Clinical Practice
JOHN E. SUTPHIN, MD, EDITOR
Treatment of Blepharitis: Recent Clinical Trials
STEPHEN C. PFLUGFELDER, MD, 1 PAUL M. KARPECKI, OD, 2
ABSTRACT Blepharitis is a chronic inammatory 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 inammation contribute to the pathology. Blepharitis
can be classied into anterior blepharitis, involving the
anterior lid margin and eyelashes, and posterior blephar-
itis, characterized by dysfunction of the meibomian glands.
Long-term management of symptoms may include daily
eyelid cleansing routines and the use of therapeutic agents
that reduce infection and inammation. A cure is not
possible in most cases, and subjective 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 trials have shown that antibiotics and topical cor-
ticosteroids can produce signicant improvement in signs
and symptoms of blepharitis. Fixed combinations of a
topical antibiotic and a corticosteroid offer an effective and
convenient treatment modality that addresses both infec-
tious and inammatory components of the disease. Further
clinical trials are needed to determine optimal therapies for
managing blepharitis.
KEY WORDS antibiotics, bacteria, blepharitis, corticosteroids,
cyclosporine, inammation, meibomian gland dysfunction
Accepted for publication May 2014.
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, USA.
Editorial assistance was funded by Bausch Lomb. The authors retained
full control of manuscript content.
The authors have no nancial or proprietary interest in any concept or
product discussed in this article.
Single-copy reprint requests to Stephen C. Pugfelder, MD (address below).
Corresponding author: Stephen C. Pugfelder, MD, Cullen Eye Institute,
Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin,
NC-205, Houston, Texas 77030 USA. Tel: 713-798-6100. Fax: 713-798-
4231. E-mail address: stevenp@bcm.edu
2014 Elsevier Inc. All rights reserved. The Ocular Surface ISSN: 1542-
0124. Pugfelder SC, Karpecki PM, Perez VL. Treatment of blepharitis:
Recent clinical trials. 2014;12(4):273-284.
THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
AND VICTOR L. PEREZ, MD3
I. INTRODUCTION
B
lepharitis, a chronic inammatory 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 supercial keratopathy, corneal neovasculariza-
tion, or ulceration.3
A. Incidence and Prevalence
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 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 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 asymptomatic and
symptomatic meibomian gland dysfunction (a condition
closely linked with posterior blepharitis) of 21.9% and
8.6% of individuals, respectively.4
B. Classication
Various classication systems have been used to categorize
blepharitis over the years, and some controversy remains with
regard to blepharitis terminology. The most recent American
Academy of Ophthalmology (AAO) Preferred Practice
Pattern for blepharitis classies the condition according to
anatomic location.1 Anterior blepharitis affects the base of the
eyelashes and follicles and includes the traditional classica-
tions of staphylococcal and seborrheic blepharitis. Posterior
blepharitis involves the posterior lid margin (segment that
contacts the 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 evapo-
ration of tear lm; this change in protective function leaves the
eye susceptible to surface damage and discomfort.3 Other caus-
ative factors in posterior blepharitis include infectious (herpes
simplex, varicella zoster) and inammatory conditions (e.g.,
meibomitis, atopic blepharoconjunctivitis, graft vs host disease,
chalazia). To further complicate the classication of blepharitis,
273
 TREATMENT OF BLEPHARITIS / Pugfelder, et al

overlap, certain signs and symptoms are more commonly asso-

OUTLINE
ciated with particular subtypes.1 Patients with staphylococcal
I. Introduction (anterior) blepharitis frequently exhibit eyelash loss and/or
A. Incidence and Prevalence misdirection, signs that are rarely seen with other types of ble-
B. Classication pharitis. Other signs of staphylococcal blepharitis can include
C. Clinical Characteristics eyelid ulceration (severe cases), eyelid scarring, hordeolum,
D. Etiology mild-to-moderate conjunctival injection, corneal changes (ero-
II. Overview of Current Treatments sions, inltrates, scarring, neovascularization and pannus, thin-
A. Lid Hygiene ning, phlyctenules), and matted, hard scales/collarettes.
B. Pharmaceutical Interventions Seborrheic (anterior) blepharitis is often accompanied by seb-
1. Antibiotics
orrheic dermatitis, with ocular ndings typied by oily or
greasy eyelid deposits, mild conjunctival injection, and inferior
2. Steroids
punctate epithelial erosions. Eyelash changes are rare.
C. Other
Posterior blepharitis/MGD, often associated with rosa-
III. Review of Recent Clinical Trials cea, typically features plugging or displacement of the ductal
A. Selection of Studies for Inclusion openings, dilated and telangiectatic lid margin blood vessels,
B. Findings of Clinical Trials and decreased lipid secretion with foamy tears. Chalazia
1. Dietary Supplementation may be a cause or consequence of MGD. Eyelash misdirec-
2. Topical Antibiotics tion and eyelid scarring can occur in long-standing posterior
a. Azithromycin blepharitis, and corneal changes can include inferior punc-
b. Fluoroquinolones tate epithelial erosions, marginal inltrates, scarring, neovas-
c. Aminoglycosides cularization and pannus, and ulceration.
d. Conclusion Aqueous tear deciency is a frequent nding in all types
3. Topical Antibiotic/Steroid Combinations
of blepharitis.1 Cases of suspected Demodex blepharitis are
often associated with rosacea and individuals over the age
4. Oral Antibiotics
of 70, but can affect any patient.6 The presentation is charac-
5. Topical Cyclosporine
terized by chronic inammation of the base of the lashes and
IV. Summary and Conclusions eyelid margins, a clear sleeve or scurf surrounding the base
of the lashes with signicant debris, irregular eyelid margins,
it is common for patients to have a mixture of anterior and madarosis, and symptoms of itching and irritation.6,7
posterior lid margin disease.1,5
D. Etiology
C. Clinical Characteristics The underlying causes of blepharitis and associated
Figure 1 illustrates various presentations of blepharitis. inammation are not fully understood but probably involve
While the clinical features of the blepharitis categories can several pathogenic mechanisms.

Figure 1. Clinical photographs of (A) staphy-

lococcal blepharitis with matting of the eyelids,
(B) severe blepharitis, (C) Demodex blepharitis in
a patient complaining of itchy eyelid margins.

274 THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com

Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
Chronic low-grade bacterial infection is a likely factor in
some cases, with effects mediated through bacterial toxins,
direct tissue invasion, and inammation stimulated by
bacterial components.5,8 Normal, or commensal, bacteria
may be present in excess, a different species may be colo-
nizing, and/or there may be an imbalance of the species
that normally colonize the eyelids.1
Demodex mites may play a role in some cases of anterior
and posterior blepharitis, although the association has not
been rmly established because Demodex can also be found
in 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 inammatory
response.3 A recent meta-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 from random effect
models of 4.89 (95% condence interval, 3.00-7.97), suggest-
ing that examination for Demodex mites is warranted when
conventional blepharitis treatment is ineffective.10
Environmental factors may contribute to the pathogen-
esis of blepharitis. Ocular exposure 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 ofces, was found to increase con-
centrations of certain inammatory 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, atopic dermatitis, and graft vs host
disease.3,5
II. OVERVIEW OF CURRENT TREATMENTS
Blepharitis is a chronic condition with frequent exacer-
bation. Currently, standard therapy is directed at control
of symptoms and inammatory signs, and patients should
be counseled that cure is not likely.
There are no FDA-approved products specically
studied and indicated for blepharitis, nor are there
denitive treatment recommendations for chronic blephari-
tis, although the International Workshop on Meibomian
Gland Dysfunction published guidelines in 2011 which
include a 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 for blepharitis from the AAO suggests the following
to be helpful: warm compresses, eyelid hygiene, antibiotics
(topical and/or systemic), and topical anti-inammatory
agents (e.g., corticosteroids, cyclosporine).1
A. Lid Hygiene
Lid hygiene (warm compresses, eyelid scrubs) has been
shown to produce symptomatic benet3 and should be
considered in the patients regular routine to reduce and
manage symptom recurrence. In posterior blepharitis/
MGD, topical lubricants such as articial tears are recom-
mended for dry eye symptoms, based on growing experience
THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
with their benets in 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 consi-
dered. In one study, this regimen was found to be effective
in a subset of patients with Demodex mite infection who
had not responded to conventional treatment.16 Oral iver-
mectin has been shown to reduce the number of Demodex
organisms and improve signs and symptoms in patients
with refractory posterior blepharitis and conrmed pre-
treatment presence of the mites in lash samples.9,17
B. Pharmaceutical Interventions
Pharmaceutical interventions can lessen the bacterial
load, reducing inammation and improving meibomian
gland function.2
1. Antibiotics
For anterior blepharitis, topical antibiotics have been
found useful for symptomatic relief and effective in eradi-
cating 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 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 iso-
lates in general, and in blepharoconjunctivitis cases specif-
ically.18 In a cross-sectional study of 915 ocular isolates
collected between 1998 and 2006, the proportion of MRSA
isolates increased during that time-frame from 4.1% to
16.7%.18 Among patients with ocular MRSA infection,
78.0% had a diagnosis of blepharoconjunctivitis. These
trends may warrant the use of ocular antibacterials having
relatively higher activity against MRSA, such as besioxacin
and trimethoprim.19-21
Oral antibiotics such as tetracyclines (tetracycline, doxy-
cycline, minocycline) or macrolides (erythromycin, azithro-
mycin) 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-inammatory and lipid-regulating prop-
erties.13 Treatment can be tailored to response, and therapy
can be started and stopped as needed. The tetracyclines and
related drugs 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, or patients
sensitive to this class of drugs.1
2. Steroids
Short courses of topical steroids have been found
benecial for symptomatic relief in cases with clinically sig-
nicant ocular inammation.3 Corticosteroid drops or oint-
ment can be applied several times daily to the eyelids or
ocular surface until the inammation is reduced. These
agents can be tapered over time and gradually discontinued,
then reintroduced as needed. The minimally effective dose
275
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
with the shortest duration of use should be used to reduce
the risk of increased intraocular pressure (IOP) and cata-
racts. Corticosteroids with a decreased risk of IOP elevation
and cataract formation (e.g., loteprednol etabonate [LE]22)
or limited ocular penetration (e.g., uoromethalone) are
preferable.1
Topical combinations of an antibiotic and corticosteroid
such as tobramycin/dexamethasone or tobramycin/lote-
prednol have been shown to signicantly improve signs
and symptoms of blepharitis.3 Topical application of the
calcineurin inhibitor cyclosporine has also been reported
to have efcacy for treating signs and symptoms of posterior
blepharitis. Consistent with the immunomodulatory/anti-
inammatory activity of cyclosporine, treatment of posterior
blepharitis/meibomian gland disease for 3 months with
cyclosporine resulted in signicantly greater improvement
in eyelid margin inammatory signs, including injection
and vascular telangiectasia, than the comparator group e
articial tears23,24 or tobramycin/dexamethasone.25
C. Other
Changes in the meibomian glands and tear lm may
contribute to the cascade of inammation and 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
Recently, intraductal meibomian gland probing was re-
ported to provide rapid and lasting symptom relief in a
case series of patients with obstructive MGD.26
III. REVIEW OF RECENT CLINICAL TRIALS
A. Selection of Studies for Inclusion
The medical literature was searched to identify recent
human studies on the treatment of 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 treat-
ment, and blepharokeratoconjunctivitis treatment. Studies
were included only if they involved pharmaceutical treat-
ments that are commercially available in a broad interna-
tional market. Investigations of procedural interventions
(e.g., thermodynamic techniques) are not reviewed here.
The search initially identied 48 unique citations. Of
these, 31 were excluded because:
1) Treatment used involved obscure, regionally marketed
products or non-commercially available products (tea
tree oil eyelid scrub, bibrocathol, diquafosol, sea buck-
thorn oil, topical N-acetylcysteine).
2) Primary diagnosis was not blepharitis (dry eye, graft-
vs-host disease, glaucoma, feline eosinophilic kera-
titis, infectious keratitis, inammatory bowel disease,
atopic keratoconjunctivitis, cystic brosis, Sjgren
syndrome).
3) Treatment involved procedural interventions (e.g.,
thermal treatments).
As an additional search measure, BIOSIS was searched
for the same time interval for any relevant yet unpublished
276 THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
data presented at medical/scientic meetings in abstract or
poster form.
B. Findings of Clinical Trials
1. Dietary Supplementation
Supplementation with EFAs has been postulated to
change the composition of tear lm secretions from the
meibomian glands and improve tear stability.27 Modulating
inammation is another mechanism by which EFAs may
impact dry eye. Ocular surface inammation contributes
to the irritation symptoms and ocular surface disease that
can develop in dry eye, while the U-6 fatty acid gamma-
linolenic acid (GLA) and the U-3 fatty acids eicosapentae-
noic and docosahexaenoic acid (EPA, DHA) produce
anti-inammatory activity.27 Recent clinical studies have
demonstrated measurable benets from oral supplementa-
tion with EFAs (U-3 FAs from sh oil and U-6 FAs from
GLA derived via Black Currant Seed oil) in improving dry
eye symptoms and ocular comfort in non-blepharitis condi-
tions, such as dry eye syndrome,28,29 contact lens-associated
dry eye,30 keratoconjunctivitis sicca,31,32 and Sjgren syn-
drome.33 These studies administered GLA-containing oils
alone or in combination with EPA and DHA.
Two randomized studies investigated dietary supple-
mentation with EFAs in patients with MGD and/or
blepharitis.
In a randomized, placebo-controlled, masked trial,27
Mascai assigned 38 patients with MGD and blepharitis to
supplementation with oral U-3 FAs (two 1000-mg axseed
oil capsules) or control olive oil capsules, each given three
times daily (TID). Among subjects who completed 1 year
of treatment (axseed oil group, n14; control group,
n16), the axseed oil group demonstrated 36% and 31%
reductions in U-6 to U-3 FA ratios in plasma and RBCs,
respectively, while no such changes were observed in the
control group. Subjects completed the 12-item Ocular Sur-
face 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 axseed oil group, signicant de-
creases (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 symptoms were signicantly
improved from baseline (-9.5; P<.01). Tear lm break-up
time (TFBUT) and meibum scores improved signicantly
in both treatment groups, but ndings were not signicantly
different between the two groups.
Pinna et al conducted a prospective, randomized trial in
57 patients with MGD, comparing daily oral supplementa-
tion with 28.5 mg of linoleic acid and 15 mg of gamma lino-
leic acid (U-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 examinations. While improve-
ments were noted in all three treatment groups, the combi-
nation group demonstrated the greatest decrease from
baseline at 180 days in the percentages of patients
 TREATMENT OF BLEPHARITIS / Pugfelder, et al

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 evidence of foam in the meniscus (42% to 6%;
P.02) and corneal staining with uorescein (32% to 0%;
P.02).
These recent studies suggest at least modest benets of
dietary supplementation with essential fatty acids in patients
with MGD and/or associated blepharitis.
2. Topical Antibiotics
Bacterial infection appears to play a role in the etiology
of blepharitis. However, it is not always clear whether bacte-
rial infection is the root cause of the inammatory environ-
ment 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 the disease.3,8,35
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-inamma-
tory properties that penetrates the conjunctiva and eyelids40,42
and has a long post-antibiotic effect.43 Azithromycin is avail-
able 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.

Table 1. Recently published studies of topical azithromycin (AZM) in patients with blepharitis
Study Design Population (Patients [pts]) Treatment Topline Findings
Fadlallah Randomized, 67 pts with chronic, Group 1 (n33): AZM 1.5% Group 1 showed signicant
201236 investigator- moderate to severe BID for 3 days. improvement in signs and
masked. anterior and/or posterior Group 2 (n34): AZM 1.5% symptoms at 1-week follow-up.
blepharitis. BID for 3 days then HS Group 2 showed more pronounced
for a total of 30 days. and longer-lasting improvement
All pts used warm that persisted after 3 months of
compresses and follow-up.
eye-friendly soap BID.
Torkildsen Multicenter, 122 pts with moderate to Group 1 61 pts: AZM 1%; Group 1: Signicantly lower mean
201137 randomized, severe blepharitis/ BID for 2 days, then QD global score (P0.0002) with DM/T
investigator- blepharoconjunctivitis. for 12 days. compared with AZM at day 8.
masked, Group 2 61 pts: DM/T Group 2: DM/T provided faster
active- 0.05%/T 0.3%; QID for inammation relief than AZM.
controlled. 14 >days.
Opitz Open-label 26 pts with posterior AZM 1% BID for 2 days, At 30 days, signicant improvements
201138 blepharitis (MGD) then every evening for a from baseline in tear break-up
total of 30 days. time, Schirmer score, reductions in
corneal and conjunctival staining,
lid margin scores, and symptom
scores.
Foulks Open-label 17 pts with symptomatic AZM 1% BID for 2 days, At 4 weeks, signicant improvements
201039 MGD. then QD for total of 4 in subject-reported symptom
weeks. severity, as well as improved signs
of eyelid margin disease.
Haque Open-label 26 pts with moderate to AZM 1% BID for 2 days, At 30 days, signicant decreases from
201040 severe blepharitis. then every evening for a baseline in investigator-rated signs
total of 28 days. and subject-reported symptoms,
which persisted 4 weeks post-
treatment.
Luchs Open-label 21 pts with posterior AZM 1% (plus warm AZM plus warm compresses was
200841 blepharitis. compresses) BID for 2 signicantly more effective than
days then daily for the warm compresses alone in
next 12 days (n10) or improving meibomian gland
warm compresses only plugging, secretions, and eyelid
(n11) redness.
AZMazithromycin; BIDtwice daily; DMdexamethasone; HSat bedtime; MGDmeibomian gland dysfunction; QDonce daily; QID4
times daily; Ttobramycin.

THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com 277

Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
Fadlallah et al found that treatment with azithromycin
ophthalmic solution 1.5% twice daily (BID) for 3 days
then once daily (QD) for a total of 30 days was more effec-
tive in improving eyelid redness/swelling and meibomian
gland secretions than treatment administered BID for
3 days only in patients (n67) 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 treat-
ment groups showed signicant improvements from base-
line in blepharitis symptoms (P.01) and ocular signs,
including lid collarettes (P.01) and lid redness/swelling
(P.05). Total MGD score was signicantly improved at
one month (P.02) only for the group that received azithro-
mycin for the entire month. After 3 months of follow-up,
both treatment groups continued to report improved symp-
toms; however, only the regimen with continued treatment
QD for 1 month maintained improvements in objective
signs of disease (lid redness/swelling, plugging and quality
of meibomian gland secretions).
In an open-label study, Opitz and Tyler treated 33
patients with posterior blepharitis (MGD) with azithromy-
cin ophthalmic solution 1% BID for 2 days, then every eve-
ning for a total of 30 days.38 In the 26 patients who
completed the study, there were signicant 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
staining (67.9% reduction, P<.0001), and lid margin scores
(33.9% reduction, P<.0001). Patient-rated symptom scores
were signicantly 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 (lowering) of phase tran-
sition 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 lm and ocular surface. These
objective ndings 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,
amount of lid margin erythema, ease of expression of the
meibomian glands, and the character of meibomian gland
secretion.
In another open-label study by Haque et al, patients with
moderate-to-severe 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
278 THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
At the end of treatment, signicant (P<.001) decreases
from baseline were noted in all subject-rated symptoms
(eyelid itching, foreign body sensation/sandiness/grittiness,
ocular 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 signicant (P .002) imp-
rovement at 28 days. All improvements persisted for 4
weeks post-treatment. Eyelid margin culture showed
signicant decreases in the most commonly isolated organ-
isms, including coagulase-negative staphylococci (CoNS
[P.037]) and Corynebacterium xerosis bacteria (P<.001).
In an open-label study by Luchs, 21 patients with poste-
rior blepharitis were randomized to treatment with topical
azithromycin ophthalmic solution 1% (1 drop) plus warm
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 signicantly greater
improvements from baseline in meibomian gland plugging
and redness of the eyelid margins, and improved quality
of meibomian gland secretions compared to the patients
using compresses alone (all comparisons, P<.001). Evalua-
tions of lid debris and lid swelling showed greater numerical
improvement in the azithromycin group, but neither
achieved statistical signicance. More patients in the azi-
thromycin group rated symptom relief efcacy as excellent
(22%) or good (44%), compared with 0% and 18%, respec-
tively, of patients using compresses alone.
b. Fluoroquinolones
The uoroquinolone class of antibiotics has been
demonstrated to have potent in vitro activity against a
wide range of gram-negative and gram-positive micro-
organisms, with some differences in activity among the
uoroquinolone generations.20
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
levooxacin 0.5% QID; or topical levooxacin 0.5% QID
plus eyelid scrub (preceding each instillation of levooxacin)
for 7 days. Conjunctival sac cultures were obtained using a
thioglycolate-moistened swab and inoculated onto both aer-
obic and anaerobic media. As expected, patients with
chronic blepharoconjunctivitis had signicantly higher rates
of culture-positive eyes at baseline compared to healthy con-
trols (95% vs 58%; P<.0001). As early as day 3, treatment
with levooxacin 0.5% with or without eyelid scrub
produced a signicant reduction in the number of culture-
positive eyes compared with non-treatment (60% and
56%, respectively, vs. 88%; P<.05). By day 7, 29% of eyes
in the levooxacin monotherapy group had culture-
positive eyes compared with 95% of eyes in the no-
treatment group (P<.05). Statistically, the levooxacin plus
eyelid scrub treatment was not any more effective in
reducing culture-positive eyes than levooxacin therapy
alone on day 7 (50% vs 29%, P.1533), although both treat-
ments were statistically better than the no-treatment group
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
in this regard (P<.05). Although clinical efcacy was not
evaluated, this study conrmed that levooxacin signi-
cantly reduced the bacterial load in patients with
blepharoconjunctivitis.
In a comparative study by John, another topical uoro-
quinolone, besioxacin 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 identied 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
hygiene (warm washcloth with diluted baby shampoo). Af-
ter 2 weeks, all patients demonstrated clinically signicant
(P<.005) improvements in blepharitis signs and symptoms.
Among 13 Staphylococcal cases treated with besioxacin, 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.
c. Aminoglycosides
Tobramycin is an aminoglycoside with broad-spectrum
activity that has been utilized in a variety of ocular indica-
tions.46 Tobramycin has been shown to have an efcacy
and safety prole similar to that of azithromycin as therapy
for bacterial conjunctivitis.47,48 However, the Antibiotic
Resistance Monitoring in Ocular micRorganisms (ARMOR)
2009 surveillance study 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 for isolates of Streptococcus pneumonia
(8-fold); however, azithromycin was 2-fold more potent
than tobramycin for isolates of Haemophilus inuenza.19
d. Conclusion
These recent studies of topical antibacterial treatment
strategies conrm measurable benets in patients with ble-
pharitis treated for periods up to 30 days. Additional
comparative studies would be useful to further clarify the
most useful agents and treatment regimens.
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 inammation
commonly coexist. Having both agents in the same formu-
lation facilitates use and provides appropriate 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 inamma-
tion, adverse effects are associated with their long-term use
(e.g., increased IOP, cataract formation).46,49
THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
Several recent studies have compared antibiotic/cortico-
steroid formulations in the treatment 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%
ophthalmic suspension (Zylet, Bausch and Lomb, Roches-
ter, 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 pa-
tients with blepharokeratoconjunctivitis.50 Patients instilled
one drop of either drug QID for 14 days. The primary ef-
cacy endpoint was change from baseline 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 0none to 4severe, allowing
for a range of possible composite scores of 0-52. The
mean change from baseline to day 15 in composite score
was signicant with both LE/T (-11.63) and DM/T
(-12.41) (both P<.0001 vs baseline). Non-inferiority of LE/
T was established, given that the upper bound of the 90%
CI (0.75) was less than the predened non-inferiority limit
(2.5). Visual acuity improved with both treatments. There
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 (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 administered QID for
14 days to 276 patients clinically diagnosed with blepharo-
keratoconjunctivitis.51 The primary efcacy outcome was
change from baseline to day 15 in a composite score reect-
ing the total of individual severity ratings for the following:
blepharitis signs (lid hyperemia, lid scaling or crusting, lid
margin hypertrophy); conjunctivitis signs (conjunctival hy-
peremia, discharge, and chemosis); keratitis signs (corneal
punctate epithelial keratopathy); and ocular symptoms
(itchiness, foreign body sensation, blurred vision, light sensi-
tivity, painful or sore eyes, burning). Each sign and symp-
tom 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 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 (PNS). LE/T was
shown to be non-inferior to DM/T. There were signicantly
more elevations in mean IOP in the 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.0091) and overall
(2.3 vs 1.6 mm Hg; P.0208). Visual acuity and bio-
microscopy ndings were unremarkable.
A small trial by Rhee and Mah compared the effective-
ness of LE/T to DM/T in the management of blepharocon-
junctivitis.52 Forty patients were treated with LE/T or DM/T
given BID for 3 to 5 days, a dose and treatment duration less
279
 TREATMENT OF BLEPHARITIS / Pugfelder, et al

Table 2. Recently published studies comparing topical antibiotic/steroid combinations in patients with blepharitis
Study Design Population (Patients [pts]) Treatment Topline Findings
Loteprednol etabonate/tobramycin (LE/T) vs dexamethasone/tobramycin (DM/T)
50
Chen 2012 Multicenter, randomized, 308 pts with BKC 4 times Both treatments produced signicant
parallel group, (156 LE/T, 152 DM/T) daily for CFB in composite signs/symptoms
investigator masked. 14 days. at day 15 (P<.0001).
DM/T was associated with signicantly
greater increase in mean CFB in IOP
than LE/T and signicantly more
IOP elevations 5 mm Hg.
White Multicenter, randomized, 276 pts with BKC 4 times CFB in signs and symptoms composite
200851 investigator-masked, (138 LE/T, 138 DM/T). daily for score was similar between treatments
parallel group. 14 days. at day 15.
DM/T was associated with a signicantly
greater mean increase in IOP
compared with LE/T.
Rhee 200752 Randomized, parallel- 40 patients with moderate Twice daily At day 3-5, DM/T was associated with
group, double- to extensive inammation for 3-5 signicantly lower total ocular surface
masked. associated with BKC. days. (P.002), blepharitis (P.17), and
discharge (P.25) and conjunctivitis
surface (P.013) scores compared
with LE/T. Corneal PEK scores were
similar.
No safety ndings reported.
Moxioxacin/dexamethasone
Belfort Randomized, double- 102 pts with blepharitis 4 times Clinical resolution was similar in both
201256 masked, active control, (49 xed combination; 48 daily for treatment groups at day 7
parallel group. concomitant regimen*) 7 days. (approximately 82% of eyes).
Both regimens were safe and well
tolerated.
* Patients randomized to either 1) a xed combination of moxioxacin 0.5%/dexamethasone 0.1% plus placebo drops, or 2) moxioxacin 0.5%
and dexamethasone 0.1% administered separately (concomitant regimen).
BKC blepharokeratoconjunctivitis; CFBchange from baseline; IOPintraocular pressure; PEKpunctate epithelial keratopathy.

than that recommended in the FDA-approved labels for
these products.53,54 There were numerically greater reduc-
tions in symptom severity and statistically signicant
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.
Any topical ocular preparation must be comfortable for the
patient to administer and not 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 and DM/T,
in 306 healthy volunteers who instilled either agent QID for
28 days.55 The primary endpoint was the difference in com-
fort/tolerability ratings at week 4 (normalized for baseline rat-
ings using articial 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 arti-
cial tears used for standardization than subjects using DM/T.
In a randomized, double-masked, active-controlled,
parallel-group trial by Belfort et al, the efcacy and safety
of a moxioxacin 0.5%/dexamethasone 0.1% (MXF/D) xed
combination was compared to administration of both drugs
separately in 97 patients diagnosed with bacterial blephari-
tis.56 Patients instilled either an MXF/D combination or
MXF and D individually QID for 7 days. The primary ef-
cacy endpoint was clinical resolution of ocular signs (bulbar
conjunctival hyperemia, palpebral conjunctiva, conjunctival
exudate/discharge, lid erythema, and lid scaling/crusting) at
study completion. Secondary efcacy variables included
microbiological success, dened as the eradication of base-
line pathogens after 7 days of treatment. Rates for clinical
resolution were high in both groups (81.6% of eyes in the
xed-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 resolution of eyelid
erythema (100% vs 92.7%; P.0194) and eyelid crusting
(98% vs 89.6%; P.0337). Overall rates of bacterial eradica-
tion were similar for the xed-dose group (84%) and 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 xed-dose combination

280 THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com

Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
was therapeutically equivalent to the agents dosed separately
and both regimens were well tolerated.
In a randomized, investigator-masked study by Torkild-
sen et al, azithromycin ophthalmic solution 1% (1 drop BID
for 2 days, followed by 1 drop QD for 12 days) was
compared with 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 blephar-
oconjunctivitis.37 There was a statistically signicant differ-
ence in the seven-item global signs and symptoms score
(lower score less bothersome) at day 8, favoring tobramy-
cin/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 was smaller, but still better in
the tobramycin/dexamethasone group than in the azithro-
mycin group(4.8 vs 5.7; P.0487).
These studies demonstrate that a short course of an anti-
biotic/corticosteroid combination signicantly 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 dexameth-
asone, consistent with previously reported experience.22,57-60
LE is a unique corticosteroid, having a C-20 ester in lieu of
the C-20 ketone on the core prednisolone structure; this
modication results in rapid deesterication to inactive
metabolites and a favorable IOP-safety prole.61-63 More-
over, 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 com-
mon rst step implicated in cataract formation.22 Chronic or
intermittent pulse corticosteroid therapy is most appropri-
ately prescribed by eye care practitioners who can monitor
patients for complications.
4. Oral Antibiotics
Oral antibiotics, particularly those with anti-inammatory
activity, have been advocated for severe or resistant cases
of chronic blepharitis.5,35 Several recent studies investigated
the use of oral antibiotics in patients with blepharitis/
MGD, including azithromycin,64 doxycycline,65,66 and
minocycline.67,68
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 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 inter-
vals without treatment. Clinical outcomes were assessed
1 day before and 30 days after the last treatment (53 days
after initiation of the drug). Subject ratings of blepharitis
symptoms before and after treatment (scale, 0no symp-
toms to 5 severe symptoms) showed signicant improve-
ments 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), ocular hyperemia (2.93 vs 2.18;
P.0041), ocular mucus secretion (2.00 vs 0.71; P.003),
photophobia (2.00 vs 1.14; P.002), and dry eye sensation
THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
(2.14 vs 0.64; P.002); foreign body sensation was not
signicantly improved (0.71 vs 0.71). The average TFBUT
improved signicantly (6.64 to 9.75 sec; P.0005); however,
no statistical improvement was observed in Schirmer test
value or corneal uorescein or rose bengal staining.
Yoo et al compared two dose regimens of oral doxycy-
cline in a randomized placebo-controlled trial in 150
patients (300 eyes) with chronic MGD refractory to stan-
dard therapy (lid hygiene, topical drops, or ointments not
otherwise specied).65 Both high-dose (200 mg BID) and
low-dose (20 mg BID) doxycycline groups were statistically
superior to placebo in improving TFBUT, Schirmer score,
number of symptoms reported, and subjective symptoms af-
ter 1 month of treatment. Most efcacy outcomes were not
signicantly 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 benets were likely due to
anti-inammatory properties and inhibitory effects of doxy-
cycline on collagenase, as the low-dose doxycycline regimen
was too low to provide any antimicrobial efcacy.
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 signicant 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 signicantly (P<.05), and all subjects
reported an absence of burning symptoms. A highly signif-
icant improvement in TFBUT was also observed at 8 weeks
(P<.001). The authors compared these ndings with their
prior investigation of topical azithromycin in MGD39; oral
doxycycline was found to be slightly 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 0clear to 3solid paste).
Lee et al studied the use of oral minocycline 50 mg BID
plus articial tears QID versus articial tears QID alone in a
randomized trial involving 60 patients (60 eyes) with
moderate-to-severe MGD.67 After 2 months of treatment,
patients treated with minocycline plus articial tears showed
signicant (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 TFBUT,
corneal staining, lid margin abnormality, and meibum qual-
ity were signicantly (P<.05) greater compared with use of
articial tears alone.
Vargas et al reported preliminary ndings from a
prospective, non-randomized trial of a 3-month course of
oral minocycline (dose not specied) in 10 patients (20
eyes) with chronic blepharitis.68 The investigators specif-
ically looked at tear lm production, vital staining of the
ocular surface, and meibography before and after minocy-
cline therapy. Decreases were noted in mean tear ow
(P.10), tear volume (P.03), and evaporation (P.43),
281
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
while tear turnover 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 lm lipid layer (decreased
evaporation).
These studies suggest that oral antibiotics with anti-
inammatory activity can be benecial in patients with
refractory cases of MGD. Optimal duration of therapy and
long-term outcomes remain to be determined.
5. Topical Cyclosporine
Cyclosporine A (CsA; Restasis, Allergan Pharmaceuti-
cals) is an immunomodulatory agent that has been found
useful in treating a variety of ocular conditions. In patients
whose tear production is presumed to be suppressed due to
ocular inammation associated with keratoconjunctivitis
sicca, cyclosporine emulsion is thought to act as a partial
immunomodulator, although the exact mechanism of action
is unknown.69 The efcacy of topical administration of CsA
0.05% emulsion in symptomatic MGD or posterior blephar-
itis was recently evaluated in two studies versus articial
tears23,24 and one trial with an active drug comparator.25
In a prospective, double-masked study, Perry and col-
leagues evaluated the use of CsA 0.05% compared to arti-
cial tears administered 1 drop BID for 3 months in 33
patients with symptomatic MGD (26 completed the
study).23 At 3 months, there were signicant improvements
in several objective clinical ndings with CsA compared
with placebo, including a 50% decrease in meibomian gland
inclusions (no change in the placebo group; P.001), lid
margin vascular injection (P.001), tarsal telangiectasis
(P.03), and uorescein staining (P.01). Mean ocular
symptom scores (maximum score32; higher scoremore
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 signicant. Changes in TFBUT
and Schirmer test values were also not statistically different
between groups.
In a 3-month randomized, double-masked, parallel-
group study by Prabhasawat et al, 70 patients with symp-
tomatic MGD and unstable tear lm (TFBUT <8 seconds)
were 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 signicant improvements
from baseline in mean OSDI (P<0.01), noninvasive and
invasive TFBUTs (P<.01), lid margin inammation
(P<.001), meibomian gland expressibility (P<.05), and
tarsal injection (P<.001). In contrast, only the OSDI showed
a signicant improvement from baseline in the control
group.
Rubin and Rao compared the efcacy of CsA 0.05% to
dexamethasone 0.1%/tobramycin 0.3% ophthalmic suspen-
sion (DM/T), each administered one drop every 12 hours
for 12 weeks, in 30 patients with posterior blepharitis.25
282 THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
Following 12 weeks of treatment, eyelid health and the
mean signs and symptoms of posterior blepharitis were
signicantly improved for both treatment groups. CsA pro-
vided greater improvements in Schirmer values (mean
improvement, 2.33 vs 0.9 mm; P<.001), TFBUT (mean
change, 1.87 vs 1.30 seconds; P.018), and meibomian
gland secretion quality (graded on a scale of 0 [clear excreta
with small particles] to 3 [secreta that retained shape after
digital expression], with mean improvement of 0.77 vs 0.3;
P.015). Moreover, a higher percentage of patients in the
CsA group had improvements in symptoms of blurred
vision, burning, and itching, and more patients experienced
resolution of lid telangiectasia.
These small studies suggest that CsA has potential
benet in controlling symptoms of posterior blepharitis
and producing improvements in objective measures,
pending further evaluation in larger-scale clinical trials.
IV. SUMMARY AND CONCLUSIONS
Blepharitis is a commonly occurring, chronic ocular
condition that is difcult to manage satisfactorily. There is
no general consensus on treatment, and currently there
are no ofcial guidelines or FDA-approved drug products
specically studied for this condition. A number of different
treatment strategies have been shown to offer symptom
improvement to some degree. Unfortunately, it is difcult
to compare individual studies because of variations in
methodologies, measured outcomes, and patient/disease
characteristics, and head-to-head trials are lacking. Eyelid
hygiene combined with an antibiotic or antibiotic/cortico-
steroid combination appears to be a safe and effective strat-
egy 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 comparative clinical
studies are needed to further identify the most effective
drugs and regimens for the various forms of blepharitis.
ACKNOWLEDGEMENTS
The authors wish to thank Carol Tozzi, PhD and Sandra Westra,
PharmD of Churchill Communications (Maplewood, NJ) for assistance
in preparing this manuscript. This assistance was funded by
Bausch Lomb. The authors retained full control of manuscript content.
REFERENCES
1. American Academy of Ophthalmology. Preferred Practice Pattern: Ble-
pharitis. October 2011 revision. Available at: http://one.aao.org/CE/
PracticeGuidelines/PPP_Content.aspx?cid500cd9ca-173c-4c31-b6ea-
a258e3549474. Accessed June 6, 2013
2. Lemp MA, Nichols KK. Blepharitis in the United States 2009: a survey-
based perspective on prevalence and treatment. Ocul Surf 2009;7(2
suppl):S1-14
3. Lindsley K, Matsumura S, Hatef E, Akpek EK. Interventions for chronic
blepharitis (Review). Cochrane Database Syst Rev 2012;16:5. CD005556
4. Viso E, Rodrguez-Ares MT, Abelenda D, et al. Prevalence of asymp-
tomatic and symptomatic meibomian gland dysfunction in the general
population of Spain. Invest Ophthalmol Vis Sci 2012;53:2601-6
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
5. Bernardes TF, Bonoli AA. Blepharitis. Semin Ophthalmol 2010;25:
79-83
6. Hom MM, Martinson JR, Knapp LL, Paugh JR. Prevalence of Meibo-
mian gland dysfunction. Optom Vis Sci 1990;67:710-20
7. Patel KG, Raju VK. Ocular demodicosis. W V Med J 2013;109:16-8
8. OBrien TP. The role of bacteria in blepharitis. Ocul Surf 2009;7(2
suppl):S21-2
9. Filho PAN, Hazarbassanov RM, Grisolia ABD, et al. The efcacy of oral
ivermectin for the treatment of chronic blepharitis in patients tested
positive for Demodex spp. Br J Ophthalmol 2011;95:893-5
10. Zhao YE, Wu LP, Hu L, Xu JR. Association of blepharitis with Demo-
dex: a meta-analysis. Ophthalmic Epidemiol 2012;19:95-102
11. Malerbi FK, Martins LC, Saldiva PH, Braga AL. Ambient levels of air
pollution induce clinical worsening of blepharitis. Environ Res
2012;112:199-203
12. Tesn M, Gonzlez-Garcia MJ, Lpez-Miguel A, et al. Inuence of a
controlled environment simulating an in-ight airplane cabin on dry
eye disease. Invest Ophthalmol Vis Sci 2013;54:2093-9
13. Geerling G, Tauber J, Baudouin C, et al. The international workshop on
meibomian gland dysfunction: report of the subcommittee on manage-
ment and treatment of meibomian gland dysfunction. Invest Ophthal-
mol Vis Sci 2011;52:2050-64
14. Scafdi RC, Korb DR. Comparison of the efcacy of two lipid emulsion
eye drops in increasing tear lm lipid layer thickness. Eye Contact Lens
2007;33:38-44
15. Sindt CW, Foulks GN. Efcacy of an articial tear emulsion in patients
with dry eye associated with meibomian gland dysfunction. Clin Oph-
thalmol 2013;7:1713-22
16. Kheirkhah A, Casas V, Li W, et al. Corneal manifestations of ocular
demodex infestation. Am J Ophthalmol 2007;143:743-9
17. Holzchuh FG, Hida RY, Moscovici BK, et al. Clinical treatment of
ocular Demodex folliculorum by systemic ivermectin. Am J Ophthalmol
2011;151:1030-4
18. Freidlin J, Acharya N, Lietman TM, et al. Spectrum of eye disease
caused by methicillin-resistant Staphylococcus aureus. Am J Ophthal-
mol 2007;144:313-5
19. Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in
ocular microorganisms: results from the Antibiotic Resistance Moni-
toring in Ocular micRorganisms (ARMOR) 2009 surveillance study.
Am J Ophthalmol 2011;152:567-74
20. Miller D, Chang JS, Flynn HW, Alfonso EC. Comparative in vitro
susceptibility of besioxacin and seven comparators against ciprooxa-
cin- and methicillin-susceptible/nonsusceptible staphylococci. J Ocul
Pharmacol Ther 2013;29:339-44
21. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimi-
crobial susceptibility patterns in ocular isolates. Am J Ophthalmol
2008;145:951-8
22. Pleyer U, Ursell PG, Rama P. Intraocular pressure effects of common
topical steroids for post-cataract inammation: are they the same? Oph-
thalmol Ther 2013. http://dx.doi.org/10.1007/s40123-013-0020-5
23. Perry HD, Doshi-Carnevale S, Donnenfeld ED, et al. Efcacy of
commercially available topical cyclosporine A 0.05% in the treatment
of meibomian gland dysfunction. Cornea 2006;25:171-5
24. Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-
masked study of 0.05% cyclosporine ophthalmic emulsion in the
treatment of meibomian gland dysfunction. Cornea 2012;31:
1386-93
25. Rubin M, Rao SN. Efcacy of topical cyclosporine 0.05% in the
treatment of posterior blepharitis. J Ocul Pharmacol Ther 2006;22:
47-53
26. Maskin SL. Intraductal meibomian gland probing relieves symptoms of
obstructive meibomian gland dysfunction. Cornea 2010;29:1145-52
THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
27. Macsai MS. The role of omega-3 dietary supplementation in blepharitis
and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthal-
mol Soc 2008;106:336-56
28. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic acid ther-
apy in dry eye syndrome with an inammatory component. Cornea
2003;22:97-101
29. Creuzot-Garcher C, Baudouin C, Labetoulle M, et al. Efcacy assess-
ment of Nutrilarm a per os omega-3 and omega-6 polyunsaturated
essential fatty acid dietary formulation versus placebo in patients with
bilateral treated moderate dry eye syndrome. J Fr Ophthamol 2011;34:
448-55
30. Kokke KH, Morris JA, Lawrenson JG. Oral omega-6 essential fatty acid
treatment in contact lens associated dry eye. Cont Lens Anterior Eye
2008;31:141-6
31. Sheppard Jr JD, Singh R, McClellan AJ, et al. Long-term supplementa-
tion with n-6 and n-3 PUFAs improves moderate-to-severe keratocon-
junctivitis sicca: a randomized double-blind clinical trial. Cornea
2013;32:1297-304
32. Brignole-Baudouin F, Baudouin C, Aragona P, et al. A multicenter,
double-masked, randomized, controlled trial assessing the effect of
oral supplementation of omega-3 and omega-6 fatty acids on a
conjunctival inammatory marker in dry eye patients. Acta Ophthalmol
2011;89:e591-7
33. Aragona P, Buculo C, Spinella R, et al. Systemic omega-6 essential fatty
acid treatment and PGE1 tear content in Sjgrens syndrome patients.
Invest Ophthalmol Vis Sci 2005;46:4474-9
34. Pinna A, Piccinini P, Carta F. Effect of oral linoleic and gamma-
linolenic acid on meibomian gland dysfunction. Cornea 2007;26:260-4
35. Jackson WB. Blepharitis: current strategies for diagnosis and manage-
ment. Can J Ophthalmol 2008;43:170-9
36. Fadlallah A, Rami HE, Fahd D, et al. Azithromycin 1.5% ophthalmic
solution: efcacy and treatment modalities in chronic blepharitis. Arq
Bras Oftalmol 2012;75:178-82
37. Torkildsen GL, Cockrum P, Meier E, et al. Evaluation of clinical efcacy
and safety of tobramycin/dexamethasone ophthalmic suspension 0.
3%/0.05% compared to azithromycin ophthalmic solution 1% in the
treatment of moderate to severe acute blepharitis/blepharoconjunctivi-
tis. Curr Med Res Opin 2011;27:171-8
38. Opitz DL, Tyler KF. Efcacy of azithromycin 1% ophthalmic solution
for treatment of ocular surface disease from posterior blepharitis. Clin
Exp Optom 2011;94:200-6
39. Foulks GN, Borchman D, Yappert M, et al. Topical azithromycin ther-
apy of meibomian gland dysfunction: clinical response and lipid alter-
ations. Cornea 2010;29:781-8
40. Haque RM, Torkildsen GL, Brubaker K, et al. Multicenter open-label
study evaluating the efcacy of azithromycin ophthalmic solution 1%
on the signs and symptoms of subjects with blepharitis. Cornea
2010;29:871-7
41. Luchs J. Efcacy of topical azithromycin ophthalmic solution 1% in the
treatment of posterior blepharitis. Adv Ther 2008;25:858-70
42. Akpek EK, Vittitow J, Verhoeven RS, et al. Ocular surface distribution
and pharmacokinetics of a novel ophthalmic 1% azithromycin formu-
lation. J Ocul Pharmacol Ther 2009;25:433-9
43. Wang MG, Zhang YY, Zhu DM, et al. Postantibiotic effects of eleven
antimicrobials on ve bacteria. Acta Pharmacol Sin 2001;22:804-8
44. Yactayo-Miranda Y, Ta CN, He L, et al. A prospective study deter-
mining the efcacy of topical 0.5% levooxacin on bacterial ora of pa-
tients with chronic blepharoconjunctivitis. Graefes Arch Clin Exp
Ophthalmol 2009;247:993-8
45. John G. A comparative study in the clinical and microbial efcacy of
topical besioxacin ophthalmic suspension 0.6% with erythromycin
ophthalmic ointment 0.5% for the management of acute blepharitis
283
 TREATMENT OF BLEPHARITIS / Pugfelder, et al
(poster). Presented at the Annual Meeting of the Association for
Research in Vision and Ophthalmology, Fort Lauderdale, FL, May
6-9, 2012
46. Comstock TL, Holland EJ. Loteprednol and tobramycin in combina-
tion: a review of their impact on current treatment regimens. Expert
Opin Pharmacother 2010;11:843-52
47. Cochereau I, Meddeb-Ouertani A, Khairallah M, et al. 3-day treatment
with azithromycin 1.5% eye drops versus 7-day treatment with tobra-
mycin 0.3% for purulent bacterial conjunctivitis: multicentre, rando-
mised and controlled trial in adults and children. Br J Ophthalmol
2007;91:465-9
48. Protzko E, Bowman L, Abelson M, Shapiro A. AzaSite Clinical Study
Group. Phase 3 safety comparisons for 1.0% azithromycin in polymeric
mucoadhesive eye drops versus 0.3% tobramycin eye drops for bacterial
conjunctivitis. Invest Ophthalmol Vis Sci 2007;48:3425-9
49. Clark AF. Basic sciences in clinical glaucoma: steroids, ocular hyperten-
sion, and glaucoma. J Glaucoma 1995;4:354-69
50. Chen M, Gong L, Sun X, et al. A multicenter, randomized, parallel-
group, clinical trial comparing the safety and efcacy of loteprednol eta-
bonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.
3% in the treatment of Chinese patients with blepharokeratoconjuncti-
vitis. Curr Med Res Opin 2012;28:385-94
51. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the
safety and efcacy of loteprednol 0.5%/tobramycin 0.3% with dexa-
methasone 0.1%/tobramycin 0.3% in the treatment of blepharokerato-
conjunctivitis. Curr Med Res Opin 2008;24:287-96
52. Rhee SS, Mah FS. Comparison of tobramycin 0.3%/dexamethasone 0.
1% and tobramycin 0.3%/loteprednol 0.5% in the management of ble-
pharo-keratoconjunctivitis. Adv Ther 2007;24:60-7
53. Zylet [package insert]. Tampa, FL: Bausch & Lomb Inc; 2013
54. Tobradex [package insert]. Fort Worth, TX: Alcon Laboratories; 2009
55. Bartlett JD, Holland EJ, Usner DW, et al. Tolerability of loteprednol/
tobramycin versus dexamethasone/tobramycin in healthy volunteers:
results of a 4-week, randomized, double-masked, parallel-group study.
Curr Med Res Opin 2008;24:2219-27
56. Belfort Jr R, Gabriel L, Martins Bispo PJ, et al. Safety and efcacy of
moxioxacin-dexamethasone eyedrops as treatment for bacterial ocular
infection associated with bacterial blepharitis. Adv Ther 2012;29:416-26
57. Dell SJ, Shulman DG, Lowry GM, Howes J. A controlled evaluation of
the efcacy and safety of loteprednol etabonate in the prophylactic
284 THE OCULAR SURFACE / OCTOBER 2014, VOL. 12 NO. 4 / www.theocularsurface.com
Downloaded for Ary Setiawan Nheu (arysetiawannheu@gmail.com) at Universitas Tarumanagara from ClinicalKey.com by Elsevier on September 30, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
treatment of seasonal allergic conjunctivitis. Loteprednol Allergic
Conjunctivitis Study Group. Am J Ophthalmol 1997;123:791-7
58. Stewart R, Horwitz B, Howes J, et al. Double-masked, placebo-
controlled evaluation of loteprednol etabonate 0.5% for postoperative
inammation. Loteprednol Etabonate Post-operative Inammation
Study Group 1. J Cataract Refract Surg 1998;24:1480-9
59. Comstock TL, Paterno MR, Singh A, et al. Safety and efcacy of lote-
prednol etabonate ophthalmic ointment 0.5% for the treatment of
inammation and pain following cataract surgery. Clin Ophthalmol
2011;5:177-86
60. Holland EJ, Bartlett JD, Paterno MR, et al. Effects of loteprednol/tobra-
mycin versus dexamethasone/tobramycin on intraocular pressure in
healthy volunteers. Cornea 2008;27:50-5
61. Bodor N, Loftsson T, Wu WM. Metabolism, distribution, and trans-
dermal permeation of a soft corticosteroid, loteprednol etabonate.
Pharm Res 1992;9:1275-8
62. Bodor N, Buchwald P. Soft drug design: general principles and recent
applications. Med Res Rev 2000;20:58-101
63. Comstock TL, Decory HH. Advances in corticosteroid therapy for
ocular inammation: loteprednol etabonate. Int J Inam 2012;2012:
789623. http://dx.doi.org/10.1155/2012/789623
64. Igami TZ, Holzchuh R, Osaki TH, et al. Oral azithromycin for treat-
ment of posterior blepharitis. Cornea 2011;30:1145-9
65. Yoo SE, Lee DC, Chang MH. The effect of low-dose doxycycline ther-
apy in chronic meibomian gland dysfunction. Korean J Ophthalmol
2005;19:258-63
66. Foulks GN, Borchman D, Yappert M, Kakar S. Topical azithromycin
and oral doxycycline therapy of meibomian gland dysfunction: a
comparative clinical and spectroscopic pilot study. Cornea 2013;32:
44-53
67. Lee H, Min K, Kim EK, Kim TI. Minocycline controls clinical outcomes
and inammatory cytokines in moderate and severe meibomian gland
dysfunction. Am J Ophthalmol 2012;154:949-57
68. Vargas JM, Aronowicz J, Shine WE, et al. Short-term treatment of
chronic blepharitis with oral minocycline [abstract]. Annual Meeting
of the Association for Research in Vision and Ophthalmology, Fort
Lauderdale, FL, USA; May 4-8, 2003
69. Gumus K, Cavanagh DH. The role of inammation and antiinamma-
tion therapies in keratoconjunctivitis sicca. Clin Ophthalmol 2009;3:
57-67