled. Lid scrubs can be performed with either dilute baby shampoo (e.g. Johnsons® Natural® baby shampoo) or commercially available scrubs, such as OcuSoft® Lid Scrub®.

Patients should be instructed not to use cotton tipped applicators or cotton swabs for the lid scrubs, since these are generally ineffective.

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Figure 1: Pediculosis infestation of the eyelashes.

Figure 2: Blepharitis with seborrhea

Figure 3: Corneal thinning and perforation in the setting of severe ocular rosacea Lid scrubs help control the impetus for inflammation by removing not only debris but also any bacterial toxins, and by reducing the bacterial load of the eyelids. Cosmetics should be avoided during flares. Make-up may incite inflammation and prevent clearance of debris from the lid margin.

Improving the local surface can prove to be difficult in contact lens wearers, since the lens may act as a reservoir for debris and can lead to the formation of more depositis.11 It may be best for patients wearing extended-wear soft contact lenses to switch to daily wear lenses or rigid gas permeable lenses. Discontinuation of contact lens wear may be necessary.

The local environment must be approached differently in patients with anterior blepharitis in combination with seborrhea. It is thought that fungi and yeast may feed on lipids in the skin and perpetuate the inflammatory response in patients with seborrhea.8 Cleansing the 68

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periocular skin and eyebrows with a gentle, non-detergent antifungal shampoo in addition to warm compresses and lid scrubs can be helpful.

Given that dry eye states and tear film insufficiency often accompany anterior blepharitis, artificial tears can provide substantial symptomatic relief. Preserved tears may be adequate between flares. However, when the patient is acutely symptomatic, nonpreserved tears should be used since they can be used frequently (i.e. more than four times a day) without fear of worsening preservativerelated surface toxicity. Thicker formulations such as gels and ointments can be used for more severe cases.

Antibiotic therapy is warranted for moderate to severe cases of anterior blepharitis.

Traditionally, this has been accomplished with bacitracin and aminoglycosides (gentamicin and tobramycin).12 More recently, macrolide antibiotics (including azithromycin and erythromycin) have been advocated due to possible anti-inflammatory properties in addition to their anti-infective properties.13 Azithromycin is particularly desirable, since it has a long half-life in both oral and topical forms. Using ointments, which are best tolerated when instilled at bedtime due to their propensity to blur vision, can increase contact time of the drug with the eye. One must be wary of the acute worsening of symptoms after initiating an antibiotic as an indication of a possible allergic reaction to the drug. Use of the antibiotic should be stopped immediately, and the reaction should be allowed to subside prior to initiation of another drug.

Antibiotic therapy can be helpful in not only the acute stage, but in long-term therapy as well. Azithromycin can be dosed at 1 gram by mouth weekly for three consecutive weeks.

This can then be repeated after a 3-4 week period, until symptom control is achieved and on an “as needed” basis thereafter. Azithromycin is relatively well tolerated when taken orally; however, there have been cases of acute cardiac arrest induced by the medication.14 Although more recent studies have disputed this15, it may be best to obtain clearance from a cardiologist prior to initiating systemic azithromycin therapy in patients with a cardiac history. Topical azithromycin is used twice daily in the acute phase for rapid control of the bacterial load and inflammation but can be used once daily on a long-term basis for prevention.

Treatment for rosacea requires long-term therapy as well. Oral tetracyclines have been established as efficacious in the treatment of ocular rosacea.16 Doxycycline is the preferred agent, since it is better tolerated than first-

generation tetracyclines and possesses antiangiogenic and anti-inflammatory properties (via anti-matrix metalloproteinase inhibition) as well. The treatment dose for doxycycline usually starts at 100mg once or twice daily for a period of 6-12 weeks.17 It often takes a few weeks for the therapeutic effect of doxycycline to be realized, so the aforementioned methods of immediate symptomatic control should be used early in the treatment course. Oracea® is a controlled-release tablet of doxycycline that has been used for the treatment of rosacea. It contains 30 mg of an immediate-release form and 10 mg as a delayed-release doxycycline that can be taken once daily. It has been shown to improve symptoms and findings of ocular rosacea significantly with minimal side effects.

Doxycycline is also beneficial in those patients with moderate to severe staphylococcal-related anterior blepharitis.

Severe cases of blepharitis often necessitate a short course of topical corticosteroid treatment to modulate the inflammatory component of the disease. It is crucial to start with the lowest effective dose of steroid to avoid any of the potential complications of chronic topical corticosteroid use, such as cataract formation, ocular hypertension, and exacerbation of the infectious process leading to a superinfection.19 Induction therapy during an acute flare can be accomplished by using a steroid-antibiotic combination, such as tobramycin with dexamethasone. However, some severe cases require long-term treatment with steroids, in which case it would be best to use low-dose formulations with less intraocular penetration and activity than their counterparts, such as fluorometholone 0.1% or loteprednol 0.5%.

Corticosteroid use can also be avoided all together in patients requiring long term therapy by using topical cyclosporine 0.05%.20 Cases of anterior blepharitis that are resistant to the above therapies should raise concern for less common etiologies. Herpes simplex-related blepharitis will require therapy with systemic and/ or local antiviral therapy. Demodex-related disease can be treated with eyelid scrubs combined with tea tree oil or sulfur oil.21 Phthiriasis pubisrelated disease is treated by carefully removing the lice and louse eggs and local application of a pediculocide. Sexual contacts will also need treatment to prevent re-infestation.

Treatment of posterior blepharitis

There is significant overlap in the modalities used in anterior and posterior blepharitis, particularly since some etiologies are a combination of anterior and posterior

Mand P, Mannis MJ. Treatment of severe blepharitis.

disease (e.g. rosacea). With that said, the treatment of posterior blepharitis is primarily focused on the meibomian glands.

Similar to anterior blepharitis, the first goal of therapy should be improvement of the local environment. Patient education, eyelid hygiene, warm compresses, and eyelid massage should be the basis of treatment of anyone with symptomatic meibomian gland dysfunction. Warm compresses are typically applied with a washcloth soaked in warm water, but other methods have been described.

These include warming a soaked washcloth or potato in the microwave or by using commercially available warm compresses or masks. Care must be taken not to overheat the compresses, since facial burns can result.

These measures can be supplemented with oral supplementation with omega-3 essential fatty acids. Optimal dosage for omega-3 supplementation has not been established, but dosages between 2000 to 6000 milligrams per day are typically used. A one-year study evaluating patients taking two 1000 milligram capsules of omega-3 fatty acids three times a day found that patients on the fatty acid supplementation had improved tear break up time and fewer dry eye symptoms than those not taking the capsules.22 It is not advised to start omega-3 fatty acid supplementation in patients on anti-coagulants because of an increased risk of bleeding.

Further symptomatic relief can be obtained by supporting the tear film with topical lubricants, since dry eye is often a complicating factor in posterior blepharitis. This is best achieved with lipid-promoting artificial tears as lipid layer dysfunction is often the source of dry eye symptoms in these patients.24 Tetracyclines and azithromycin are also beneficial in the treatment of posterior blepharitis. In addition to their aforementioned anti-inflammatory properties, tetracyclines are also thought to alter abnormal meibum.

This is, in part, secondary to alteration in lipase enzyme activity, thereby preventing degradation into smaller diglycerides. Both doxycycline and azithromycin are thought to increase the amount of carotenoids in the meibum, thus stabilizing the tear film and improving symptoms of dry eye.25 Azithromycin has also been shown to promote phospholipidosis of the meibomian gland epithelial cells, further stabilizing the ocular surface.26 The two therapies are similar in efficacy; however, four weeks of topical azithromycin treatment has been shown to be slightly more effective than oral doxycycline in improving foreign body sensation and signs

of plugging of the meibomian gland orifices.25 Control of inflammation is an important part of the treatment of meibomian gland disease. This is partly modulated with the use of tetracyclines and azithromycin, but can necessitate the use of topical corticosteroids for more rapid and complete control of inflammation in severe cases. Additionally, the use of corticosteroids will often be necessary when blepharitis is complicated by phlyctenular keratitis. The previous discussion on the need for caution during the use of corticosteroids is applicable to posterior disease as well.

Multiple other modalities have been proposed as therapies for treatment of meibomian gland disease. The LipiFlow® system is a newer thermodynamic method of expressing meibum from obstructed glands. It consists of an eye cup that is placed on the external surface of the eye and a lid warmer that is placed in the inner surface of the lid.

The lid warmer is insulated, thus shielding heat from the eye and vaults over the surface of the cornea to prevent contact. The lid warmer applies continuously-monitored directional heat to the inner eyelid while inflatable air bladders underneath the eye cup apply variable pressure to the outer eyelids.

This facilitates expression of meibum into the eye cup. A single LipiFlow treatment has been shown to be at least as effective in the treatment of meibomian gland dysfunction as a 3-month, twice daily lid margin regimen of warming and lid massage.27 Intraductal meibomian gland probing has also been proposed as a method of relieving meibomian gland obstruction. Topical anesthesia is administhered and a 2-mm probe is passed through the meibomian gland orificies. This is then followed by a 4-mm probe for deeper probing and expression of the meibum. This has been reported to provide instant relief of symptoms in 96% of patients (24/25), with all patients achieving relief at 4 weeks.28

Conclusion and recommendation

Blepharitis is a common ocular condition and is a frequent cause for office visits. The presentation can be varied, but signs and symptoms often reflect underlying dry eye, infection/infestation, and inflammation. Once the etiology has been elucidated and the severity of signs and symptoms has been graded, therapy can be individualized.

All therapy should start with patient education, lid hygiene and warm compresses.

Management of remaining symptoms can be

accomplished with appropriate topical and systemic drug therapy. Inflammation must also be controlled to improve symptoms and prevent long-term damage. Once the acute flare is resolved, the therapy can be tailored and tapered to a regimen focused on preventing recurrence.

REFERENCES 1. Hom MM, Martinson JR, Knapp LL, et al. Prevalence of meibomian gland dysfunction. Optom Vis Sci 1990;67:710-2.

2. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a survey based perspective on prevalence and treatment. Ocul Suft 2009;7(Suppl. 2):S1-S14.

3. Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland dysfunction in chronic blepharitis. Cornea 1991;10:277-285.

4. Thygeson P. Etiology and treatment of blepharitis. Arch Ophthalmol 1946; 36:445-77.

5. McCulley JP, Dougherty JM, Deneau DG. Classification of chronic blepharitis. Ophthalmology 1982;89:1173-90.

6. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern® Guidelines. Blepharitis. San Francisco, CA: American Academy of Ophthalmology; 2013.

7. Jackson WB. Blepharitis: current strategies for diagnosis and management. Can J Ophthalmol 2008;43:170-9.

8. McCulley JP, Dougherty JM. Blepharitis associated with acne rosacea and seborrheic dermatitis. Int Ophthamol Clin 1985;25:159-72.

9. Nelson JD, Shimazaki J, Beitez-del-Castillo JL, et al. The International Workshop on Meibomian Gland Dysfunction: report of the definition and classification subcommittee. Invest Ophthalmol Vis Sci 2011;52:1930-7.

10. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the eyelids: personal experience with 60 cases. Ophthalmology 2004;111:2151-7. Review.

11. Holland EJ, Mannis MJ, Lee WB. Ocular Surface Disease: Cornea, Conjunctiva, and Tear Film. Elsevier Inc. 2013. p55-76 12. Abelson M, Shapiro A, Tobey C. Breaking down blepharitis. Rev Ophthalmol 2011;74-8.

13. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents 2008;31:12-20.

14. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-1890.

15. Khosropour CM, Capizzi JD, Schafer SD, et al. Lack of association between azithromycin and death from cardiovascular causes. N Engl J Med 2014;370:1961-2.

16. Stone DU, Chodosh J. Oral tetracyclines for ocular rosacea: an evidence-based review of the literature. Cornea. 2004;23:106-9.

17. Vieira AC, Hofling-Lima AL, Mannis MJ. Ocular rosacea—a review. Arq Bras Oftalmol. 2012;75:363-9.

18. Pfeffer I, Borelli C, Zierhut M. Treatment of ocular rosacea with 40 mg doxycycline in a slow release form. J Dtsch Dermatol Ges. 2011;9:904-7.

19. David DS, Berkowitz JS. Ocular effects of topical and systemic corticosteroids. Lancet 1969;294:149-51.

20. Donnenfeld E, Pflugfelder SC. Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv Ophthalmol 2009;54:32138.

21. Kheirkhah A, Casas V, Li W, et al. Corneal manifestations of ocular Demodex infestation. Am J Ophthalmol 2007;143:743-9.

22. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis).

Trans Am Ophthalmol Soc 2008;106:336-56.

23. Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracycline in chronic blepharitis-Inhibition of lipase production in staphylococci. Invest Ophthalmol Vis Sci 1991;32:2970-5.

24. enelli U. Systane lubricant eye drops in the management of ocular dryness. Clin Ophthalmol 2011;5:783-90.

25. Foulks GN, Borchman D, Yappert M, et al. Topical azithromycin and oral doxycycline therapy of meibomian gland dysfunction: a comparative clinical and spectroscopic pilot study. Cornea 2013;32:44-53.

26. Liu Y, Kam WR, Dinj J, et al. One man’s poison is another man’s meat: using azithromycin-induced phospholipidosis to promote ocular surface health. Toxicology 2014;320:1-5.

27. Finis D, Hayajneh J, Konig C, et al. Evaluation of an automated thermodynamic treatment (LipiFlow®) system for meibomian gland dysfunction: a prospective, randomized, observer-masked trial. Ocul Surf 2014;12:146-54.

28. Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland dysfunction. Cornea.

2010;29:1145-1152.

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Management of acute bacterial keratitis: Fortified antibiotics or fluoroquinolones?

Ana Luisa Höfling-Lima MD, PhD1, Francisco Bandeira e Silva MD2

Corresponding author:

1. Professor of Ophthalmology and Chair, Federal University of Sao Paulo, Brazil.

Ana Luisa Höfling-Lima Av. Ibijau, 331 - 17o. andar Moema - SP - Brasil 04524.020 Email: analhofling@gmail.com

2. Post-graduate cornea fellow, Department of Ophthalmology, Federal University of Sao Paulo, Brazil.

Funding: None Proprietary/financial interest: None

Abstract

Bacterial keratitis (BK) is one of the most frequent causes for emergency hospital admissions.1 Identifying the causative microorganism promptly and properly is mandatory to achieve acceptable outcomes.

Nevertheless, appropriate initial management of these cases requires laboratory-based diagnosis and even a modest laboratory set may not always be available at some clinical settings.

Key words: bacterial keratitis; diagnosis; treatment.

Relevant evidence-based information

Guidelines support an empiric approach for initial treatment of bacterial keratitis2-5 but, there is still no consensus over which antibiotics should be a clinician start the treatment.6,7 For about four decades, a combination of fortified antibiotics was the preferred therapy, usually with an amynoglicoside (gentamicin

or tobramycin) and a cephalosporin (cefazolin) in order to cover both Gram-positive and Gram-negative bacteria, with special concern to Staphylococcus spp., Streptococcus spp. and Pseudomonas aeruginosa.8 In the 1990’s, quinolones have been made widely accessible for topical use in ophthalmology.9 Structural changes over the years led to the production of different molecules of fluoroquinolones presenting with distinct pharmacokinetic and pharmacodynamic properties. The characteristics of 4th generation fluoroquinolones , which includes gatifloxacin and moxifloxacin, made them an excellent choice for initial therapy of bacterial keratitis with the perks of a very broad spectrum, higher activity against Gram-positive pathogens, readily accessibility, improved aqueous humor and corneal penetration10 and no special conditions for conservation.11,12 Fourth generation fluoroquinolones have been used worldwide for the last decade; however,

Table 1. Resistance rates of 539 cultured bacterial isolates from keratitis, São Paulo, Brazil MRSA (methicillin-resistant Staphylococcus aureus); MRCNS (methicillin-resistant coagulase-negative Staphylococcus); MSCNS (methicillin-susceptible coagulase-negative Staphylococcus). † Total number of samples cultured for each group of bacteria. * Total number of samples submitted to antimicrobial susceptibility testing. a) Only third generation cephalosporins presented anti-pseudomonas activity. b,c,d) Reference used was based on disk diffusion breakpoints provided by CLSI. e) Breakpoints used were based on MICs and disk diffusion test provided by CLSI. f) Reference used for Pseudomonas spp was adapted from disk diffusion breakpoints provided by CLSI for urinary tract isolates. Other references were based on provided MICs and disk diffusion breakpoints in the CLSI. g) The only breakpoint available for moxifloxacin in the CLSI referred to Staphylococci spp (both S. aureus and Coagulase-negative Staphylococci; susceptible or resistant to methicillin). Breakpoints for disk diffusion were used as reference.

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there is a lack of consensus regarding which fluoroquinolone generation is most suitable for empirical therapy. For instance, in some countries, such as the UK, the preferred initial therapy is still ciprofloxacin, which is partly justified due to better in vitro activity against Pseudomonas aeruginosa.13 However, there have been some case reports and retrospective studies showing the development of bacterial resistance to these new fluoroquinolones, probably due to over-the-counter availability in some places and widespread topical and systemic use for both prophylaxis and infection.

Results

Choy et al14 found that 11% of 65 Pseudomonas aeruginosa isolates in both contact lens- and non-contact lens-related keratitis were non-susceptible in vitro to both ofloxacin and moxifloxacin, an increasing trend compared to previous years. Betanzoscabreras et al15 found a resistance rate of 14.2% to gatifloxacin and moxifloxacin resistance after analyzing S. epidermidis isolates recovered from corneal ulcers.

National surveillance studies in the United States have reported a high frequency of resistant to the fluoroquinolones among ocular staphylococci isolates, particularly for methicillin-resistant strains.16 Along with these alarming findings, the controversy about the best choice for empirical therapy has been brought back into the light again.

We conducted a retrospective analysis of samples from 893 cases of BK with positive culture and studied separately 75 Pseudomonas spp; 21 methicillin-resistant S. aureus (MRSA), 129 methicillin-resistant (MRCNS) and 314 susceptible S. coagulase-negative staphylococci (MSCNS). Resistance rates are displayed individually for cephalothin, amikacin,

Hรถfling-Lima AL, Bandeira e Silva F. Management of acute bacterial keratitis.

tobramycin, gentamicin, moxifloxacin and gatifloxacin (Table 1).

Our findings display an overall high rate of resistance to 4th generation fluoroquinolones comparable to the resistance rates found for cephalothin and amynoglicosides. MRSA and MRCNS seem to be the most concerning bacterial agents, since resistance levels for both fortified combinations and 4th generation fluoroquinolones are the highest found among our isolates. Newer reviews show that main aspects one has to take into account when choosing an empirical antibiotic therapy are the following: treatment success, time to treat, serious complications of infection and adverse effects of the medication.7 Studies had compared and reviewed thoroughly the sensitivity profile, advantages and drawbacks related to commercial accessibility, bioavailability presentation, toxicity, preservation, and effectiveness of each drug.10,17 Treatment outcomes with either group vary greatly according to geographical differences, patient profile (severe or nonsevere keratitis), clinical setting (hospital and outpatient clinics). Absolute data seems solid at first in most of these papers; however, when their design is unraveled, results often lose power. The main reason for that is related to the criteria used to recruit patients and protocol used to determine which antibiotics and posology would be applied, which often, do not match with other studies. A metanalysis evaluation of this data is not very feasible.

Besides, when it comes to bacterial resistance to antibiotics, analysis becomes even more difficult since culture and antimicrobial susceptibility methods vary widely among the studies and in several publications the amount of positive samples for each identified microorganism is small for a reliable statistical evaluation. Another hiccup for microbiology studies in BK is that methods for antimicrobial susceptibility testing for ophthalmology purposes are bound to major groups, such as Clinical and Laboratory Standards Institute and EUCAST, and all of their data is based on the levels of antibiotics achieved in tissues after systemic use, which may not work the same way for topical application of drugs, since the relationship between drug bioavailability and ocular penetration depends on other factors related to the specific anatomy of ocular structures. Furthermore, some of the drugs used in ophthalmology are not available

for systemic use, hence, they are not listed in these guidelines. For instance, 2014 EUCAST provided a guidance document on breakpoints for topical use of antimicrobial agents. However, topical breakpoints for 4th generation fluoroquinolones or other amynoglicosides other than gentamicin are not listed in this document. Alternatively to the status-quo dilemma, new treatments are under evaluation such as the effect of crosslinking on antimicrobial activity18 and effectiveness of besifloxacin. Besifloxacin, for topical use, is a new fluoroquinolone that has an adhesive component in its composition, allowing it to remain for longer periods in the ocular surface, thus providing a greater concentration over time when compared to antibiotics that are quickly removed by blinking and/or tear drainage. Nevertheless, there are no clinical trials evaluating the role of besifloxacin in BK. In one of the few papers available on the matter, Chung et al compared the penetration of four fluoroquinolones and demonstrated that besifloxacin does not reach high levels within corneal tissues.19 Furthermore, when there is already epithelial disruption, such as in BK, it would probably penetrate better20 and, since its retention time is the longest of all topical antibiotics, it may be taken into account as a therapeutic option. McDonald and colleagues conducted a thorough systematic review and metanalysis that resulted in 16 high quality clinical trials concerning topical antibiotics for management of BK and concluded that none of the trials took into consideration cost analysis and time without antibiotics until treatment. They support that there are significant differences between fluoroquinolones and fortified antibiotics when it comes to ready accessibility, and suggest that whereas fluoroquinolones are easily dispensed from hospitals or community pharmacies and can be kept in room temperature, fortified aminoglycosidecephalosporin combination must be prepared in compound pharmacies and must remain refrigerated for approximately 4 days. In their review, they also denote that the time requirement for fortified antibiotics formulation might be hazardous for patients with severe corneal infections and melting that require immediate treatment, such as in P. aeruginosa keratitis. Although we are in agreement with both statements, we believe that the rise in fluoroquinolone resistance is a major factor PAN-AMERICA

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REVIEW / Vis. Pan-Am. 2014;13(3):70-72

to take into account when choosing an initial therapy. Antibiotic resistance due to genetic mutation is the most dreaded phenomena to infectious diseases experts, while there have been some published papers on the subject21-24 but we also agree that lack of fluoroquinolones susceptibility for some bacteria may be due to intrinsic antibiotic, rather than acquired resistance through mutation.25 Nevertheless, some bacteria that show resistance to ciprofloxacin have a high probability to be resistant to treatment with 4th generation quinolones, disregarding the mechanism of resistance. This hypothesis is supported based on several essays demonstrating that ciprofloxacin is the most active fluorquinolone against P. aeruginosa.26 However, further research has not been able to show strains that are resistant to ciprofloxacin and susceptible to other generation of fluorquinolones, such as 4th generation.27,28 On that account, in a community setting with a high prevalence of P. aeruginosa, ciprofloxacin could be preferred initial treatment over fourth generation fluoroquinolones for BK. In most South American ophthalmology hospitals and outpatient wards, the preferred initial treatment for BK starts with 4th generation fluoroquinolones. We suggest that for both severe and non-severe BK, treatment should be initiated with 4th generation fluoroquinolones and adjusted according to clinical course and culture/antimicrobial susceptibility results. In the setting of severe and/or fast evolving infections, the time taken in order to get results from cultures and antimicrobial infections is golden; because a delay in the decision taking of exchanging 4th generation fluoroquinolones for fortified antibiotics might result in poorer outcomes.

Sometimes, the sole identification of pathologic bacteria may help in choosing whether and when to start fortified antibiotics, specially if there is previous epidemiologic data available for BK.

Conclusion and recommendation

In conclusion, gold standard initial therapy for BK is far from a clinical and academic consensus. Bacterial resistance to the antimicrobials used in ophthalmology varies greatly according to geographic location, and initial treatment choice should be guided by local antimicrobial resistance profile data, clinical course and laboratory evidence of antibiotic

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susceptibility. In severe cases that need prompt treatment, 4th generation fluoroquinolones seem to be a more suitable option, once they are readily available virtually anywhere and they do not need special conditions for storage. Clinical course will dictate further change in therapy to fortified antibiotics, when there is no objective or subjective evidence of clinical improvement, and laboratory results are unavailable.

Acknowledgements: Maria CecĂ­lia Zorat Yu, Thomas ChagasNeto and Paulo JosĂŠ Martins Bispo.

REFERENCES 1. Suwan-Apichon O, Reyes JM, Herretes S, et al. Topical corticosteroids as adjunctive therapy for bacterial keratitis. Cochrane Database Syst Rev 2007(4):CD005430.

2. Blanton CL, Rapuano CJ, Cohen EJ, Laibson PR. Initial treatment of microbial keratitis. CLAO J 1996;22(2):136-40.

3. Bennett HG, Hay J, Kirkness CM, et al. Antimicrobial management of presumed microbial keratitis: guidelines for treatment of central and peripheral ulcers. Br J Ophthalmol 1998;82(2):13745.

4. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern Guidelines: Bacterial Keratitis-Limited Revision. San Francisco, CA: American Academy of Ophthalmology, 2011.

5. International Clinical Guidelines: Bacterial Keratitis. International Council of Ophthalmology.

International Council of Ophtalmology, 2010.

6. Shah VM, Tandon R, Satpathy G, et al. Randomized clinical study for comparative evaluation of fourth-generation fluoroquinolones with the combination of fortified antibiotics in the treatment of bacterial corneal ulcers. Cornea 2010;29(7):751-7.

7. McDonald EM, Ram FS, Patel DV, McGhee CN. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials. Br J Ophthalmol 2014.

8. Baum JL. Initial therapy of suspected microbial corneal ulcers. I. Broad antibiotic therapy based on prevalence of organisms. Surv Ophthalmol 1979;24(2):97-105.

9. Wong RL, Gangwani RA, Yu LW, Lai JS. New treatments for bacterial keratitis. J Ophthalmol 2012;2012:831502.

10. Robertson SM, Curtis MA, Schlech BA, et al. Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans. Surv Ophthalmol 2005;50 Suppl 1:S32-45.

11. Fisher LM, Gould KA, Pan XS, et al. Analysis of dual active fluoroquinolones in Streptococcus pneumoniae. J Antimicrob Chemother 2003;52(2):312-3; author reply 3-4.

12. Fisher LM, Heaton VJ. Dual activity of fluoroquinolones against Streptococcus pneumoniae. J Antimicrob Chemother 2003;51(2):463-4; author reply 4-5.

13. Shalchi Z, Gurbaxani A, Baker M, Nash J. Antibiotic resistance in microbial keratitis: ten-year experience of corneal scrapes in the United Kingdom. Ophthalmology 2011;118(11):2161-5.

14. Choy MH, Stapleton F, Willcox MD, Zhu H. Comparison of virulence factors in Pseudomonas aeruginosa strains isolated from contact lens- and non-contact lens-related keratitis. J Med Microbiol 2008;57(Pt 12):1539-46.

15. Betanzos-Cabrera G, Juarez-Verdayes MA, Gonzalez-Gonzalez G, et al. Gatifloxacin, moxifloxacin, and balofloxacin resistance due to mutations in the gyrA and parC genes of Staphylococcus epidermidis strains isolated from patients with endophthalmitis, corneal ulcers and conjunctivitis.

Ophthalmic Res 2009;42(1):43-8.

16. Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. Am J Ophthalmol 2011;152(4):567-74 e3.

17. Wilhelmus KR, Gilbert ML, Osato MS. Tobramycin in ophthalmology. Surv Ophthalmol 1987;32(2):111-22.

18. Iseli HP, Thiel MA, Hafezi F, et al. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea 2008;27(5):590-4.

19. Chung JL, Lim EH, Song SW, et al. Comparative intraocular penetration of 4 fluoroquinolones after topical instillation. Cornea 2013;32(7):1046-51.

20. Fukuda M, Inoue A, Sasaki K, Takahashi N. The effect of the corneal epithelium on the intraocular penetration of fluoroquinolone ophthalmic solution. Jpn J Ophthalmol 2004;48(2):93-6.

21. Agnello M, Wong-Beringer A. Differentiation in quinolone resistance by virulence genotype in Pseudomonas aeruginosa. PLoS One 2012;7(8):e42973.

22. Mouneimne H, Robert J, Jarlier V, Cambau E. Type II topoisomerase mutations in ciprofloxacinresistant strains of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1999;43(1):62-6.

23. Nakano M, Deguchi T, Kawamura T, et al. Mutations in the gyrA and parC genes in fluoroquinolone-resistant clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1997;41(10):2289-91.

24. Higgins PG, Fluit AC, Milatovic D, et al. Mutations in GyrA, ParC, MexR and NfxB in clinical isolates of Pseudomonas aeruginosa. Int J Antimicrob Agents 2003;21(5):409-13.

25. Agarwal T, Jhanji V, Satpathy G, et al. Moxifloxacin resistance: intrinsic to antibiotic or related to mutation? Optom Vis Sci 2012;89(12):1721-4.

26. Swiatlo E, Moore E, Watt J, McDaniel LS. In vitro activity of four fluoroquinolones against clinical isolates of Pseudomonas aeruginosa determined by the E test. Int J Antimicrob Agents 2000;15(1):73-6.

27. Duggirala A, Joseph J, Sharma S, et al. Activity of newer fluoroquinolones against gram-positive and gram-negative bacteria isolated from ocular infections: an in vitro comparison. Indian J Ophthalmol 2007;55(1):15-9.

28. Moshirfar M, Mirzaian G, Feiz V, Kang PC. Fourth-generation fluoroquinolone-resistant bacterial keratitis after refractive surgery. J Cataract Refract Surg 2006;32(3):515-8.

Miller D, Alfonso EC. Management of fungal keratitis: Topical or systemic therapy?

Management of fungal keratitis: Topical or Systemic therapy?

Darlene Miller1, DHSc, MPH, CIC, Eduardo C. Alfonso2, MD

Corresponding author:

1. Research Associate Professor, Scientific Director Ocular Microbiology Laboratory, Department of Ophthalmology, University of Miami School of Medicine

Eduardo C. Alfonso, MD Department of Ophthalmology, Bascom Palmer Eye Institute University of Miami, Miller School of Medicine P.O Box 016880 Miami, Florida 33101-6880

2. Kathleen and Stanley J. Glaser Professor, Chairman and Director, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine Funding: None Proprietary/Financial Disclosures: None

Abstract

Currently, there are no level one evidence-based studies comparing systemic vs topical therapy for the management of fungal keratitis.

Information on systemic efficacy alone or in combination with topical use is rare. Selection of the most appropriate antifungal for fungal keratitis remains a challenge, hindered by the diverse clinical presentation in fungal keratitis, delay in clinical and laboratory diagnosis, limited supply of effective antifungals, lack of ocular pharmacological profiles for current antifungals, nonstandard dosing intervals/routes of administrations, expanding list of causative agents, geographic diversity and the emergence of resistance.

Efficacy is gleamed from personal observations, clinical experience, literature reviews, or retrospective data from small or single cases studies and or chart reviews. Taken together, the level of existing evidence is insufficient to determine the role of systemic vs topical therapy for fungal keratitis. Topical therapy remains the standard for treatment of fungal keratitis. Adjunctive therapy with oral or intravenous antifungals may be required for severe or recalcitrant ulcers. Well-powered randomized clinical trials involving diverse and common topical vs systemic therapies are needed to address this question.

Key words: keratitis; fungal; diagnosis, therapy.

Relevant evidence-based information: Level of evidence for this review.1

A literature search was conducted of PubMed and Medline for relevant articles and abstracts on medical management of fungal keratitis, antifungals and fungal keratitis spanning the period of January 2000 to May 2014 for this review. The quality and level of evidence used for this review are outlined in Table 1.

Medical management of fungal keratitis remains a challenge worldwide.

The greatest Public Health burden is seen in agricultural based countries such as India and China, with increasing cases among contact lens wears worldwide (Figure 1). The difficulty lies in the types and diversity of pathogens, geographical specificity, limited formulary (Table 2), lack of ocular pharmacological profiles and delay in diagnosis.2-6 A review of the literature reveals significant variation in selection and actual use of antifungals in the management of mycotic or fungal keratitis.7-12 Practice patterns including drug selection and mode of administration (topical or systemic) are dependent on type of fungi (yeast vs filamentous), drug availability, cost, prior clinical experience and reports from the literature.

In a 2007 survey, sent out by the Cornea Society, 92 respondents (N=92/800, 11.5%), from the United States (59%), Asia (21%), South America (12%), Europe (3%) and Australia (3%) identified Natamycin (96%)

Level

Types of Studies

Number found

1

1. Systemtatic Review 2. Randomized controlled trial (RCT) 3. Meta-analysis

1 1 0

2

1. Systematic Reviews (no analysis) 2. Prospective comparative study (therapeutic) 3. Cohort control Study 4. Meta-analysis of Level 2 studies

10 2 0 0

3

1. Retrospective studies 2. Case control study 3. Meta-analysis of Level 3 4. Comparative study (chart reviews) 5. Observational surveys (>80% response rate)

0 0 0 16 0

4

1. Case Series 2. Observational surveys (<80% response rate)

8 1

5

1. Case Reports 2. Expert Opinion 3. Personal observation

20 3

6

1. Laboratory Studies 2. Animal Studies

3 1

Table 1: Level of Evidence; Topical vs Systemic Medications as the most commonly used antifungal for the treatment of keratitis due to filamentous fungi followed by amphotericin B (75%) and voriconazole (63%). Itraconazole, econazole, and posconazole were used as treatment in < 20% of the patients.13 Amphotericin (92%) was the most common selected antifungal for the treatment of keratitis caused by yeasts, followed by natamycin (68%), and voriconazole (49%). Similarly, itraconazole, econazole, posconazole and other antifungals were used as treatment < 20% of the time for management of ulcers due to yeast.

Combination therapy with two or more antifungals was reported by more than 50% of the respondents (56%). Natamycin and voriconazole (41%) was the most common combination, followed by natamycin and amphotericin B (13%) and amphotericin and voriconazole (13%) for filamentous fungi. The amphotericin and voriconazole (83%) was the most common combination reported for management of keratitis caused by yeasts.

Systemic therapy was used to supplement topical therapy in 92% of the respondents. Among this group, 10% used adjunctive systemic therapy for all cases, 55% used it in most cases, 27% in some of the cases, while 8% never used systemic therapy in the management of fungal keratitis.

Correlation with the use of systemic antifungal and effectiveness or topical versus systemic outcomes were not assessed in this review.13 PAN-AMERICA

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Figure 1: Frequency and Distributions of Common Ocular Fungal Keratitis Pathogens

Percent

Spectrum of Fungal Pathogens 70 60 50 40 30 20 10 0

Aspergillus sp

Fusarium sp

Candida sp

Combination therapy: Topical

USA (Avg cases/yr, N=105)

UK (Avg cases/yr, N=13)

Country

South America (Avg cases/yr, N=12)

Spectrum of Fungal Pathogens 70

Aspergillus sp

Fusarium sp

Candida sp

Percent

60 50 40 30 20 10 0

South India (Avg cases/yr, N=105)

North India (Avg cases/yr, N=11)

Eastern India (Avg cases/yr, N=83)

China (Avg cases/yr, N=153)

Country

Data Summary from references: 5, 6, 7, 24, 33, 34, 37, 38.

Evidence: Topical Therapy 3, 2010-December 31, 2011), Topical antifungal therapy is the current standard for the management of fungal keratitis. A diverse array of topical antifungals (Table 2) and dosing schedules are currently used for the management of fungal keratitis. No single antifungal provides efficacy against the spectrum of pathogens recovered from fungal keratitis.

A 2008 Cochrane Review examining the efficacy of different antifungals in the management of fungal keratitis identified nine clinical randomized clinical trials, involving 568 patients, treated with different combinations of antifungals and disinfectants. Because of the variable quality and small number of participants, the authors found no evidence that any particular drug or combination of drugs was more effective in the medical management of fungal keratitis.14 Since the 2012 Cochrane update, results from the Mycotic Ulcer Treatment Trial I (MUTT I), a large, well powered, randomized clinical trial designed to determine the efficacy of topical natamycin vs topical voriconazole for the treatment of filamentous fungal keratitis in 323 patients in South India (April 74

results with voriconazole efficacy against Fusarium species and Aspergillus species (Table 3, 4).17-27 In the 2008 review of the use of voriconazole in the treatment of fungal eye infections, Hariprasad et al document 12 cases where systemic voriconazole or posconazole were used as primary or savage treatment of fungal keratitis. Rescue success (no PK or recurrence) for this review was a little more than half (58%, 7/12 cases).28

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have been published.15 The primary outcome was best spectaclecorrected visual acuity (BSCVA) at 3 months. Isolates spectrum in this study included 128 Fusarium species (40%), 54 Aspergillus species (17%).

Patients treated with natamycin had significant better BSCVA, clinical and microbiological outcomes at 3 months than those treated with topical voriconazole. Patients with Fusarium keratitis fared better with natamycin than with voriconazole.

The authors recommended not using voriconazole as monotherapy or as primary treatment for fungal keratitis.

The results of the MUTT l study were further validated by Sun et al using Bayesian analysis.16 According to the authors, Bayesian analysis suggested that natamycin was superior to voriconazole when filamentous cases were analyzed as a group. In addition, subgroup analysis of Fusarium cases found improvement with natamycin compared with voriconazole, whereas there was almost no difference between treatments for non-Fusarium cases.

Multiple single cases and case series in the literature, report mixed

Combination therapy with two or more antifungals has become the standard for the management of fungal keratitis. The rational for combination therapy includes a broader spectrum of coverage, reduced treatment time and to prevent the emergence of resistant strains.

Frequently natamycin and amphotericin are combined to treat severe fungal keratitis. There is no evidence that this combination is efficacious in managing clinical disease. Laitha et al found no synergy in vitro when evaluating the combination of natamycin and amphotericin against Fusarium and Aspergillus fungal isolates.29 Amphotericin B and natamycin are not synergistic in vitro against Fusarium and Aspergillus species.

In an earlier study, that shared a similar protocol with the MUTT l study, Sharma et al demonstrated that the addition of topical voriconazole to topical natamycin (Group 1-N=20) was more effective in rescue of recalcitrant fungal keratitis than intrastromal injection (50 ug/0.1 ml-Group 2-N=20) against filamentous fungal pathogen.30 Eighty percent (12/15, 80%) of the isolates recovered in culture were Aspergillus species. No Candida or other yeast isolates were among this group. Nineteen of the twenty patients receiving adjunctive topical natamycin healed (95%) versus sixteen of the twenty patients (80%) receiving adjunctive intrastromal therapy. The authors concluded that topical voriconazole was a useful adjunct to topical natamycin for cases that were unresponsive to natamycin alone. There was no benefit to adding intrastromal voriconazole.30

Evidence: Systemic Therapy

Systemic antifungal therapy is used as adjunctive therapy for initial management of fungal keratitis and or savage therapy to rescue vision and prevent surgical intervention especially in patients with deep stromal infections.31-34 There has been mixed success. Therapeutic penetrating keratoplasty in patients treated with adjunctive systemic therapy ranges from 10-26%.

Only one of the RCT in the 2008 Cochrane Review compared the efficacy of topical vs topical and systemic therapy for the management of fungal keratitis. Agarwal et al compared the efficacy of 1% topical itraconazole versus 1% topical itraconazole and oral itraconazole (BID) in 54 patients, Group I (N=22, new patients, not previously treated) vs Group II (N=32, patients with prior treatment with other antifungals). 72.7% in Group I and 81.2% in Group II, (NS) responded favorably to the treatment regimen. Of 12 patients (6 in each group), who did failed, Fusarium was the etiological agent in 4 of the patients. No significant advantaged was documented in this study for the addition of systemic itraconazole.14-17 In a prospective, randomized study, Parachand et al compared the efficacy of oral and topical voriconazole 1% (Group I,-N=15) vs oral voriconazole and topical natamycin 5% (Group II, N=15) and oral itraconazole and topical natamycin (Group III, N=15) in 45 patients with severe fungal keratitis.22 The primary outcomes for the study included time to resolution of the epithelial defect and the presence or absence of a hypoyon. Nature of the corneal opacity and best-corrected visual acuity at 3 months were secondary measures for this study. Inclusion criteria include a positive fungal smear of growth of organisms in culture. Culture positive rates for the 3 groups were: 46.6%, 20% and 46.6%, respectively. There were no significant difference among the three groups for closure of epithelial defect (average number

Miller D, Alfonso EC. Management of fungal keratitis: Topical or systemic therapy?

Table 2-Common Antifungals and Routes of Administration for Medical Management of Fungal Keratitis Drug

Mechanism of action

Pharmacologic Profile

Route of Administration

a

Topical Polyenes

Binds to fungal cell membranes, altering membrane permeability

Oral

b

Intravenous

Amphotericin B

First line therapy for Candida species.

0.05-.30%

Not available

0.5-0.7 mg/kg

Natamycin (Pimiracin)

Fusarium, Aspergillus, less effective against Candida species; first line treatment for fungal keratitis in US, 2% bioavailability

2.5-5%

Not available

Not available

Azoles

Inhibitor of ergosterol biosynthesis of the fungal cell wall, through action on the cytochrome P-450-dependent enzyme. This leads to cell membrane destabilization and

Fungistatic

1% topical 1% cream

Econazole

Effective against Fusarium, Aspergillus and Candida species

0.02-2%

50-100 mg/day

Fluconazole

Effective against yeast, minimal activity against filamentous fungi

0.5-1%

100-400 mg/day

Ketoconazole

Effective against Candida, Aspergillus, limited effectiveness against Fusarium species.

1-2%

200-400 mg/day

Itraconazole

Aspergillus, Candida species, not effective against Fusarium

1%

200-400 mg/day

Miconazole

Effective against Paecilomyces, Scedosporium species

1%

Posaconazole

Limited information, has been used as savage rescue for Fusarium, Scedosporim

Voriconazole

Fungicidal or fungistatic depending on concentration Candida sp., Aspergillus species. non Fusarium solani species, Scedosporium apiospermum Blocks fungal cell wall beta glucan synthesis

Anidulafungin

1-2%

600-1200/day

5 mg/0.5 ml

200-400 mg/day

5 mg/ml

50MG/0.1 ml

Concentration dependent killing Fungicidal effective against yeasts, Aspergillus species; not effective against Fusarium species In vivo efficacy: best predicted by Cmax/MIC >10 or AUC/MIC >25 Limited ocular data 05%

Micafungin

0.1% Block fungal thymidine synthesis

Concentration dependent killing In vivo efficacy best predicted by %T>MIC; 20-40%; effective against yeast

Flucytosine Allyamine

0.8-1.0 mg

200 mg x3/day

Capsofungin

Fluorinated pyrimidines

Intracameral

Concentration independent killing (Time dependent) Mainly Fungistatic, can be fungicidal at high concentrations or growth phase of the fungi In vivo efficacy best predicted by pharmacodynamics parameter: AUC/MIC >25 Two classes: Imidazoles (clotrimazole, ketoconazole, miconazole). Do not penetrate intact cornea epithelium very well Triazoles (fluconazole, itraconazole, voriconazole and posconazole); Good penetration of intact corneal epithilium Recommended dosing: Initial loading dose has not been determined.

Clotrimazole

Echinocandins

Intrastromal

Concentration dependent killing Fungicidal or fungistatic depending on the concentration.

In vivo-efficacy best predicted by pharmacodynamics parameters: AUC/MIC > 25 and or Cmax/MIC >10 Optimal frequency for topical administration undetermined.

Recommended Dosing: Initial loading dose of one drop every half hour with a gradual reduction to six to eight times a day. Do not penetrate intact epithelial barrier

25-37.5 mg/ kg x4 Inhibits squalene epoxidase in the fungal membrane which leads to inhibition and or alteration of ergosterol biosynthesis

Concentration dependent Fungicidal and or fungistatic depending on concentration at the site.

Effective against Aspergillus, Fusarium, Scedosporium and Candida. Demonstrates synergy with amphotericin B and the azoles.

Cmax/MIC or AUC/MIC, levels and ratios undetermined

Terbinafine

of days 30.66 (SD 10.1), l-31.16 (11.4), ll29.26 (8.2), lll-31.86 (11.4) or presence of hypoyon % /days to disappearance l-40%, 9.86 (1.7) days, ll-67%, 12.36 (3.6) days, lll53%, 16 (10.5) days. There were no significant differences in the rate of leukomatous corneal capacity or best-corrected visual acuity at 3 months.22 This study may suffer from low patient numbers and the low overall culture positive rate (48%). It does add to the number of cases that suggest that a combination of topical and oral antifungal therapy might be

0.25%

250 mg/day

useful for severe fungal keratitis cases.

Tu et al used oral and IV posconazole to successfully treat and resolve Fusarium keratitis refractive to treatment with voriconazole and a combination of amphotericin and natamycin.

All 3 cases had been treated aggressively with topical (amphotericin B, natamycin) and oral voriconazole.35 Sonego-Krone et al compared the efficacy of topical fluconazole vs topical fluconazole and oral ketoconazole for the treatment of filamentous keratitis in 23 patients in Paraguay. Organisms

Cmax/MIC=peak concentration over the MIC, >10; optimal dosing large infrequent doses, concentration dependent antifungals (polyenes, allyamines) %T>MIC percent of the time above or near the MIC; optimal dosing smaller more frequent dosing AUC/MIC= average concentration over 24 hours; optimal dosing; concentration over time. b Natamycin is the only commercially available antifungal. All other ocular formulations are prepared extemporaneously (Data compiled from 2, 4, 31, 43) a

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Table 3. Efficacy and Comparison of Clinical Trials for Topical Therapy for Fungal Keratitis Author/Year/Geographic Location

Study Design

Intervention

Number of Patients/History

Outcome Criteria

Organisms

Outcomes

Observation

Prajna NV etal, 2003, south India,

Randomized controlled trial

2% econazole vs 5% natamycin

Group 1 (N=59, econazole)

BSCVA at 3 months, time to heal

Fusarium species Natamycin -60.4%% Econazole-54.2%

Failure rate Natamycin -12% (46/52, 88.5%)

No difference between the two drugs in time to heal

reference #23

Group 2 (N=52, 47.3%)

Kalavathy et al, 2004, south India,

Therapeutic trail

5% natamycin vs 1% itraconazole

reference #19

Liang et al 2009, Beijing, China,

Retrospective clinical trial

0.25 terbinafine vs 5% natamycin

reference #20

100 1st 50-5% natamycin 2nd-50-1% itraconazole

Healing

Group 1 (terbinafine, N=45)

Healing

Fusarium, Aspergillus, Curvularia

Fusarium 22/90 (24.4%)

Group 2 (natamycin, N=45)

Prajna NV etal, 2010, south India reference #24

Matsumoto et al, 2010, Tokyo, Japan

Multicenterdoubled masked, randomized therapeutic exploratory clinical Trial

1% voriconazole vs 5% natamycin

Prospective clinical trial

Arora et al, 2011, North India

Prospective randomized pilot study

BSCVA at 3months

0.1% micafungin vs 0.2% fluconazole

Group 1: micafungin (N=12)

Healing, BCVA

1% voriconazole vs 5% natamycin

N=30

Fusarium (44, 36.7%), 21-received natamycin (35%), 23 received voriconazole (38%)

72% (36) Fusarium: 19/24 (79%) vs 8/18 (44%) for itraconazole Group 1 (45/45, 100% response)

Time to resolution of the ulcer

Group A-N=15; natamycin

BSCVA-natamycin group-20/100 (.69 logMAR) BSCVA-voriconazole group-20/80 (.63 logMAR) Perforation, Group 1 (0) Group 2 ( 11.8)

Group 2 (fluconazole) N=17

15 patients in each group

Overall Success

Group 2 (45/45, 100% response)

N= 120 60 patients randomized to each arm

reference #21

reference #18

Econazole-17% (49/59, 83%)

Aspergillus species (12/40%) Curvularia species (9/30%) Fusarium (3/10%) Culture negative (5/17%)

Overall 29/30 (96.7%) with complete resolution Group 1 (Natamycin-15/15-100%) Group2 (14/15; 93.3%)

reference #15

MUTT lRandomized, double-masked clinical trial

1% voriconazole vs 5% natamycin

Natamycin group (N=162) Voriconazole group (N=163)

included Acremonium (10,43%), Fusarium species (6,26%), Curvularia (4, 17%) and Aspergillus (2, 9%). There was no significant difference in the clinical outcome of patients treated with 2% fluconazole and those with fluconazole plus oral ketoconazole. The overall success rate was 70%, with one third of the Fusarium species, 30% of Acremonium cases and 25% of the Curvularia species demonstrating clinical failure.36 A review of retrospective cases series from India, and the United States confirms that more than 80% of clinicians add oral or systemic adjunctive therapy to their regimen for the management of fungal keratitis.6-11,37,38 Data from the MUTT II clinical trial on the efficacy of oral vs systemic voriconazole in the treatment of fungal keratitis in South 76

N=323

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Patients had better outcomes with natamycin for Fusarium than itraconazole.

RR 0.5614 95 C1 .3220-0.9787 P=.0418 Most ulcers were superficial and treated early, No difference in treatment outcome

No significant difference in visual acuity, scar size and perforation between the groups. (p=.29)

No significant differences in the healing period between the two groups (p=.66) for treating Candida keratitis No significant difference in the efficacy of 1% voriconazole vs 5% natamycin. No added advantage of using 1% voriconazole to treat primary fungal keratitis RR 0.9355 95CI .7810-1.12 (p=.4690)

Group B-N=15voriconazole Prajna NV et al, 2013, South India

RR 1.065 95 CI, .9155 to 1.2393 P=.4139

3 month BSCVA

Fusarium (40%, 128), Aspergillus species (17%, 54) and other filamentous fungi (43%) Fusarium species Natamycin (N=62, 39%) Voriconazole (N=66, 41%)

India have not yet been published, but might provide some insight into the efficacy of systemic vs oral therapy.14 Results: Existing evidence from available clinical trials, case studies and clinical experience is insufficient to determine the efficacy of topical vs systemic therapy for the management of fungal keratitis. Medical management of fungal keratitis continues to be a challenge.

Topical antifungal therapy remains the standard for treatment of fungal keratitis.

Adjunctive therapy with oral or intravenous antifungals may offer additional coverage required for severe or recalcitrant ulcers.

Conclusion and Recommendation: Laboratories studies providing antifungal susceptibility data for natamycin and

Natamycin treated patients had significantly better BSCVA, clinical and microbiology outcomes compared to those treated with voriconazole. (p=.006)

Natamycin was superior to voriconazole for the treatment or Fusarium species (p= <.001)

voriconazole against Aspergillus and Fusarium species indicate that the efficacy of current antifungals is species as well as geography specific.39-42 Minimal inhibitory concentrations (MIC90) suggest in general, increasing poorer outcomes with increasing minimal inhibitory levels for natamycin.

Inconsistent or equivalent results are available for the MIC levels and voriconazole.

This lack of evidence for efficacy of topical, or topical vs systemic antifungal therapy or failure of in vitro susceptibility to predict clinical success might be due to lack of consideration and application of the appropriate pharmacological and dosing profiles. Dosing regiments for concentrationdependent antifungals such as amphotericin B, natamycin or capofungin might differ

Miller D, Alfonso EC. Management of fungal keratitis: Topical or systemic therapy?

Table 4: Efficacy of Topical vs Systemic Antifungal Therapy.

Author/Year

Study Design

Intervention

Number of Patients/ History

Outcome Criteria

Organisms

Outcomes

Observation

Agarwal et al, 2000 Eastern India,

Randomized controlled Trials

1% itraconazole vs 1% itraconazole and oral itraconazole

54 Group 1 (new, topical, N=26)

Healing with 6 weeks

Aspergillus-81% Fusarium-7.4%

Overall-42/54 (77.78%)

No significant advantage for adding systemic itraconazole

Group 1- 19 (72.7%)

(p=.4684)

reference #17

Sonego-Krone et al, 2004, Paraguay, South America

Retrospective Case Series

reference #36

Parchand et al, 2012 Northern India

prospective case series (severe fungal ulcers)

reference #22

Sharma et al, 2013, New Delhi, North India

Randomized clinical trial

reference #25

Group 1= 26 (81.2%

0.2% topical fluconazole vs topical fluconazole and oral ketoconazole

N=23, Group 1-N=12, topical fluconazole; Group 2-N=11, topical fluconazole and oral ketoconazole 200 mg BID

favorable, healing of the ulcer

oral voriconazole (400 mg) bid on day one, then 200 bid, with hourly topical voriconazole (1%)

Group I (N=15)

Oral voriconazole and topical natamycin

Group II (N=15)

oral itraconazole 200 mg bid and topical natamycin

Group III (N=15)

Topical voriconazole + natamycin vs intrastromal voriconazole + natamycin

Group 1 (N=20)topical voriconazole 1%

considerably than for drugs that are concentration-independent (time dependent) such as voriconazole.2,43 (Table 2).

Combining the in vivo pharmacological profile with the in vitro potency of selected antifungals might be the missing link in establishing the efficacy of antifungal therapy in the management of fungal keratitis.

Current Recommendations

Group 2 (N=32, prior antifungal treatment with natamycin)

Evidence-based studies are needed to help determine the selection, route of administration and treatment duration for the management of fungal keratitis.

Acremonium sp (10, 43.85%), Fusarium species (6,26.`1%); Curvularia species (4, 17.4%) Aspergillus species (2, 8.7); Cladosporidium (1, 4.3%)

Overall 16/23 (69.56%) Group 1 (9/12-75%); Group2 (7/1164%)

Addition of oral ketoconazole did not improve clinical outcome, no debridement was performed

Success-resolution of corneal infiltrate with scarring, disappearance of corneal endothelial plaque and hypopyon and closure of epithelial defect

4-Aspergillus sp 1-Curvularia 2-Fusarium sp 8- No growths (53.3%)

10/15 (66.7%)

Voriconazole effective against severe cases of severe keratitis.

No significant differences between oral and topical voriconazole, vs oral and topical natamycin vs

Failure-increase in size by 2 mm or more in size or increaae in the size of the hypopyon and closure of the endothelial plaque continued to enlarge for 3 consecutive days or perforation

1-Aspergillus sp 1-Curvularia 1-Fusarium sp 12- No growths (80%)

11/15 (73.3%)

Oral and topical itraconazole and natamycin.

1-Acremonium sp 3-Aspergillus sp 3-Fusarium sp 8- No growths (80%)

10/15 (66.7%)

Aspergillus species (12/40/30%) Fusarium (7/17.5%) Curvularia (5/12.5%) 15 (37.5%)-No growth

Group 1, 18/20, 90% (topical)

Topical voriconazole was a useful adjunct to topical natamycin in recalcitrant ulcers.

Group 2, 16/20, 80% (intrastromal)

Intrastromal injections did not offer any additional benefit.

BSCVA at 3 months

Group 2 (N=20) intrastromal voriconazole 50 ug/0.1

(p=0.55)

(p=.902)

VA was better in the topical voriconazole group (p.0.008)

REFERENCES 1. Lai TY, Leung GM, Wong VW, Lam RF, Cheng AC, Lam DS. How evidence-based are publications in clinical ophthalmic journals? Invest Ophthalmol Vis Sci. 2006. 47(5):1831-8.

2. Oâ&#x20AC;&#x2122; Day D. W Head. Ocular Pharmacology of Antifungal Drugs, in Duaneâ&#x20AC;&#x2122;s Ophthalmology, T. W and J. Edward, Editors. 2010, Lippincott, Williams and WIlliams: China. 30.

3. Thomas PA, J Kaliamurthy. Mycotic keratitis: epidemiology, diagnosis and management. Clin Microbiol Infect, 2013.

19(3): 210-20.

4. Alfonso, E., A. Galor, and D. Miller, Fungal Keratitis, in Cornea, Fundamentals, Diagnosis and management, J. Krachmer, M. Mannis, and E. Holland, Editors. 2011, Mosby.

5. Keay, L.J., et al., Clinical and microbiological characteristics of fungal keratitis in the United States, 2001-2007: a multicenter study. Ophthalmology, 2011. 118(5): 920-6.

6. Saha, S., et al., Systemic Evaluation on Antifungal Susceptibility of Keratitis Associated Fungal Pathogens in Eastern India. J Med Microbiol Diagn, 2014. 3.

7. Gopinathan, U., et al., The epidemiological features and laboratory results of fungal keratitis: a 10-year review at a referral eye care center in South India. Cornea, 2002. 21(6): 555-9.

8. Iyer, S.A., S.S. Tuli, and R.C. Wagoner, Fungal keratitis: emerging trends and treatment outcomes. Eye Contact Lens, 2006. 32(6): 267-71.

9. Jurkunas, U., I. Behlau, and K. Colby, Fungal keratitis: changing pathogens and risk factors. Cornea, 2009. 28(6): 638-43.

10. Ritterband, D.C., et al., Fungal keratitis at the new york eye and ear infirmary. Cornea, 2006. 25(3): 264-7.

11. Rogers, G.M., et al., Outcomes of treatment of fungal keratitis at the University of Iowa Hospitals and Clinics: a 10-year retrospective analysis. Cornea, 2013. 32(8): 1131-6.

12. Sharma, S., Diagnosis of fungal keratitis: current options.

Expert Opin Med Diagn, 2012. 6(5): 449-55.

13. Loh, A.R., et al., Practice patterns in the management of fungal corneal ulcers. Cornea, 2009. 28(8): 856-9.

14. FlorCruz, N.V., I.V. Peczon, and J.R. Evans, Medical interventions for fungal keratitis. Cochrane Database Syst Rev, 2012.

2: CD004241.

15. Prajna, N.V., et al., The mycotic ulcer treatment trial: a

randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol, 2013. 131(4): 422-9.

16. Sun, C.Q., et al., Expert prior elicitation and Bayesian analysis of the Mycotic Ulcer Treatment Trial I. Invest Ophthalmol Vis Sci, 2013. 54(6): 4167-73.

17. Agarwal, P.K., et al., Efficacy of topical and systemic itraconazole as a broad-spectrum antifungal agent in mycotic corneal ulcer. A preliminary study. Indian J Ophthalmol, 2001.

49(3): 173-6.

18. Arora, R., et al., Voriconazole versus natamycin as primary treatment in fungal corneal ulcers. Clin Experiment Ophthalmol, 2011. 39(5): 434-40.

19. Kalavathy, C.M., et al., Comparison of topical itraconazole 1% with topical natamycin 5% for the treatment of filamentous fungal keratitis. Cornea, 2005. 24(4): 449-52.

20. Liang, Q.F., et al., Effect of topical application of terbinafine on fungal keratitis. Chin Med J (Engl), 2009. 122(16): 1884-8.

21. Matsumoto, Y., et al., The comparison of solitary topical micafungin or fluconazole application in the treatment of Candida fungal keratitis. Br J Ophthalmol, 2011. 95(10): 1406-9.

22. Parchand, S., et al., Voriconazole for fungal corneal ulcers.

Ophthalmology, 2012. 119(5): 1083.

23. Prajna, N.V., et al., A randomised clinical trial comparing 2% econazole and 5% natamycin for the treatment of fungal keratitis. Br J Ophthalmol, 2003. 87(10): 1235-7.

24. Prajna, N.V., et al., Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol, 2010.

128(6): 672-8.

25. Sharma, N., et al., Comparative evaluation of topical versus intrastromal voriconazole as an adjunct to natamycin in recalcitrant fungal keratitis. Ophthalmology, 2013. 120(4): 677-81.

26. Sponsel, W., et al., Topical voriconazole as a novel treatment for fungal keratitis. Antimicrob Agents Chemother, 2006.

50(1): 262-8.

27. Sponsel, W.E., et al., Ocular and systemic posaconazole(SCH-56592) treatment of invasive Fusarium solani keratitis and endophthalmitis. Br J Ophthalmol, 2002.

86(7): 829-30.

28. Hariprasad, S.M., et al., Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol, 2008. 92(7): 871-8.

29. Lalitha, P., et al., Amphotericin B and natamycin are not synergistic in vitro against Fusarium and Aspergillus spp. isolated from keratitis. Br J Ophthalmol, 2011. 95(5): 744-5.

30. Sharma, N., et al., Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: case series. Br J Ophthalmol, 2011. 95(12): 1735-7.

31. P., B., et al., Fungal Keratitis. Expert Rev Ophalmology, 2011.

6(5): 529-540.

32. Said, D.G., et al., The challenge of fungal keratitis. Br J Ophthalmol, 2011. 95(12): 1623-4.

33. Tuft, S.J. and A.B. Tullo, Fungal keratitis in the United Kingdom 2003-2005. Eye (Lond), 2009. 23(6): 1308-13.

34. Tuli, S.S., Fungal keratitis. Clin Ophthalmol, 2011. 5: 275-9.

35. Tu, E.Y., et al., Successful treatment of resistant ocular fusariosis with posaconazole (SCH-56592). Am J Ophthalmol, 2007. 143(2): 222-227.

36. Sonego-Krone, S., et al., Clinical results of topical fluconazole for the treatment of filamentous fungal keratitis. Graefes Arch Clin Exp Ophthalmol, 2006. 244(7): 782-7.

37. Chowdhary, A. and K. Singh, Spectrum of fungal keratitis in North India. Cornea, 2005. 24(1): 8-15.

38. Tanure, M.A., et al., Spectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania. Cornea, 2000.

19(3): 307-12.

39. Lalitha, P., et al., Risk factors for treatment outcome in fungal keratitis. Ophthalmology, 2006. 113(4): 526-30.

40. Oechsler, R.A., et al., Fusarium keratitis: genotyping, in vitro susceptibility and clinical outcomes. Cornea, 2013.

32(5): 667-73.

41. Sun, C.Q., et al., Association between In Vitro Susceptibility to Natamycin and Voriconazole and Clinical Outcomes in Fungal Keratitis. Ophthalmology, 2014.

42. Shapiro, B.L., et al., Susceptibility testing and clinical outcome in fungal keratitis. Br J Ophthalmol, 2010. 94(3): 384-5.

43. Andes, D., Antifungal pharmacokinetics and pharmacodynamics: understanding the implications for antifungal drug resistance. Drug Resist Updat, 2004. 7(3): 185-94.

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REVIEW / Vis. Pan-Am. 2014;13(3):78-81

What is the best therapeutic scheme for Acanthamoeba keratitis?

Denise de Freitas1, MD, Fábio Ramos de Sousa Carvalho2, PhD

Corresponding author address:

1. Associate Professor

Denise de Freitas, MD Rua Botucatu, 821, 04023-062. São Paulo, SP, Brazil

2. Affiliated Professor

Funding: None

Department of Ophthalmology and Visual Sciences, Paulista School of Medicina, São Paulo Hospital, Federal University of São Paulo.

Proprietary/financial interest: None

Abstract

Cyst form

Trophozoite form

Figure 1: Acanthamoeba sp: trophozoite and cyst (arrow points for the cyst operculum).

Figure 2: Pseudodendrite formation in Acanthamoeba keratitis.

Figure 3: Acanthamoeba keratitis presenting multiples perineural infiltrates (perineuritis) 78

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Acanthamoeba keratitis is a sight-threatening disease that carries a favorable prognosis when diagnosed and treated early in the disease course. In some countries, the disease is more common than fungal keratitis, thus showing the importance of knowing and understanding this intriguing infection.

Key words: keratitis; Acanthamoeba; therapy.

Relevant evidence-based information

Amoebae of the genus Acanthamoeba are free-living protozoa and well known facultative human parasites that may cause granulomatous amebic encephalitis, cutaneous acanthamoebiasis, disseminated granulomatous amebic disease, and amebic keratitis, with amebic keratitis being the most common Acanthamoeba infection. Individuals who develop encephalitis or disseminated disease are usually immunocompromised; whereas, those with amebic keratitis are usually immunocompetent.1 Acanthamoeba keratitis is a sight-threatening disease that carries a favorable prognosis when diagnosed and treated early in the disease course. Keratitis is usually associated with a history of improper wearing and cleaning of contact lenses, use of contaminated lens care solutions, and swimming in fresh or swimming pool water while wearing contact lenses.2 In non–lens users Acanthamoeba keratitis is usually associated with trauma and exposure to contaminated water or soil, often in agricultural workers.

Acanthamoeba spp, one of the most common free-living amoebae, are ubiquitous eukaryotic organisms in the environment and have been isolated from soil, water (including natural and treated water), air, and dust. Most people have evidence of prior exposure to the protozoa during their lifetime as 50-100% of healthy people have serum antibodies directed against Acanthamoeba.1 Acanthamoeba genotyping is a useful tool for specific characterization at specie level and investigation of molecular clonality of the protozoan for epidemiological studies of the disease. Up to 18 genotypes designated as T1, T2, T3, etc., have been identified based on 18S rRNA gene sequencing by molecular techniques and the majority of the keratitis-causing Acanthamoeba isolates are genotype T4.4 Acanthamoeba keratitis was first described in 19755,6 but cases substantially increased in the 1980s with the introduction of disposable soft contact lenses and homemade saline solution. The estimated rates of Acanthamoeba keratitis vary among studies depending on the prevalence of contact lens use, the use of contact lens care systems, and exposure to contaminated water and solutions. In the United States

Freitas D, Carvalho FRS. Therapeutic scheme for Acanthamoeba keratitis.

the rate is about 0.15 per million where as in the United Kingdom is 1.4 per million.7 In some countries, the incidence of Acanthamoeba keratitis has exceeded the incidence of fungal keratitis.8 Acanthamoeba has two forms: trophozoite and cyst (Figure 1). The trophozoite is the motile form, which is characterized by locomotion, proliferation, and feeding and has an asexual reproduction by binary fission.

The cyst is the dormant form highly resistant to adverse environment, nutrient deficiency, and chemicals, and is the form responsible for persistent corneal infection.

Common symptoms of Acanthamoeba keratitis include foreign-body sensation, pain, redness, tearing, photophobia, blepharospasm, and blurred vision. Patients may have periods of symptom remission with a waxing and waning course. Severe pain disproportionate to the clinical signs is a hallmark of the disease, although some patients are pain free.

Clinical findings of Acanthamoeba keratitis include epitheliopathy, such as punctate keratopathy and pseudodendrites (Figure 2), epithelial or subepithelial infiltrates, epithelial ulceration, perineural infiltrates/perineuritis (Figure 3), ring stromal infiltrate (Figure 4), focal, multifocal and diffuse stromal infiltration, corneal abscess, corneal melt, and corneal perforation. A slit-lamp grading of corneal disease stage or depth of involvement at presentation provides a practical method to identify high-risk patients in whom clinicians should consider a more aggressive therapy.9 Although primarily a corneal disease, Acanthamoeba keratitis can present with extracorneal manifestations such as cataract, iris atrophy, glaucoma, anterior uveitis with hypopyon, scleritis, and posterior segment inflammation. Acanthamoeba keratitis often presents as a unilateral infection but bilateral involvement is found in 2% to 15% of cases, frequently contact lens users.10,11 Acanthamoeba keratitis has been linked to a number of coinfections, including bacterial, fungal, and viral pathogens12. Infectious crystalline keratopathy is one of these coinfections reported in the literature.13 As a primary factor in the development of infectious crystalline keratopathy in Acanthamoeba keratitis is the chronic corticosteroid use in the setting of a compromised ocular surface. These patients generally require surgical intervention but successful medical management is possible with early recognition of the polymicrobial disease and aggressive treatment. Anti-Acanthamoeba drugs have a broad spectrum of antimicrobial activity, but

alone are not sufficiently prophylactic against the rise of infectious crystalline keratopathy, suggesting that the use of more effective, specific antibacterial drugs may be required in certain patients.12 It seems that patients with coinfection have worst outcomes in comparison to patients having only the amoebic infection.

Acanthamoeba trophozoites or cysts can be demonstrated with corneal scrapings or a biopsy sample by culturing method, fluorescent and histological staining techniques. Motile trophozoites may be seen in a wet-mount preparation or culture onto the non-nutrient agar seeded with avirulent and inactivated Escherichia coli strain. Corneal scrapings can be stained with Giemsa. The earlier detection of young and mature cystic forms of Acanthamoeba spp in corneal scrapings can be provided by the application of fluorescent microscopy technique using the Calcofluor White staining (Figure 5).

Histological analysis of the tissue sections for detection of cysts and trophozoites include several staining techniques, for example, hematoxylin and eosin, periodic acidSchiff and Gomoriâ&#x20AC;&#x2122;s methenamine-silver.

Polymerase chain reaction can be conducted on corneal scrapings and biopsy specimens.14 In addition, tandem scanning confocal corneal microscopy is a noninvasive method also for diagnosis of Acanthamoeba keratitis.15

Results

Medical therapy for Acanthamoeba infection is not well established but in recent years there has been great improvement in the treatment outcome with the use of some antiamebic agents.7 Early diagnosis and treatment are mandatory for improving outcome. Diagnostic delay usually occurs when the diagnosis is presumed to be a herpetic infection.16 Eradication of Acanthamoeba from the infection site is difficult because under adverse conditions, the amoebas encyst and medical therapy is less effective against cysts than trophozoites due to their rigid double wall.17 Because the cysts are the responsible for persistent infection, cysticidal drugs are required in the treatment. Acanthamoeba trophozoites are sensitive to most available chemotherapeutic agents.

The aromatic diamidines, which inhibit DNA synthesis, and the cationic antiseptics biguanides, which inhibit cell membranes, are currently the most effective cysticidal drugs in vitro and their use is supported by substantial case series.7

Polyhexamethylene biguanide, PHMB (0.02% to 0.06%) and chlorhexidine (0.02% to 0.2%), for the class of biguanide, and propamidine isethionate (0.1%) and hexamidine (0.1%), for the class of diamidines, are the four drugs most used in the topical treatment of Acanthamoeba keratitis.

Biguanides are the first-line treatment either alone as monotherapy or in combination with diamidines. Diamidines should not be used as monotherapy because they usually have high values of minimal cysticidal concentrations.

Use of multiple agents has been advocated because they may have a synergic activity and greater cysticidal effect than individual drug application.18 However, combination therapy has the potential disadvantage of epithelial toxicity. Although in vitro studies have shown an additive and or synergistic effect between biguanides and diamidines, there is no clinical evidence to suggest that combined therapy is more effective than monotherapy with biguanides.19 The mainstay of treatment for Acanthamoeba keratitis is topical therapy with biguanides (PHMB 0.02% or chlorhexidine 0.02%) and diamidines (propamidine 0.1% or hexamidine 0.1%) at a frequency of hourly day and night for the first two or three days, depending on toxicity, then reduced in frequency to hourly by day for an additional week, and then tapered as the symptoms and signs improve with the goal of maintaining topical therapy four times daily for several weeks, in an average four weeks (time that we keep the medication q.i.d, completing a total of 4 to 6 months of treatment. About 2 weeks high frequency, about 2 months tapering, and than about 4 weeks qid â&#x20AC;&#x201C; total of 4 months).

Some cases may not respond to the usual protocol and may present persistently positive cultures. In this situation, as a first step, we should increase the drug concentration (PHMB up to 0.06% and chlorhexidine up to 0.2%). If still no response, we should switch drugs, first the biguanides (switch between PHMB and chlorhexidine) and then the diamidines (switch between propamidine and hexamidine). Topical neomycin, frequently prescribed in the past, often encounters resistance from cysts and is no longer used.20 Sensitivity assays against the new antifungal voriconazole are controversial with some studies showing the drug to be active against tested strains21 and in resistant Acanthamoeba keratitis cases22 while some show significant in vitro resistance.23 Systemic use of antifungal drugs is then PAN-AMERICA

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Figure 4: Acanthamoeba keratitis presenting a ring stromal infiltrate

Figure 5: Fluorescence photomicrograph showing a high amount of Acanthamoeba cysts in a corneal scraping by Calcofluor white staining. Magnification 400x.

Figure 6: Recurrence of the Acanthamoeba keratitis after a therapeutic corneal graft

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indicated for persistently culture-positive keratitis highly resistant to usual medical therapy protocol.

The role of steroids is controversial. Animal models have shown that in the absence of antiamebic drugs, corticosteroids promote excystment of Acanthamoeba cysts and proliferation of trophozoites.24 Steroids may be useful for control of inflammation when administered in combination with antiamebic drugs.7 Corticosteroid use before diagnosis of Acanthamoeba keratitis is highly predictive of a poorer visual outcome.25 It has been a common practice to withhold corticosteroids until a minimum of two weeks treatment has been completed and the patient presents improvement of symptoms and signs. Mild corticosteroids (0.1% prednisolone acetate or 0.05% dexamethasone) are the first choice of corticosteroids but some cases may require stronger steroids, such as 0.1% dexamethasone or 1% prednisolone acetate to control severe inflammation. It should be kept in mind that the goal of therapy in Acanthamoeba keratitis is the eradication of viable organisms but also suppression of the inflammatory response elicited by the amoeba antigens.

It is important to discuss the dilemma of persistent inflammation against persistent infection, mainly by the fact that a negative culture result does exclude active infection and false-negative cultures are not uncommon. Several studies suggest that, in some subjects, persistent inflammation may be the result of an immune response to nonviable cysts, whereas in others it is due to viable organisms remaining in the corneal tissue.26 Only corneal scrapes or biopsies culture can discriminate between these two situations as clinical signs are the same, and neither polymerase chain reaction nor confocal microscopy can distinguish between viable and nonviable organisms. It is prudent to assume that the active keratitis is due to viable organisms, unless repeated microbiology is culture negative and, in these cases, the judicious and balanced use of antiamebic drugs and corticosteroids offers clue for the treatment.7 The most challenging cases are those presenting persistently positive cultures after treatment with diamidines and or biguanides.

It has been suggested that late diagnosis is the principal risk factor for persistently culture positive Acanthamoeba keratitis.27 These cases may require a susceptibility test, although a standardized method has not been established, though various methods have been reported.28 As an example, a recent publication on the susceptibility test of seven agents that are clinically used topically against Acanthamoeba isolates revealed that Acanthamoeba cysts were most susceptible to 5% natamycin, followed by 1% povidone-iodine, 0.05% benzalkonium chloride, 0.02% polyhexamethylene biguanide, 0.1% propamidine isethionate, and 0.02% chlorhexidine gluconate. None of the strains was susceptible to 1% voriconazole. The susceptibilities to 0.02% polyhexamethylene biguanide and 0.02% chlorhexidine gluconate may be time dependent and to 0.1% propamidine isethionate may be concentration-dependent.23 Cases of scleritis associated with Acanthamoeba keratitis produce significant pain and tissue destruction, making this extracorneal manifestation one of the most challenging ocular inflammations to control. It is unknown whether the scleral inflammation has an infective or immune-mediated origin. Scleritis associated with Acanthamoeba keratitis can be treated, depending on the clinical severity, with oral nonsteroidal or steroidal anti-inflammatory drugs but some cases may require systemic immunosuppression to control the disease.29 The mean duration of treatment for Acanthamoeba keratitis has been between 4 and 6 months, but there are reports in the literature with

Freitas D, Carvalho FRS. Therapeutic scheme for Acanthamoeba keratitis.

a total of 20 months of medical treatment.27 Once medical cure has been achieved, the disease process may have affected visual acuity requiring rigid or scleral contact lens adaptation or even corneal surgery, phototherapeutic keratectomy or corneal graft for visual rehabilitation.

In relation to prognosis, keratitis usually responds to medical therapy depending on the interval between the onset of symptoms and the start of effective therapy. It is well accepted by the majority of cases reported in the literature that more than four weeks of diagnosis delay, compromises the prognosis.

Therapeutic keratoplasty should be indicated for cases of medical treatment failure or for corneal complications due to the infection such as perforation, that does not respond to corneal gluing, fulminant abscess, and cases of progressive mydriasis, intumescent cataract and or glaucoma.30 Complications of the therapeutic keratoplasty for Acanthamoeba keratitis are recurrence of the disease in the corneal graft (Figure 6), graft failure, graft rejection, glaucoma, and phthisis.31 Visual restoration after Acanthamoeba keratitis with penetrating keratoplasty appears to have an excellent long-term prognosis, provided amoebic infection has resolved and concurrent glaucoma is controlled.32,33 In relation to the post-operative therapy in a case of therapeutic/tectonic keratoplasty, Dr. John K. G. Dart and colleagues from Moorfields Eye Hospital, London, UK, have suggested the use of PHMB 0.02% 6 to 8 times daily immediately after surgery, with an adequate level of topical steroid to control inflammation.

They recommend that this therapy should be continued for at least 3 weeks while results of culture of the host keratectomy specimen are awaited. If viable organisms are cultured it is prudent to continue anti-amoebic therapy 4 times daily while high-doses of steroids are needed, usually 6 months after surgery, as recurrent Acanthamoeba keratitis has occurred up to 3 months after an initially successful transplant. If culture of the excised host cornea is negative after 3 weeks we assume that most viable amoebae have been treated, and the topical anti-amoebic therapy is reduced to 4 times daily and stopped after 1 month.7 Prevention includes avoidance use of potentially contaminated solutions or contaminated waters (swimming pools, lakes) while wearing contacts, and follow manufacturer’s guidelines regarding wearing and cleaning contact lenses. The elimination of the rubbing step of contact lens cleaning may

be one of the mechanisms putting patients at risk for atypical infectious such as Acanthamoeba keratitis. Also, patients frequently top off rather than replace their contact lens solutions; also lens cases are not replaced regularly. Patients should be counseled that overnight wear of contact lenses increases the risk of infection and that lenses should be promptly removed if there are any symptoms of ocular irritation.34

Conclusion and Recommendations

Acanthamoeba keratitis usually responds to medical therapy depending on the interval between the onset of symptoms and the start of effective therapy. An interval more than four weeks of diagnosis delay compromises the disease prognosis. The mean duration of treatment for Acanthamoeba keratitis has been between 4 and 6 months. The role of steroids is controversial, but they should be withheld until a minimum of two weeks of antiamebic drugs has been completed and the patient presents improvement of symptoms and signs. Therapeutic keratoplasty should be indicated for cases of unresponsive medical treatment or for severe corneal complications.

REFERENCES 1. Visvesvara GS. Infections with free-living amebae. Hand Clin Neurol. 2013;114:153-68.

2. Mascarenhas J, Lalitha P, Prajna NV, Srinivasan M, Das M, D’Silva SS, et al. Acanthamoeba, fungal, and bacterial keratitis: a comparison of risk factors and clinical features. Am J Ophthalmol. 2014 Jan;157(1):56-62.

3. Erdem E, Evcil Y, Yagmur M, Eroglu F, Koltas S, Ersoz R. Non-contact lens use-related Acanthamoeba keratitis in southern Turkey: evaluation of risk factors and clinical features. Eur J Ophthalmol. 2014 Mar-Apr;24(2):164-72.

4. Ledee DR, Iovieno A, Miller D, Mandal N, Diaz M, Fell J, et al. Molecular identification of t4 and t5 genotypes in isolates from acanthamoeba keratitis patients. J Clin Microbiol. 2009 May;47(5):1458-62. PubMed PMID: 19321730.

5. Jones BR, McGill JI, Steele AD. Recurrent suppurative kerato-uveitis with loss of eye due to infection by Acanthamoeba castellani. Trans Ophthalmol Soc U K. 1975;95(2):210-3.

6. Jones DB, Visvesvara GS, Robinson NM. Acanthamoeba polyphaga keratitis and Acenthamoeba uveitis associated with fatal meningoencephalitis. Trans Ophthalmol Soc U K. 1975 Jul;95(2):221-32.

7. Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update 2009. Am J Ophthalmol. 2009 Oct;148(4):487-99 e2.

8. Carvalho FR, Foronda AS, Mannis MJ, Hofling-Lima AL, Belfort R, Jr., de Freitas D. Twenty years of acanthamoeba keratitis. Cornea. 2009 Jun;28(5):516-9.

9. Tu EY, Joslin CE, Sugar J, Shoff ME, Booton GC. Prognostic factors affecting visual outcome in Acanthamoeba keratitis.

Ophthalmology. 2008 Nov;115(11):1998-2003.

10. Kim EC, Kim MS. Bilateral acanthamoeba keratitis after orthokeratology. Cornea. 2010 Jun;29(6):680-2.

11. Lee WB, Gotay A. Bilateral Acanthamoeba keratitis in Synergeyes contact lens wear: clinical and confocal microscopy findings. Eye Contact Lens. 2010 May;36(3):164-9.

12. Tu EY, Joslin CE, Nijm LM, Feder RS, Jain S, Shoff ME. Polymicrobial keratitis: Acanthamoeba and infectious crystalline keratopathy. Am J Ophthalmol. 2009 Jul;148(1):13-9 e2.

13. Davis RM, Schroeder RP, Rowsey JJ, Jensen HG, Tripathi RC. Acanthamoeba keratitis and infectious crystalline keratopathy.

Arch Ophthalmol. 1987 Nov;105(11):1524-7.

14. Ikeda Y, Miyazaki D, Yakura K, Kawaguchi A, Ishikura R, Inoue Y, et al. Assessment of real-time polymerase chain reaction detection of Acanthamoeba and prognosis determinants of Acanthamoeba keratitis. Ophthalmology. 2012 Jun;119(6):1111-9.

15. Nakano E, Oliveira M, Portellinha W, de Freitas D, Nakano K. Confocal microscopy in early diagnosis of Acanthamoeba keratitis. J Refract Surg. 2004 Sep-Oct;20(5 Suppl):S737-40.

16. Johns KJ, O’Day DM, Head WS, Neff RJ, Elliott JH. Herpes simplex masquerade syndrome: acanthamoeba keratitis. Curr Eye Res. 1987 Jan;6(1):207-12.

17. Malatyali E, Tepe B, Degerli S, Berk S. In vitro amoebicidal activities of Satureja cuneifolia and Melissa officinalis on Acanthamoeba castellanii cysts and trophozoites. Parasitol Res. 2012 Jun;110(6):2175-80.

18. Mafra CS, Carrijo-Carvalho LC, Chudzinski-Tavassi AM, Taguchi FM, Foronda AS, Carvalho FR, et al. Antimicrobial action of biguanides on the viability of Acanthamoeba cysts and assessment of cell toxicity. Invest Ophthalmol Vis Sci. 2013 Sep;54(9):6363-72.

19. Oldenburg CE, Acharya NR, Tu EY, Zegans ME, Mannis MJ, Gaynor BD, et al. Practice patterns and opinions in the treatment of acanthamoeba keratitis. Cornea. 2011 Dec;30(12):1363-8.

20. Seal DV. Acanthamoeba keratitis update-incidence, molecular epidemiology and new drugs for treatment. Eye. 2003 Nov;17(8):893-905.

21. Cabello-Vílchez AM, Martín-Navarro CM, LópezArencibia A, Reyes-Batlle M, Sifaoui I, Valladares B, et al.

Voriconazole as a first-line treatment against potentially pathogenic Acanthamoeba strains from Peru. Parasitol Res. 2014;113(2):755-9.

22. Bang S, Edell E, Eghrari AO, Gottsch JD. Treatment with voriconazole in 3 eyes with resistant Acanthamoeba keratitis.

Am J Ophthalmol. 2010 Jan;149(1):66-9.

23. Sunada A, Kimura K, Nishi I, Toyokawa M, Ueda A, Sakata T, et al. In Vitro Evaluations of Topical Agents to Treat Acanthamoeba Keratitis. Ophthalmology. 2014 May 28.

24. McClellan K, Howard K, Niederkorn JY, Alizadeh H. Effect of steroids on Acanthamoeba cysts and trophozoites. Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2885-93.

25. Robaei D, Carnt N, Minassian DC, Dart JK. The Impact of Topical Corticosteroid Use before Diagnosis on the Outcome of Acanthamoeba Keratitis. Ophthalmology. 2014;[Epub ahead of print]].

26. Yang YF, Matheson M, Dart JK, Cree IA. Persistence of acanthamoeba antigen following acanthamoeba keratitis. Br J Ophthalmol. 2001 Mar;85(3):277-80.

27. Perez-Santonja JJ, Kilvington S, Hughes R, Tufail A, Matheson M, Dart JK. Persistently culture positive acanthamoeba keratitis: in vivo resistance and in vitro sensitivity. Ophthalmology. 2003 Aug;110(8):1593-600.

28. Kowalski RP, Abdel Aziz S, Romanowski EG, Shanks RM, Nau AC, Raju LV. Development of a practical complete-kill assay to evaluate anti-Acanthamoeba drugs. JAMA Ophthalmol. 2013 Nov;131(11):1459-62.

29. Lee GA, Gray TB, Dart JK, Pavesio CE, Ficker LA, Larkin DF, et al. Acanthamoeba sclerokeratitis: treatment with systemic immunosuppression. Ophthalmology. 2002 Jun;109(6):1178-82.

30. Herz NL, Matoba AY, Wilhelmus KR. Rapidly progressive cataract and iris atrophy during treatment of Acanthamoeba keratitis. Ophthalmology. 2008 May;115(5):866-9.

31. 31.

Kashiwabuchi RT, de Freitas D, Alvarenga LS, Vieira L, Contarini P, Sato E, et al. Corneal graft survival after therapeutic keratoplasty for Acanthamoeba keratitis. Acta Ophthalmol. 2008 Sep;86(6):666-9.

32. Awwad ST, Parmar DN, Heilman M, Bowman RW, McCulley JP, Cavanagh HD. Results of penetrating keratoplasty for visual rehabilitation after Acanthamoeba keratitis. Am J Ophthalmol. 2005 Dec;140(6):1080-4.

33. Kitzmann AS, Goins KM, Sutphin JE, Wagoner MD. Keratoplasty for treatment of Acanthamoeba keratitis. Ophthalmology. 2009 May;116(5):864-9.

34. Acharya NR, Lietman TM, Margolis TP. Parasites on the rise: a new epidemic of Acanthamoeba keratitis. Am J Ophthalmol.

2007 Aug;144(2):292-3.

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Herpetic Keratitis: A review of the evidence Enrique O. Graue-Hernández1, MD, MSc, Eduardo Arenas2, MD

Corresponding author address:

1. Córnea y Enfermedades Externas. Instituto de Oftalmología, Fundación Conde de Valencina. Mexico D.F. México

Enrique O. Graue-Hernández, MD Chimalpopoca 14, Obrera, Cuauhtémoc, 06800 Ciudad de México, Distrito Federal Email: egraueh@gmail.com

2. Fundación Santa Fé de Bogotá , Bogotá, Colombia.

Funding: None

Eduardo Arenas Archila MD Carrera 21 No. 100-20 Cons. 701Bogotá, DC Colombia Email: earenascable@gmail.com

Proprietary/financial interest: None

Introduction

Herpetic eye disease remains a major cause of corneal blindness, with an estimated incidence between 5.9 to 20 /105 of the population per year, with a prevalence of approximately 149/105 individuals in developed countries.1 Of the eight herpes viruses known to infect humans, only five cause significant ocular disease and include herpes simplex types I and II, varicella zoster, cytomegalovirus and EpsteinBarr virus (Table 1). Humans are the only known reservoir for HSV and although its epidemiology has changed, it is generally accepted that its prevalence increases with age and can be identified in the trigeminal ganglia of over 90% of the population 60 years or older.2 Despite infecting most humans, ocular disease affects less tan 1% of the exposed population.3

Pathogenesis

Figure 1. Flourecein staining of a dendritic corneal ulcer.

Figure 2. Rose Bengal staining of a geographic corneal ulcer Virus

Ophthalmic manifestations

Herpes simplex virus 1 (HSV-1)

Blepharitis, conjunctivitis, keratitis, anterior uveitis, retinal necrosis (a combination of the above)

Herpes simplex virus 2 (HSV-2)

Same as above

Varicella zoster virus (VZV)

Same as above

Epstein-Barr virus (EBV)

Epithelial and stromal keratitis

Cytomegalovirus (CMV)

Epithelial and stromal keratitis, endothelitis, and retinitis (or a combination of the above)

Table 1. Herpesvirus associated with ophthalmic manifestations 82

Primary infection occurs often during childhood after contact with infected skin lesions, saliva (HSV-1) or genital secretions (HSV-2) of a shedding carrier.4 Although usually asymptomatic, up to 6% may present with oropharyngeal lesions, characteristic of HSV. Rarely is the eye involved but primary lesions typically evolve rapidly spreading dendrites or geographic ulcers of the corneal epithelium. It is from the trigeminal ganglia that the virus is released.5 Following initial infection, HSV establishes lifelong latency in the trigeminal ganglia. Initial ocular episodes generally happen much later in life characterized by the classical dendritic ulceration. Upon reactivation, virus travels in retrograde fashion through the nerve axon to provoke new lesions.4 In contrast to primary infection, recurrent disease appears in the context of a hypersensitive immune response.4 However limited to the corneal epithelium, in most cases the immune reaction causes variable degrees of stromal edema. Studies suggest that approximately 10 % of patients with epithelial keratitis will eventually experience stromal disease. It is the stromal disease that may affect vision the most and is the most difficult to treat.6

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Graue-HernĂĄndez EO, Arenas E. Herpetic keratitis.

Presentation

The great majority presents unilaterally, with bilateral disease being more common in immunocompromised patients.7 Blepharo-conjunctivitis: It can happen either in the primary infection or as a recurrent disease. Lesions are characteristic, with small vesicles appearing over the eyelid, usually accompanied by edema and moderate pain. In the conjunctiva, it can cause a follicular reaction; occasionally conjunctival dendrites can be identified.8 Epithelial keratitis: Early in disease, clear and raised small vesicles can be identified. As the disease evolves, they coalesce and ulcerate to form the characteristic branching dendrite with raised edges and terminal bulbs containing live virus (Figure 1).4 A geographic ulcer can appear in the setting of topical steroid treatment and immunocompromised individuals (Figure 2).6 Marginal ulcerative keratitis is another form of epithelial disease, usually associated with stromal infiltrate with significantly more pain and increased treatment failure rates (Figure 3). Repeated episodes of inflammation may scar the cornea and decrease its sensitivity, leading to neurotrophic keratopathy.9 Stromal Keratitis: Primary stromal disease can be divided into distinct categories that may have overlapping features.

Immune stromal keratitis is the consequence of antigen-antibody response and appears as uni or multifocal stromal edema and haze with or without neovascularisation (Figure 4).4 As inflammation diminishes, scarring is the rule. Necrotizing stromal keratitis is a rare but fulminant manifestation of HSV, appearing as a dense area of suppurative ulcerative keratitis, with a greyish to white stromal abscess, corneal edema, keratic precipitates, severe iridociclitis and raised intraocular pressure. The intense inflammatory response may lead to corneal thinning and perforation. This form of stromal disease is due to direct viral invasion and inflammation.3 Stromal diseases accounts for 2% of initial presentations and 20 to 50 % of recurrent herpetic disease1 Endothelitis: Endothelitis is thought to be an immunologically mediated manifestation or herpetic eye disease. It reveals itself as keratic precipitates associated with stromal edema and anterior uveitis in various degrees. Three different forms have been identified: disciform, diffuse and linear. Disciform disease is the most common and is seen as a disc shaped area or stromal edema, diffuse and linear disease is much less common.6 Iridociclitis: This manifestation may appear alone or in conjunction with corneal disease and findings may include anterior chamber inflammation with fine cell keratic precipitates and raised intraocular pressure.9

Diagnosis

Diagnosis is based on clinical findings, although laboratory tests are indicated when the clinical diagnosis is ambiguous. Viral culture remains the gold standard, however it is still unavailable for most clinical settings. Viral antigen and PCR can be useful in certain cases of epithelial keratitis.10

Treatment

Drugs are directed to interrupt viral replication without disturbing the host cellular metabolism and while interfering with key steps such viral adsorption, penetration, uncoating, transcription and synthesis and release of viral proteins.11 The host cellular machinery directed by virus specific proteins does transcription. Crucial proteins in these

processes are the thymidine kinase and DNA polymerase, which are virus specific.12

Agents

Trifluridine is pyrimidine nucleoside analogue, that non-specifically inhibits viral and cellular thymidilate synthetase blocking DNA thymidine uptake.11 Acyclovir on the other hand is a synthetic purine nucleoside that is converted to acyclovir monophosphate by the virus- encoded enzyme thymidine kinase and to acyclovir triphosphate by host enzymes. Acyclovir triphosphate is a preferential substrate for viral thymidine, therefore provoking DNA chain termination.12 Valacyclovir (1-valine ester of acyclovir) is pro-drug of acyclovir with increased bioavailability (5 times more).13 Famciclovir is an acyclic guanine derivative, an oral prodrug that is converted by first pass metabolism to penciclovir.14 Penciclovir triphosphate then preferentially inhibits viral DNA polymerase. Compared to acyclovir it has lower affinity for viral DNA polymerase but has a longer intracellular half-life. It is active against HSV-1, HSV-2, VZV and EBV.15,16 Gancyclovir and its prodrug valgancyclovir are is a synthetic analogues of 2-deoxyguanosine (acyclic purine nucleoside).

Ganciclovir triphosphate is a competitive inhibitor of deoxy-guanosine triphosphate incorporation into DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases.15,16 In addition, ganciclovir triphosphate serves as a poor substrate for chain elongation, disrupting viral DNA synthesis by a second route.

Vidarabine is an analogue of adenosine.15 This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand.

Vidarabine triphosphate (Ara-ATP) also inhibits RNA polyadenylation preventing transmethylation reactions.17 Vidarabine is more toxic and less metabolically stable than many of the other current antivirals such as acyclovir and ganciclovir.15 Interferons (IFNs) are glycoproteins made and released by host cells in response to the presence of pathogens. Interferons are named after their ability to â&#x20AC;&#x153;interfereâ&#x20AC;? with viral replication within host cells but have other functions: they activate immune cells, such as natural killer cells and macrophages; they increase recognition of infection or tumour cells by up-regulating antigen presentation; and they increase the ability of uninfected host cells to resist new infection.18 By interacting PAN-AMERICA

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of an antiviral with interferon (RR 1.03; 95% CI 0.99 to 1.07) or with debridement (RR 1.04; 95% CI 0.95 to 1.14) did not yield significantly better outcomes. The corneal epithelial healing outcome improved when antiviral therapy followed debridement (RR 1.21; 95% CI 1.04 to 1.42).18 Intrastromal injections of depot bethametasone and acyclovir aimed at prolonged delivery into the avascular corneal tissue have been used with success.20

Herpetic Stromal Disease

Figure 3. Marginal keratitis

Figure 4. Stromal keratitis with their specific receptors, IFNs activate signal transducers and activators of transcription (STAT) complexes; STATs are a family of transcription factors that regulate the expression of certain immune system genes through the Janus kinase-STAT (JAK-STAT) signalling pathway and several other signalling cascades.15,19

Herpetic Epithelial keratitis

Most cases resolve spontaneously within the first three weeks. The rational for treatment is to lessen discomfort, decrease duration and to diminish stromal damage and scaring. Gentle epithelial debridement may be performed to accelerate healing.

Several systematic reviews have recently analysed the available treatments for epithelial herpetic disease.18 In general, all available antivirals topical or oral are better than placebo and are thus recommended. No significant differences in healing were found in comparisons between acyclovir and trifluridine. The comparison of ganciclovir to acyclovir is still limited by heterogeneity of available studies and possible publication bias. The joint use of two topical antivirals (RR 1.00; 95% CI 0.89 to 1.12) and the use of oral acyclovir alone (RR 0.92; 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.08; 95% CI 0.99 to 1.17) appeared as effective as single topical antiviral therapy. Compared to antiviral monotherapy, the combination 84

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The Herpetic Eye Disease Study was designed to evaluate oral acyclovir for herpetic stromal keratitis.21 Five randomized double masked placebo controlled multicentre trials studied specific therapeutic protocols as follow: A. Controlled trial of oral acyclovir for herpes simplex keratitis: Designed to evaluate the efficacy of oral acyclovir in treating stromal keratitis in patients receiving concomitant topical steroids and trifluridine. one hundred four patients randomized to receive a 10â&#x20AC;&#x201C;week course of oral acyclovir 400 mg five times daily or placebo. By 16 weeks approximately two thirds of patients on either group had failed treatment. This trial concluded that there was no clinically significant beneficial effect of oral acyclovir in treating HSV stromal keratitis in patients receiving topical steroids and antiviral.22 B. Controlled trial of topical corticosteroids for herpes simplex stromal keratitis.

This trial studied the efficacy of topical steroids in stromal keratitis. One hundred six patients with active stromal disease who had not received steroids were enrolled. Patients were randomized to placebo or steroid group (n=49 and 57 respectively). Regimens were tapered over the next 10 weeks. Both groups received topical trifluridine.

Compared with placebo, patients on steroid treatment reduced the risk of persistent or progressive stromal kerato-uveitis by 68%. The treatment group had a significantly shorter time to resolution. It is important to note that delaying treatment (steroid) did not have a negative effect on the visual outcome at 6 months and the recurrence rate was not altered by the use of steroids. The conclusion from this trial is that topical steroid treatment was better than placebo in herpetic stromal keratitis.23

Graue-Hernández EO, Arenas E. Herpetic keratitis.

Treatment recommendation Blepharo-conjunctivitis

• Oral acyclovir (400 mg 5 times a day for 7 days • Oral valacyclovir 500 mgs 3 times a day for 7 days

Epithelial disease

• Aciclovir 3% / ganciclovir 0.15% ointment 5 times a day until the ulcer heals continued with 3 times a day for 7 more days. Alternatively use trifluridine every 2 hours while awake until re-epithelialization followed by 5 times a day for one more week.

• Oral acyclovir or valacycovir

Stromal disease

• Oral and or topical antiviral treatment as above plus topical prednisolone acetate 1% every 2 hours while awake tapered as needed until inflammation resolves.

Iridocyclitis / endothelial disease

• Oral antiviral (as above) and topical steroids as needed to control inflammation.

C. Controlled clinical trial of oral acyclovir for iridociclitis caused by herpes simplex virus: This study was performed to evaluate the use of oral acyclovir added to a regime of topical steroids and trifluridine in patients with HSV iridociclitis.

Patients were randomized to a 10week course of acyclovir 400 mg 5 times daily or placebo while using topical steroids and trifluridine. The trial was stopped before conclusion because of difficulties related to recruitment; however, treatment failure occurred in 50% of the treatment group and in 68% of the placebo and the results suggested a possible benefit of oral acyclovir in the treatment of iridociclitis.24 D. Controlled clinical trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with HSV epithelial keratitis: Patients were randomized to receive a 3-week course of oral acyclovir 400 mg five times a day or placebo.

The conclusion of this study revealed that there is no apparent benefit of oral treatment added to topical trifluridine for the prevention of stromal disease or anterior uveitis.25 E. Controlled clinical trial of oral acyclovir for prevention of recurrent HSV eye disease: 703 patients with history of HSV eye disease in the preceding 12 months were enrolled and randomized to 400 mgs of oral acyclovir or placebo.

The probability of HSV during the 12-month period was 19% and 32 % for the treatment and placebo groups respectively. The conclusion of this trial is that long term oral prophylaxis reduces the rate of recurrences especially in the subgroup of patients with previous history of stromal HSV.25

The different conclusions for the HEDS study and the different systematic reviews available are good starting point for the planning of a therapeutic strategy for a given patient. Treatment should be designed on an individual perspective, based on the available evidence but taking into account the patients medical and ocular history, previous therapeutic failures or successes, the severity of the disease and visual threat, the potential for visual rehabilitation and the socio-economic environment in which the patient lives.

Prophylaxis may also vary from patient to patient but we recommend oral treatment since long-term use of topical antivirals

is toxic to the ocular surface.11 Lifelong treatment may be necessary for patients with recurrent severe stromal disease, those with corneal transplantation for HSV disease or those with single eye. We recommend oral acyclovir 400 mgs twice daily or oral valacyclovir 500 mgs daily.

The renal function has to be monitored. In the given scenario that a patient with HSV ocular disease may require ocular surgery of any type, prophylaxis is recommended starting at least 7 days before the procedure and continued for a reasonable time afterwards (1 to 18 months) depending on the severity of the previous episodes, visual function and surgery performed.26

REFERENCES 1. Young RC, Hodge DO, Liesegang TJ, Baratz KH. Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: the effect of oral antiviral prophylaxis.

Arch Ophthalmol. 2010 Sep;128(9):1178-83.

2. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001 Jan;20(1):1-13.

3. Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012 Sep;57(5):448-62.

4. Rowe AM, St Leger AJ, Jeon S, Dhaliwal DK, Knickelbein JE, Hendricks RL. Herpes keratitis. Prog Retinal Eye Res. 2013 Jan;32:88-101.

5. Toma HS, Murina AT, Areaux RG, Jr., Neumann DM, Bhattacharjee PS, Foster TP, et al. Ocular HSV-1 latency, reactivation and recurrent disease. Sem Ophthalmol. 2008 Jul-Aug;23(4):249-73.

6. Holland EJ, Schwartz GS. Classification of herpes simplex virus keratitis.

Cornea. 1999 Mar;18(2):144-54.

7. Nwosu NN. HIV/AIDS in ophthalmic patients: The Guinness Eye Centre Onitsha experience. Nig Postgrad Med J. 2008 Mar;15(1):24-7.

8. Edell AR, Cohen EJ. Herpes simplex and herpes zoster eye disease: presentation and management at a city hospital for the underserved in the United States. Eye Cont Lens. 2013 Jul;39(4):311-4.

9. Green LK, Pavan-Langston D. Herpes simplex ocular inflammatory disease. Intern Ophthalmol Clin. 2006 Spring;46(2):27-37.

10. Inoue T, Ohashi Y. Utility of real-time PCR analysis for appropriate diagnosis for keratitis. Cornea. 2013 Nov;32 Suppl 1:S71-6.

11. Wilhelmus KR. The treatment of herpes simplex virus epithelial keratitis.

Trans Am Ophthalmol Soc. 2000;98:505-32.

12. Revere K, Davidson SL. Update on management of herpes keratitis in children. Curr Opin Ophthalmology. 2013 Jul;24(4):343-7.

13. Goldblum D, Bachmann C, Tappeiner C, Garweg J, Frueh BE. Comparison of oral antiviral therapy with valacyclovir or acyclovir after penetrating keratoplasty for herpetic keratitis. Br J Ophthalmol. 2008 Sep;92(9):1201-5.

14. Schenkel F, Csajka C, Baglivo E, Kondo-Oestreicher M, Dayer P, Gex-Fabry M, et al. Intraocular penetration of penciclovir after oral administration of famciclovir: a population pharmacokinetic model. J Antimicrob Chemot. 2013 Jul;68(7):1635-41.

15. Vere Hodge RA, Field HJ. Antiviral agents for herpes simplex virus. Adv Pharmacol. 2013;67:1-38.

16. Kaufman HE, Haw WH. Ganciclovir ophthalmic gel 0.15%: safety and efficacy of a new treatment for herpes simplex keratitis. Curr Eye Res. 2012 Jul;37(7):654-60.

17. Whitley R, Alford C, Hess F, Buchanan R. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use.

Drugs. 1980 Oct;20(4):267-82.

18. Wilhelmus KR. Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis. Cochrane Database Syst Rev. 2010 (12):CD002898.

19. Taylor JL, Punda-Polic V, O’Brien WJ. Combined anti-herpes virus activity of nucleoside analogs and interferon. Curr Eye Res. 1991;10 Suppl:205-11.

20. Arenas E TL, Martínez JE. Uso de Inyecciones intraestromales con corticoide de depòsito para el tratamiento de enfermedades inflamatorias de la cornea y el segmento anterior. Vis Panam.

2009 (8):234-7.

21. Dawson CR, Jones DB, Kaufman HE, Barron BA, Hauck WW, Wilhelmus KR. Design and organization of the herpetic eye disease study (HEDS). Curr Eye Res. 1991;10 Suppl:105-10.

22. Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis.

Herpetic Eye Disease Study Group. Arch Ophthalmol. 2000 Aug;118(8):1030-6.

23. Wilhelmus KR, Gee L, Hauck WW, Kurinij N, Dawson CR, Jones DB, et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994 Dec;101(12):1883-95; discussion 95-6.

24. A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. The Herpetic Eye Disease Study Group.

Arch Ophthalmol. 1996 Sep;114(9):1065-72.

25. A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. The Epithelial Keratitis Trial. The Herpetic Eye Disease Study Group. Arch Ophthalmol. 1997 Jun;115(6):703-12.

26. van Rooij J, Rijneveld WJ, Remeijer L, Volker-Dieben HJ, Eggink CA, Geerards AJ, et al. Effect of oral acyclovir after penetrating keratoplasty for herpetic keratitis: a placebo-controlled multicenter trial. Ophthalmology. 2003 Oct;110(10):1916-9; discussion 9.

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Management of Ocular Surface Tumors: Excision vs. Topical Treatment Sotiria Palioura, MD, PhD, Anat Galor, MD, and Carol L. Karp, MD

Corresponding author address:

From Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA Funding: NIH Center Core Grant P30EY014801, RPB Unrestricted Award and Career Development Awards, Department of Defense (DOD- Grant#W81XWH-09-1-0675)The Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Jimmy and Gaye Bryan Grant, and the Richard Azar Family Grant (institutional grants).

Carol L. Karp, MD University of Miami Miller School of Medicine 900 NW 17th St., Miami, FL 33136, USA E-mail: ckarp@med.miami.edu

Proprietary/financial interest: None

Abstract

Ocular surface squamous neoplasia (OSSN) encompasses a range of corneal and conjunctival lesions from intraepithelial dysplasia to invasive squamous cell carcinoma. The mainstay of treatment for OSSN has traditionally been surgical excision with wide margins and cryotherapy.

Increasing evidence on the efficacy and safety of medical therapy and the avoidance of surgical complications has made topical chemotherapy increasingly popular among corneal specialists. The most common topical agents used for the treatment of OSSN include mitomycin C, 5-fluorouracil, and interferon a2b. Herein, we review recent advances in the surgical and medical management of OSSN and discuss advantages and disadvantages of each approach. The role of ultra highresolution optical coherence tomography in the diagnosis and treatment of primary and recurrent OSSN lesions is also discussed.

Key words: ocular surface squamous neoplasia; interferon a2b; mitomycin C; 5-fluorouracil; ultra-high-resolution optical coherence tomography.

Relevant evidence-based information Introduction

Ocular surface squamous neoplasia (OSSN) is the most common non-pigmented tumor of the ocular surface.1 The term “OSSN” encompasses a broad clinical and pathological spectrum of neoplastic squamous epithelial disorders ranging from intraepithelial dysplasia to conjunctival or corneal intraepithelial neoplasia (CIN) (also known as carcinoma in situ) to frank squamous cell carcinoma of the cornea and conjunctiva.2,3 In 86

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a survey of 771 nonmelanocytic conjunctival tumors from a single ocular oncology center 23% (179 tumors) were classified as OSSN.1 Clinically, OSSN lesions can have a gelatinous, papillary, opalescent or leukoplakic appearance, they can be flat or raised, localized or diffuse, and may have a feeder conjunctival vessel.4 OSSN is thought to arise from the limbal stem cells. Thus, it is most commonly found in the interpalpebral region involving the cornea and/or bulbar conjunctiva with the tarsal conjunctiva being less frequently involved.5 The incidence of OSSN is higher in equatorial regions and in older white men (mean age at presentation, 56 years).6 For example, its incidence in the United States is 0.3-8.4 per million people per year7,8, while in Australia it has been reported as high as 19 per million people per year6 and in Uganda as 12 per million people per year.9 Putative mutagenic factors implicated in the pathogenesis of OSSN include ultraviolet radiation10, smoking, immunosuppression, genetics, ocular surface injury, exposure to chemicals (petroleum products, beryllium, trifluridine, arsenic), and vitamin A deficiency.11 Though the human papilloma virus (HPV) is known to be carcinogenic in cervical and head and neck squamous cell carcinomas, current data regarding HPV infection in the pathogenesis of OSSN is still unclear, but it can be a cofactor in its development in already susceptible hosts.12 Though a disease of the elderly, when OSSN is found in younger patients, an underlying immunosuppressive condition, such as infection with the human immunodeficiency virus (HIV)13,14, or genetic predisposition as in xeroderma pigmentosum15, should be sought.

Surgical Excision: Goals and Limitations

Historically, the mainstay of treatment for OSSN has been surgical excision with a “no-touch” technique and additional cryotherapy.16 The principles of this technique include obtaining wide margins (typically 4 mm) and avoiding any contact of the surgical instruments with the tumor to prevent tumor seeding. The lesion is removed en bloc. For tightly adherent tumors, a partial sclerectomy may be required. For tumors involving or abutting the cornea, absolute alcohol is applied first and then the devitalized epithelium is scraped again taking 3-4 mm margins. The scleral bed is cauterized to ensure hemostasis and kill any residual tumor cells and cryotherapy (via a double freezethaw cycle) is applied to the limbus and the conjunctival margins. For closure, we favor an amniotic membrane transplant is secured over the resultant conjunctival defect with tissue glue rather than pro-inflammatory sutures.

Primary closure is an option used by others.

Fresh instruments are used during this final step again as an additional measure to prevent tumor seeding.

Surgical excision with cryotherapy has been the gold standard as the initial management strategy of OSSN because it is both diagnostic and therapeutic. It quickly establishes the diagnosis, provides complete control of the disease if the margins are clear, and is covered by most insurers.

However, the track record for prevention of recurrences after surgery alone has been relatively poor. Microscopic subclinical residual disease is thought to be responsible for the reported recurrence rates of 33% with negative surgical margins17,18 and up to 56% when margins are positive.18 Moreover,

Palioura S et al. Management of Ocular Surface Tumors.

extensive surgical excision can lead to limbal stem cell deficiency or diplopia due to subsequent scarring and symblepharon formation. Infection, formation of pyogenic granuloma, and damage to the sclera and retina from excessive cryotherapy are less frequent complications.

Topical treatment: primary and adjunct role

The aforementioned limitations led to the development of alternative and complimentary medical therapies to surgical excision over the last couple of decades. The three most effective compounds are mitomycin C (MMC)19-26, 5-fluorouracil (5-FU)27-29, and interferon a2b (IFN-a2b).30-32 Other topical agents with less established efficacy include anti-vascular endothelial growth factor (antiVEGF)(33, 34) and retinoic acid.35,36 Mitomycin C is an alkylating agent that inhibits cell division by causing DNA crosslinking. The two most common dosing regimens for the treatment of OSSN are either 0.02% or 0.04% topical drops. The 0.02% formulation is gentler to the corneal epithelium and can has been given four times daily continuously for 28 days or until the lesion resolves.20 Treatment with the 0.02% topical drops for 2 weeks or less is associated with a recurrence rate of 35%.20 The 0.04% formulation causes greater epithelial toxicity and is, thus, typically used four times daily in week on-week off cycles until clinical resolution.37 Reported rates for resolution of OSSN with topical MMC range from 75-100%.

Recurrences were seen in 0-35% of treated cases; most of them were successfully reretreated with MMC. It has also been used intra-operatively (0.02% on the scleral bed for 5 minutes) as an adjunct to surgical excision and pre-operatively as chemoreduction.19-25 The efficacy of topical MMC for the treatment of OSSN was confirmed by a randomized placebo-controlled study with 24 out of 26 MMC-treated OSSN lesions resolving clinically, whereas none of 20 placebo-treated OSSN lesions responded to therapy.26 The major limitation of topical MMC is the pain and corneal epitheliopathy that it induces. Administration in alternate weeks with a topical steroid and frequent lubrication reduces discomfort and enhances patient compliance.37 Long-term complications of topical MMC include punctal stenosis and limbal stem cell deficiency. The use of punctal plugs is, thus, indicated as a preventative measure since, at least in one study, 14%

Figure 1. Slit lamp photograph of an ocular surface squamous neoplasia with gelatinous and papillary features before (A) and after (B) treatment with 2 one week-on, three weeks-off cycles of topical 5-fluorouracil 1% four times daily. The lesion resolved completely after a total of 4 cycles of treatment.

Figure 2. Slit lamp photograph of a papillary ocular surface squamous neoplasia with feeder vessels before (A) and 4 months after (B) treatment with topical interferon a2b 1 million IU/ml drops four times daily. of treated patients developed epiphora from punctal stenosis.38 Recurrent corneal erosion and limbal stem cell deficiency have been reported in about 17% of patients that received MMC for OSSN lesions.39,40 Other limitations for the use of topical MMC include its cost at about $250/cycle at the time of this writing, the requirement of a compounding pharmacy and its instability at room temperature.41 5-Fluorouracil is a pyrimidine analogue that inhibits the enzyme responsible for the synthesis of the DNA base thymidine. Thus, rapidly dividing tumor cells that rely on DNA synthesis for proliferation are preferentially affected. The most common protocol for its administration is 1% 5-FU drops four times daily for 7 days, followed by 30 days off. Similar to MMC, 5-FU can be used as primary treatment for OSSN lesions or as an adjunct to surgical excision (Figure 1). Clinical resolution with topical 5-FU has been reported in about 85% of cases with recurrence rates ranging from 12.5 to 43%.27-29 However, its efficacy for the treatment of invasive OSSN (i.e. squamous cell carcinoma) remains controversial.

Though not as painful as MMC, 5-FU also causes significant corneal toxicity that can partly

be alleviated with the concurrent use of topical steroids and lubricating drops. It is less expensive ($75/cycle) and more stable than MMC, but it does require a compounding pharmacy. The main complication of 5-FU is transient conjunctival hyperemia.42 Although systemic administration of 5-FU is known to cause punctal and canalicular stenosis,43 these complications have not yet been reported with topical ocular use.

Interferons are low molecular weight glycoproteins produced by human leukocytes.

They act as immunomodulators with anti-viral and anti-neoplastic properties. They have been shown to inhibit viral multiplication, halt cancer cell proliferation, and activate killer leukocytes.

Interferon a was first cloned and produced in a recombinant form by genetically-modified Escherichia coli cells in 1980.44 Since then systemic interferon has been used for the treatment of chronic hepatitis B and C, hairy cell leukemia, Kaposiâ&#x20AC;&#x2122;s sarcoma, metastatic malignant melanoma, cervical intraepitehial neoplasia, and cutaneous squamous cell carcinoma among others.45 Interferon a2b can be used for the treatment of OSSN either as a topical PAN-AMERICA

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drop or as a subconjunctival perilesional injection.31,32,46-55 For the topical drops, treatment doses of 1-3 million international units (IU)/ml lead to clinical response. The efficacy of 1 million IU/ml is similar to the higher dose of 3 million IU/ml, albeit with less side effects.48 Thus, the most common treatment regimen is 1 million IU/ml four times daily until resolution, followed by two additional months after resolution (Figure 2).

The average time to resolution is about 12 weeks. The drops are very well tolerated with minimal side effects, such as mild irritation and/or follicular conjunctivitis. Similar to MMC and 5-FU, compounding is required.

The cost is about $250/month.

Subconjunctival perilesional IFN-a2b injections have similar efficacy to topical drops. They are generally given at a dose of 3 million IU/0.5 ml weekly until clinical resolution. The average time to resolution is 4-5 injections.46 Others have used doses of 10 MIU given monthly.56 Pegylated IFN-a2b injections at a dose of 80 mg/ 0.5 ml have also been used successfully in a small number of patients with the goal of prolonging the effect of the drug.47 In contrast to all other topical drop therapies, no compounding is required as IFN-a2b is commercially available in 18 million IU multidose vial. Other advantages include the rapid resolution of the lesion and ensured patient compliance. The main disadvantage over the topical drops is a “flulike” syndrome after each injection that can be controlled with oral acetaminophen.46 The overall success rate with topical or subconjunctival IFN-a2b is 76-100%, with a

recurrence rate of 0-20%. Most recurrences are successfully retreated with interferon a2b.31,32,46-55 Finally, topical interferon drops have been used successfully in patients with positive margins after primary surgical excision of OSSN. Use of topical IFN-a2b drops for a mean of 2 months after surgical excision with positive margins resulted in 4% recurrence rate. This is similar to the recurrence rate after surgical excision with negative margins and is much lower than the 13% recurrence rate that was observed after surgical excision with positive margins and no post-operative interferon use.57 There is some very limited evidence that anti-VEGF agents may have a role in the treatment of extensive squamous cell carcinoma. Out of five patients with diffuse invasive squamous cell carcinoma that received a median of 22 ranibizumab injections, three experienced complete regression of their disease.34 In contrast, no clinical response was noted after a single injection of bevacizumab in a recalcitrant OSSN lesion that had already been treated with topical (MMC and 5-FU) and intra-lesional (IFN-a2b) chemotherapy.33 Retinoic acid, a synthetic analogue of vitamin A, has also been used alone33 or in combination with interferon36 for the treatment of OSSN lesions. In a series of 89 patients that received combination therapy, complete tumor resolution was achieved in 98% of them with a recurrence rate of 2.3% after a mean follow up of more than four years.36

Results

Advantages of medical therapy for the treatment of OSSN include its ability to treat

the entire ocular surface, theoretically thus also treating any microscopic or subclinical disease. Extensive surgical excisions and their complications (e.g. limbal stem cell deficiency) are avoided and inexcisable, diffuse or recurrent lesions can be controlled successfully. One of the criticisms for the use of topical chemotherapy as monotherapy for clinically diagnosed OSSN lesions has been the lack of tissue diagnosis. Biopsy of any suspicious lesion that lacks the typical features of OSSN should be undertaken prior to initiation of topical chemotherapy; this can easily be done at the slit lamp with topical anesthesia.

Alternatively, an “optical” biopsy can be done using ultra high-resolution optical coherence tomography (UHR-OCT).58,59 Studies using a custom built UHR-OCT providing up to 2 mm resolution have been useful in the diagnosis and treatment of OSSN.58-60 Distinctive features for the diagnosis of OSSN and its differentiation from other ocular surface pathologies include the presence of a thickened hyper-reflective epithelial layer, an abrupt transition from normal to diseased epithelium, and a distinct plane between the lesion and underlying tissue (if the lesion is adequately thin) (Figure 3).60 UHR-OCT can detect subclinical disease and define the “margins” of the lesions, which are commonly different than what is apparent on clinical examination. Thus, management can be tailored accordingly to ensure that the neoplasia has been treated completely before topical chemotherapy is stopped.58-60

Figure 3. Slit lamp photograph (A) and ultra high-resolution optical coherence tomography (UHR-OCT) image of an ocular surface squamous neoplasia at the corneoscleral limbus. The UHR-OCT section shown is indicated with a black line in (A) and in the inset in (B). A thickened hyper-reflective epithelium and an abrupt transition zone from normal to abnormal epithelium (arrow) are characteristic features of ocular surface squamous neoplasia lesions on UHR-OCT. 88

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Palioura S et al. Management of Ocular Surface Tumors.

The standard of care for the treatment of OSSN appears to have undergone a noticeable shift over the last decade. The use of topical agents as monotherapy or in conjunction with surgery has become increasingly popular among corneal specialists according to the results of a 2003 and a 2012 web-based survey and the rate of surgical excision alone has been declining.61,62 This paradigm shift from surgery to topical therapy can be attributed to the increasing evidence that topical chemotherapy, and in particular, interferon, provides comparable tumor control to surgical excision.53,63 In the only studies that compared the use of medical therapy (topical or subconjunctival interferon) to surgical excision for the treatment of primary OSSN, there was no statistically significant difference in the rate of tumor recurrence between the two groups.53,63 Regarding the agent of choice for topical therapy, MMC was the preferred one in 2003, while interferon became the most popular one in the 2012 survey. This is not surprising given the increasing evidence over the last decade on the adverse effects of MMC and 5-FU and the favorable safety profile of interferon.61,62

Conclusion and Recommendation

Surgical excision with wide margins, a “no-touch” technique, and cryotherapy has been the traditional gold standard for the treatment of OSSN lesions. It is, however, associated with high recurrence rates and extensive excisions can potentially lead to limbal stem cell deficiency.

Topical chemotherapeutic agents have the theoretical advantage of treating the entire ocular surface including subclinical and microscopic disease. They are thus useful alternatives or adjuncts in recurrent, corneal, or diffuse disease. The main options include MMC, 5-FU, and IFNa2b drops or subconjunctival injections.

Topical interferon can be successfully used as an adjunct in patients with positive margins after surgical excision. The use of topical chemotherapy as monotherapy has become increasingly popular among corneal specialists over the last decade. We predict that with the advent of new imaging techniques such as UHR-OCT that allow for early diagnosis and management of subtle or recurrent lesions, the pendulum will continue to swing away from surgical excision and towards medical therapy.

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Stone DU, Butt AL, Chodosh J. Ocular surface squamous neoplasia: a standard of care survey. Cornea. 2005;24(3):297300.

Adler E, Turner JR, Stone DU. Ocular surface squamous neoplasia: a survey of changes in the standard of care from 2003 to 2012. Cornea. 2013;32(12):1558-61.

Nanji AA, Moon CS, Galor A, Sein J, Oellers P, Karp CL. Surgical versus Medical Treatment of Ocular Surface Squamous Neoplasia: A Comparison of Recurrences and Complications. Ophthalmology.

2014;121(5):994-1000.

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Management of acute and chronic ocular allergy Maria Cristina Nishiwaki-Dantas, MD

Corresponding author address:

Professor of Ophthalmology, Department of Ophthalmology

M. Cristina Nishiwaki-Dantas Rua Martinico prado 26, conj. 181/182 CEP 01224-010 São Paulo Brazil Email: mcristinand@uol.com.br

Santa Casa of São Paulo, São Paulo Brazil Funding: None Proprietary/financial interest: None

Abstract

FIGURE 1. Giant papillae in a patient with vernal keratoconjunctivitis

Pressure to practice evidence-based medicine is increasing and has the potential to reduce malpractice claims. Sometimes the evidence may prove a specific therapy to be ineffective, but practice says it is effective.

In Medicine, however, if you do not trust the evidence, you may expose yourself and your patients to untoward consequences. When we face a complex problem, most of the time it is better to rely on scientific evidence rather than on expert personal opinion.

Key words: ocular allergy; clinical treatment; surgery.

Relevant evidence-based information

Considering ocular allergy, some points can be interestingly discussed:

Is tacrolimus good for all allergic patients? Does tacrolimus work for severe VKC (keratitis, shield ulcer)? Can it replace steroids?

• Opinion: Tacrolimus works for all allergic patients easily replacing topical steroids, especially for shield ulcers.

• Evidence1,9,16,18,27 Tacrolimus (FK 506) is an immunosuppressive drug produced by Streptomyces tsukubaensis. Its mechanism of action includes inhibiting the activation of T lymphocytes and the release of interleukins (IL-2, 3, 4, 5 and interferon g). In regards to potency, tacrolimus is ten times stronger than cyclosporine.

Tacrolimus is indicated for severe dermatitis.22 In Ophthalmology, it has been used for severe atopic dermatoconjunctivitis

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and severe vernal keratoconjunctivitis with corneal involvement and also in nonresponsive cases to routine anti-allergy drugs and steroids.

Tacrolimus (ophthalmic formulation) is available via compounding pharmacies as 0,03% - 0,1% ointment and eyedrops.

It has been used long-term 2-4 times a day in children (over the age of 2 years), adolescents and adults for between 6 weeks and 14 months.

Studies have shown improvement of signs and symptoms, especially when combined with topical antiallergic drugs or topical steroids. It does not replace steroids for severe shield ulcers or keratitis, but often improves the signs and symptoms of severe keratitis. Topical tacrolimus is not associated with severe side effects, but local burning, headache and increasing skin sensitivity to cold have been reported. Studies have shown that tacrolimus is not detectable in the patient’s blood after topical application.

Does topical cyclosporine replace topical steroids for patients with shield ulcers?

Is cyclosporine better for shield ulcers when combined with topical steroids?

• Opinion: topical cyclosporine replaces topical steroids for shield ulcers and may be considered a better option, because it does not have the same serious side effects.

• Evidence5,6,8,11,16,20,28,29 Cyclosporine inactivates T-cell lymphocyte and inhibits pro-inflammatory cytokines (IL-

Nishiwaki-Dantas MC. Management of acute and chronic ocular allergy

2). Cyclosporine is indicated for severe refractory atopic dermatoconjunctivitis and severe vernal keratoconjunctivitis, steroid dependent atopic dermatoconjunctivitis and vernal keratoconjunctivitis. As well as tacrolimus, cyclosporine does not replace steroids for keratitis or shield ulcers, but can be used in conjunction with topical steroids to reduce signs and symptoms and as maintenance therapy when steroids are tapered. Topical cyclosporine is available as 0.05%, 1% and 2% eyedrops and is usually recommended 2-4 times a day for 4 weeks to 6 months, without severe side effects. Side effects include: • Burning (worse than tacrolimus): 9,1% • Irritation: 4,4% • Secondary infection with opportunistic agents.

Topical cyclosporine used two-four times a day for more than 7 years is not detectable on blood.

Thirty percent of steroid dependent patients are able to stop the steroid drops when the steroid treatment is combined with topical cyclosporine.

Debridement is the best way to manage shield ulcer?

• Opinion 1: All shield ulcers should be managed with debridement.

• Opinion 2: Debridement is never indicated for shield ulcer.

• Evidence4,21,24 The characteristic shield ulcer is an oval, sterile and horizontal epithelial defect located in the superior third of the cornea. It is caused by an immune reaction, but also the mechanical trauma caused by the giant papillae rubbing on the cornea plays a role in the pathogenesis of shield ulcer. The corneal defect may range from epithelial punctate keratitis to a frank ulcer.

Cameron4 proposed the following classification: • Punctate erosion • G I – ulcer with transparent base • GII – ulcer with translucid base and white-yellowish deposit • GIII – ulcer with elevated plaque Plaques usually do not resolve with standard conservative measures. Failure to epithelialize may be a result of the plaque material extending below the edges of adjacent epithelium.

Shield ulcers grade II and III do not heal without debridement.

After debridement, complete epithelialization usually occurs within 1-4 weeks. Shield ulcers grade I (without deposit or plaque) do not require debridement.

Does amniotic membrane play an important role in the management of shield ulcer healing?

• Opinion: Shield ulcer healing is always a challenge and additional therapy, like amniotic membrane transplantation, is usually necessary.

• Evidence23,25 Shield ulcers (without deposit/plaque) heal easily with high doses of potent topical corticosteroids. When there is deposit / plaques, debridement is recommended. The patient should also be simultaneously treated with topical corticosteroids However, in persistent shield ulcers that do not respond to conventional treatment, amniotic membrane used as a therapeutic patch, may promote epithelial healing and reduction of inflammation.

Is prophylactic topical antibiotic therapy necessary to prevent secondary shield ulcer infection?

• Opinion: all shield ulcers need prophylactic antibiotics in order to prevent secondary infection that is very common in allergic patients.

• Evidence2,10,13,14,15,26 It is very important to remember that the characteristic shield ulcer in vernal keratoconjunctivitis is usually superficial and frequently has a whitish and elevated plaque that might be similar to an infectious infiltrate, but it is not infectious in nature.

Secondary infection of shield ulcers has been reported occasionally. There are no more than 10 case reports in the literature, although Reddy21 reported an incidence of 10% of secondary bacterial infections.

Therefore, prophylactic antibiotics are usually not indicated to prevent these rare secondary corneal infections unless the patient has other co-morbidities.

FIGURE 2. Day 1 post-surgical removal of giant papillae in a patient with vernal keratoconjunctivitis

FIGURE 3. Day 30 post-surgical removal of giant papillae in a patient with vernal keratoconjunctivitis

Should giant papillae always be surgically removed?

• Opinion 1: if surgery is available, all giant papillae should be removed because they never disappear.

• Opinion 2: Surgical removal of giant papillae is not an option because the underlying allergy will not get better with surgery.

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• Opinion 3: Giant papillae always recur after removal.

• Evidence12,19 Inflammatory mediators play an important role in the immune-mediated pathogenesis of shield ulcers. Giant papillae also play an important role as a mechanical causative agent. The main course of treatment consists of using frequent application of potent topical steroids.

However, if the patient becomes dependent on topical steroids, or if the ulcer is not resolving, other associated treatments should be considered, such as surgical excision of giant papillae.

Not all giant papillae have to be removed. However if they are associated with frequent corneal erosions, especially when the patient is highly dependent on topical corticosteroids, it should be considered.

After removal of the giant papillae, scar tissue similar to trachoma’s Arlt line can be produced and friction of this scar with the corneal surface can cause as much corneal pathology as did the giant papillae. Consequently the excision of the giant papillae should be combined with resurfacing the bare area with some soft tissue, such as lower ​​bulbar conjunctiva (to avoid producing symblepharon) or amniotic membrane.

Surgical technique consists of everting the upper eyelid and maintaining this area with a chalazion forceps.

The giant papillae are removed with a 15 Beaver blade.

Moving the eyeball upward, lower bulbar conjunctiva is harvested and this tissue is sutured to the bare tarsal area, preferably with interrupted absorbable sutures. One of the drawbacks of surgical removal is that typically the patients are children and the surgery must be done under general anesthesia. In one of our published studies, there was no recurrence in 6 eyes of 5 patients followed from 9-27 months. (Figures 1, 2, 3).18 Amniotic membrane is another option that may be used to cover the tarsal conjunctival defect, with a study reporting no recurrence in 13 eyes of 9 patients followed for 14.2 ± 4.2 months.1 2Patients should be maintained on their clinical treatment for vernal keratoconjunctivitis.

Is keratoconus related to ocular allergy?

• Opinion: Patients with ocular allergy have higher incidence of keratoconus.

• Evidence3,7,17 The opinion is correct. Dantas et al7 showed in their study that from 142 eyes of 71 vernal keratoconjunctivitis patients, 9,85% had clinical signs of keratoconus and 22,53% had a topographical diagnosis of keratoconus.

This is compared to a control group of 200 eyes of 100 patients without ocular allergy, none of who presented clinical signs or topographical characteristics compatible with keratoconus.

REFERENCES 1. Al-Amri AM. Long-term follow-up of tacrolimus ointment for treatment of atopic keratoconjunctivitis. Am J Ophthalmol 157:280-6, 2014.

2. Arora R, Gupta S, Raina UK, Mehta DK, Taneja M. Penicillium keratitis in vernal keratoconjunctivitis. Indian J Ophthalmol 50(3):215-6, 2002.

3. Cameron JA, Al-Rajhi AA, Badr JA. Corneal ectasia in vernal keratoconjunctivitis.

Ophthalmology 96(11):1615-23, 1989.

4. Cameron JA. Shield ulcers and plaques of the cornea in vernal keratoconjunctivitis.

Ophthalmology 02(6):985-93, 1995.

5. Caputo R, Pucci N, Mori F, De Libero C, Di Grande L, Bacci GM. Surgical debridement plus topical cyclosporine A in the treatment of vernal shield ulcers. Int J Immunopathol Pharmacol 25(3):775-80, 2012.

6. Daniell M1, Constantinou M, Vu HT, Taylor HR. Randomised controlled trial of topical ciclosporin A in steroid dependent allergic conjunctivitis. Br J Ophthalmol 90(4):461-4, 2006.

7. Dantas PE, Alves MR, Nishiwaki-Dantas MC. Topographic corneal changes in patients with vernal keratoconjunctivitis. Arq Bras Oftalmol 68(5):593-8, 2005 8. De Smedt S, Nkurikiye J, Fonteyne Y, Tuft S, De Bacquer D, Gilbert C, Kestelyn P. Topical ciclosporin in the treatment of vernal keratoconjunctivitis in Rwanda, Central Africa: a prospective, randomised, double-masked, controlled clinical trial. Br J Ophthalmol 96(3):323-8, 2012.

9. Ebihara N, Ohashi Y, Fujishima H, Fukushima A, Nakagawa Y, Namba K, Okamoto S, Shoji J, Takamura E, Uchio E, Miyazaki D. Blood level of tacrolimus in patients with severe allergic conjunctivitis treated by 0.1% tacrolimus ophthalmic suspension.

Allergol Int 61(2):275-82, 2012.

10. Gedik S1, Akova YA, Gür S. Secondary bacterial keratitis associated with shield ulcer caused by vernal conjunctivitis. Cornea 25(8):974-6, 2006.

11. González-López JJ1, López-Alcalde J, Morcillo Laiz R, Fernández Buenaga R, Rebolleda Fernández G. Topical cyclosporine for atopic keratoconjunctivitis. Cochrane Database Syst Rev 12;9:CD009078. doi: 10.1002/14651858.CD009078.pub2, 2012.

12. Guo P1, Kheirkhah A, Zhou WW, Qin L, Shen XL. Surgical resection and amniotic membrane transplantation for treatment of refractory giant papillae in vernal keratoconjunctivitis. Cornea 32(6):816-20, 2013.

13. Gupta A1, Sharma A, Mohan K, Gupta A. Mycotic keratitis in non-steroid exposed vernal keratoconjunctivitis. Acta Ophthalmol Scand 77(2):229-31, 1999.

14. Jain V1, Mhatre K, Nair AG, Shome D, Natarajan S. Aspergillus keratitis in vernal shield ulcer--a case report and review. Int Ophthalmol 30(6):641-4, 2010.

15. Kerr N1, Stern GA. Bacterial keratitis associated with vernal keratoconjunctivitis.

Cornea 11(4):355-9, 1992.

16. Labcharoenwongs P, Jirapongsananuruk O, Visitsunthorn N, Kosrirukvongs P, Saengin P, Vichyanond P. A double-masked comparison of 0.1% tacrolimus ointment and 2%

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cyclosporine eye drops in the treatment of vernal keratoconjunctivitis in children.

Asian Pac J Allergy Immunol 30(3):177-84, 2012 Lapid-Gortzak R, Rosen S, Weitzman S, Lifshitz T. Videokeratography findings in children with vernal keratoconjunctivitis versus those of healthy children. Ophthalmology 109(11):2018-23, 2002.

Nishiwaki-Dantas MC, Dantas PE, Pezzutti S, Finzi S. Surgical resection of giant papillae and autologous conjunctival graft in patients with severe vernal keratoconjunctivitis and giant papillae. Ophthal Plast Reconstr Surg 6(16):438-42, 2000.

Ohashi Y, Ebihara N, Fujishima H, Fukushima A, Kumagai N, Nakagawa Y, Namba K, Okamoto S, Shoji J, Takamura E, Hayashi K. A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis.

J Ocul Pharmacol Ther 26(2):165-74, 2010.

Pucci N, Caputo R, Mori F, De Libero C, Di Grande L, Massai C, Bernardini R, Novembre E. Long-term safety and efficacy of topical cyclosporine in 156 children with vernal keratoconjunctivitis. Int J Immunopathol Pharmacol 23(3):865-71, 2010.

Reddy JC1, Basu S, Saboo US, Murthy SI, Vaddavalli PK, Sangwan VS. Management, clinical outcomes, and complications of shield ulcers in vernal keratoconjunctivitis.

Am J Ophthalmol 155(3):550-59, 2013 Rikkers SM, Holland GN, Drayton GE, Michel FK, Torres MF, Takahashi S.Topical tacrolimus treatment of atopic eyelid disease. Am J Ophthalmol 135(3):297-302, 2003.

Rouher N1, Pilon F, Dalens H, Fauquert JL, Kemeny JL, Rigal D, Chiambaretta F. Implantation of preserved human amniotic membrane for the treatment of shield ulcers and persistent corneal epithelial defects in chronic allergic keratoconjunctivitis.

J Fr Ophtalmol 27(10):1091-7, 2004.

Solomon A1, Zamir E, Levartovsky S, Frucht-Pery J. Surgical management of corneal plaques in vernal keratoconjunctivitis: a clinicopathologic study. Cornea 23(6):60812, 2004.

Sridhar MS, Sangwan VS, Bansal AK, Rao GN. Amniotic membrane transplantation in the management of shield ulcers of vernal keratoconjunctivitis. Ophthalmology 108(7):1218-22, 2001.

Sridhar MS1, Gopinathan U, Rao GN. Fungal keratitis associated with vernal keratoconjunctivitis. Cornea 22(1):80-1, 2003.

Tam PM, Young AL, Cheng LL, Lam PT. Topical tacrolimus 0.03% monotherapy for vernal keratoconjunctivitis-case series. Br J Ophthalmol 94(10):1405-6, 2010 Vichyanond P, Kosrirukvongs P. Use of cyclosporine A and tacrolimus in treatment of vernal keratoconjunctivitis. Curr Allergy Asthma Rep 13(3):308-14, 2013 Wan KH1, Chen LJ, Rong SS, Pang CP, Young AL. Topical cyclosporine in the treatment of allergic conjunctivitis: a meta-analysis. Ophthalmology 120(11):2197-203, 2013.

Lichtinger A. Corneal graft rejection.

Prevention and management of corneal graft rejection Alejandro Lichtinger, MD

Corresponding author address:

From Instituto de Ciencias Oftalmológicas, Hospital Ángeles Lomas

Alejandro Lichtinger, MD Hospital Ángeles Lomas Torre de Especialidades, consultorio TE-430 Av. Vialidad de la Barranca s/n Col. Valle de las Palmas, Huixquilucan, Estado de México C.P 52763

Cornea, Cataract and Refractive Surgery Funding: None Proprietary/Financial interest: None

Abstract

Corneal graft rejection is the most frequent cause for graft failure after penetrating keratoplasty (PK), an area in which we can improve by better prevention and management strategies. Corticosteroids remain the mainstay for both prevention and treatment of rejection; there seems to be a benefit of long-term topical steroids as prophylaxis and the use of pulsed IV steroids in the treatment of rejection itself. It is difficult to determine the role of other immunosuppressant’s, but cyclosporine A, mycophenolate mofetil and tacrolimus are frequently used with good results in some studies. There is a need for well-designed randomized clinical trials to really evaluate the therapeutic benefit of these medications and new approaches on the pipeline.

Key words: corneal transplant; rejection; immunosuppressive therapy.

Relevant evidence-based information

The success rate of corneal transplantation is less than is generally appreciated. The Australian Corneal Graft Registry reports overall 1-year survival for penetrating keratoplasty (PK) to be 87%; which diminishes to approximately 73% at 5 years and 62% at 10 years. In high risk cases, the 10 year survival rate can be less than 40%.1,2 The prognosis decreases substantially with the number of previous grafts, and the survival rates for third and fourth re-grafts range between 50% and 0%.3 For a relatively immunologically privileged site, long term PK survival is just comparable to that of renal transplantation.(2) Studies

have shown that unlike the cornea, most solid organ transplantations have demonstrated improvements in survival rates.1 The immune privilege of corneal allografts is the product of 3 fundamental adaptations that: a) block the induction of destructive alloimmune responses; b) deviate alloimmune responses toward a tolerogenic pathway; and c) block expression of immune effector elements at the graft/host junction interface;(4) but this immune privilege is readily eroded by the sequelae of inflammation.5 Endothelial rejection is the most frequent cause for graft failure after normal risk PK;3 rejection is often reversible, but even if it can be reversed, it carries a poor prognosis for the occurrence of subsequent episodes and ultimate graft failure.5 The use of glucocorticoids remains the backbone for both prevention and treatment of corneal graft rejection as well as other immunosuppressant’s that are used alone or in combination with corticosteroids for the same purpose.

Glucocorticoids

From a clinical perspective, glucocorticosteroids are the standard treatment for both prevention and therapy of corneal graft rejection.2,3 Glucocorticoids achieve this through multiple mechanisms,6 one of the most important of which is to inhibit leukocyte migration into the cornea, thereby abrogating the efferent arm of the immune response.

There is however, considerable debate on the optimal administration route, time and dosage;7,8 all of which will be addressed in this review.

There is great discrepancy as to how long to use steroids after a normal risk PK; A study by Koay et al8 surveyed the “Bowman club” members and the mean duration of topical steroids was just 8.7 months while only 5.5% of responders used topical corticosteroid treatment indefinitely.

In the last 7 years, at least two prospective1,3 and one large retrospective study9 have suggested that the use of long term topical steroids protects against immunologic graft rejection. The first study, published by Nguyen et al3 randomized 406 eyes 6 months after PK and topical 1% prednisolone acetate to either stop topical steroids or continue steroid once a day for another 12 months, 9.1% of patients in the non-steroid group developed a rejection compared with only 4.9% in the long treatment group (p = 0.001).

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The second study published by Ross et al1 looked into the survival of PKs performed for visual improvement in 1033 pseudophakic bullous keratopathy (PBK) cases. They found a 3-year survival of 65% and that grafts not receiving steroids were 1.5 times as likely to fail (hazard ratio, 1.5; 95% CI, 1.0 â&#x20AC;&#x201C; 2.2; p<0.03). They conclude that long term postoperative corticosteroids improved graft survival after PK for PBK and that baring any contraindication, patients should be on longterm corticosteroid maintenance.

Shimazaki et al9 performed a randomized trial in which they enrolled 42 patients who underwent PK and had clear grafts for over 1 year and then assigned to use either 0.1% fluorometholone 3 times a day or to discontinue all steroid use. They had 1 rejection in the steroid group and 6 cases in the non-steroid group (x2 test, p = 0.027, log-rank test, P =0.032), demonstrating a clear benefit of continued use of low-dose corticosteroids.

These studies suggest that continued use of corticosteroids, baring any contraindication, is protective against rejection and should be considered to improve overall graft survival.

Topical corticosteroids are enough to revert a mild rejection, while other periocular or systemic delivery modalities are recommended for severe cases.10 A couple of studies have demonstrated that pulsed IV methylprednisolone is effective and superior to oral steroids in the management of severe endothelial rejection.11-13 A study by Hill et al11 randomized 48 patients with severe endothelial rejection to receive either hourly topical prednisolone 1% and a single 500mg pulse of methylprednisolone or hourly topical prednisolone and oral prednisone 60-80mg a day and found that in patients who sought treatment within the first week survival rates were 92.3% with pulsed therapy and 54.5% in the oral group (p <0.05) The IV treatment also seemed to prevent subsequent rejection episodes when compared to oral therapy (p < 0.025). A second study by Costa et al13 found similar outcomes, with significant better survival when a pulse of 500mg of methylprednisolone was used in addition to topical prednisolone 1% (p < 0.05).

Another study by Dr. Hill´s group14 evaluated the benefit of adding a second pulse of IV methylprednisolone at either 24 or 48 hours, finding no improvement from a single pulse.

A study by Costa et al15 compared the effectiveness of a subconjunctival injection of triamcinolone acetonide (20mg) in 94

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combination with topical prednisolone acetate 1% in 16 patients, as compared with retrospectively matched patients who received a single intravenous injection of 500mg of methylprednisolone in combination with topical 1% prednisolone. Their results showed significant better outcome regarding reversibility of the rejection episode with the subonjunctival injection (p= 0.025). Although these results have not been confirmed by a randomized, controlled trial, the use of a subconjunctival injection is a good alternative that can be used at the office without further delay or referral for the intravenous treatment or when this treatment is contraindicated due to systemic comorbidities.

Other routes of corticosteroid administration have been reported, such as Intracameral16-18, intravitreal19 and intrastromal.20 The use of intracameral corticosteroids for graft rejection was first reported by Reinhart and Sundmacher16,17 in a pilot study with apparent good results as an adjunctive measure. The use of intracameral triamcinolone acetonide 4mg in 0.1ml was reported by Maris et al.18 In the case of intravitreal injection of triamcinolone acetonide 4mg in 0.1ml in addition to conventional treatment, including systemic and topical steroids and cyclosporine A. A pilot study by You and Yoon showed a reduction in the time to improvement(p =0.04) with no difference on the recurrence rate.19 The risks of these intraocular injections should not be understated. Known complications include cataract formation, increased intraocular pressure and infectious endophthalmitis. All of these potential complications need to be considered before opting for these modalities.

Other immunosuppressants

The search for an effective, tolerable and minimally toxic immunosuppressant is crucial especially for high-risk cases, the medications that are used today are cyclosporine A (CsA), mycophenolate mofetil (MMF) and tacrolimus (FK506), all of which will be discussed in detail. Other agents such as rapamycin, sirolimus and basiliximab have been tested in a few studies, but are not yet proven and the available literature is scarce.

Cyclosporine A (CsA)

CsA is a potent immunosuppressant that has been used systemically or topically and either alone or in combination with corticosteroids and other agents with mixed results.

There were promising results early on with the use of topical CsA.21 Cosar et al22 showed a reduced graft rejection rate in pediatric cases when CsA 2% was used with topical steroids (p =0.465). A retrospective study by Inoue et al23 found the same effect when using CsA in high risk grafts (p= 0.03). Recent literature has not found topical cyclosporine to reduce the risk of rejection in either 0.05% nor 2% concentration. One of these prospective studies, found that 0.05% cyclosporine on 3 different regimens was not as effective as topical prednisolone acetate 1% for prevention of rejection even in low-risk transplants24, in the case of high-risk grafts, another study showed that the addition of cyclosporine 0.05% to topical steroids did not reduce the rejection rate.25 Javadi and cols26 evaluated adding 2% topical CsA to a corticosteroid regimen in 22 eyes with previous history of rejection, and found no advantage with the use of CsA. A randomized trial evaluated 2% CsA in addition to topical steroids, in the prevention of graft rejection in 78 high risk cases and found no difference when compared to steroids alone.27 Systemic CsA is the most frequently used immunosuppressant for high-risk keratoplasty after corticosteroids. Hill28 reported a study comparing topical steroids vs. topical + oral steroids vs. topical + oral steroids + systemic CsA in high risk PK, and found a significant improvement in survival with the addition of CsA (p= 0.0001). He later reported on a prospective series comparing 3 groups, topical steroids, steroids + 4-6 months of CsA and steroids + 12 months of CsA and found a significant improvement in both rejection (p= 0.025) and reversibility (p= 0.002) and better performance overall with the long term treatment.29 Sundmacher et al30 reported 6 years experience of using CsA in high risk grafts in 1992, and although this was a retrospective report, they conclude that CsA increased the rate of success. A study by the same group reported a drop on high risk graft failure from 28% to 0% within 3 years when using CsA.31 Recent studies have found only a limited to no benefit of adding oral CsA in high risk PKs. A retrospective study by Inoue et al32 compared the benefit of adding systemic CsA to topical steroids on high-risk grafts and found no difference in rejection rate or survival. A retrospective case-control study by Poon et al33 compared rejection and failure rates between 49 highs risk cases receiving systemic CsA and 49

Lichtinger A. Corneal graft rejection.

controls, rejection occurred in 36.7% and 53.1% (p= 0.16) of cases in the CsA and control groups from which 8.2% and 16.3% failed (p= 0.36). Furthermore, CsA was discontinued due to side effects in 10.2% of cases. They concluded that the benefit of CsA is moderate at best and that a randomized trial was needed to determine the true value of CsA. Such a randomized study was performed by Shimazaki.et al34.

Forty high risk patients were randomized, endothelial rejection developed in 6 and 2 eyes in the CsA and control groups respectively, no difference was observed in the rates of graft clarity between groups (p= 0.16) with a mean follow-up of 42.7 months. Seven patients discontinued CsA within 6 moths due to side effects. A lack of positive effect and a relatively high incidence of side effects, lead them to conclude that systemic CsA should not be recommended for corneal transplantation.

One of the issues with systemic CsA is its wide range of side effects, (diabetogenicity, hypertension, hyperlipidaemia, nephrotoxicity). Another downside is the need to adjust the daily dose to keep blood levels within optimal range, which requires often and expensive monitoring. With the vast differences in the results of these studies, it is difficult to make evidence based clinical guidelines on the use of systemic CsA. More randomized trials are necessary to reach valid conclusions in this regard.

Mycophenolate Mofetil (MMF)

MMF has been shown to be an effective immunosuppressant and it has been incorporated into the majority of the immunosuppressive combinations that are used in kidney transplantation, substantially decreasing rejection rates. MMF does not negativelly impact blood pressure, lipid profile, or glycemic metabolism and it is not nephrotoxic35 thus having a favorable side effect profile compared to CsA. Compared to a control group receiving topical and oral steroids, the addition of MMF 1000mg, twice a day for 6 months demonstrated in a randomized study an improvement in rejection free grafts at 1 year of 67% to 89% (P = 0.03).(36) suggesting that MMF is effective in the prevention of graft rejection in high risk cases.

Reis et al39 randomized 41 high risk grafts to receive CsA or MMF for 6 months in addition to oral and topical steroids.

They had 2 cases of reversible rejection per

group, demonstrating that MMF was just as effective as CsA. A 3 years follow-up report had already enrolled 29 patients to MMF and 27 to CsA. At 3 years, 74% and 69% of grafts were clear respectively. They propose that pharmacologically induced relative immunological tolerance decreases at about two years, so that long-term administration of MMF should be evaluated further to try to maintain the immune tolerance.38 A retrospective study, analyzed longterm results of 417 high-risk keratoplasties of which 252 were given CsA, 149 MMF and both medications in 16 cases. Sixty percent of grafts in the CsA and 72% in the MMF group were rejection-free 3 years postoperatively (P=0.03). Clear graft survival after 3 years was 77% and 87%, respectively. This study found a statistical significant benefit in favor of MMF regarding rejection and survival, with fewer side effects and a shorter administration time.39 Currently literature on the use of MMF for high-risk keratoplasty, demonstrate it is as effective if not better than CsA, with an improved side effect profile and the advantage of not requiring an extensive blood level monitoring.

Tacrolimus

FK506 is a macrolide with a similar mechanism of action to that of CsA. It has been widely used in solid organ transplantation to replace CsA.40 Some case series have reported good outcomes with systemic administration.41,42 One of these studies reported on 23 high risk grafts treated with a mean dosage of 4.4mg a day, with a mean follow-up of 24 months, they had no cases of irreversible rejection and only 3 rejections associated with low tacrolimus levels.41 The use of topical FK506 has also been explored. Dhaliwal et al40 reported on 4 cases using commercially available ointment (0.03%), twice daily. All cases responded to treatment and had no further rejection episodes. A recent cohort study, compared the irreversible rejection rate of high risk grafts that received either topical steroids (36 eyes) or topical steroids + topical tacrolimus 0.03% drops(36 eyes); Seven grafts (19.4%) lost transparency in the FK506 group compared to 16 (44.4%) in the steroids group (p <0.05).43 A prospective randomized trial evaluated the efficacy of topical FK506 0.06% drops for 6 months in normal risk PK. Twenty patients received FK506 drops and another 20 received topical steroids. At 1 year, 100% of the

FK506 patients and 84% of the steroid cases remained rejection free (p= 0.09), suggesting that topical FK506 might be effective for immunoprophylaxis even in normal risk-PK, although 8 patients discontinued FK506 due to local discomfort, something that could be improved with the formulation.44

Conclusions and recomendations

After assessing the peer reviewed literature on the topic and without this being a systematic review to emit clinical guidelines or recommendations, it is evident that most of the literature discussed in this manuscript lacks the methodological clarity and planning to be considered for level 1 evidence; most of the studies included are either retrospective or small case series and even most of the prospective studies are either small, non randomized, not double or even single blinded or lacking information regarding randomization and treatment allocation, so that my recommendations may not have the foundation I would have liked but it shows us that there are still many questions to be answered and a lot of clinical research to be done.

To put things in perspective, when we compare the stable graft survival in cornea with the increased survival in renal transplantation, we find that 3 major developments have contributed to the 50% improvement in renal graft outcomes; better histocompatibility matching, improved systemic immunosuppression and the use of living related donors. Neither matching, nor the use of systemic immunosuppression is widely practiced in corneal transplantation.

The use of living-related donors is clearly not justifiable.5 Human leukocyte antigen (HLA) matching has not found favor among clinicians, in part because the American Collaborative Corneal Transplant Study reported no benefit from HLA class I and Class II matching. In other parts of the world such as the United Kingdom, Germany, and Holland a benefit from matching has been reported, with improvements in high risk cases as high as 40%.45 A cost-effectiveness study published this year found the incremental costeffectiveness ratio of HLA matching for corneal transplantation to be acceptable. Furthermore, matching may be the only currently available intervention that can improve outcomes in high-risk cases without exposing patients to the side effects of immunosuppressants.

Another strategy that improves corneal graft survival is the use when indicated, of PAN-AMERICA

95

REVIEW / Vis. Pan-Am. 2014;13(3):93-96

lamellar grafting techniques, which allow the transplantation of smaller quantities of tissue, thereby reducing the antigen load, these techniques have demonstrated reduced rejection rates when compared to PK.46 There is no question that corticosteroids have a role on the prevention and treatment of corneal graft rejection. It seems safe to state that the addition of a single 500mg IV pulse of methylprednisolone on diagnosis of a severe rejection episode improves the reversal rates and should be considered over oral steroids, the evidence on subconjunctival triamcinolone acetonide 20mg is not as sound, but it should be considered when systemic comorbidities would contraindicate systemic steroids or when difficulty in arranging for the IV pulse would delay treatment.

Other immunosuppressive agents have shown some promise in the prophylaxis and treatment of corneal graft rejection. CsA is the most frequently used immunosuppressant, various studies have demonstrated its lack of effect when used topically, and there is conflicting evidence on its systemic administration. MMF has been demonstrated to be at least as effective as CsA but with a better side effect profile and easier monitoring, which make it an interesting option. Tacrolimus has been used both systemically and topically with apparent good results and may have a role in the future as a steroid sparing agent, if results about its topical effect when compared to steroids in normal risk PK are confirmed and reproduced.

We still don’t know what the safest and most effective way of improving graft survival after corneal transplantation is. We have come a long way but we need to embrace what has been learned from transplantation of other organs and perform properly designed studies to find the best evidence-based prevention and treatment protocols.

Some new local experimental approaches for immunosuppression will probably be applied in the future, such as the use of antibody based regimens and gene therapy, to slow release devices that are placed subconjunctivally or in the anterior chamber.

This may help eliminate patient compliance as a factor in treatment failures, permit for local administration reducing systemic toxicity and allow for a more convenient dosing regimen for the patient in the future.

96

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Preserva la visión alcanzando las menores presiones-objetivo en más pacientes Investigadores de diversos estudios, (AGIS, Shirakashi, Shields) han comprobado que alcanzar y mantener la PIO entre 14 y 15 mmHg reduce la progresión de pérdida del campo visual1,2,3.

Lumigan® alcanza la PIO-objetivo de 14/15 mmHg en un mayor número de pacientes: ®

vs. timolol 4

®

vs.

dorzolamida/ timolol 5

®

vs. latanoprost 6

Porcentaje de Pacientes que alcanzaron la PIO-Objetivo ≤14

21%

9%

17%

2%

19%

9%

Porcentaje de Pacientes que alcanzaron la PIO-Objetivo ≤15

31%

16%

24%

9%

29%

14%

Lumigan ® (bimatoprost) Forma farmacéutica y pr esentación.

Composición. Cada ml contiene: 0,3 mg de bimatoprost. Vehículo: cloreto de sódio, fosfato de sódio presentación. esentación.Frascos cuenta-gotas conteniendo 5 ml de solución oftalmológica estéril de bimatoprost a 0,03%. USO ADULTO.Composición. hepta-hidratado, ácido cítrico mono-hidratado, ácido clorídrico y/o hidróxido de sódio, cloruro de benzalconio y agua purificada qsp. Indicaciones. LUMIGAN® (bimatoprost) es indicado para la reducción de la presión intra-ocular elevada en pacientes con glaucona o hipertensión ecauciones y Adver tencias. Advertencias. Fueron relatados aumento gradual del crescimiento Contraindicaciones. LUMIGAN ® (bimatoprost) está contraindicado en pacientes con hipersensibilidad al bimatoprost o cualquier otro componente de la fórmula del producto. Pr Precauciones Advertencias. ocular.Contraindicaciones. de las pestañas en el largo y espesura, y oscurecimiento de las pestañas (en 22% de los pacientes después 3 meses, y 36% después 6 meses de tratamiento), y, oscurecimiento de los párpados (en 1 a <3% de los pacientes después 3 meses y 3 a 10% de los pacientes después 6 meses de tratamiento). También fue relatado oscurecimiento del íris en 0,2% de los pacientes tratados durante 3 meses y en 1,1% de los pacientes tratados durante 6 meses. Algunas de esas alteraciones pueden ser permanentes. Pacientes que deben recibir el tratamiento ® ecauciones LUMIGAN (bimatoprost) no fue estudiado en pacientes con insuficiencia renal o hepática y por lo tanto debe ser utilizado con cautela en tales pacientes.Las lentes de contacto deben Precauciones de apenas uno de los ojos, deben ser informados a respecto de esas reacciones. Pr ser retiradas antes de la instilación de LUMIGAN® (bimatoprost) y pueden ser recolocadas 15 minutos después. Los pacientes deben ser advertidos de que el producto contiene cloruro de benzalconio, que es absorvido por las lentes hidrofílicas.Si más que un medicamento de uso tópico ocular estuviera siendo utilizado, se debe respetar un intervalo de por lo menos 5 minutos entre las aplicaciones.No está previsto que LUMIGAN® (bimatoprost) presente influencia sobre la capacidad del paciente conducir vehículos u operar máquinas, sin embargo, así como para cualquier colírio, puede ocurrir visión borrosa transitoria después de la instilación; en estos casos el paciente debe aguardar que la visión se normalice antes de conducir u operar máquinas. Interacciones medicamentosas. medicamentosas.Considerando que las concentraciones circulantes sistemicas de bimatoprost son extremadamente bajas después múltiplas instilaciones oculares (menos de 0,2 ng/ml), y, que hay varias vías encimáticas envueltas en la biotransformación de bimatoprost, no son previstas interacciones medicamentosas en humanos. eacciones adversas. LUMIGAN® (bimatoprost) es bien tolerado, pudiendo causar eventos adversos oculares leves a moderados y no graves.Eventos adversos ocurriendo en 10-40% de los pacientes que recibieron doses únicas diarias, durante No son conocidas incompatibilidades. RReacciones 3 meses, en orden decreciente de incidencia fueron: hiperenia conjuntival, crecimento de las pestañas y prurito ocular.Eventos adversos ocurriendo en aproximadamente 3 a < 10% de los pacientes, en orden decreciente de incidencia, incluyeron: sequedad ocular, ardor ocular, sensación de cuerpo estraño en el ojo, dolor ocular y distúrbios de la visión.Eventos adversos ocurriendo en 1 a <3% de los pacientes fueron: cefalea, eritema de los párpados, pigmentación de la piel periocular, irritación ocular, secreción ocular, astenopia, conjuntivitis alérgica, lagrimeo, y fotofobia.En menos de 1% de los pacientes fueron relatadas: inflamación intra-ocular, mencionada como iritis y pigmentación del íris, ceratitis puntiforme superficial, alteración de las pruebas de función hepática e infecciones (principalmente resfriados e infecciones de las vías respiratorias).Con tratamientos de 6 meses de duración fueron observados, además de los eventos adversos relatados más arriba, en aproximadamente 1 a <3% de los pacientes, edema conjuntival, blefaritis y astenia. En tratamientos de asociación con betabloqueador, durante 6 meses, además de los eventos de más arriba, fueron observados en aproximadamente 1 a <3% de los pacientes, erosión de la córnea, y empeoramiento de la acuidad visual. En menos de 1% de los pacientes, blefarospasmo, depresión, retracción de los párpados, Posología y Administración. hemorragia retiniana y vértigo.La frecuencia y gravedad de los eventos adversos fueron relacionados a la dosis, y, en general, ocurrieron cuando la dosis recomendada no fue seguida.Posología Administración.Aplicar una gota en el ojo afectado, una vez al día, a la noche.

La dosis no debe exceder a una dosis única diaria, pues fue demostrado que la administración más frecuente puede disminuir el efecto hipotensor sobre la hipertensión ocular.LUMIGAN® (bimatoprost) puede ser administrado concomitantemente con otros productos oftálmicos tópicos para reducir la hipertensión intra-ocular, respetándose el intervalo de por lo menos 5 minutos entre la administración de los medicamentos. VENTA BAJO PRESCRIPCIÓN MÉDICA.“ESTE PRODUCTO ES UM MEDICAMENTO NUEVO AUNQUE LAS INVESTIGACIONES HAYAN INDICADO EFICACIA Y SEGURIDAD, CUANDO CORRECTAMENTE INDICADO, PUEDEN SURGIR REACCIONES ADVERSAS NO PREVISTAS, AÚN NO DESCRIPTAS O CONOCIDAS, EN CASO DE SOSPECHA DE REACCIÓN ADVERSA, EL MÉDICO RESPONSABLE DEBE SER NOTIFICADO. 1. The AGIS Investigators: The Advanced Glaucoma Intervetion Study - The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. Am. J. Ophthalmol, 130 (4): 429-40, 2000. 2. Shirakashi, M. et al: Intraocular Pressure-Dependent Progression of Visual Field Loss in Advanced Primary Open-Angle Glaucoma: A 15-Year Follow-Up. Ophthalmologica, 207: 1-5, 1993. 3. Mao, LK; Stewart, WC; Shields, MB: Correlation Between Intraocular Pressure Control and Progressive Glaucomatous Damage in Primary Open-Angle Glaucoma. Am. J. Ophthalmol, 111: 51-55, 1991. 4. Higginbotham, EJ et al. One-Year Comparison of Bimatoprost with Timolol in Patients with Glaucoma or Ocular Hypertension. Presented at American Academy Ophthalmology, Nov 11-14, 2001. 5. Gandolfi, S et al. Three-Month Comparison of Bimatoprost and Latanoprost in Patients with Glaucoma and Ocular Hypertension. Adv. Ther, 18 (3): 110-121, 2001. 6. Coleman, AL et al: A 3-Month Comparison of Bimatoprost with Timolol/Dorzolamide in Patients with Glaucoma or Ocular Hypertension. Presented at American Acedemy of Ophthalmol, New Orleans, La, 2001.

Mejor comodidad posológica: 1 vez al día.

No requiere refrigeración.

Presentación conteniendo 3 ml.