Accepted Manuscript

Treatment of Blepharitis: Recent Clinical Trials

Stephen Pflugfelder, MD Paul Karpecki, OD Victor L. Perez, MD

PII: S1542-0124(14)00126-8
DOI: 10.1016/j.jtos.2014.05.005
Reference: JTOS 102

To appear in: Ocular Surface

Received Date: 21 February 2014

Revised Date: 16 May 2014
Accepted Date: 16 May 2014

Please cite this article as: Pflugfelder S, Karpecki P, Perez VL, Treatment of Blepharitis: Recent Clinical
Trials, Ocular Surface (2014), doi: 10.1016/j.jtos.2014.05.005.

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 ACCEPTED MANUSCRIPT

SECTION: Clinical Practice, John E. Sutphin, MD, Editor

TITLE: Treatment of Blepharitis: Recent Clinical Trials

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Authors: Stephen Pflugfelder, MD,1 Paul Karpecki, OD,2 and Victor L. Perez, MD3
SHORT TITLE: TREATMENT OF BLEPHARITIS/Pflugelder et al

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Footnotes
Accepted for publication May 2014.

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From 1Baylor College of Medicine, Houston, TX, 2Kentucky Center for Vision, Lexington, KY,
and 3Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL,

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USA.

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Editorial assistance was funded by Bausch + Lomb. The authors retained full control of manuscript
content.
The authors have no financial or proprietary interest in any concept or product discussed in this
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article.
Single-copy reprint requests to: Stephen Pflugfelder, MD (address below).
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Corresponding author: Stephen Pflugfelder, MD, Cullen Eye Institute, Department of

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Ophthalmology, Baylor College of Medicine, 6565 Fannin, NC-205, Houston, Texas 77030 USA.
Tel: 713-798-6100. Fax: 713-798-4231. E-mail: stevenp@bcm.edu
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KEY WORDS antibiotics, bacteria, blepharitis, corticosteroids, cyclosporine, inflammation,

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meibomian gland dysfunction

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ABSTRACT Blepharitis is a chronic inflammatory disease of the eyelids that is frequently

encountered in clinical practice. The etiology of the disorder is complex and not fully understood,
but the general consensus is that bacteria and inflammation contribute to the pathology. Blepharitis
can be classified into anterior blepharitis, involving the anterior lid margin and eyelashes, and
posterior blepharitis, characterized by dysfunction of the meibomian glands. Long-term

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management of symptoms may include daily eyelid cleansing routines and the use of therapeutic
agents that reduce infection and inflammation. A cure is not possible in most cases, and subjective

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symptoms may persist even when a clinical assessment of signs indicates that the condition has
improved. There are no established guidelines regarding therapeutic regimens, but recent clinical

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trials have shown that antibiotics and topical corticosteroids can produce significant improvement
in signs and symptoms of blepharitis. Fixed combinations of a topical antibiotic and a

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corticosteroid offer an effective and convenient treatment modality that addresses both infectious
and inflammatory components of the disease. Further clinical trials are needed to determine
optimal therapies for managing blepharitis.
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KEY WORDS antibiotics, blepharitis, corticosteroids, cyclosporine A, infecction, inflammation
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Outline

I. Introduction
A. Incidence and Prevalence
B. Classification
C. Clinical Characteristics

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D. Etiology
II. Overview of Current Treatments
A. Lid Hygiene

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B. Pharmaceutical Interventions
1. Antibiotics

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2. Steroids
C. Other
III. Review of Recent Clinical Trials

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A. Selection of Studies for Inclusion
B. Findings of Clinical Trials
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1. Dietary Supplementation
2. Topical Antibiotics
a. Azithromycin
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b. Fluoroquinolones
c. Aminoglycosides
d. Conclusion
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3. Topical Antibiotic/Steroid Combinations

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4. Oral Antibiotics
5. Topical Cyclosporine
IV. Summary and Conclusions
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I. Introduction

Blepharitis, a chronic inflammatory condition of the eyelid margin, is one of the most
common ocular disorders seen by ophthalmic practitioners.1,2 While generally not sight-
threatening, blepharitis can induce permanent eyelid margin alterations and even vision loss from

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superficial keratopathy, corneal neovascularization, or ulceration.3

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A. Incidence and Prevalence

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Blepharitis affects all age and ethnic groups.2,3 While children can develop blepharitis,
onset is typically during middle age.1 Although blepharitis is commonly encountered in clinical

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practice, its true incidence and prevalence in the general population has not been well documented
apart from some regional studies. In one survey, ophthalmologists and optometrists in the United
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States reported that 37% to 47% of their patients had evidence of blepharitis.2 A recent cross-
sectional study in Spain based on a randomly selected sampling population reported rates of
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asymptomatic and symptomatic meibomian gland dysfunction (a condition closely linked with
posterior blepharitis) of 21.9% and 8.6% of individuals, respectively.4
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B. Classification
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Various classification systems have been used to categorize blepharitis over the years, and
some controversy remains with regard to blepharitis terminology. The most recent American
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Academy of Ophthalmology (AAO) Preferred Practice Patterns on blepharitis classifies the

condition according to anatomic location.1 Anterior blepharitis affects the base of the eyelashes
and follicles and includes the traditional classifications of staphylococcal and seborrheic
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blepharitis. Posterior blepharitis involves the posterior lid margin (segment that contacts the
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cornea and bulbar conjunctiva) and has a range of potential etiologies, the primary cause being
meibomian gland dysfunction (MGD). MGD is characterized by functional abnormalities of the
meibomian glands and altered secretion of meibum, which plays an important role in slowing the
evaporation of tear film; this change in protective function leaves the eye susceptible to surface
damage and discomfort.3 Other causative factors in posterior blepharitis include infectious (herpes
simplex, varicella zoster) and inflammatory conditions (e.g., meibomitis, atopic

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blepharoconjunctivitis, graft vs host disease, chalazia). To further complicate the classification of

blepharitis, it is common for patients to have a mixture of anterior and posterior lid margin
disease.1,5

C. Clinical Characteristics

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Figure 1 illustrates various presentations of blepharitis. While the clinical features of the
blepharitis categories can overlap, certain signs and symptoms are more commonly associated with
particular subtypes.1 Patients with staphylococcal (anterior) blepharitis frequently exhibit eyelash

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loss and/or misdirection, signs that are rarely seen with other types of blepharitis. Other signs of

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staphylococcal blepharitis can include eyelid ulceration (severe cases), eyelid scarring, hordeolum,
mild- to-moderate conjunctival injection, corneal changes (erosions, infiltrates, scarring,
neovascularization and pannus, thinning, phlyctenules), and matted, hard scales/collarettes.

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Seborrheic (anterior) blepharitis is often accompanied by seborrheic dermatitis, with ocular
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findings typified by oily or greasy eyelid deposits, mild conjunctival injection, and inferior
punctate epithelial erosions. Eyelash changes are rare.
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Posterior blepharitis/MGD, often associated with rosacea, typically features plugging or
displacement of the ductal openings, dilated and telangiectatic lid margin blood vessels, and
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decreased lipid secretion with foamy tears. Chalazia may be a cause or consequence of MGD.
Eyelash misdirection and eyelid scarring can occur in long-standing posterior blepharitis, and
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corneal changes can include inferior punctate epithelial erosions, marginal infiltrates, scarring,
neovascularization and pannus, and ulceration.
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Aqueous tear deficiency is a frequent finding in all types of blepharitis.1 Cases of suspected
Demodex blepharitis are often associated with rosacea and individuals over the age of 70, but can
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affect any patient.6 The presentation is characterized by chronic inflammation of the base of the
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lashes and eyelid margins, a clear ”sleeve” or scurf surrounding the base of the lashes with
significant debris, irregular eyelid margins, madarosis, and symptoms of itching and irritation.6,7

D. Etiology

The underlying causes of blepharitis and associated inflammation are not fully understood

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but probably involve several pathogenic mechanisms.

Chronic low-grade bacterial infection is a likely factor in some cases, with effects mediated
through bacterial toxins, direct tissue invasion, and inflammation stimulated by bacterial
components.5,8 Normal, or commensal, bacteria may be present in excess, a different species may
be colonizing, and/or there may be an imbalance of the species that normally colonize the eyelids.1

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Demodex mites may play a role in some cases of anterior and posterior blepharitis,
although the association has not been firmly established because Demodex can also be found in

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asymptomatic patients.5,9 The infestation and waste produced by the mites has been theorized to
cause follicle and gland blockage, as well as to trigger an inflammatory response.3 A recent meta-

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analysis of the association between Demodex infestation and blepharitis based on 13 published
case-control series (2098 subjects with blepharitis; 2643 controls) reported a pooled odds ratio

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from random effect models of 4.89 (95% confidence interval, 3.00-7.97), suggesting that
examination for Demodex mites is warranted when conventional blepharitis treatment is
ineffective.10
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Environmental factors may contribute to the pathogenesis of blepharitis. Ocular exposure
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to air pollution has been linked with an increase in blepharitis cases.11 Additionally, exposure to a
drafty, low humidity environment, similar to that of air-conditioned offices, was found to increase
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concentrations of certain inflammatory factors in tears that could affect health of the lid margins.12
Blepharitis can also be associated with systemic diseases, such as rosacea, seborrheic dermatitis,
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atopic dermatitis, and graft vs host disease.3,5

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II. Overview of Current Treatments

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Blepharitis is a chronic condition with frequent exacerbation. Currently, standard therapy is

directed at control of symptoms and inflammatory signs, and patients should be counseled that
cure is not likely.

There are no FDA-approved products specifically studied and indicated for blepharitis, nor
are there definitive treatment recommendations for chronic blepharitis, although the International
Workshop on Meibomian Gland Dysfunction published guidelines in 2011 which include a

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treatment algorithm.3 A recent Cochrane review evaluated 34 chronic blepharitis intervention

studies and found no strong evidence to suggest that any of the studied treatments resulted in a
cure.3 The latest Preferred Practice Pattern (PPP) on blepharitis from the AAO suggests the
following to be helpful: warm compresses, eyelid hygiene, antibiotics (topical and/or systemic),
and topical anti-inflammatory agents (e.g., corticosteroids, cyclosporine).1

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A. Lid Hygiene

Lid hygiene (warm compresses, eyelid scrubs) has been shown to produce symptomatic

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benefit3 and should be considered in the patient’s regular routine to reduce and manage symptom
recurrence. In posterior blepharitis/MGD, topical lubricants such as artificial tears are

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recommended for dry eye symptoms, based on growing experience with their benefits in

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evaporative dry eye.13-15 If Demodex infestation is suspected, the hygiene regimen should include a
weekly scrub with 50% tea-tree oil solution, and a daily scrub with tea-tree shampoo for 6 weeks
should be considered. In one study, this regimen was found to be effective in a subset of patients
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with Demodex mite infection who had not responded to conventional treatment.16 Oral ivermectin
has been shown to reduce the number of Demodex organisms and improve signs and symptoms in
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patients with refractory posterior blepharitis and confirmed pre-treatment presence of the mites in
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lash samples.9,17
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B. Pharmaceutical Interventions

Pharmaceutical interventions can lessen the bacterial load, reducing inflammation and
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improving meibomian gland function.2

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1. Antibiotics

For anterior blepharitis, topical antibiotics have been found useful for symptomatic relief
and effective in eradicating bacteria from the eyelid margins.3 Topical ointments such as bacitracin
or erythromycin may be applied to the eyelid margins one or more times daily or before bed for 7

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days or longer, depending on response to treatment. Data published within the past 10 years
suggest an increase in methicillin-resistant S. aureus (MRSA) among ocular isolates in general,
and in blepharoconjunctivitis cases specifically.18 In a cross-sectional study of 915 ocular isolates
collected between 1998 and 2006, the proportion of MRSA isolates increased during that
timeframe from 4.1% to 16.7%.18 Among patients with ocular MRSA infection, 78.0% had a

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diagnosis of blepharoconjunctivitis. These trends may warrant the use of ocular antibacterials
having relatively higher activity against MRSA, such as besifloxacin and trimethoprim.19-21

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Oral antibiotics such as tetracyclines (tetracycline, doxycycline, minocycline) or

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macrolides (erythromycin, azithromycin) are recommended for patients with MGD not controlled
with eyelid hygiene or patients with associated rosacea.1 In such cases, the oral antibiotics are used
in large part for their anti-inflammatory and lipid-regulating properties.13 Treatment can be tailored

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to response, and therapy can be started and stopped as needed. The tetracyclines and related drugs
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have several well-documented side effects, including photosensitization, gastrointestinal upset, and
vaginitis. Tetracyclines should not be given to pregnant or nursing women, children under 10 years
of age, and patients sensitive to this class of drugs.1
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2. Steroids
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Short courses of topical steroids have been found beneficial for symptomatic relief in cases
with clinically significant ocular inflammation.3 Corticosteroid drops or ointment can be applied
several times daily to the eyelids or ocular surface until the inflammation is reduced. These agents
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can be tapered over time and gradually discontinued, then reintroduced as needed. The minimally
effective dose with the shortest duration of use should be used to reduce the risk of increased
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intraocular pressure (IOP) and cataracts. Corticosteroids with a decreased risk of IOP elevation
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and cataract formation (e.g., loteprednol etabonate [LE]22) or limited ocular penetration (e.g.,
fluoromethalone) are preferable.1
Topical combinations of an antibiotic and corticosteroid such as tobramycin/dexamethasone or
tobramycin/loteprednol have been shown to significantly improve signs and symptoms of
blepharitis.3 Topical application of the calcineurin inhibitor, cyclosporine has also been reported to
have efficacy for treating signs and symptoms of posterior blepharitis. Consistent with its
immunomodulatory/anti-inflammatory activity, treatment of posterior blepharitis/meibomian gland

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disease for 3 months with cyclosporine resulted in significantly greater improvement in eyelid
margin inflammatory signs, including injection and vascular telangiectasia, than the comparator
group -- artificial tears23,24 or tobramycin/dexamethasone.25

C. Other

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Changes in the meibomian glands and tear film may contribute to the cascade of inflammation and

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infection that leads to chronic blepharitis. Increased intake of essential fatty acids (EFAs) was
recommended by the International Workshop on MGD for cases of mild-to-severe MGD.13

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Recently, intraductal meibomian gland probing was reported to provide rapid and lasting symptom
relief in a case series of patients with obstructive MGD.26

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III. Review of Recent Clinical Trials

A. Selection of Studies for Inclusion AN

The medical literature was searched to identify recent human studies on the treatment of
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blepharitis. PubMed was searched for English-language clinical studies published during the past
decade (2003-2013) using the search terms blepharitis treatment, meibomian gland dysfunction
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treatment, and blepharokeratoconjunctivitis treatment. Studies were included only if they involved
pharmaceutical treatments that are commercially available in a broad international market.
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Investigations of procedural interventions (e.g., thermodynamic techniques) are not reviewed here.

The search initially identified 48 unique citations. Of these, 31 were excluded because:
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1) Treatment used was obscure, regionally marketed products or non-commercially

available products (tea tree oil eyelid scrub, bibrocathol, diquafosol, sea
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buckthorn oil, topical N-acetylcysteine).

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2) Primary diagnosis was not blepharitis (dry eye, graft-vs-host disease, glaucoma,
feline eosinophilic keratitis, infectious keratitis, inflammatory bowel disease,
atopic keratoconjunctivitis, cystic fibrosis, Sjögren syndrome).

3) Treatment involved procedural interventions (e.g., thermal treatments).

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As an additional search measure, BIOSIS was searched for the same time interval for any
relevant yet unpublished data presented at medical/scientific meetings in abstract or poster form.

B. Findings of Clinical Trials

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1. Dietary Supplementation

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Supplementation with EFAs has been postulated to change the composition of tear film
secretions from the meibomian glands and improve tear stability.27 Modulating inflammation is

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another mechanism by which EFAs may impact dry eye. Ocular surface inflammation contributes
to the irritation symptoms and ocular surface disease that can develop in dry eye, while the Ω-6

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fatty acid gamma-linolenic acid (GLA) and the Ω-3 fatty acids eicosapentaenoic and
docosahexaenoic acid (EPA, DHA) produce anti-inflammatory activity.27 Recent clinical studies
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have demonstrated measurable benefits from oral supplementation with EFAs (Ω-3 FAs from fish
oil and Ω-6 FAs from GLA derived via Black Currant Seed oil) in improving dry eye symptoms
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and ocular comfort in non-blepharitis conditions, such as dry eye syndrome,28,29 contact lens-
associated dry eye,30 keratoconjunctivitis sicca,31,32 and Sjögren syndrome.33 These studies
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administered GLA-containing oils alone or in combination with EPA and DHA.

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Two randomized studies investigated dietary supplementation with EFAs in patients with
MGD and/or blepharitis.
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In a randomized, placebo-controlled, masked trial,27 Mascai assigned 38 patients with

MGD and blepharitis to supplementation with oral Ω-3 FAs (two 1000-mg flaxseed oil capsules)
or control olive oil capsules, each given three times daily (TID). Among subjects who completed 1
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year of treatment (flaxseed oil group, n=14; control group, n=16), the flaxseed oil group
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demonstrated 36% and 31% reductions in Ω-6 to Ω-3 FA ratios in plasma and RBCs, respectively,
with while no such changes were observed in the control group. Subjects completed the 12-item
Ocular Surface Disease Index (OSDI) every 3 months for 1 year, with possible total scores ranging
from 0 (normal eye) to 100 (severe dry eye). In the flaxseed oil group, significant decreases
(improvements) from baseline were observed in OSDI overall score (-11.6; P=.02), environmental
triggers (-16.7; P=.04), and ocular symptoms (-19.1; P=.02). In the control group, only ocular

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symptoms were significantly improved from baseline (-9.5; P<0.01). Tear film break-up time
(TFBUT) and meibum scores improved significantly in both treatment groups, but findings were
not significantly different between the two groups.

Pinna et al conducted a prospective, randomized trial in 57 patients with MGD, comparing

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daily oral supplementation with 28.5 mg of linoleic acid and 15 mg of gamma linoleic acid (Ω-6
FAs) to lid hygiene alone once daily or a combination of lid hygiene plus oral supplementation for
180 days.34 Assessments included patient self-evaluation questionnaires and slit-lamp

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examinations. While improvements were noted in all three treatment groups, the combination

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group demonstrated the greatest decrease from baseline at 180 days in the percentages of patients
manifesting eyelid edema (42% to 0%; P=.003), meibomian gland obstruction (100% to 31%;
P=.0001), and meibomian secretion turbidity (79% to 13%; P=.0001), as well as those showing

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evidence of foam in the meniscus (42% to 6%; P=.02) and corneal staining with fluorescein (32%
to 0%; P=.02). AN
These recent studies suggest at least modest benefits of dietary supplementation with
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essential fatty acids in patients with MGD and/or associated blepharitis.
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2. Topical Antibiotics
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Bacterial infection appears to play a role in the etiology of blepharitis. However,

it is not always clear whether bacterial infection is the root cause of the inflammatory environment
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observed in blepharitis, or a secondary infection resulting from such an environment. Regardless,

reduction of bacterial load is recognized as an important step in improving signs and symptoms of
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the disease.3,8,35
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a. Azithromycin

Several recent clinical trials have evaluated the use of topical azithromycin in
patients with anterior and/or posterior blepharitis (Table 1).36-41Azithromycin is a broad-spectrum
macrolide antibiotic with low-level anti-inflammatory properties that penetrates the conjunctiva

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and eyelids40,42 and has a long post-antibiotic effect.43 Azithromycin is available commercially as a
1.0% ophthalmic solution (AzaSite®, Inspire Pharmaceuticals, Inc, Durham, NC, USA),
formulated with DuraSite®, a polycarbophil based-vehicle designed to prolong drug residence
time on the ocular surface, and outside the US as a 1.5% ophthalmic solution (Azyter®, Thea
Laboratories, France), which is not polycarbophil-based.

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Fadlallah et al found that treatment with azithromycin ophthalmic solution 1.5%

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twice daily (BID) for 3 days then once daily (QD) for a total of 30 days was more effective in
improving eyelid redness/swelling and meibomian gland secretions than treatment administered

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BID for 3 days only in patients (n=67) with moderate-to-severe chronic anterior and/or posterior
blepharitis.36 All patients also applied warm compresses and performed lid hygiene with an eye-
friendly soap twice daily for the duration of the trial. At 1-week and at 1-month follow-up, both

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treatment groups showed significant improvements from baseline in blepharitis symptoms (P=.01)
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and ocular signs, including lid collarettes (P=.01) and lid redness/swelling (P<.05). Total MGD
score was significantly improved at one month (P<.02) only for the group that received
azithromycin for the entire month. After 3 months of follow-up, both treatment groups continued
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to report improved symptoms; however, only the regimen with continued treatment QD for 1
month maintained improvements in objective signs of disease (lid redness/swelling, plugging and
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quality of meibomian gland secretions).

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In an open-label study, Opitz and Tyler treated 33 patients with posterior

blepharitis (MGD) with azithromycin ophthalmic solution 1% BID for 2 days, then every evening
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for a total of 30 days.38 In the 26 patients who completed the study, there were significant
improvements from baseline in TFBUT (52.7% increase, P<.0001); Schirmer test value (24%
increase, P<.05); and reductions in corneal staining (83.2% reduction,P<.0001), conjunctival
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staining (67.9% reduction, P<.0001), and lid margin scores (33.9% reduction, P<.0001). Patient-
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rated symptom scores were significantly improved from baseline after 30 days of treatment (2.73
vs 2.21; P<.01), and mean OSDI improved from 34.44 to 13.15 (P<.0001).

Twenty-two subjects with symptomatic MGD were enrolled in a prospective,

observational, open-label trial by Foulks et al. They were treated with azithromycin ophthalmic
solution 1% one drop BID for two days, then once daily for a total treatment duration of 4 weeks.39
Among 17 patients who completed the study, changes in spectroscopic behavior and altered

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(lowering) of phase transition temperature were observed. A lower phase transition temperature of
meibomian gland lipids would be expected to allow for greater mobility of lipid secretions from
glandular ducts to the tear film and ocular surface. These objective findings were accompanied by
subject-reported improvements in symptom severity from baseline (P<.001), as well as
improvements in signs of eyelid margin disease, as evaluated by number of obstructed glands,

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amount of lid margin erythema, ease of expression of the meibomian glands, and the character of
meibomian gland secretion.

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In another open-label study by Haque et al, patients with moderate-to-severe

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anterior and posterior blepharitis were treated with azithromycin ophthalmic solution 1% BID for 2
days, then once daily for a total treatment duration of 28 days, all without warm compresses or
eyelid scrubs.40 At the end of treatment, significant (P<.001) decreases from baseline were noted in

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all subject-rated symptoms (eyelid itching, foreign body sensation/sandiness/grittiness, ocular
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dryness, ocular burning/pain, swollen/heavy eyelids). Investigator-rated signs of meibomian gland
plugging, eyelid margin redness, palpebral conjunctival redness, and ocular discharge also showed
significant (P <.002) improvement at 28 days. All improvements persisted for 4 weeks post-
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treatment. Eyelid margin culture showed significant decreases in the most commonly isolated
organisms, including coagulase-negative staphylococci (CoNS [P=0.037]) and Corynebacterium
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xerosis bacteria (P<.001).

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In an open-label study by Luchs, 21 patients with posterior blepharitis were

randomized to treatment with topical azithromycin ophthalmic solution 1% (1 drop) plus warm
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compresses BID for 2 days then once daily for 12 days, or warm compresses alone.41 At the end of

treatment, patients using azithromycin demonstrated significantly greater improvements from

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baseline in meibomian gland plugging and redness of the eyelid margins, and improved quality of
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meibomian gland secretions compared to the patients using compresses alone (all comparisons,

P<.001). Evaluations of lid debris and lid swelling showed greater numerical improvement in the

azithromycin group, but neither achieved statistical significance. More patients in the azithromycin

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group rated symptom relief efficacy as excellent (22%) or good (44%), compared with 0% and

18%, respectively, of patients using compresses alone.

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b. Fluoroquinolones

The fluoroquinolone class of antibiotics has been demonstrated to have potent in

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vitro activity against a wide range of gram-negative and gram-positive microorganisms, with some
differences in activity among the fluoroquinolone generations.20

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In a prospective study by Yactayo-Miranda et al,44 60 patients with chronic
blepharoconjunctivitis were randomly assigned to one of three groups: no treatment; topical

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levofloxacin 0.5% QID; or topical levofloxacin 0.5% QID plus eyelid scrub (preceding each
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instillation of levofloxacin) for 7 days. Conjunctival sac cultures were obtained using a
thioglycolate-moistened swab and inoculated onto both aerobic and anaerobic media. As expected,
patients with chronic blepharoconjunctivitis had significantly higher rates of culture-positive eyes
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at baseline compared to healthy controls (95% vs 58%; P<.0001). As early as day 3, treatment with
levofloxacin 0.5% with or without eyelid scrub produced a significant reduction in the number of
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culture-positive eyes compared with non-treatment (60% and 56%, respectively, vs. 88%; P<.05).
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By day 7, 29% of eyes in the levofloxacin monotherapy group had culture-positive eyes compared
with 95% of eyes in the no-treatment group (P<.05). Statistically, the levofloxacin plus eyelid
scrub treatment was not any more effective in reducing culture-positive eyes than levofloxacin
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therapy alone on day 7 (50% vs 29%, P=.1533), although both treatments were statistically better
than the no-treatment group in this regard (P<.05). Although clinical efficacy was not evaluated,
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this study confirmed that levofloxacin significantly reduced the bacterial load in patients with
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blepharoconjunctivitis.

In a comparative study by John, another topical fluoroquinolone, besifloxacin

ophthalmic suspension 0.6%, was compared with topical erythromycin ophthalmic ointment 0.5%
in 30 patients with acute symptomatic anterior or mixed blepharitis.45 Lid cultures identified
primarily gram-positive organisms, with S. epidermidis present in 20/30 cases and S. aureus in
7/30 cases. All patients were treated BID for 2 weeks with the study medication, along with lid

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hygiene (warm washcloth with diluted baby shampoo). After 2 weeks, all patients demonstrated
clinically significant (P<.005) improvements in blepharitis signs and symptoms. Among 13
Staphylococcal cases treated with besifloxacin, lid cultures of 6 showed no growth and 7 showed
minimal growth of S. epidermidis after treatment. In contrast, lid cultures of 6 cases treated with
erythromycin demonstrated increased growth of organisms following treatment.

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c. Aminoglycosides

Tobramycin is an aminoglycoside with broad-spectrum activity that has been

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utilized in a variety of ocular indications.46 Tobramycin has been shown to have an efficacy and
safety profile similar to that of azithromycin as therapy for bacterial conjunctivitis.47,48 However,

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the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study

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(ARMOR) found that the in vitro potency of tobramycin was greater than that of azithromycin for
methicillin-sensitive ocular isolates of S. aureus (512-fold greater MIC90) and CoNS (128-fold
greater), methicillin-resistant strains of S. aureus (2-fold greater) and CoNS (8-fold greater), and
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for isolates of Streptococcus pneumonia (8-fold); however, azithromycin was 2-fold more potent
than tobramycin for isolates of Haemophilus influenza.19
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d. Conclusion
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These recent studies of topical antibacterial treatment strategies confirm

measurable benefits in patients with blepharitis treated for periods up to 30 days. Additional
comparative studies would be useful to further clarify the most useful agents and treatment
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regimens.
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3. Topical Antibiotic/Steroid Combinations

The combination of a topical antibiotic/corticosteroid can be useful in treatment

of blepharitis because lid and ocular surface bacterial infection and inflammation commonly
coexist. Having both agents in the same formulation facilitates use and provides appropriate

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dosage levels. Various formulations of antibiotics combined with several classes of corticosteroids
are available for ocular use

It should be cautioned that while topical corticosteroids reduce the signs and symptoms of
ocular surface inflammation, adverse effects are associated with their long-term use (e.g.,

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increased IOP, cataract formation).46,49

Several recent studies have compared antibiotic/corticosteroid formulations in the treatment

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of blepharitis (Table 2).37,50-52,56 One of the largest studies, a multicenter, randomized, parallel-
group, clinical trial by Chen et al, compared loteprednol etabonate 0.5%/tobramycin 0.3%

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ophthalmic suspension (Zylet®, Bausch and Lomb, Rochester, NY; or LE/T) to dexamethasone
0.1%/tobramycin 0.3% ophthalmic suspension (Tobradex®, Alcon Laboratories, Fort Worth, TX;
or DM/T) in a group of 308 Chinese patients with blepharokeratoconjunctivitis.50 Patients instilled

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one drop of either drug QID for 14 days. The primary efficacy endpoint was change from baseline
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to day 15 in the signs and symptoms composite score using a non-inferiority analysis. Thirteen
different signs and symptoms were recorded on a scale of 0=none to 4=severe, allowing for a
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range of possible composite scores of 0-52. The mean change from baseline to day 15 in composite
score was significant with both LE/T (-11.63) and DM/T (-12.41) (both P<0.0001 vs baseline).
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Non-inferiority of LE/T was established, given that the upper bound of the 90% CI (0.75) was less
than the predefined non-inferiority limit (2.5). Visual acuity improved with both treatments. There
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were no serious adverse events in either group; however, twice as many patients in the DM/T
group compared to the LE/T group experienced IOP increases of 5 mm Hg or more above baseline
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(26.0% vs 13.0%; P=.002).

In a large 14-day, single-masked, non-inferiority study by White et al, LE/T or DM/T were
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administered QID for 14 days to 276 patients clinically diagnosed with

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blepharokeratoconjunctivitis.51 The primary efficacy outcome was change from baseline to day 15
in a composite score reflecting the total of individual severity ratings for the following: blepharitis
signs (lid hyperemia, lid scaling or crusting, lid margin hypertrophy); conjunctivitis signs
(conjunctival hyperemia, discharge, and chemosis); keratitis signs (corneal punctate epithelial
keratopathy); and ocular symptoms (itchiness, foreign body sensation, blurred vision, light
sensitivity, painful or sore eyes, burning). Each sign and symptom was rated on a scale of 0 (none)
to 4 (severe), for a possible range in composite score from 0 to 52. The mean (SD) changes in

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composite scores at day 15 with LE/T and DM/T respectively were -15.2 (7.3) and -15.6 (7.7),
satisfying non-inferiority criteria for LE/T. In general, the degree of improvement correlated with
baseline disease severity. The percentages of eyes considered “cured” at day 15 with LE/T and
DM/T by investigator global assessment were 43.6% and 40.9%, respectively (P=NS). LE/T was
shown to be non-inferior to DM/T. There were significantly more elevations in mean IOP in the

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DM/T group compared to LE/T at day 7 (+0.6 vs -0.1 mm Hg; P=.0339), day 15 (+1.0 vs -0.1 mm
Hg; P=0.0091) and overall (+2.3 vs +1.6 mm Hg; P=.0208). Visual acuity and biomicroscopy

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findings were unremarkable.

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A small trial by Rhee and Mah compared the effectiveness of LE/T to DM/T in the
management of blepharoconjunctivitis.52 Forty patients were treated with LE/T or DM/T given
BID for 3 to 5 days, a dose and treatment duration less than that recommended in the FDA-

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approved labels for these products.53,54 There were numerically greater reductions in symptom
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severity and statistically significant improvement in signs of blepharitis, conjunctivitis and ocular
discharge with DM/T compared to LE/T. There were no adverse events and IOP was similar in
both groups pre- and post-treatment.
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Any topical ocular preparation must be comfortable for the patient to administer and not
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cause further irritation. In a tolerability study, Bartlett et al compared subjective ratings for pain,
stinging/burning, irritation, itchiness, foreign-body sensation, dryness and light sensitivity of LE/T
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and DM/T, 306 healthy volunteers instilled either agent QID for 28 days.55 The primary endpoint
was the difference in comfort/tolerability ratings at week 4 (normalized for baseline ratings using
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artificial tears) between the treatment groups. The results showed that LE/T was non-inferior to
DM/T in comfort and tolerability and subjects receiving LE/T were more likely to report better
comfort/tolerability ratings relative to the artificial tears used for standardization than subjects
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using DM/T.
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In a randomized, double-masked, active-controlled, parallel-group trial by Belfort et al, the

efficacy and safety of a moxifloxacin 0.5%/dexamethasone 0.1% (MXF/D) fixed combination was
compared to administration of both drugs separately in 97 patients diagnosed with bacterial
blepharitis.56 Patients instilled either an MXF/D combination or MXF and D individually QID for
7 days. The primary efficacy endpoint was clinical resolution of ocular signs (bulbar conjunctival
hyperemia, palpebral conjunctiva, conjunctival exudate/discharge, lid erythema, and lid

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scaling/crusting) at study completion. Secondary efficacy variables included microbiological

success, defined as the eradication of baseline pathogens after 7 days of treatment. Rates for
clinical resolution were high in both groups (81.6% of eyes in the fixed dose groups vs. 82.3% of
eyes in the group that dosed each drug separately). Ocular symptoms and signs were improved
similarly in both groups, except greater numbers of patients in the MXF/D group showed

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resolution of eyelid erythema (100% vs 92.7%; P=.0194) and eyelid crusting (98% vs 89.6%;
P=.0337). Overall rates of bacterial eradication were similar for the fixed dose group (84%) and

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the individually dosed regimen (83%). There was one report of increased IOP in the MXF and D
group, which was considered a mild elevation. The fixed dose combination was therapeutically

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equivalent to the agents dosed separately and both regimens were well tolerated.

In a randomized, investigator-masked study by Torkildsen et al, azithromycin ophthalmic

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solution 1% (1 drop BID for 2 days, followed by 1 drop QD for 12 days) was compared with
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tobramycin/dexamethasone 0.3%/0.05% suspension (1 drop 4 times daily [QID] for 14 days) in
122 patients with moderate-to-severe blepharitis or blepharoconjunctivitis.37 There was a
statistically significant difference in the seven-item global signs and symptoms score (lower score
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= less bothersome) at day 8, favoring tobramycin/dexamethasone compared to azithromycin (5.1
vs 7.1; P=.0002). At the end of treatment (Day 15), the difference between groups in global score
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was smaller, but still better in the tobramycin/dexamethasone group than in the azithromycin
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group(4.8 vs 5.7; P=.0487).

These studies demonstrate that a short course of an antibiotic/corticosteroid combination

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significantly improves ocular signs and symptoms in blepharitis. Treatment with LE demonstrated
a reduced propensity to cause an increase in IOP relative to the C-20 ketone corticosteroid
dexamethasone, consistent with previously reported experience.22,57-60 LE is a unique
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corticosteroid, having a C-20 ester in lieu of the C-20 ketone on the core prednisolone structure;
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this modification results in rapid deesterification to inactive metabolites and a favorable IOP-safety
profile.61-63 Moreover, the absence of a ketone group at position C-20 should reduce the molecular
interaction with lysine in ocular lens proteins and formation of Schiff base intermediates, a
common first step implicated in cataract formation.22 Chronic or intermittent pulse corticosteroid
therapy is most appropriately prescribed by eye care practitioners who can monitor patients for
complications.

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4. Oral Antibiotics

Oral antibiotics, particularly those with antiinflammatory activity, have been advocated for
severe or resistant cases of chronic blepharitis.5,35 Several recent studies investigated the use of

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oral antibiotics in patients with blepharitis/MGD, including azithromycin,64 doxycycline,65,66 and
minocycline.67,68

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Igami et al studied oral azithromycin in the treatment of posterior blepharitis in 13 patients
(26 eyes) with a history of unsuccessful treatment with other topical and/or oral therapy.64 Patients

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were instructed to use oral azithromycin 500 mg per day in a pulsed-dosing regimen, which
included three treatment periods of 3 days separated by 7-day intervals without treatment. Clinical

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outcomes were assessed 1 day before and 30 days after the last treatment (53 days after initiation

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of the drug). Subject ratings of blepharitis symptoms before and after treatment (scale, 0=no
symptoms to 5 = severe symptoms) showed significant improvements in eyelid itching (4.28 vs
2.04; P<.0001), ocular itching (3.54 vs 1.68; P<.0001), eyelid hyperemia (2.79 vs 2.14; P=.0151),
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ocular hyperemia (2.93 vs 2.18; P=0.0041), ocular mucus secretion (2.00 vs 0.71; P=.003),
photophobia (2.00 vs 1.14; P=.002), and dry eye sensation (2.14 vs 0.64; P=.002); foreign body
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sensation was not significantly improved (0.71 vs 0.71). The average TFBUT improved
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significantly (6.64 to 9.75 sec; P=.0005); however, no statistical improvement was observed in
Schirmer test value or corneal fluorescein or rose bengal staining.
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Yoo et al compared two dose regimens of oral doxycycline in a randomized placebo-

controlled trial in 150 patients (300 eyes) with chronic MGD refractory to standard therapy (lid
hygiene, topical drops, or ointments not otherwise specified).65 Both high-dose (200 mg BID) and
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low-dose (20 mg BID) doxycycline groups were statistically superior to placebo in improving
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TFBUT, Schirmer score, number of symptoms reported, and subjective symptoms after 1 month of
treatment. Most efficacy outcomes were not significantly different between the two doxycycline
groups, although the incidence of side effects was greater in the higher-dose regimen (39% vs
17%; P=.002). The authors postulated that the observed benefits were likely due to anti-
inflammatory properties and inhibitory effects of doxycycline on collagenase, as the low-dose
doxycycline regimen was too low to provide any antimicrobial efficacy.

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In a small study by Foulks et al, 9 patients with MGD were treated with oral doxycycline
100 mg BID for 8 weeks.66 Statistically significant improvements were noted after 4 weeks in
number of plugged glands (P<.05), redness (P<.05), and swelling (P<.05). At the end of 8 weeks of
therapy, mean symptom severity scores for itching and swelling decreased significantly (P<.05),
and all subjects reported an absence of burning symptoms. A highly significant improvement in

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TFBUT was also observed at 8 weeks (P<.001). The authors compared these findings with their
prior investigation of topical azithromycin in MGD39; oral doxycycline was found to be slightly

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less effective than topical azithromycin with regard to improving foreign body sensation, number
of plugged glands, and grading of MG secretion (rated on a scale of 0=clear to 3=solid paste).

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Lee et al studied the use of oral minocycline 50 mg BID plus artificial tears QID versus
artificial tears QID alone in a randomized trial involving 60 patients (60 eyes) with moderate-to-

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severe MGD.67 After 2 months of treatment, patients treated with minocycline plus artificial tears
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showed significant (P<.001) improvements from baseline in all clinical signs and symptoms of
MGD, including TFBUT, Schirmer value, corneal staining, lid margin abnormalities, meibum
quality, OSDI, and Oxford and DEWS (Dry Eye Workshop) staining scores. Improvements in
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TFBUT, corneal staining, lid margin abnormality, and meibum quality were significantly (P<.05)
greater compared with use of artificial tears alone.
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Vargas et al reported preliminary findings from a prospective, non-randomized trial of a 3-

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month course of oral minocycline (dose not specified) in 10 patients (20 eyes) with chronic

blepharitis.68 The investigators specifically looked at tear film production, vital staining of the
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ocular surface, and meibography before and after minocycline therapy. Decreases were noted in
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mean tear flow (P=.10), tear volume (P=.03), and evaporation (P=.43), while tear turnover
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increased (P=.87). Schirmer test values decreased from 18.75 to 13.00, P=.016). The investigators

concluded that short-term (3 months) treatment with oral minocycline may have an adverse effect

on aqueous tears (decreased tear volume and Schirmer test value), but may act to stabilize the tear

film lipid layer (decreased evaporation).

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These studies suggest that oral antibiotics with anti-inflammatory activity can be beneficial
in patients with refractory cases of MGD. Optimal duration of therapy and long-term outcomes
remain to be determined.

5. Topical Cyclosporine

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Cyclosporine A (CsA; Restasis®, Allergan Pharmaceuticals) is an
immunomodulatory agent that has been found useful in treating a variety of ocular conditions. In

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patients whose tear production is presumed to be suppressed due to ocular inflammation associated
with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial

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immunomodulator, although the exact mechanism of action is unknown.69 The efficacy of topical
administration of CsA 0.05% emulsion in symptomatic MGD or posterior blepharitis was recently
evaluated in two studies versus artificial tears23,24 and one trial with an active drug comparator.25

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In a prospective, double-masked study, Perry and colleagues evaluated the use
of CsA 0.05% compared to artificial tears administered 1 drop BID for 3 months in 33 patients
with symptomatic MGD (26 completed the study).23 At 3 months, there were significant
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improvements in several objective clinical findings with CsA compared with placebo, including a
50% decrease in meibomian gland inclusions (no change in the placebo group; P=.001), lid margin
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vascular injection (P=.001), tarsal telangiectasis (P=.03), and fluorescein staining (P=.01). Mean
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ocular symptom scores (maximum score=32; higher score=more severe symptoms) were lower
(better) at 3 months in the CsA group (5.8 vs 9.3), but the difference compared with placebo was
not statistically significant. Changes in TFBUT and Schirmer test values were also not statistically
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different between groups.

In a 3-month randomized, double-masked, parallel-group study by Prabhasawat

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et al, 70 patients with symptomatic MGD and unstable tear film (TFBUT <8 seconds) were
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randomized to 3 months of treatment with topical CsA 0.05% or 0.5% carboxymethylcellulose

(control group), each instilled twice daily for 3 months.24 After 3 months, patients treated with
CsA showed significant improvements from baseline in mean OSDI (P<0.01), noninvasive and
invasive TFBUTs (P<.01), lid margin inflammation (P<.001), meibomian gland expressibility
(P<.05), and tarsal injection (P<.001). In contrast, only the OSDI showed a significant
improvement from baseline in the control group.

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Rubin and Rao compared the efficacy of CsA 0.05% to dexamethasone

0.1%/tobramycin 0.3% ophthalmic suspension (DM/T), each administered one drop every 12
hours for 12 weeks, in 30 patients with posterior blepharitis.25 Following 12 weeks of treatment,
eyelid health and the mean signs and symptoms of posterior blepharitis were significantly
improved for both treatment groups. CsA provided greater improvements in Schirmer values

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(mean improvement, 2.33 vs 0.9 mm; P<0.001), TFBUT (mean change, 1.87 vs 1.30 seconds;
P=0.018), and meibomian gland secretion quality (graded on a scale of 0 [clear excreta with small

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particles] to 3 [secreta that retained shape after digital expression], with mean improvement of 0.77
vs 0.3; P=0.015). Moreover, a higher percentage of patients in the CsA group had improvements in

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symptoms of blurred vision, burning, and itching, and more patients experienced resolution of lid
telangiectasia.

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These small studies suggest that CsA has potential benefit in controlling
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symptoms of posterior blepharitis and producing improvements in objective measures, pending
further evaluation in larger-scale clinical trials.
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IV. Summary and Conclusions

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Blepharitis is a commonly occurring, chronic ocular condition that is difficult to manage

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satisfactorily. There is no general consensus on treatment, and currently there are no official
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guidelines or FDA-approved drug products specifically studied for this condition. A number of

different treatment strategies have been shown to offer symptom improvement to some degree.
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Unfortunately, it is difficult to compare individual studies because of variations in methodologies,

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measured outcomes, and patient/disease characteristics, and head-to-head trials are lacking. Eyelid

hygiene combined with an antibiotic or antibiotic/corticosteroid combination appears to be a safe

and effective strategy for managing the disorder. Multiple studies with topical azithromycin and

LE/T combination have demonstrated good clinical outcomes and a high degree of safety. When

steroids are indicated, LE appears to be a safer option than other compounds. Additional

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comparative clinical studies are needed to further identify the most effective drugs and regimens

for the various forms of blepharitis.

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Acknowledgements
The authors wish to thank Carol Tozzi, PhD and Sandra Westra, PharmD of Churchill

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Communications (Maplewood, NJ) for assistance in preparing this manuscript. This assistance was
funded by Bausch + Lomb. The authors retained full control of manuscript content.

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M
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dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chinese patients with

blepharokeratoconjunctivitis. Curr Med Res Opin 2012;28:385-94

51. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy
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meibomian gland dysfunction. Korean J Ophthalmol 2005;19:258-63
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Figure Legend

Figure 1. Clinical photographs of a) staphylococcal blepharitis with matting of the eyelids, b)

severe blepharitis, c) Demodex blepharitis in a patient complaining of itchy eyelid margins.

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Table 1. Recently published studies of topical azithromycin (AZM) in patients with blepharitis

Study Design Population (Patients Treatment Topline Findings

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[pts])
Fadlallah Randomized, 67 pts with chronic, Group 1 (n=33): Group 1 showed significant

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201236 investigator- moderate to severe AZM 1.5% BID improvement in signs and
masked. anterior and/or
posterior blepharitis.
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for 3 days. symptoms at 1-week follow-
up.
Group 2 (n=34): Group 2 showed more
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AZM 1.5% BID pronounced and longer-
for 3 days then HS lasting improvement that
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for a total of 30 persisted after 3 months of

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days. follow-up.
All pts used warm
compresses and
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eye-friendly soap
BID.
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Torkildsen Multicenter, 122 pts with moderate Group 1-- 61 pts: Group 1: Significantly lower
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201137 randomized, to severe blepharitis/ AZM 1%; BID for mean global score
investigator- blepharoconjunctivitis. 2 days, then QD (P=0.0002) with DM/T
masked, for 12 days. compared with AZM at day
active- 8.
controlled. Group 2-- 61 pts: Group 2: DM/T provided
DM/T 0.05%/T faster inflammation relief

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0.3%; QID for 14 than AZM.

days.

Opitz Open-label 26 pts with posterior AZM 1% BID for At 30 days, significant
201138 blepharitis (MGD) 2 days, then every improvements from baseline

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evening for a total in tear break-up time,
of 30 days. Schirmer score, reductions

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in corneal and conjunctival
staining, lid margin scores,

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and symptom scores.
Foulks Open-label 17 pts with AZM 1% BID for At 4 weeks, significant

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201039 symptomatic MGD. 2 days, then QD improvements in subject-
for total of 4 reported symptom severity,
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weeks. as well as improved signs of
eyelid margin disease.
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Haque Open-label 26 pts with moderate AZM 1% BID for At 30 days, significant
201040 to severe blepharitis. 2 days, then every decreases from baseline in
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evening for a total investigator-rated signs and

of 28 days. subject-reported symptoms,
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which persisted 4 weeks

post-treatment.
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Luchs Open-label 21 pts with posterior AZM 1% (plus AZM plus warm compresses
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2008 blepharitis. warm compresses) was significantly more
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BID for 2 days effective than warm

then daily for the compresses alone in
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next 12 days improving meibomian gland

(n=10) or warm plugging, secretions, and
compresses only eyelid redness.
(n=11)
AZM=azithromycin; BID=twice daily; DM=dexamethasone; HS=at bedtime; MGD=meibomian
gland dysfunction; QD=once daily; QID=4 times daily; T=tobramycin.

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Table 2. Recently published studies comparing topical antibiotic/steroid combinations in patients

with blepharitis

Study Design Population Treatment Topline Findings

(Patients

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[pts])
Loteprednol etabonate/tobramycin (LE/T) vs dexamethasone/tobramycin (DM/T)

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Chen Multicenter, 308 pts with 4 times daily Both treatments produced significant CFB in
201250 randomized, BKC for 14 days. composite signs/symptoms at day 15

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parallel (156 LE/T, (P<.0001).
group, 152 DM/T) DM/T was associated with significantly
investigator greater increase in mean CFB in IOP than

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masked. LE/T and significantly more IOP elevations

White Multicenter, 276 pts with

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4 times daily
>5 mm Hg.
CFB in signs and symptoms composite
200851 randomized, BKC for 14 days. score was similar between treatments at day
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investigator- (138 LE/T, 15.
masked, 138 DM/T). DM/T was associated with a significantly
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parallel greater mean increase in IOP compared with

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group. LE/T.
Rhee Randomized, 40 patients Twice daily At day 3-5, DM/T was associated with
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2007 parallel- with for 3-5 days. significantly lower total ocular surface
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group, moderate to (P=.002), blepharitis (P=.17), and discharge

double- extensive (P=.25) and conjunctivitis surface (P=.013)
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masked. inflammation scores compared with LE/T. Corneal PEK

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associated scores were similar.

with BKC. No safety findings reported.
Moxifloxacin/dexamethasone
Belfort Randomized, 102 pts with 4 times daily Clinical resolution was similar in both
201256 double- blepharitis for 7 days. treatment groups at day 7 (approximately
masked, (49 fixed 82% of eyes).

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active control, combination; Both regimens were safe and well tolerated.
parallel 48
group. concomitant
regimen*)
BKC= blepharokeratoconjunctivitis; CFB=change from baseline; IOP=intraocular pressure;

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PEK=punctate epithelial keratopathy.
* Patients randomized to either 1) a fixed combination of moxifloxacin 0.5%/dexamethasone 0.1%

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plus placebo drops, or 2) moxifloxacin 0.5% and dexamethasone 0.1% administered separately
(“concomitant regimen”).

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Figure Legends

Figure 1. Photographs of blepharitis cases: a) staphylococcal blepharitis with matting of

the eyelids, b) severe blepharitis, c) Demodex blepharitis in a patient complaining of

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itchy eyelid margins

a)

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b)

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c)
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