Kelompok 9 - Farmakoterapi VI Praktikum 5 - Anisah, Beatris, Missio

Kelompok 9 :
- Anisah / 21190002
- Beatriss / 21200003
- Missionira D.V Wea / 21200013
Praktikum 5 Farmakoterapi VI
Kasus 1
Bandingkan effektivitas untuk pengobatan konjungtivitis bakteri akut antara Azitromisin 1%
dan Besifloxacin 0,6% mana yang lebih effektif dan berikan data pendukung jurnalnya.
- Besifloxacin efektif menunjukkan kemanjuran dan keamanan dalam pengobatan pasien

konjungtivitis bakteri. Dalam uji coba fase 3 secara acak, multisenter, bertopeng ganda,
dan terkontrol dengan terhadap 390 pasien dengan konjungtivitis bakteri. Sedangkan
Azitromisin kemungkinan besar memiliki efektivitas yang sebanding dengan
kebanyakan antibiotik lain yang digunakan untuk mengobati konjungtivitis bakteri akut.
Kasus 7
Bandingkan efektivitas untuk pengobatan konjungtivitis alergi Prednisolon atau Deksametason
mana yang lebih effektif dan berikan data pendukung jurnalnya.
- Secara intrinsik Dexametason lebih kuat dari pada hidrokortisone 25-30x. Prednisolone
6x lebih baik secara molar dari pada Dexametasone. Dari pernyataan tersebut,
Prednisolone lebih efektif dari pada Dexametason.
-
Kasus 10
Bandingkan effektivitas untuk pengobatan keratitis herpes zoster Asiklovir 3% dan

Valasiklovir mana yang lebih effektif dan berikan data pendukung jurnalnya.
- Antivirus Acyclovir 3% vs Valacyclovir untuk pengobatan keratitis herpes zoster:
dalam studi ini, terdapat ketidakpastian dalam bukti bahwa Valasiklovir sebagai pilihan
pengobatan sistemik untuk herpes zoster opthalmicus berbeda atau sebanding dengan
Asiklovir.
(https://drive.google.com/file/d/1izMV4mKLqIzd2d5IKvTiqccontEOkRqW/view?usp
=sharing)
Received: 23 July 2019 Revised: 21 November 2019 Accepted: 9 December 2019
DOI: 10.1111/ceo.13702
REVIEW
Local delivery of corticosteroids in clinical ophthalmology:

A review
Adrian T. Fung MMed FRANZCO1,2,3 | Tuan Tran MBBS MMed3 |

Lyndell L. Lim DMedSci FRANZCO4,5,6 |
Chameen Samarawickrama PhD FRANZCO1,3,7 | Jennifer Arnold FRANZCO8 |
Mark Gillies PhD FRANZCO3 | Caroline Catt MMed FRANZCO3,9 |
Logan Mitchell MOphth FRANZCO10 | Andrew Symons PhD FRANZCO11 |
Robert Buttery PhD FRANZCO12 | Lisa Cottee MBA FRCOphth13 |
Krishna Tumuluri FRANZCO1,2,3 | Paul Beaumont FRANZCO13
1
Westmead Clinical School, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, Sydney, New South Wales, Australia
2
Department of Ophthalmology, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
3
Save Sight Institute, Central Clinical School, Discipline of Clinical Ophthalmology and Eye Health, University of Sydney, Sydney, New South Wales,
Australia
4
Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
5
Centre for Eye Research Australia, Melbourne, Victoria, Australia
6
University of Melbourne, Melbourne, Victoria, Australia
7
Liverpool Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
8
Marsden Eye Specialists, Sydney, New South Wales, Australia
9
Children's Hospital Westmead, Westmead, New South Wales, Australia
10
University of Otago, Dunedin, New Zealand
11
Royal Melbourne Hospital, Melbourne, Victoria, Australia
12
Melbourne Retina Associates, Melbourne, Victoria, Australia
13
Eye Doctors Mona Vale, Sydney, New South Wales, Australia
Correspondence
Adrian T. Fung, MMed, FRANZCO, Abstract
Department of Ophthalmology, Westmead Locally administered steroids have a long history in ophthalmology for the
Hospital, Corner of Hawkesbury and
treatment of inflammatory conditions. Anterior segment conditions tend to be
Darcy Roads, Westmead, New South
Wales 2145, Australia. treated with topical steroids whilst posterior segment conditions generally
Email: adrian.fung@sydney.edu.au require periocular, intravitreal or systemic administration for penetration. Over
recent decades, the clinical applications of periocular steroid delivery have
expanded to a wide range of conditions including macular oedema from
retino-vascular conditions. Formulations have been developed with the aim to
provide practical, targeted, longer-term and more efficacious therapy whilst
minimizing side effects. Herein, we provide a comprehensive overview of the
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2019 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of
Ophthalmologists.
366 wileyonlinelibrary.com/journal/ceo Clin Experiment Ophthalmol. 2020;48:366–401.

14429071, 2020, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ceo.13702 by Nat Prov Indonesia, Wiley Online Library on [21/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
FUNG ET AL. 367
types of periocular steroid delivery, their clinical applications in ophthalmol-

ogy and their side effects.
KEYWORDS
corticosteroid, dexamethasone, Fluocinolone acetonide, prednisolone acetate, triamcinolone
acetonide
1 | INTRODUCTION corticosteroids (glucocorticoids and mineralocorticoids)

and sex steroids (progestogens, androgens and estrogens;
The first use of corticosteroids in ophthalmology by Figure 1).2
Gordon and McLean1 in the 1950s was a landmark event Most steroids used in ophthalmology are glucocorti-
that revolutionized the management of inflammatory eye coids, which have anti-inflammatory and immunosup-
disease. The following decades led to further research into pressive activity. The synthetic steroid prednisolone has
the mechanisms and immunological pathways within the both glucocorticoid and mineralocorticoid receptor
eye, as well as the development of various forms of steroid activity, whilst the other three main ocular steroids (tri-
that are locally administered in clinical practice today. amcinolone acetonide [TA], dexamethasone acetonide
Variations in ocular steroid delivery sites, dosages and [DA] and fluocinolone acetonide [FA]) are predomi-
preparations have all improved efficacy and durability nantly active against glucocorticoid receptors (Table 1).2
whilst minimizing side effects. Despite development of sys- The therapeutic effect of glucocorticoids are mediated
temic immunomodulatory (steroid-sparing) agents and via the glucocorticoid receptor in the cytosol which upon
intravitreal monoclonal antibodies, locally administered activation, undergoes conformational changes and translo-
steroids continue to retain a fundamental role in the man- cate toward the cell nucleus. This activated glucocorticoid
agement of many ophthalmic diseases. This paper reviews receptor signals the transactivation or trans-repression of
the mechanism of action, preparations, indications and gene transcription factors which cause both therapeutic and
side effects of locally administered steroids. side effects. There are over 40 distinct isoforms of the gluco-
corticoid receptor which have varying distribution within
the tissues of the eye, each with different downstream sig-
2 | STEROID SUBTYPES AND nalling effects allowing for diverse cell-specific actions.4
M E C HA N IS M O F AC T I ON The anti-inflammatory effect of steroids is caused by
inhibiting the transcription of inflammatory and immune
Steroids are organic compounds with 17 core carbon genes. These actions block the release of arachidonic acid
atoms bonded in three fused cyclohexane and one and its subsequent eicosanoids (prostaglandins, throm-
fused cyclopentane ring. The main two groups are boxanes, prostacyclins and leukotrienes).5 This affects the
F I G U R E 1 Classification of
steroids and actions
368 FUNG ET AL.
blood-retinal barrier with a reduction in fibroblast prolif- levels of ocular delivery (intravitreal steroid bypasses the
eration, collagen and scar formation, retinal oedema, blood-retinal barrier) whilst minimizing systemic side
fibrin deposition, capillary leakage, intraretinal migration effects. An overview of steroid preparations and their
of inflammatory cells and levels of vascular endothelial local delivery methods are presented in Table 2.
growth factor (VEGF).
3.1 | Topical
3 | STEROID PREPARATIONS AND
M E T H O DS OF LO C A L Topical steroids are used to treat inflammation of the
ADMINISTRATION TO TREAT conjunctiva, cornea and the anterior segment. In certain
OPHTHALMIC DIS EASE circumstances they can also be useful in treating uveitic
or postoperative macular oedema. Penetration into the
Glucocorticoids may be locally administered in the fol- aqueous humour occurs by diffusion across the cornea.6
lowing ways: topical, sub-conjunctival, periocular (sub- Dexamethasone is approximately 25 to 30 times
Tenon, orbital floor, peribulbar) and intravitreal intrinsically more potent than hydrocortisone.7 However,
(Figure 2). Regional administration allows for high the efficacy of each preparation depends not only on the
TABLE 1 Potency in receptor activation determined in engineered human HeLa cells3
Glucocorticoid receptor activation potency Mineralocorticoid receptor activation potency

HeLa cells HeLa cells
Absolute (nM) Relative to Cortisol Absolute (nM) Relative to cortisol

Short acting
• Cortisol 72 100% 0.04 100%
Intermediate-acting
• Prednisone/prednisolone 8 900% 0.015 267%
• Triamcinolone 1 7200% >100 <0.04%
Long-acting
• Dexamethasone 3 2400% 0.3 13%
• Fluocinolone 0.4 18 000% >100 <0.04%
F I G U R E 2 Common locally
administered ophthalmic steroids
FUNG ET AL. 369
TABLE 2 Ocular steroid preparations and their delivery sites, generic name (trade name)
1. Topical Dexamethasone sodium phosphate 0.1% (MAXIDEX, Decadron)

Dexamethasone sodium phosphate ointment 0.05% (Dexadron)
Prednisolone acetate 1% (Pred Forte, Econopred Plus, AK-Tate)
Prednisolone acetate 0.12% (Pred Mild, Econopred)
Prednisolone sodium phosphate 1% (Inflamase Forte, AK-Pred)
Prednisolone sodium phosphate 0.5% (Prednisolone Minims,
Metreton)
Prednisolone phosphate 0.5%, 0.25% ointment (Hydeltrasol)
Fluorometholone alcohol 0.1% or 0.25% suspension (FML Forte, FML,
FML liquifilm)
Fluorometholone ointment 0.1% (FML SOP)
Fluorometholone acetate 0.1% (FLAREX)
Hydrocortisone acetate 1% ointment (Siguent Hycor)
Medrysone 1% suspension (HMS)
Rimexolone 1% (Vexol)
Medroxyprogesterone acetate 1% (Provera)
Loteprednol etabonate 0.5% (Lotemax, Alrex)
Difluprednate 0.05% emulsion (Durezol)
2. Sub-conjunctival Hydrocortisone 100 to 1000 mg powder (hydrocortisone sodium
succinate)
Methylprednisolone sodium succinate 40 mg/mL, 125 mg/mL,
2 g/40 mL solution (Solu-Medrol)
Methylprednisolone acetate 40 mg/mL (Depo-Medrol)
Triamcinolone diacetate 25 to 40 mg/mL suspension (Aristocort)
Triamcinolone acetonide 10 to 40 mg/mL suspension (Kenalog,
Kenacort-A 10, Kenacort-A 40)
Triamcinolone acetonide 40 mg/mL (Triescence)
Dexamethasone acetate 6 to 16 mg/mL (Decadron-LA)
Betamethasone acetate and sodium phosphate 3 mg/mL suspension
(Celestone Soluspan)
3. Periocular (intra-lesional [eyelids], Juxtascleral, sub-Tenon, Hydrocortisone 100 to 1000 mg powder (hydrocortisone sodium
orbital floor, peribulbar) succinate)
Methylprednisolone sodium succinate 40 mg/mL, 125 mg/mL,
2 g/40 mL solution (Solu-Medrol)
Methylprednisolone acetate 20 to 80 mg/mL (Depo-Medrol)
Triamcinolone diacetate 25 to 40 mg/mL suspension (Aristocort)
Triamcinolone acetonide 10 to 40 mg/mL suspension (Kenalog,
Dexamethasone 0.4 mg implant (Dextenza), inserted into lacrimal
puncta
Dexamethasone acetate 6 to 16 mg/mL (Decadron-LA)
Dexamethasone sodium phosphate 4, 10, 24 mg/mL solution
(Decadron Phosphate)
Betamethasone acetate and sodium phosphate 3 mg/mL suspension
(Celestone Soluspan)
4. Intravitreal Triamcinolone acetonide 10 to 40 mg/mL suspension (Kenalog,
Dexamethasone solution 9% (DEXYCU)
Dexamethasone 0.7 mg implant (OZURDEX)
Fluocinolone acetonide 0.19 mg implant (Iluvien)
Fluocinolone acetonide 0.18 mg implant (Yutiq)
Fluocinolone acetonide 0.59 mg implant (Retisert)
370 FUNG ET AL.
drug's intrinsic potency, but its penetration and durabil- 6 months. Although its efficacy in neovascular age-
ity. Acetate preparations are more lipophilic than those related macular degeneration (AMD) was shown against
with phosphate preparations, and hence have greater cor- placebo,16 it did not strongly demonstrate significant ben-
neal penetration.8 Although prednisolone acetate is six efit against photodynamic therapy with verteporforin.17
times less potent on a molar basis than dexamethasone The role of anecortave acetate was soon superceded by
or betamethasone, due to the acetate preparation, topical the emergence of intravitreal anti-VEGF.
prednisolone acetate 1% provides greater anti-
inflammatory effect than either dexamethasone or bet-
amethasone phosphate 0.1%.9 Solutions with preserva- 3.4 | Intravitreal
tives also have greater penetrance than those without, as
the preservative disrupts tight junctions between Steroids are most potent against retinal disease when
corneal epithelial cells. The frequency of application delivered intravitreally. Intravitreal steroids are used for
also increases the anti-inflammatory effect. A study on macular oedema, uveitis and to stain the vitreous during
corneal inflammation demonstrated greater anti- intraocular surgery for improved visualization. As the
inflammatory effects when topical prednisolone acetate is procedure involves globe penetration, it must be done
applied every 15 minutes (or five doses at 1 minute inter- under aseptic conditions. It may be given as an intra-
vals each hour) versus hourly.10 It is important that sus- vitreal injection (Kenacort, Triesence), or as a slow-
pensions are shaken immediately prior to use, otherwise release intravitreal implant (OZURDEX, Iluvien,
the administered dosage will vary. Retisert).
3.2 | Sub-conjunctival 3.4.1 | Triamcinolone acetonide
Sub-conjunctival steroids are frequently administered at the TA is a minimally water-soluble suspension. After intra-
conclusion of intraocular surgery. The most common prepa- vitreal injection, triamcinolone crystals slowly dissolve
ration used is dexamethasone, although methylpredniso- into the vitreous. This creates a diffusional gradient from
lone may also be given.11 Dexamethasone has been shown the vitreous to the macula with minimal systemic expo-
to achieve good ocular penetration following sub- sure. While a portion of the drug targets the macula,
conjunctival injection, with higher levels of concentration another portion either clears through the retina or dif-
in the aqueous and vitreous than when it is administered as fuses to the anterior segment where it can cause cataract
a peribulbar injection or orally.12 Sub-conjunctival TA has or elevation of intraocular pressures (IOPs).
been shown to be efficacious and safe for anterior uveitis Kenacort was formulated for intra-articular and
and non-necrotising, non-infectious anterior scleritis.13,14 intramuscular injection and thus its application in oph-
thalmology is off-label. In contrast, Triesence is a
preservative-free preparation of TA. The pharmacokinet-
3.3 | Periocular ics and pharmacodynamics of different TA preparations
have been shown to differ in animal studies.18,19 Since
Sub-Tenon, orbital floor and peribulbar steroids are fre- only dissolved free triamcinolone has a therapeutic effect,
quently used to treat ocular inflammatory conditions, durability depends on multiple factors such as pH, parti-
particularly when there is associated macular oedema cle size (smaller and more uniform for Triesence com-
and in whom systemic side effects are less desirable. After pared with Kenacort), crystallinity, solubility and
30 days following a single sub-Tenon injection of 40 mg dissolution kinetics in the vitreous.19 The duration of
of TA, corticosteroid levels can be found in all ocular tis- effect of intravitreal TA (IVTA) lasts between 320 and 621
sues, with highest levels within the choroid and retinal months in non-vitrectomised eyes, but is up to six times
pigment epithelium, whilst systemic levels remain low.15 shorter in vitrectomised eyes.20
The drug of choice is usually TA, formulations of which Kenacort comes in two dosages: Kenacort-A
include Kenacort and Triesence. 10 (10 mg/ml) and Kenacort-A 40 (40 mg/ml). As its use
Posterior juxtascleral depot injection of anecortave in ophthalmology is off-label, no specific dosage is rec-
acetate was previously used to treat choroidal ommended however most studies for diabetic macular
neovascularisation. Anecortave acetate (Retaane) is a oedema (DMO) have injected 4 mg in 0.1 mL. The SCORE
synthetic angiostatic steroid that was formulated to be studies for macular oedema secondary to retinal vein
devoid of glucocorticoid receptor-mediated activity. It occlusion showed no significant differences between the
was delivered as a posterior juxtascleral depot every 1 mg/0.1 mL and 4 mg/0.1 mL preservative-free IVTA
FUNG ET AL. 371
(Trivaris Allergan, Inc., Irvine, California) arms.22,23 The sustained release for up to 36 months. Fluocinolone is
manufacturer of Triesence (Alcon) recommends an initial contained in the core of a polyamide polymeric cylinder
dosage of 4 mg/0.1 ml for therapeutic purposes, and 1 to (3.5 × 0.37 mm) with a permeable polyvinyl alcohol
4 mg for visualization during vitrectomy.24 membrane. It is injected by a pre-loaded sterile applicator
with a 25-gauge needle. The drug delivers an approxi-
mate initial rate of 0.2 μg daily followed by 0.1 μg daily
3.4.2 | Dexamethasone intravitreal over 36 months.30
implant
OZURDEX is a biodegradable intravitreal implant that 4 | USES OF LOCALLY

contains 0.7 mg dexamethasone in a NOVADUR solid ADMINISTERED STEROIDS
rod-shaped polymer drug delivery system. It is designed
to release drug over 3 to 6 months in a biphasic fashion An outline of studies on the local delivery of corticoste-
with higher doses in the initial 6 weeks followed by lower roids in clinical ophthalmology is presented in Table 3.
doses for up to 6 months. It is injected using a single-use
intravitreal applicator with a stepped technique. It is used
to treat DMO, macular oedema due to branch or central 4.1 | Ocular adnexae-eyelids, lacrimal
retinal vein occlusion (BRVO, CRVO) and non-infectious gland and orbit
posterior uveitis.
OZURDEX is contraindicated if there is active ocular Oculoplastic uses of topical or intra-lesional steroids is
infection, hypersensitivity to the drug, advanced glau- limited to a few conditions.
coma or posterior lens capsule rupture.25 In vitrectomised
eyes, there may be an advantage in using the dexametha-
sone intravitreal implant (DII) over other bolus 4.1.1 | Thyroid eye disease
intravitreal therapies which have a reduced half-life.20
Rabbit-studies have shown no difference in clearance Peribulbar and intra-orbital steroids have been used in
rates of DII in vitrectomised and non-vitrectomised management of active thyroid eye disease (TED). Two
eyes.26 The efficacy of DII has also been shown to be sim- randomized studies, with small patient numbers, showed
ilar in vitrectomised and non-vitrectomised eyes when reduction in clinical activity score and extraocular muscle
used to treat macular oedema secondary to CRVO.27 size.31,32 Both studies required multiple peribulbar injec-
tions of TA 20 mg. There were few reported side effects-
only two cases developed raised IOP. Although they can
3.4.3 | FA implant have an adjunctive role in active TED, they are not first-
line therapy.
Fluocinolone acetonide implants are synthetic corticoste- Peribulbar and sub-conjunctival steroids have also
roid with low solubility in aqueous allowing extended been used for upper eyelid retraction in TED.33-36 Studies
drug release. show that repeat injections of 20 mg of TA are required
Iluvien is an injectable intravitreal 0.19 mg implant (one to four injections at monthly intervals) and the
within a rod-shaped (3.5 × 0.37 mm) non-biodegradable res- response rate is better in patients with recent onset of
ervoir that has a duration of action of 18 to 36 months. The upper lid retraction or active disease. Xu et al37 noted an
FAMOUS study demonstrated a sustained release by mea- improvement in 83.3% of patients with symptom duration
suring aqueous concentrations, with levels of slightly more less than 6 months, compared to 36.4% who responded if
than 2 ng/mL for the first 3 months followed by maintained symptoms were greater than 6 months. Joos et al36
concentrations of 0.5 to 1.0 ng/mL from 6 to 36 months.28 showed that a superior orbital peri-levator injection tech-
Retisert is a non-biodegradable disc-shaped intra- nique improved lid retraction and demonstrated reduc-
vitreal implant containing 0.59 mg of FA within a sili- tion in size of the levator/superior rectus complex on
cone elastomer. It is surgically inserted through a pars MRI imaging after repeat injections.
plana incision and removed by a second surgical proce-
dure. It has a duration of 18 to 30 months with an initial
active drug release of 0.6 μg/day to an eventual steady- 4.1.2 | Histiocytic orbital lesions
state release of 0.3 to 0.4 μg/day for 30 months.29
Yutiq is a recently developed intravitreal implant con- Histiocytic lesions are divided into Langerhans cell
taining 0.18 mg of FA which is designed to deliver histiocytosis (LCH) and non-LCH lesions, of which
372 FUNG ET AL.
Juvenile Xanthogranuloma (JXG) is the most common. show equally effective results with 0.2 to 0.4 mL of
Langerhans cell histiocytosis can be monofocal (often 10 mg/mL intra-lesional triamcinolone.46,47 A meta-
seen in the frontal bone of the orbit), or systemic. It often analysis of randomized studies showed incision and
presents in children, but can occur in all age groups. It curettage was more effective than steroid injection as a
results in bone destruction and secondary soft tissue single procedure, but with repeat procedures similar out-
expansion.38 The treatment of choice for orbital LCH is comes were shown.48 Intra-lesional steroid for chalazia is
incisional biopsy with curettage of the lesion and intra- an acceptable treatment for primary and recurrent
lesional steroids (triamcinolone 40 mg/mL or chalazia.
methylprednisone).39,40 JXG often presents with cutane-
ous involvement. Eyelid and orbital lesions are rare and
can be managed with a combination of intra-lesional ste- 4.1.6 | Periocular scarring
roids with or without surgical debulking.41
Hypertrophic scarring following surgery or trauma has
traditionally been managed with a mixture of topical or
4.1.3 | Periorbital capillary intra-lesional steroids or surgery. Recently, combination
haemangiomas therapy of intra-lesional triamcinolone and 5-FU has
shown great promise in improving periocular scarring
The treatment of choice for periorbital infantile post-surgery.49
haemangiomas has traditionally been intra-lesional and
systemic steroids. In 2008 Léaute-Labrèze et al42 publi-
shed a series of 11 cases of infantile haemangioma cases 4.2 | Anterior segment
managed with propranolol which has revolutionized
treatment. Two systematic reviews show both intra- Steroids are used frequently in anterior segment
lesional steroids and propranolol are effective, though diseases,4 however there is a considerable lack of ran-
less side effects occur with propranolol.37,43 Propranolol domized control trials (RCTs) to guide treatment.
is now the mainstay of treatment for periorbital infantile
haemangioma and intra-lesional steroids are used as an
adjunct in resistant cases. 4.2.1 | Corneal transplants
Corticosteroids are the principle medication in the man-

4.1.4 | Nasolacrimal disease agement of corneal transplantation. They are readily
absorbed through the cornea and achieve a high concen-
Topical steroid drops and steroid nasal spray have been tration in the anterior chamber through topical applica-
used in management of nasolacrimal duct obstruction tion. Prednisolone and dexamethasone are the most
(NLDO), with little evidence for their use. In functional commonly used forms.50 Multiple treatment regimes
NLDO with associated symptoms of rhinitis, topical ste- exist, but as a guide prednisolone 1% or dexamethasone
roid nasal spray (eg, mometasone and budesonide) may 0.1% drops are used every 2 hours initially, tapered over a
improve epiphora.44 The anecdotal improvement of period of 6 to 12 months, and a mild steroid used daily
epiphora and mucus discharge in complete NLDO with for maintenance treatment in endothelial keratoplasties.
topical steroid drops is likely secondary to the anti- Some have advocated for the use of steroids prior to
inflammatory effect and reduced mucus in the lacrimal high-risk transplantation50-53 but this has been variably
sac. Mansur et al45 recently assessed the lacrimal compli- adopted. A survey of the Bowman's Club (The UK Society
cations associated with systemic chemotherapy agents and of corneal surgeons) found that topical dexamethasone
suggested minor canalicular blockages may be effectively was used in 33%, oral prednisolone by 22% and single
treated with probing and topical steroid drops. If there is a dose IV methylprednisolone (IVMP) by 14%.54
more significant blockage or likely long-term chemother- During corneal allograft rejection, topical, sub-
apy, then lacrimal surgery is advised.45 conjunctival, periocular and/or systemic corticosteroid
use is the treatment of choice, with the majority of cor-
neal specialists favouring topical formulations (with a
4.1.5 | Chalazia preference for prednisolone acetate 1%).55,56 In severe
cases of allograft rejection oral or IVMP is often added,
Traditionally non-resolving or large chalazia of the eye- and one prospective study suggested that a single dose of
lids are treated by surgical incision. However, studies 500 mg of IVMP is more effective and better tolerated
FUNG ET AL. 373
than daily oral prednisolone.57 Unfortunately there are compared to 73% on trifluridine plus placebo (p < .001).
no RCTs to add weight to this study. The study also demonstrated that a 10-week tapering
course of steroids was too brief as 50% developed a recur-
rence within 6 weeks. Thus, for non-necrotising stromal
4.2.2 | Bacterial keratitis keratitis without an epithelial defect, antiviral treatment
in conjunction with topical steroids for at least 10 weeks
The greatest evidence for the use of steroids in bacterial is recommended.
keratitis come from the Steroids for Corneal Ulcers Trials Endothelial disease typically presents independently
(SCUT).58-60 A cochrane review of steroid use in bacterial of other forms of HSV keratitis and only few studies are
keratitis61 found four RCTs that met inclusion criteria, available to guide treatment.63-65 These compare topical
but only the SCUT trial was of sufficient power to deter- betamethasone with topical acyclovir against topical acy-
mine the effect of steroids in bacterial keratitis. clovir alone (all five times a day) and found that the addi-
This SCUT trial examined the outcomes of 500 cases tion of steroid resulted in a faster response and fewer
of culture-positive bacterial keratitis where fungal, treatment failures than antiviral alone. Thus, the recom-
acanthamoeba, HSV, impending perforation and previ- mendation for HSV endothelial disease is the combina-
ous corneal transplant patients were all excluded. All tion of antiviral treatments with topical steroids, tapered
cases received moxifloxacin q1h for 48 hours prior to ran- according to patient signs and symptoms.
domization; at randomization, half the patients received
prednisolone 1% for a total of 3 weeks only (QID for
1 week, BD for 1 week and daily for 1 week) compared to 4.2.4 | Allergic eye diseases
placebo. In both 3 and 12 months reports, there were no
difference between groups in any parameters measured Allergic eye diseases cover a spectrum from seasonal
(best-subjective corrected visual acuity [BSCVA], scar allergic disease through to vernal keratoconjunctivitis
size, rate of re-epithelialization, rate of perforation). This (VKC) and atopic keratoconjunctivitis. Corticosteroids
report added to the weight of evidence that steroids do play an important role in controlling acute exacerbations;
not cause corneal perforation in bacterial keratitis. The however, they should not be used as long-term mainte-
IOP was lower in the steroid group at 3 months as nance due to their side effects.66 In children with severe
inflammation was better controlled (p = .04). VKC, intraocular pressure rises have been reported in up
However, subsequent subgroup analysis demon- to 28.3% of patients, with 5.5% progressing to glaucoma.67
strated a benefit for the use of steroids. In the 3-month Various regimes of topical steroids can be employed
report, those with baseline BSCVA of CF or worse and depending on severity of disease with early introduction
those with an infiltrate covering the central 4 mm of the of a steroid-sparing agent when the patient is expected to
cornea performed better with early introduction of ste- require long-term disease control.
roids compared to placebo (a two-line difference in Supratarsal injection of steroid is effective in refrac-
vision, p < .05) indicating that there is a benefit of ste- tory, severe and challenging cases of allergic eye dis-
roids in severe, central infections in the early stage of eases.68 Two prospective, randomized, double-masked,
recovery. At 12 months, when Nocardia infections were case-control trials showed no difference between dexa-
removed from the cohort, those who had steroids after methasone sodium (2 mg) phosphate, TA (10-20 mg) and
48 hours of antibiotic treatment had a one-line improve- hydrocortisone sodium succinate (50 mg) in improving
ment in BSCVA compared to those who did not have severe refractory VKC with resolution of many symptoms
steroids. by 3 weeks.69,70 However, symptoms recurred about
12 weeks post-treatment without anti-allergy
69
medication.
4.2.3 | Herpes simplex keratitis
Steroid use in herpes simples keratitis (HSK) is mainly 4.2.5 | Corneal neovascularization
for stromal and endothelial keratitis. Much of the evi-
dence for the use of steroids in HSK comes from the dou- Topical steroids are the mainstay of treatment for the sup-
ble blind, placebo-controlled RCT known as the Herpetic pression of early proliferating corneal vessels.71-75 They act
Eye Disease Study (HEDS).62 The HEDS demonstrated a primarily due to suppression of inflammation associated
clear benefit of the use of topical prednisolone in the with new vessels and are not necessarily angio-regres-
treatment of stromal keratitis.62 Those on trifluridine plus sive.76 As such, steroids are most effective when applied
prednisolone had a treatment failure rate of 26% before, or immediately after corneal injury.71
374 FUNG ET AL.
4.2.6 | Keratoconjunctivitis sicca the first week after which they should be tapered due to
the risk of corneal thinning. Their use alone has been
Topical steroids have a role for treating keratoconjuncti- cautioned as it has been shown to cause further cor-
vitis sicca (KCS), as outlined in the Tear Film and Ocular neoscleral melt.91 Monitoring for infection or prophylac-
Surface Society Dry Eye Workshop II (TFOS DEWS II) tically adding topical antibiotics prior to
report.77 This report summarizes the currently available epithelialisation is also recommended. One study found
evidence on managing dry eye disease, including results a risk of corneoscleral melting if topical steroids were
from several RCTs,78-87 and concluded that short courses used after 10 days of the chemical injury. The timing
of corticosteroid are effective in improving symptoms of coincides where suppression of keratocyte collagen pro-
KCS. However, this is not an effective long-term strategy duction by corticosteroids may outweigh the advantages
due to potential side effects. Typically, low strength ste- of inflammatory cells suppression and collagenase inhi-
roids such as FML were used QID. bition to promote corneal ulceration.90 Davis et al and
Brodovsky et al, found in their retrospective series that
the prolonged use of topical prednisolone 0.5% used
4.2.7 | Graft vs host disease concurrently with topical ascorbate 10% was not associ-
ated with corneoscleral melt.92,93
Ocular involvement of Graft Versus Host Disease (GVHD)
may cause an acute or chronic immunologically mediated Ocular cicatricial pemphigoid/mucous membrane
inflammatory disease of the ocular surface. Whilst sys- pemphigoid
temic corticosteroids are the mainstay of controlling the Mucous membrane pemphigoid is a systemic disease pri-
acute exacerbations of chronic GVHD, adjunctive topical marily affecting mucous membranes. When localized to
steroids is often used to allow tapering and cessation of the conjunctiva, the condition is known as ocular cicatri-
systemic immunosuppression. Small series have retrospec- cial pemphigoid. It manifests as a chronically progressive
tively demonstrated efficacy of topical steroid treatment in conjunctival inflammation causing bilateral blindness.
controlling acute conjunctival inflammation and reducing Systemic immunosuppression is required to halt the pro-
scarring, however signs of KCS remained.88 gressive inflammation and achieve adequate long-term
Long-term topical steroids are not recommended remission.94 Topical and sub-conjunctival corticosteroids
after the acute inflammatory phase, when other anti- are used adjunctively with systemic therapy. They may
inflammatory agents, such as cyclosporin A and offer short-term relief of symptoms but are not effective
tacrolimus may be employed. This is supported by a in halting progression of the systemic autoimmune
recent RCT of 42 patients that assessed dry eye disease in disease.95 Due to the infrequency and nature of the con-
chronic GVHD. Topical loteprednol etabonate 0.5% was dition, there have been no studies assessing their
found to have a minimal effect in ocular surface disease role. Other topical agents shown to give variable
index (OSDI) and corneal fluorescein staining compared results include: calcineurin inhibitors, cyclosporine A,
to topical lubricants.89 tacrolimus and mitomycin C.94
4.2.8 | Cicatrising conjunctival disorders 4.2.9 | Anterior uveitis
Chemical and thermal injury Topical corticosteroids are the mainstay of treating
The goal of therapy following chemical and thermal ante- uncomplicated anterior uveitis as it has fewer local and
rior segment injuries is to restore the ocular surface systemic side effects compared to periocular or systemic
and maintain long-term corneal clarity by preventing administration. The interval of drop instillation is tai-
cicatrisation and limbal stem-cell deficiency. Along with lored to each patient; however, it is generally initiated on
other important aspects of treatment, topical steroids may frequent intervals then slowly tapered according to the
be used to limit the profound associated inflammation and clinical response to prevent rebound inflammation.
promote healing. However, there has been controversy Where anterior uveitis has not adequately responded to
regarding the use and timing of topical corticosteroids. topical corticosteroids, periocular steroids such as sub-
Corticosteroids may have beneficial effects on inflam- conjunctival dexamethasone may provide greater thera-
matory cell suppression and collagenase inhibition, how- peutic effect with a short duration of action of 1 to
ever they may also suppress keratocyte migration and 2 days.96 Similarly, sub-conjunctival triamcinolone or
collagen production and thus cause corneal thinning.90 betamethasone has also been shown to be safe and effec-
Generally, their anti-inflammatory effect is maximal in tive in severe cases of anterior uveitis.14
FUNG ET AL. 375
4.2.10 | Non-necrotising, non-infectious pilot series,101 In contrast, the only prospective random-
anterior scleritis ized study comparing postoperative topical steroids to
postoperative topical steroids in addition to steroid depot
Sub-conjunctival TA may be given for the treatment of injection of TA found no significant differences in out-
non-necrotising, non-infectious anterior scleritis.13,97 comes.102 Nevertheless, since the introduction of locally
administered antimetabolites such as 5-fluorouracil and
mitomycin C were found to be more potent in impairing
4.3 | Glaucoma surgery wound healing and thus increase long-term success rates
of trabeculectomy, the potential role of perioperative sub-
The use of corticosteroids in modulating conjunctival conjunctival steroid administration had become less
wound healing is essential in glaucoma surgery. Topical significant.103
corticosteroids are routinely used postoperatively and Currently, locally administered antimetabolite ther-
their frequency is often titrated according to the desired apy is routinely used in conjunction with topical postop-
effect on wound healing. Sub-conjunctival corticosteroids erative corticosteroids to modulate conjunctival wound
are also often injected at the end of surgery, though not healing in glaucoma filtration surgery. Corticosteroids
usually at the surgical filtration site. predominantly modulate wound healing by reducing the
release of acute inflammatory mediators and fibroblast
recruitment. They also have a lesser effect in the prolifer-
4.3.1 | Glaucoma filtration surgery ative phase of wound healing by limiting fibroblast activ-
ity. In contrast, antimetabolites modulate wound
Glaucoma filtration surgery is aimed at creating a filter- healing by inhibiting proliferation of fibroblasts and
ing bleb which allows aqueous drainage and thus lowers their profibrotic mechanisms.104,105 Modulating both the
the IOP. The long-term success of surgery is dependent inflammatory and proliferative phases of the wound
on modulating wound healing at the site of filtration, healing response with these agents increases the likeli-
namely the scleral flap and overlying conjunctiva and hood of long-term filtration and lower postoperative
Tenon's capsule. IOPs.106
Topical postoperative corticosteroids after
trabeculectomy have been widely used since the apparent
effect on filtering blebs was first described in 1965.98 The 4.3.2 | Aqueous shunt surgery
beneficial effects of steroids after trabeculectomy were first
demonstrated in a prospective study in 1985, before the Modulation of wound healing is important in the process
revolutionary widespread use of adjunctive local antime- of bleb encapsulation in aqueous shunt surgery. The use
tabolites.99 Forty-six eyes of 35 patients with a diagnosis of of corticosteroids to control postoperative inflammation
primary open-angle glaucoma or primary angle-closure is thought to influence the hypertensive phase after glau-
glaucoma underwent trabeculectomy were randomized coma drainage implantation. The hypertensive phase is
into three groups. Group 1 received no additional steroids, characterized by a rise in IOP due to bleb encapsulation
group 2 received topical 1% prednisolone acetate initially or capsular fibrosis that occurs at approximately 1 to
every 3 hours then tapered over 20 days, group 3 received 3 months postoperatively.107 It is particularly observed
the same treatment as in group 2 with additional of oral after implantation of non-valved glaucoma drainage
prednisone (80 mg daily) with a progressive taper over devices such as the Ahmed glaucoma device where it
16 days. The results were followed after 1.5 years, and may occur in 56% to 82%.108 It has been reported that in
long-term data were later published at 5 and 10 years on 72% of these cases, the elevated IOP does not resolve indi-
58 and 46 eyes, respectively. At 10 years, patients in group cating early surgical failure.109
1 (who did not have steroids) had a significantly higher Turalba and Pasquale110 retrospectively compared
rate (66.7%) of additional glaucoma procedures compared patients who received intraoperative sub-Tenon during
to those in group 2 (11.1%) and group 3 (38.5%). Further- Ahmed device implantation with those who did not. The
more, patients in group 1 had higher IOPs, were treated hypertensive phase was found to be 26% in those who
with more glaucoma drops and had lower rate of stabilized received triamcinolone compared to those without (52%).
glaucoma (based on optic disc photography and visual There was no difference in final IOP outcomes and the
fields).100 authors warned of a higher rate of early complications
Perioperative injection of sub-conjunctival corticoste- including tube erosion and endophthalmitis. Yadnazi
roids at the filtering site have been demonstrated to give et al111 demonstrated in a prospective randomized trial of
favourable bleb formation and IOP control in a small 90 eyes that adjunctive sub-Tenon TA during Ahmed
376 FUNG ET AL.
valve implantation had significantly lower IOPs at showed greater improvement in BCVA compared with
1 month and lower peak IOPs, however had no difference laser alone. Although overall the TA + prompt laser arm
in the rates of success or incidence of a hypertensive did not do as well as the ranibizumab arms, TA was
phase. shown to be as effective as ranibizumab when only
pseudophakic patients were analysed. However, at 5-year
follow-up the TA arm was inferior to ranibizumab arms,
4.4 | Posterior segment even when only analysing pseudophakic patients and all-
owing for the addition of “very deferred ranibizumab”
Ocular steroids are used to treat macular oedema of var- after 74 weeks from baseline.117
ied aetiology (diabetic, retinal vein occlusion, postopera-
tive and inflammatory), intraocular inflammation DII for diabetic macular oedema
including uveitis and scleritis and to assist visualization The MEAD study included two 3-year, multi-centre,
of the vitreous during vitrectomy. masked, randomized controlled phase III clinical trials
that compared a minimum of 6-monthly dosing with DII
0.7 mg, 0.35 mg and sham procedure. Patients had
4.4.1 | Diabetic macular oedema centre-involving DMO, visual acuities between 6/15 and
6/60 and central retinal thickness ≥300 μm on optical
Diabetic macular oedema is the most common cause of coherence tomography scans.118 The main outcome mea-
vision loss in people with diabetes.112 The pathogenesis sures were proportion of patients achieving ≥15 LogMAR
of DMO is multifactorial, with not only VEGF but other letters of improvement in BCVA and safety profile. At
pro-inflammatory factors involved in breaking down the baseline there were 1048 patients enrolled, and 57.9%
blood-retinal barrier and increasing vascular permeabil- completed the 3-year study. Both DII doses had a signifi-
ity.113 Although intravitreal anti-VEGF therapy remains cantly greater proportion of patients achieving ≥15-letters
first-line treatment for centre-involving DMO in of improvement in BCVA (22.2% for 0.7 mg, 18.4% for
phakic patients, ocular steroids may be considered for 0.35 mg and 12.0% for sham).
pseudophakic patients, those with planned cataract The BEVORDEX study was a prospective, multi-cen-
surgery, or in patients with suboptimal response or con- tre, randomized single-masked clinical trial comparing
traindication to intravitreal anti-VEGF therapy.114 A sub- 4-weekly bevacizumab and DII 0.7 mg (OZURDEX) that
optimal response to intravitreal anti-VEGF therapy is not could be given more frequently (4-monthly) in 88 eyes of
uncommon. In the RISE/RIDE registration trials, BCVA 61 patients with centre-involving DMO.119 The main out-
was worse than 6/12 in 42.8% of patients and central come measure was the proportion of patients achieving
foveal thickness greater than 250 μm in 24.8% of patients an improvement in vision of 10 LogMAR letters. Each
despite 2 years of monthly intravitreal ranibizumab arm had similar proportion of patients reaching the main
(0.3 mg) injections.25 outcome measure at 12 and 24120 months (40% with
bevacizumab and 41% with DII at 12 months). The group
Intravitreal TA for diabetic macular oedema receiving DII had fewer mean injections (2.7) compared
Intravitreal TA (Kenacort-A 40, Bristol-Myers Squibb to the bevacizumab arm (8.6) over the first 12 months
Pharmaceuticals, Noble Park, Australia) was first shown with a greater reduction in central macular thickness at
to be superior to sham treatment for BCVA in patients 12 but not 24 months. However, more patients in the DII
with centre-involving DMO in a prospective, double- arm lost vision, mainly because of cataract progression.
masked, placebo-controlled randomized controlled
trial.115 Compared with those receiving placebo, eyes FA intravitreal implant for diabetic macular oedema
receiving TA had a 5.7 Logarithm of Minimum Angle of Iluvien is a sustained delivery FA injectable implant that
Resolution (LogMAR) letter better improvement at has been shown to treat patients with DMO. The FAME
2 years. A and B studies were identically designed parallel-group,
The Diabetic Retinopathy Clinical Research Network phase 3 double-masked, randomized controlled phase III
(DRCR.Net) Protocol I study was a multi-centre RCT clinical trials that compared two doses (0.2 and 0.5 μg/
comparing sham injection + prompt laser, 0.5 mg day) of FA over a 3-year period. The primary end point
ranibizumab + prompt laser, 0.5 mg ranibizumab was a gain of ≥15 letters at 24 months with follow-up to
+ deferred laser and 4 mg TA + prompt laser for centre- 36 months.
involving DMO.116 The main outcome measure was A pre-planned subgroup analysis examined visual
improvement in BCVA at 1 year, and 854 study eyes of outcomes as a function of duration of DMO at randomi-
691 patients were enrolled. The ranibizumab arms zation revealed that the treatment effect resided primarily
FUNG ET AL. 377
in patients with chronic DMO (duration ≥3 years). At Study.136,137 Unlike SCORE-CRVO, there was no signifi-
month 36, a significantly higher proportion of FA treated cant difference between the arms in the proportion of
patients from both studies showed an improvement of patients achieving a ≥15 letter improvement from base-
≥15 letters from baseline compared to the sham group line to month 12.
(FAME A: 31.8% for 0.2 μg/day, 13.5% for sham; FAME
B: 36.4% for 0.2 μg/day, 13.2% for sham). In patients with Intravitreal dexamethasone implant for retinal vein
non-chronic DMO (duration <3 years), the proportion of occlusion
patients gaining ≥15 letters were similar between the FA The Global Evaluation of Implantable Dexamethasone in
and sham groups in both studies.121 In Europe and in the Retinal Vein Occlusion with Macular Edema (GENEVA)
United Kingdom, it has been approved for the treatment study included two identical multi-centre, masked,
of persistent DMO that has not sufficiently responded to 6-month, sham-controlled RCTs assessing the efficacy of
available therapies. In the USA, it is approved for the DII implant for vision loss due to macular oedema from
treatment of DMO in patients who have been previously both CRVO and BRVO.123 A total of 1267 patients were
treated with corticosteroids without a clinically signifi- randomized to receive a single treatment of DII 0.7,
cant rise in IOP. 0.35 mg, or sham procedure. Both DII groups performed
significantly better than the sham arm in the time to
reach a ≥15 letter improvement in BCVA, proportion of
4.4.2 | Macular oedema secondary to patients achieving a ≥15 letter improvement in BCVA,
retinal vein occlusion mean BCVA and proportion of patients losing ≥15
letters.
Macular oedema is the most common cause of visual loss
in RVO.22,122,123 Like DMO, anti-VEGF therapy remains Intravitreal fluocinolone implant for retinal vein
first-line treatment in phakic patients. This is based on occlusion
multiple RCTs demonstrating visual benefit of anti-VEGF There is a lack of studies on intravitreal FA implants for
for macular oedema secondary to CRVO (ranibizumab: the treatment of CMO from retinal vein occlusions. The
CRUISE124,125; aflibercept: COPERNICUS,126 GALILEO,127 Fluocinolone Acetonide Intravitreal Inserts for Vein
SCORE2128; bevacizumab: SCORE2,128 Epstein et al129) Occlusion in Retina (FAVOUR) study started recruiting
and BRVO (ranibizumab: BRAVO130,131; aflibercept: patients however the study was terminated early. Cur-
VIBRANT132,133; bevacizumab134). rently, Iluvien has not been approved for macular
oedema from retinal vein occlusions in the USA, UK or
Intravitreal TA for retinal vein occlusion Europe and any use for this indication is off-label.
Ocular steroids may be considered in pseudophakic eyes Retisert has been used for CMO in retinal vein occlu-
in which anti-VEGF is contraindicated or failing to pro- sions within a small pilot series by Ramachandran
vide an adequate result.135 Ocular steroids not only et al138 which demonstrated 69% of eyes showing visual
inhibit VEGF, but their anti-inflammatory and neuro- acuity improvement, 15% were stable and 15% lost two
protective effects may also benefit eyes with RVO.22,123 lines from baseline at 12 months. Cataract formation
The Standard Care versus Corticosteroid for Retinal occurred in almost all patients and 39% eyes required
Vein Occlusion (SCORE) studies were multi-centre ran- glaucoma filtration surgery by 12 months. A follow-up
domized clinical trials evaluating the benefit of IVTA study recruited 10 further patients and indicated
for the treatment of macular oedema secondary to reti- sustained benefit up to 30 months.139
nal vein occlusion.22,23 In the SCORE-CRVO Study
(Report 5), 271 patients were randomized to observation
(the standard of care at that time), 1 or 4 mg 4.4.3 | Posterior non-infectious uveitis
preservative-free IVTA (Trivaris).22 The main outcome
measure was the proportion of patients with ≥15 letter For patients with posterior segment inflammation and mac-
improvement from baseline to month 12. This was ular oedema, topical steroid therapy is often inadequate.
achieved in significantly more patients on 1 or 4 mg tri- These patients have the option of periocular (sub-Tenon,
amcinolone (27 and 26%, respectively) than those who orbital floor, peribulbar), intravitreal (IVTA, OZURDEX)
were observed (7%). For the SCORE-BRVO Study and systemic steroids. In an attempt to minimize the sys-
(Report 6) the observation arm was replaced with grid temic side effects (such as Cushingoid state, osteoporosis
photocoagulation because grid laser was the standard of and elevated blood glucose), local steroid is often consid-
care at that time for treating macular oedema secondary ered, especially for unilateral inflammation. In the retro-
to BRVO according to the Branch Vein Occlusion spective cohort of the Systemic Immunosuppressive
378 FUNG ET AL.
Therapy for Eye Diseases (SITE) study, over half of 1192 when their non-infectious uveitis has been quiescent.144
eyes in 914 patients with uveitis demonstrated improved As a single IVTA injection lasts approximately 3 to
visual acuity at some point within 6 months of receiving 6 months, repeated injections may be required.145
periocular steroid.140 Alternatives to IVTA for treating uveitis include DII
Intravitreal steroids are particularly useful in two or FA implants. The HURON trial demonstrated efficacy
groups of patients: those with severe vitritis or cystoid of a single OZURDEX injection in non-infectious inter-
macular oedema (CMO) that is unlikely to respond rap- mediate, posterior or panuveitis in comparison to pla-
idly to periocular corticosteroids, and those with inflam- cebo, with a reduction of inflammation and CMO in 47%,
mation that are refractory to other treatment. In patients and ≥15 letter gain in up to 43%.146
with persistent disease, these options may also be com- Most recently, the National Institute of Health (NIH)
bined effectively with systemic steroids and steroid- funded POINT trial compared all three of the above depot
sparing agents (eg, methotrexate, mycophenolate and steroid options (periocular TA, IVTA and OZURDEX) for
cyclosporin) for acute unilateral relapses or persistent dis- the treatment of CMO secondary to uveitis in a prospec-
ease activity to reduce the dosages and side effects of the tive, multi-centre RCT.147 In this trial, 235 eyes were ran-
systemic treatment. domized 1:1:1 to either periocular TA (40mg/1ml),
It should also be noted that although ongoing unpreserved IVTA (4mg/0.1ml) or OZURDEX (0.7mg
repeated depot steroid injections could be considered as a dexamethasone). The primary outcome was central sub-
treatment option for chronic persistent intermediate, pos- field macular thickness (CMT) at 8 weeks, with second-
terior or panuveitis, such a management approach must ary outcomes including visual acuity and rate of adverse
be considered with caution given the recent 7-year events over 24 weeks of follow-up. Overall, the CMT in
follow-up findings from the NIH sponsored MUST all three groups improved, however IVTA and
(Multi-centre Uveitis Steroid Treatment) trial. This study OZURDEX were found to be superior to periocular TA,
was also a prospective RCT that compared the FA con- with rates of improvement of 39% and 46%, respectively,
taining Retisert implant with standard systemic immuno- vs 23% for periocular TA (p < .0001). However, no statis-
suppression in 479 eyes. Although the implant group tically significant difference was demonstrated between
initially had a faster gain in BCVA, the systemic treat- IVTA and OZURDEX. Similarly, BCVA also improved in
ment group had a more gradual gain in BCVA such that all three groups, with greater gains (four to seven letters
there was no significant difference at 2 and 5 years.141 to more greater gains) seen with intravitreal treatments,
However, at 7 years, the systemic group overtook the with again no clinical or statistically significant differ-
implant group in terms of BCVA outcomes,142 with the ences seen between IVTA or OZURDEX. Interestingly,
implication being that the uveitis relapses occurring once despite the findings in other studies, the duration of
the depot steroid “wears off” are more severe and more effect of OZURDEX on CMT was found to decrease after
likely to result in more (irreversible) damage than lower 8 weeks (rather than 12-16 weeks) in this cohort of
grade relapses seen with systemic treatment when oral patients. This may indicate that patients with uveitic
prednisolone/immunosuppression is being gradually CMO may require intravitreal injections more frequently
weaned. than for other indications. It should be noted that the
A prospective 3-year randomized, sham-controlled POINT study design did allow the IVTA arm to have re-
study is comparing Yutiq with placebo. Yutiq is designed treatments at 8 weeks, but only at 12 weeks for the
to release FA for up to 36 months and the 12-month data OZURDEX arm.
has shown it was effective in lowering the rate of recur-
rence of posterior uveitis. At 36-months, the effect of
reducing recurrence rate was still significantly lower with 4.4.5 | Bacterial endophthalmitis
Yutiq (56.3%) compared to sham-treated eyes (92.9%).30
Intravitreal steroids have been described for the manage-
ment of acute bacterial endophthalmitis in conjunction
4.4.4 | Uveitic macular oedema with intravitreal antibiotics, although their use remains
controversial.148,149 They may tamper the inflammatory
Cystoid macular oedema is a common cause of vision loss response that causes damage to the retina, but, con-
in uveitis.24 Intravitreal TA has been shown to effectively versely, they may interfere with infection control, lower
reduce uveitic CMO.143 Visual acuity improvements are the concentration of intravitreal antibiotics and the addi-
more significant if the CMO is present for 12 months or tional volume may elevate the IOP.149 If they are used,
less and for patients aged 60 years or younger. It is useful intravitreal dexamethasone is preferred due to its rapid
in improving visual acuity in patients with CMO, even elimination from the eye.149 A dosage of 0.4 mg/0.1 mL is
FUNG ET AL. 379
usually prescribed, as higher doses have been shown to 5.1 | Procedure related complications
cause Müller cell damage in animal studies.150 Evidence
for intravitreal dexamethasone in acute endophthalmitis 5.1.1 | Periocular injections
is limited to retrospective case series which gave mixed
results, and four prospective RCTs151-154 which failed to Periocular injections can be performed using different
show statistically significant improvements in final visual techniques: into the sub-conjunctival space, into the sub-
outcomes.149 Although traditional teaching is to avoid Tenon space, into the orbital floor alongside the globe,
intraocular steroids for fungal endophthalmitis, this fear (usually inferiorly, via a transcutaneous or trans-
may be exaggerated in patients treated with vitrectomy conjunctival injection), or into the peribulbar or
and intravitreal anti-fungal therapy.155 retrobulbar space. Complications of these injections
include: orbital swelling, chemosis, proptosis, sub-
conjunctival haemorrhage, retrobulbar haemorrhage,
4.4.6 | Postoperative macular oedema globe ischaemia, posterior ischaemic optic neuropathy,
optic atrophy, globe perforation, orbital cellulitis, fat atro-
Macular oedema is a well-known complication of cata- phy, fat herniation, damage to the rectus muscles
ract surgery. Topical non-steroidal and steroidal ther- resulting in diplopia, ptosis, dural puncture and an
apy are usually first-line treatment.156 Topical and oral oculocardiac reflex.178-181
carbonic anhydrase inhibitors and intravitreal anti- The likelihood of complications differs depending on
VEGF agents have also been described, but strong evi- the site of the injection. Posterior injection reduces the
dence for these are lacking. In recalcitrant cases, local chances of unsightly sub-conjunctival plaques resulting
steroid injections may be considered. IVTA has been from anterior seepage of depot, conjunctival or cor-
shown to reduce retinal thickness and improve vision neoscleral melting, depigmentation and granuloma
in cases of persistent pseudophakic macular related to the methylcellulose vehicle of the depot injec-
oedema157-160 with an effect that may be sustained for tion. Injection into the orbital floor is easily performed
more than 6 months.158 with a 25 mm 25-gauge needle. It is well tolerated and
carries only a very small risk of globe perforation if the
needle is directed away from the globe at all times. It is
4.4.7 | Other indications for intravitreal frequently difficult to access the sub-Tenon's space of
TA and dexamethasone implant patients who have had previous surgery (notably scleral
buckling), these eyes may be more suited to an orbital
Intravitreal steroids have been used with variable results for floor injection. Peribulbar and retrobulbar injection are
a variety of other causes of macular oedema including: neo- more likely to lead to globe perforation or inadvertent
vascular AMD,161 retinal angiomatous proliferation,162 mac- intravascular injection with vascular occlusion from
ular telangiectasia,163,164 Coat's disease,165 vasoproliferative embolization. Additional caution is required in myopic
tumour,166 radiation retinopathy,167,168 retinitis patients as they have a thinner sclera and larger globes
169,170
pigmentosa, proliferative vitreoretinopathy,171-173 fol- which are at an increased risk of perforation.
lowing scleral buckling174 or vitrectomy surgery175 and from
idiopathic CMO.160,176
Intravitreal TA can be used intraoperatively to visual- 5.1.2 | Intravitreal injections
ize the vitreous. This is particularly useful for iatrogenic
induction of a posterior vitreous detachment, peeling Intravitreal injections may be associated with
internal limiting membrane and when vitreous needs to endophthalmitis, ocular inflammation, vitreous
be highlighted for clearance in complicated cataract haemorrhage, retinal tears, rhegmatogenous retinal
surgery.177 detachment, IOP elevation, cataract and lens subluxa-
tion.182 Although rare (with a reported incidence of
0.09%-0.87%),183 acute bacterial endophthalmitis is the
5 | COMPL I CATI ON S O F O CU L A R most serious of these complications and requires immedi-
A N D P E R I O C U L A R ST E R O I D ate treatment with intravitreal antibiotics. Rates of vitre-
DELIVERY ous haemorrhage,118 wound leak hypotony and retinal
tears and detachment123 may be higher with DII, as the
Complications arising from use of ocular steroids may be needle is larger (23-gauge) and the force of injection
related to the procedure itself, or the pharmacological greater than for standard 30-gauge needle intravitreal
effects of the steroids. injections. DII is contraindicated in aphakic and
380 FUNG ET AL.
pseudophakic patients with posterior capsular rupture, as Raised IOP with DII
the implant may migrate into the anterior chamber.184 If IOP elevation can also occur with DII, although possibly
this occurs, early removal is recommended to avoid at lower rates than for IVTA. In the MEAD study for
chronic corneal oedema.184 DMO, the incidence of IOP elevation ≥10 mm Hg from
baseline to 36 months at any visit for those receiving DII
0.7 mg was 27.7%.118 The cumulative incidence of at least
5.2 | Pharmacologic related one visit with IOP ≥25 mm Hg or ≥35 mm Hg was 32%
complications and 6.6%. The large majority of these patients with IOP
elevation could be managed with medical therapy. Only
The two most important pharmacologic related complica- one patient required incisional glaucoma surgery, and no
tions of ocular steroids are raised IOP and development patients required removal of the implant. Mean IOP ret-
of cataract, which are more frequent with intravitreal urned to baseline by month 6 after each injection, and
injections compared to periocular injections. there did not appear to be a cumulative effect on IOP ele-
vation with repeated injections. Similar findings were
found in a 12-month trial by the OZURDEX PLACID
5.2.1 | Raised IOP Study Group189 and a recent large retrospective analysis
of 2736 eyes of 1441 patients treated with a total of 6015
Raised IOP with subsequent development of DII in which 26.5% of eyes had an IOP rise >25 mm Hg
glaucomatous optic neuropathy is one of the most signifi- but only 0.91% required glaucoma filtration surgery.190
cant complications of locally administered corticoste-
roids. If other therapeutic options are available, ocular Raised IOP with FA intravitreal implant
steroids are best avoided in patients with pre-existing In the FAME trials, an IOP of ≥30 mm Hg developed in
glaucoma. The pathogenesis is not well understood but 16.3% of FA injectable implant treatment groups at
may involve downregulation of trabecular meshwork month 23 and 18.4% by month 36. Elevated IOP that
matrix metalloproteinase activity, increased myocilin pro- required incisional surgery by 36 months was 4.8% in the
duction and/or decreased trabecular meshwork phago- low-dose group, 8.1% in the high-dose group and 0.5% in
cytic activity that increases aqueous outflow resisance.185 the sham group.191
The susceptibility to pressure response may be due to
genetic differences and variations in corticosteroid recep- Raised IOP with periocular steroid
tors whilst the degree of effect on IOP appears to be dose- IOP elevation can also occur with periocular steroid. In a
dependent. study by Sen et al140 of patients being treated with peri-
ocularly administered corticosteroid (predominantly TA
Raised IOP with TA 40mg) for uveitis, the cumulative incidence of at least
In the SCORE Study Report 15, the proportion of 1 visit with IOP ≥24 mm Hg or ≥30 mm Hg at 12 months
patients being treated for BRVO or CRVO with a was 34% and 15%.
cumulative incidence of IOP elevation ≥10 mm Hg
from baseline to 36 months was 2% (no IVTA), 9% Raised IOP in uveitic patients
(1 mg IVTA) and 45% (4 mg IVTA). Consideration of a Corticosteroid-induced raised IOP is much more common
lower dose (1 or 2 mg) of IVTA to treat RVO may be in the uveitic population than for other indications, and
appropriate in patients at risk of an IOP-related event, even higher in paediatric patients.192-194 In the POINT trial
particularly as little difference has been reported in 20%, 30% and 41% recorded an IOP of ≥24 mm Hg by
efficacy between the 1 and 4 mg doses.22,23,185 Other 24 weeks in the periocular, IVTA and OZURDEX groups,
risk factors for an IOP-related event include higher respectively, with 9%, 18% and 39%, respectively, develop-
baseline IOP and younger age. A cumulative incidence ing an IOP rise of ≥10 mm Hg from baseline.147 Interest-
of 32% of patients in the SCORE study reached an IOP ingly, only 4% to 6% overall developed an IOP of ≥30 mm
≥25mm Hg at 12 months. The incidence of IOP eleva- Hg. Although both intravitreal treatments had a signifi-
tion in other reports is comparable.186-188 Although cantly higher rate of raised IOP when compared with peri-
most cases of IOP elevation occur in the first 1 to ocular steroid, there was no significant difference seen
2 months of initiating therapy, in some cases it may between IVTA and OZURDEX in a direct comparison.
take several months to develop (in SCORE Study
Report 15 this ranged up to 598 days), so long-term vig- Raised IOP in children
ilance is required even if no IOP rise is seen after the Children are more likely than adults to have an IOP
first few injections.185 response to steroids.195 Compared to adult patients, the
FUNG ET AL. 381
IOP rise can be more severe and resulting glaucoma may cataract surgery during the study.118 A recent large retro-
progress more rapidly and has even been reported within spective analysis of over 6000 DII injections found a sta-
hours of starting treatment.196 The effect can result from tistically significant increase in cataract progression in
topical, periocular, intravitreal, oral and intravitreal dos- eyes receiving injections (P = .004) although with a small
ing regimes. co-relation co-efficient (r = .057).190
Dexamethasone is more likely to cause a steroid In the FAME trials, the development of cataract and
response than FML in children. A study by Kwok et al195 the proportion of patients requiring cataract surgery were
included 19 Chinese children undergoing bilateral stra- significantly higher in both the low- and high-dose FA
bismus surgery, with one eye randomized to receive topi- treatment arms than in the sham-control group. At
cal dexamethasone 0.1% and the other to receive FML 36 months, the percentage of patients developing cata-
0.1% six times per day for 4 weeks postoperatively. The racts were 81.7%, 88.7% and 50.7% in the low-dose, high-
mean increase in IOP in eyes receiving dexamethasone dose and control group, respectively.199
(15.48 ± 8.71 mm Hg) was almost double that of eyes Uveitis patients may develop cataract from both intra-
receiving FML (5.83 ± 4.96 mm Hg; P = .001).195 ocular inflammation and corticosteroid treatment. In the
FML also causes ocular hypertension, in a dose- SITE cohort, 1192 eyes of 914 patients received periocular
dependent manner in children. In a study by Fan et al,197 injections (sub-Tenon's or orbital floor) for uveitis. Cata-
31 children undergoing bilateral strabismus surgery had ract development attributing to an incident reduction in
one eye randomized to receive topical FML six times per visual acuity of worse than 6/12 occurred in 20.2%, whilst
day and the other eye to receive topical FML three times cataract surgery was performed within 12 months in
per day, each for 4 weeks postoperatively. The IOP 13.8% of initially phakic eyes.140
increased significantly from baseline in both groups, but Periocular injection of corticosteroid used in the man-
the peak IOP was higher (19.0 ± 5.06 mm Hg vs 17.13 agement of paediatric uveitis is associated with a high
± 3.32 mm Hg, P < .001) and the net increase was also rate of cataract formation, [4 of 19 (21%) eyes]200 and
greater (4.37 ± 4.79 vs 2.57 ± 3.32 mm Hg, P = .005) in IVTA used to manage uveitic macular oedema in chil-
the group with more frequent dosing. More frequent dos- dren has been found to induce cataract in 6 of 11 eyes
ing was correlated with reaching peak IOP sooner (6 days (55%).145
vs 13 days; P = .033), but there was no difference in post-
operative inflammation between the groups.197
5.2.3 | Non-infectious endophthalmitis
and pseudoendophthalmitis
5.2.2 | Cataract
Although acute bacterial endophthalmitis is the most
Cataract is the other common complication of ocular and serious complication of intraocularly administered ste-
periocular delivered steroids. There are few studies that roids, acute non-infectious endophthalmitis following
directly compare rates of cataract progression with differ- IVTA injection is more common, with most studies
ent types of intravitreal steroids. However, the rates from reporting an incidence of 0.5% to 2.0%.201,202 Non-
various studies may suggest higher rates of cataract pro- infectious endophthalmitis refers to a transient, inflam-
gression with IVTA and FA than DII. A head to head matory reaction, typically with hypopyon that presents
comparison between intravitreal FA and DII in uveitis within a day or two post injection of IVTA.201 There is
patients showed a significantly higher incidence of cata- usually no or minimal inflammation of the sclera and
ract (and raised IOP) with FA.198 conjunctiva, minimal anterior chamber fibrin and pain is
In the SCORE Study Report 5 (CRVO), the estimate rare, as might be expected since steroids are anti-inflam-
through month-12 of phakic patients developing new- matory.201 The condition is usually self-limiting and
onset lens opacity or progression of existing opacity was resolves in 1 to 2 weeks but may cause persistent vitreous
18%, 26% and 33%, respectively, in the observation, 1 mg opacification in a minority of cases.
IVTA and 4 mg IVTA groups. The percentage of patients Some authors have attributed non-infectious
requiring cataract surgery by 24 months in these respec- endophthalmitis following IVTA injection to the preser-
tive groups were 0%, 0% and 33%.22 In the SCORE Study vative vehicle 0.99% benzyl alcohol found in Kenacort.202
Report 6 (BRVO) this was 13%, 25% and 35%, respec- In one study, the incidence of severe sterile
tively, in the laser, 1 mg IVTA and 4 mg IVTA groups.23 endophthalmitis fell from 13.0% to 4.3% after switching
In the MEAD study for DMO, DII 0.7 mg was associated from preserved to preservative-free TA.203 However
with cataract-related adverse events in 67.9% of patients another study found no difference in the incidence of
over the course of the 3-year study, with 59.2% requiring non-infectious endophthalmitis after removing benzyl
TABLE 3 Outline of studies on local delivery of corticosteroids in clinical ophthalmology
382
No. of eyes/ Study aims and outcome

Conditions Authors, (Year) Design (patients) Treatment steroid measures Conclusions
Adnexal
TED Bordaberry et al, RCT 21 • Peribulbar TA To assess the efficacy of Peribulbar TA reduced
(2009)31 peribulbar TA to treat inflammatory signs of
inflammatory signs of moderate Graves' orbitopathy
moderate to severe Graves' as measured by the clinical
orbitopathy and associated activity score
optic neuropathy
• Clinical activity score
• Extraocular muscle size
Ebner et al, Multi-centre RCT 41 • Peribulbar TA To assess the efficacy of Peribulbar TA is effective in
(2004)32 peribulbar TA vs control to reducing diplopia and
treat TED extraocular muscle size in
• Extraocular muscle size TED
• Binocular diplopia
Alkawas et al, RCT 12 • Peribulbar TA To assess the efficacy of No statistical difference found
(2010)226 • Oral Prednisolone peribulbar TA vs oral in study sample between
prednisolone to treat TED peribulbar TA and oral
• Modified clinical activity prednisolone in treating TED
score
• Signs/Exophthalmometry
• Complications
Lee et al, (2013)35 Single-blinded RCT (106) • Sub-conjunctival TA To assess the efficacy of Sub-conjunctival TA was
sub-conjunctival TA in effective in treating TED
treatment of TED related lid related lid retraction and
retraction persisted through to 24 weeks
• Lid retraction of follow-up
• Lid swelling
• Exophthalmos
• Lagophthalmos
• Clinical activity score
• Total eye score
Nasolacrimal McNeill et al, RCT 11 • Nasal beclomethasone To assess the efficacy of nasal Epiphoria secondary to rhinitis
disease (2005)44 corticosteroids in treating can be treated successfully
functional epiphoria in with intranasal
patients with rhinitis beclomethasone
• Epiphoria symptom score
Chalazia RCT 136 • Intra-lesional TA
FUNG ET AL.
(Continues)
TABLE 3 (Continued)

FUNG ET AL.

Goawalla and Lee, • Incision and curettage To compare intra-lesional TA, Resolution rates between
(2007)46 • Hot compresses incision and curettage and intra-lesional TA and
hot compresses in the incision and curettage were
treatment of chalazia similar and both were
• Resolution rate significantly greater than
• Pain/inconvenience score conservative group. There
• Patient satisfaction score was less pain and patient
inconvenience with
intra-lesional TA compared
to incision and curettage
Ben Simon et al, RCT 94 • Intra-lesional TA To compare intra-lesional TA Intra-lesional TA was as

(2011)47 • Incision and curettage against incision and curettage effective as incision and
for the treatment of chalazia curettage in primary chalazia
• Resolution rate
• Additional treatments
Anterior segment
Bacterial Srinivasan et al, Multi-centre placebo-controlled 500 (3 mo) • Topical prednisolone To compare the benefit in No significant differences in
keratitis (2012)60 double-blinded RCT 399 (12 mo) • Placebo clinical outcomes of clinical outcomes with topical
adjunctive topical prednisolone sodium
corticosteroids in the phosphate 1% compared to
treatment of bacterial corneal placebo in non-Nocardia
ulcers species.
• BCVA Ulcers caused by Nocardia may
• Infiltrate/scar size fare worse with topical
• Re-epithelialisation steroids
• Corneal perforation
HSK Wilhelmus et al, Multi-centre placebo-controlled 106 • Topical prednisolone To compare the benefit in Topical prednisolone phosphate
(1994)62 double-blinded RCT • Placebo clinical outcomes of was significantly better than
adjunctive topical placebo in reducing
corticosteroids in the persistence or progression of
treatment of HSV keratitis stromal inflammation (by
• Clinical resolution 68%)
Allergic eye Singh et al, Double-blinded RCT 90 (45) • Supratarsal DM To compare three types of All three drugs were equally
disease (2001)69 • Supratarsal TA supratarsal steroid injections effective with no statistically
• Supratarsal HC for the treatment of refractory significant difference in the
VKC time of resolution.
Recurrence was seen within
383
(Continues)
TABLE 3 (Continued)
384

• Symptoms and signs six in all cases irrespective of
(cobblestone papillae, lid the steroid used
oedema, conjunctival
discharge, chemosis,
Horner-Tranta dots and
shield ulcers)
• Disease recurrence
Saini et al, (1999)70 Double-blinded RCT 38 (19) • Supratarsal TA To compare supratarsal TM vs Both were equally effective in
• Supratarsal DM supratarsal DM for the controlling symptoms and
treatment of refractory VKC signs however supratarsal TM
• Symptoms and signs had a lower recurrence rate
(cobblestone papillae, lid
oedema, shield ulcer, SPK)
• Disease recurrence
KCS Pflugfelder et al, Multi-centre double-blinded 128 (64) • Topical loteprednol To assess the efficacy of Topical loteprednol etabonate
(2004)81 RCT etabonate 0.5% loteprednol etabonate 0.5% vs may be beneficial in KSC
• Placebo placebo for KCS with moderate clinical
• Symptom severity score inflammation
• Corneal fluorescein staining
• Conjunctival injection
Sheppard et al, Multi-centre double-blinded (119) • Topical loteprednol To assess the efficacy of Loteprednol showed greater
(2014)84 RCT etabonate 0.5% + topical loteprednol etabonate 0.5% efficacy in dry eye signs and
cyclosporine 0.05% with topical cyclosporin symptoms than topical
• Topical cyclosporine 0.05% 0.05% in dry eye disease cyclosporin or artificial tears
+ artificial tears • Ocular surface disease alone. It also provided rapid
index (OSDI) relief of dry eye disease
• Likert scale
• Lissamine green staining,
fluorescein staining,
Schirmer test
Lin and Gong, Multi-centre double-blinded (41) • Topical FML 0.1% To compare topical FML vs Both medications gave similar
(2015)86 RCT • Cyclosporine A 0.5% cyclosporin A for the improvement from baseline,
treatment of dry eye disease however topical FML
in Sjogren syndrome provided faster improvement
• Fluorescein staining in symptoms of ocular
• OSDI dryness
(Continues)
FUNG ET AL.
TABLE 3 (Continued)

FUNG ET AL.

• Conjunctival goblet cell
density
• Severity of conjunctival
congestion
• Tear break up time (TBUT)/
Schirmer test
Pinto-Fraga et al, Double-blinded RCT (42) • Topical FML 0.1% To assess the efficacy of topical Topical FML was effective in
(2016)87 • Artificial tears FML in dry eye disease when alleviating dry eye disease but
exposed to adverse also especially in preventing
environments exacerbation caused by
• Corneal and conjunctival exposure to a desiccating
staining stress
• Conjunctival hyperaemia
• TBUT
• Tear osmolarity
• Symptom assessment in dry
eye (SANDE)
GVHD Yin et al, (2018)89 Double-blinded RCT 42 • Topical loteprednol 0.5% To assess the efficacy of topical Topical loteprednol had a less
• Artificial tears loteprednol in dry eye disease favourable response in
associated with GVHD treating dry eye disease in
• OSDI GVHD compared to those
• Corneal fluorescein staining without GVHD
• Conjunctival lissamine green
staining
• TBUT
• Schirmer test
Chemical Injury Brodovsky et al, Retrospective series 177 (121) • Intensive Topical FML To compare treatment Patients with intensive
(2000)93 + treatment protocol outcomes of a standard treatment had a trend for
• Conservative management protocol of intensive rapid healing and better final
treatment vs conservative visual outcomes in grade 3
management in alkali-burned chemical burns but no
corneas difference in grade 4 burns
• Time to corneal
re-epithelialisation
• Final BCVA
• Time to visual recovery
• Length of hospital stay
• Complications
385
(Continues)
TABLE 3 (Continued)
386

13
Anterior scleritis Sohn et al, (2011) Retrospective multi-centre 68 (53) • Sub-conjunctival TA To assess the efficacy of After one injection
cohort sub-conjunctival TA for sub-conjunctival TA gave
non-necrotising anterior improvement of symptoms
scleritis and signs in 97% and eyes
• Resolution of symptoms and remained recurrence-free in
signs 67.6% at 24 mo.
• Recurrence Sub-conjunctival TA is a
• Adverse effects useful adjuvant therapy that
may reduce the burden of
systemic medication
Glaucoma surgery
Glaucoma Araujo et al, RCT 46 (35) • No corticosteroids To compare no adjunctive Patients treated with steroids
filtration (1995)100 • Topical 1% prednisolone steroids vs topical (groups 2 and 3) had
surgery acetate prednisolone vs topical significantly improved
• Topical 1% prednisolone prednisolone and oral outcomes compared with
acetate and oral prednisone steroids in glaucoma filtration patients without steroids
surgery after 10 y (group 1). Group 1 had more
• Final IOP in follow-up additional procedures, higher
periods IOPs, more additional
• Number of glaucoma glaucoma drops and lower
medications used rate of stabilized glaucoma
• Additional glaucoma
filtration surgery
• Visual acuity
• Stabilization of glaucoma
(disc photos, visual fields)
Yuki et al, RCT 53 • Sub-Tenon TA To assess the efficacy of Intraoperative sub-Tenon TA
(2009)102 • Control (no TA) intraoperative sub-Tenon TA neither increased
on the success rate of intermediate-term success nor
trabeculectomy in secondary decreased postoperative
glaucoma complications
• IOP reduction
• Success rate
• Indiana Bleb Appearance
Grading Scale
Breusegem et al, RCT 54 • Topical FML To compare preoperative Use of topical ketorolac or
(2010)227 • Topical ketorolac treatment of topical ketorolac fluorometholone 1 mo prior
(Continues)
FUNG ET AL.
TABLE 3 (Continued)

FUNG ET AL.

• Placebo or FML vs placebo on to trabeculectomy was
trabeculectomy outcomes associated with less
• Postoperative surgical or likelihood of postoperative
medical interventions needling and less need for
(needling, suture lysis, IOP-lowering medication
needling revision,
IOP-lowering medication)
Yazdani et al, Triple-blinded RCT 90 • Sub-Tenon TA To compare intraoperative Sub-Tenon IOP resulted in a
(2017)110 • Placebo sub-Tenon TA vs without in lower mean IOP at the first
Ahmed glaucoma valve mo and was 1.5 mmHg lower
implantation throughout the study period.
• IOP Peak postoperative IOP was
• BCVA also lower. The rates of
• Occurrence of hypertensive success, occurrence of
phase hypertensive phase and
• Peak IOP complications were similar
• Number of glaucoma between the two groups
medications
• Postoperative complications
Posterior segment
DMO Gillies et al, Double-blinded RCT 69 (43) • IVTA To assess the efficacy of IVTA had significantly greater
(2006)115 • Placebo outcomes of IVTA in the proportion of patients (56%)
treatment of refractory DMO achieving ≥15 letters of
• Improvement of BCVA improvement in BCVA than
• Central macular thickness placebo (26%). IVTA was also
• Adverse events found to reduce central
macular thickening however
adverse events included
cataract and glaucoma
Bressler et al, Multi-centre double-blinded 828 • Ranibizumab + Prompt laser To compare intravitreal Eyes receiving initial
(2010)117 RCT • Ranibizumab + deferred ranibizumab plus prompt or ranibizumab for
DRCR Protocol I laser deferred laser vs prompt laser centre-involving DMO had
• Prompt laser + sham or IVTA plus prompt laser in better long-term vision and
• IVTA + prompt laser DMO reduced central subfield
• (Latter two groups allowed • Improvement of BCVA thickness
very deferred ranibizumab) • Central subfield thickness
• Number of injections (5 y)
(Continues)
387
TABLE 3 (Continued)
388

Boyer et al, Two identical, parallel (1048) • DII (0.7 mg) To assess safety and efficacy of DII had significantly greater
(2014)118 multi-centre • DII (0.35 mg) DII in the treatment of DMO proportion of patients
MEAD study double-blinded RCT • Sham • Improvement of BCVA achieving ≥15-letters of
• Central retinal thickness improvement in BCVA (22.2%
• Adverse events for 0.7 mg, 18.4% for 0.35 mg
and 12.0% for sham)
Fraser-Bell et al, Multi-centre single-blinded 88 (61) • DII To compare DII vs intravitreal DII achieved similar rates of
(2016)120 RCT • Bevacizumab bevacizumab for the BCVA improvement with
BEVORDEX treatment of DMO bevacizumab and superior
study • Improvement of BCVA anatomic outcomes with
• CMT fewer injections at 12 mo. At
• Injection frequency 24-mo, there was no
• Adverse events significant difference of
improvement in BCVA but
less burden of injections
Callanan et al, Double-blinded multi-centre 253 • DII + laser To compare DII combined with DII combined with laser
(2013)189 RCT • Laser laser photocoagulation resulted in significantly
compared with laser alone for greater mean improvement in
treatment of diffuse DMO BCVA at all time points
• BCVA through month 9.
• Vessel leakage Combination treatment also
• Adverse events reduced areas of diffuse
vascular leakage on
angiography. At 12 mo, there
was no significant difference
between the two groups
Campochiaro Two identical parallel, 392 • IVFA implant (0.2 μg/d) To compare efficacy and safety Low-dose and high-dose IVFA
et al, (2011)121 multi-centre double-blinded • IVFA implant (0.5 μg/d) of IVFA implants for implant groups had greater
FAME A and B RCT • Sham treatment of DMO percentage of patients with
• Improvement of BCVA ≥15 letters of improvement in
• Foveal thickness BCVA at 24 mo (28.7% and
• Adverse events 28.6%) compared with sham
(16.2%). There was also more
improvement in foveal
thickness compared to sham.
A significant percentage
(7.6%) of the high-dose group
(Continues)
FUNG ET AL.
TABLE 3 (Continued)

FUNG ET AL.

required incisional glaucoma
surgery
CMO in RVO Ip et al, (2009)22 Multi-centre RCT 271 • IVTA 1 mg To assess the efficacy and safety IVTA had significantly greater
SCORE-CRVO • IVTA 4 mg of IVTA for treatment of proportion of patients with
• Standard of care macular oedema secondary to ≥15 letter improvement in
(observation) central retinal vein occlusion BCVA (27% for 1 mg, 26% for
• Improvement of BCVA 4 mg and 7% for sham).
• Centre point thickness Superior safety profile of 1 mg
• Vessel leakage, capillary dose compared with 4 mg
non-perfusion dose IVTA with respect to
• Adverse events glaucoma and cataract
Scott et al, (2009)23 Multi-centre RCT 411 • IVTA 1 mg To assess the efficacy and safety Treatment with IVTA with
SCORE-BRVO • IVTA 4 mg of IVTA for treatment of 1 mg or 4 mg or standard of
• Standard of care (grid laser) macular oedema secondary to care did not demonstrate a
branch retinal vein occlusion significant difference in visual
• Improvement of BCVA acuity outcomes in macular
• Centre point thickness oedema secondary to branch
• Vessel leakage, capillary retinal vein occlusion
non-perfusion
• Adverse events
Haller et al, Two identical, parallel 1267 • DII To assess the efficacy for DII for DII had significantly greater
(2010)123 multi-centre double-blinded • Sham treatment of macular oedema proportion of patients with
GENEVA RCT secondary to CRVO or BRVO ≥15 letter improvement in
• Improvement of BCVA BCVA, mean BCVA and less
• Central retinal thickness proportion of patients losing
• Adverse events ≥15 letters in BCVA
Posterior Sen et al, (2014)140 Retrospective review of 1192 (914) Periocular corticosteroid To assess the efficacy and safety Over 50% of eyes demonstrated
non-infectious SITE multi-centre cohort (including sub-Tenon and of periocular corticosteroid improved VA at some point
uveitis orbital floor) injections in uveitis within 6 mo of receiving
• Improvement of BCVA periocular steroid. Periocular
• Improvement of macular corticosteroids were also
oedema affecting BCVA effective in treating acute
• Intraocular inflammation inflammation or macular
• Systemic medications oedema
• Adverse events
(Continues)
389
TABLE 3 (Continued)
390

Kempen et al, Multi-centre RCT 479 (255) • IVFA implant (Retisert) To compare IV FA implant with No significant difference in
(2015)141 • Systemic therapy systemic immunosuppression BCVA at 2 and 5 y. Systemic
MUST study in the treatment of posterior immunosuppression had
non-infectious uveitis better BCVA outcome at 7 y
• BCVA
• Visual field mean deviation
• Activity of uveitis
• Presence of macular oedema
Jaffe et al, (2019)30 Multi-centre, double-blinded 129 • IVFA implant (Yutiq) To assess efficacy and safety of IVFA provided a greater
sham-controlled RCT • Sham IVFA implant on recurrence proportion of patients with
rates in chronic posterior ≥15 letter improvement as
non-infectious uveitis well as effective management
• Improvement of BCVA of intraocular inflammation
• Recurrence of uveitis and lower recurrence rates
• Macular oedema during the first 12 mo
• Adverse events
Lowder et al, Parallel-group, multi-centre, 229 • DII (0.7 mg) Efficacy of DII on treating Both doses of DII showed a
(2011)146 blinded RCT • DII (0.35 mg) inflammation and CMO in significant reduction of
HURON study • Sham non-infectious posterior posterior inflammation and
uveitis or panuveitis CMO compared to sham
• Vitreous haze which persisted through week
• BCVA 25. The proportion of patients
• Central macular thickness with ≥15 letter improvement
• Adverse events of BCVA was also
significantly higher in the DII
groups compared to sham
Thorne et al, Multi-centre, parallel-treatment 235 • Periocular TA To compare the efficacy of Improvements of CMT were
(2019)228 comparative RCT • IVTA periocular TA, IVTA and seen in all three groups,
POINT trial • DII OZURDEX for treatment of periocular TA (23%), IVTA
uveitic macular oedema (39%), OZURDEX (46%).
• Central subfield thickness Greater improvements in
• Resolution macular oedema BCVA were also seen with
• BCVA IVTA and OZURDEX. No
• IOP events significant differences
between IVTA and
OZURDEX in central subfield
thickness or BCVA
(Continues)
FUNG ET AL.
TABLE 3 (Continued)

FUNG ET AL.

151
Das et al, (1999) RCT 63 • IVDM + intravitreal To compare adjunctive IVDM A reduction of inflammation
antibiotics vs intravitreal antibiotics-only was observed in the IV DM
• Intravitreal antibiotics alone during vitrectomy for group at 1 week and 1 mo
suspected postoperative or (although topical
post-traumatic bacterial corticosteroids were not
endophthalmitis given in the intravitreal
• Inflammation scoring antibiotic-only group).
• BCVA Final visual outcomes at
3 mo were not significantly
different
Gan et al, (2005)152 RCT 29 • IVDM + intravitreal To compare adjunctive IVDM No statistically significant
antibiotics vs intravitreal antibiotics difference on visual acuity at
• Intravitreal antibiotics alone alone in postoperative 3 and 12 mo between the two
endophthalmitis groups. Trial terminated
• BCVA prematurely due to the study
drug (dexamethasone sodium
diphosphate was no longer
available)
Albrecht et al, Double-masked RCT 62 • IVDM + intravitreal To compare adjunctive IV DM No statistically significant
(2011)153 antibiotics vs intravitreal antibiotics difference in visual outcomes
• Intravitreal antibiotics alone alone in presumed bacterial in short-term (2 weeks) or
endophthalmitis intermediate-term (2–4 mo
• BCVA post-treatment) between the
two groups
Manning et al, Multi-centre RCT 167 • IVDM + intravitreal To compare adjunctive IVDM No statistically significant
(2018)154 antibiotics vs intravitreal antibiotics difference in final visual
• Intravitreal antibiotics alone alone in patients with outcomes between IVDM and
suspected bacterial placebo group
endophthalmitis post-cataract
surgery
• BCVA
Postoperative Konstantopoulos Retrospective case series 21 (20) • IVTA (4 mg) To assess efficacy and safety of All patients had significantly
CMO et al, (2008)158 IVTA in postoperative CMO improved BCVA from
• Improvement of BCVA baseline which was
• Adverse events maintained at 6 mo
(Continues)
391
392 FUNG ET AL.
alcohol204 and cases of non-infectious endophthalmitis
xanthogranuloma; KCS, keratoconjunctivits sicca; LCH, Langerhan's cell histiocytosis; MP, methylprednisolone; PA, prednisolone acetate; RCT, Randomized Controlled Clinical Trial; RVO, retinal vein occlusion; TA,
have been reported with benzyl-alcohol free Tri-
esence.205,206 In fact, one study found a higher rate of
compared to baseline for
Abbreviations: CMO, cystoid macular oedema; DM, dexamethasone; DMO, diabetic macular oedema; FML, fluoromethalone; HC, hydrocortisone; HSK, herpes simples keratitis; IV, intravitreal; JXH, Juvenile
between the two groups
improvement in BCVA
statistically significant
non-infectious endophthalmitis following administration
difference was found

To compare the retrobulbar TA There was significant
both groups but no

of Triescence compared with Kenalog-40 and
preservative-free TA.207 The authors attributed this result
Conclusions
to the smaller particle size and higher particle load of Tri-

esence. The pathogenesis for this phenomenon is likely
to be multifactorial.
A non-infectious, non-inflammatory pseudoendopthalmitis
can also occur when TA particles migrate and settle in
vs posterior sub-Tenon's TA
the anterior chamber, resembling a hypopyon.201 Whenever

Study aims and outcome
for pseudophakic CMO
there is uncertainty regarding whether an endophthalmitis is

• Resolution of CMO
refractory to topical
infectious or non-infectious, it should be managed with the

standard treatment for infectious endophthalmitis.
medications
measures
• BCVA
• IOP
5.2.4 | Activation of ocular or periocular

infection
Corticosteroids may suppress the host response and thus

• Retrobulbar TA (40 mg)
increase the hazard of secondary ocular infections. This

• Posterior sub-Tenon
can prolong the course and/or exacerbate the severity of

Treatment steroid
viral (eg, herpes simplex epithelial keratitis), bacterial

and fungal infections of the eye. In acute purulent infec-
TA (40 mg)
tions of the eye, steroids may mask infection or exacer-

bate existing infection. Since corticosteroids are known to
reduce resistance to infections, simultaneous bilateral
intraocular injections of steroids should, if possible, be
No. of eyes/
avoided to limit the potential for bilateral postoperative

(patients)
infection.208
49 (48)
Infectious scleritis is a rare complication of sub-Tenon

TA with a reported incidence of 0.04%.209 A recent review
found nine reported cases in which four were caused by
fungal organisms.210
triamcinolone; TED, thyroid eye disease; VKC, vernal keratoconjunctivitis.
Use of intraocular or periocular administered cortico-

Retrospective review
steroids may reactivate HSK and concurrent antiviral

prophylaxis for those with a history of HSK is
advised.211,212
Viral retinitis has been reported following local
Design
administration of corticosteroids. A recent review

found 30 cases with causative viruses identified as cyto-
megalovirus in 76.7%, HSV in 16.7%, with one case of
Authors, (Year)
varicella zoster virus and another unspecified.

Thach et al,
(1997)229
Steroids were administered by IVTA (33.3%), intra-

(Continued)
vitreal FA acetonide implant Retisert (33.3%), posterior

sub-Tenon TA (6.6%) and anterior sub-Tenon TA
(3.3%).208
Unmasking or activation of dormant ocular syphilitic
Conditions
infection following IVTA have been reported in five

TABLE 3
cases. All cases manifested with small round yellow reti-

nal lesions, retinovasculitis and optic disc involve-
ment.213-215 Three of these cases presented with acute
FUNG ET AL. 393
syphilitic posterior placoid chorioretinitis and all had Fellowship. Jennifer Arnold, Advisory Board work and hon-
devastating visual outcomes.213,214 oraria: Allergan, Novartis, Bayer, Alcon. Mark Gillies,
In contrast, a small series of seven patients demon- Research funding, honoraria and travel support: Novartis,
strated safety of DII in treating CMO in patients with Bayer, Allergan. Andrew Symons, Research grant: Topaz
infectious uveitis where other treatments for CMO had Study.
failed. All patients were concurrently treated on the appro-
priate antimicrobial agent and had resolution of CMO ORCID
without reactivation of the infectious ocular disease.216 Adrian T. Fung https://orcid.org/0000-0002-1117-3893
Tuan Tran https://orcid.org/0000-0002-0853-2226
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Patient Preference and Adherence Dovepress
open access to scientific and medical research
Open Access Full Text Article REVIEW
Effectiveness, tolerability and safety

of azithromycin 1% in DuraSite® for acute
bacterial conjunctivitis
This article was published in the following Dove Press journal:
Patient Preference and Adherence
21 April 2010
Number of times this article has been viewed
Susannah McLean Purpose: Bacterial eye infections are commonly treated with topical antibiotics, despite limited
Aziz Sheikh evidence of effectiveness. Azithromycin 1% in DuraSite® is a new formulation of azithromycin
in a gel polymer designed for use in acute bacterial conjunctivitis.
Centre for Population Health
Sciences: GP Section, Allergy and Methods: We conducted systematic searches of the Cochrane Database of Clinical Trials,
Respiratory Research Group, PubMed and Google Scholar to find randomized controlled trials of “azithromycin DuraSite®”.
University of Edinburgh, Medical
These searches of published literature were supplemented with searches for unpublished trials
School, Edinburgh, United Kingdom
and trials in progress.
Results: We found six reports of randomized controlled trials investigating the role of
azithromycin 1% in DuraSite® for the management of acute bacterial conjunctivitis. The quality
of these trials was judged to be moderate to high. These trials assessed effectiveness, tolerability
and safety outcomes, but we found no trials looking at cost-effectiveness. DuraSite® is a relatively
stable formulation and so azithromycin 1% in DuraSite® has a simpler dosing schedule than
other available topical antibiotics. It appears to be similar to other topical antibiotics in its
effectiveness, but minor side effects are quite common.
Conclusion: Acute bacterial conjunctivitis is a relatively mild, typically self-limiting, infection.
Antibiotics should seldom be required. If, however, a decision to prescribe antibiotics is made,
azithromycin 1% in DuraSite® is likely to be broadly comparable in its effectiveness to most other
antibiotics used to treat acute bacterial conjunctivitis. Further research is needed to determine
its cost-effectiveness.
Keywords: conjunctivitis, bacterial eye infection, azithromycin 1% in DuraSite®
Introduction
Bacterial eye infections are common, accounting for up to 1% of consultations in
primary care.1,2 Patients typically experience unpleasant symptoms of a “gritty” eye,
with blurred vision and increased lacrimation. On examination, crusted deposits can
often be seen along the line of the eyelashes and the upper and lower conjunctivae
appear infected, red, and irritated. Infection frequently spreads to involve both eyes.3
Infective conjunctivitis is either bacterial or viral and, in the latter case, mainly caused
Correspondence: Susannah McLean
Centre for Population Health Sciences: GP by adenovirus. Bacterial conjunctivitis is a relatively minor self-limiting illness without
Section, Allergy and Respiratory Research serious sequelae in those with an intact immune system.4–6 Conjunctivitis occurring
Group,The University of Edinburgh,
Medical School,Teviot Place, Edinburgh, early in the neonatal period is the main exception to this general rule. This should be
EH8 9AG, United Kingdom investigated and treated aggressively as it may indicate the presence of sight-threat-
Tel +44 131 650 9242
Fax +44 131 650 9119 ening trachoma.7 The main differential diagnoses of infective conjunctivitis include
Email susannah.mclean@ed.ac.uk allergic conjunctivitis, chemical conjunctivitis and a foreign body. Although rare, the
submit your manuscript | www.dovepress.com Patient Preference and Adherence 2010:4 69–76 69
Dovepress © 2010 McLean and Sheikh, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
McLean and Sheikh Dovepress
major complication of bacterial conjunctivitis is the possible rates. Later (days 6 to 10) data found that these early advantages
sight-threatening emergency of orbital cellulitis. in clinical (RR = 1.11; 95% CI: 1.02–1.21) and microbiological
(RR = 1.56; 95% CI: 1.17–2.09) cure rates persisted, but were
Patient considerations reduced. The majority of cases in the placebo arms of these
It is difficult to distinguish bacterial from viral conjunctivitis trials resolved spontaneously with clinical remission being
on clinical grounds. Bacterial overgrowth may occur in achieved in 65% (95% CI: 59–70) by days 2–5. No serious
the presence of viral conjunctivitis. Patients seek medical outcomes were reported in either the active or placebo arms of
attention for symptom relief and this often results in the the five trials included in this review. Synthesis of these trials
prescription of a topical antibiotic in the form of eye drops found that the prescription of topical antibiotics marginally
or ointment.8 Drops can be either soothing or irritating accelerated remission of acute bacterial conjunctivitis. None
depending on their pH and viscosity.9 Ointments frequently of the trials reported on cost-effectiveness considerations.
blur vision and therefore tend to be prescribed for patient’s Everitt et al19 conducted an innovative trial assessing
use just prior to bed time. Many of these topical antibiotics the impact of delayed prescribing of antibiotics for con-
have frequent dosing regimens of up to every two hours.10 junctivitis. Prescribing strategies did not affect the severity
Achieving good compliance with such preparations is, of symptoms, but the duration of moderate symptoms was
understandably, difficult. reduced with antibiotics: ie, no antibiotics (control) mean
of 4.8 days vs immediate antibiotics 3.3 days (RR = 0.7;
Microbiological considerations 95% CI: 0.6–0.8); control vs delayed antibiotics 3.9 days
Bacteria are responsible for an estimated 50%–70% of (RR = 0.8; 95% CI: 0.7–0.9).20
all infective conjunctivitis. The most common bacterial In this factorial trial, the researchers asked patients
p athogens are Staphylococcus aureus, Haemophilus whether they thought they needed the antibiotics and also
influenzae, Streptococcus pnuemoniae, and Moraxella whether they would re-attend the surgery in future episodes
catarrhalis. The latter is often observed in children.11 of conjunctivitis. These questions were designed to assess
There is ongoing debate as to whether widespread the impact of medicalization on likely future health-seeking
prescribing of broad-spectrum antibiotics for minor illnesses, behavior.20 Everitt et al concluded that delayed prescription of
such as azithromycin for bacterial conjunctivitis, encourages antibiotics was probably the most effective treatment strategy,
the emergence of bacterial resistance. In vitro studies have, particularly in that this approach was likely to also change
for example, found that azithromycin appears to be less patterns of health-seeking behavior for future episodes of
active against S. pneumoniae and methicillin-susceptible suspected infective conjunctivitis. However, this conclusion
S. aureus than erythromycin or clarithromycin. H. influenzae needs to be re-examined since chloramphenicol eye drops
is, however, 2–8 times more susceptible to azithromycin than recently became available in the UK from pharmacists with-
to clarithromycin or erythromycin. With increased beta- out the need for a prescription.21
lactam resistance of S. pneumoniae the search continues Another factor to be taken into account when prescribing
for effective alternatives.12,13 Also of relevance, is work by for infective conjunctivitis is that children in nursery or school
Ohnsman and Ritterband,14 who compared in vitro resistance often infect one another and so institutions may ask parents
to azithromycin and moxifloxacin in bacterial conjunctivitis to keep their children at home. The parents then may need to
isolates and found no bacterial resistance to moxifloxacin, but miss time from work to care for their children.21,22 Therefore,
a moderate to very high bacterial resistance to azithromycin pressure from parents may result in more prescriptions for
for S. epidermidis, S. pneumonia, and S. aureus.14 conjunctivitis so that children can return to childcare and
parents can return to work as rapidly as possible.
Management issues The present review seeks to assess the place of azithro-
The key management question is whether the prescription of an mycin 1% in DuraSite® (Insite Vision, Alameda, CA, USA),
antibiotic is warranted. A recently updated Cochrane review4 a new preparation for the management of acute bacterial
of five trials,15–19 which included a total of 1034 participants, conjunctivitis.
found evidence that the application of topical antibiotics
overall improved early (days 2 to 5) clinical (relative risk Methods
[RR] = 1.24; 95% confidence interval [CI]: 1.05–1.45) and We used systematic review principles to search the Cochrane
microbiological (RR = 1.77; 95% CI: 1.23–2.54) remission Central Database of Clinical Trials, PubMed and Google
70 submit your manuscript | www.dovepress.com Patient Preference and Adherence 2010:4

Dovepress
Dovepress DuraSite® and acute bacterial conjunctivitis
Scholar with the keywords “azithromycin DuraSite®” for the mucus. Polycarbophil is therefore sometimes described as
period 1990–2009 in order to identify randomized controlled being muco-adhesive. This delivery mechanism ensures that
trials. Key data were extracted from studies and the data the azithromycin is “glued” to the eye conjunctiva, where it
were narratively synthesized, together with a wider body of persists for longer than less “sticky” alternatives, which offers
literature on azithromycin DuraSite® to provide a broader the benefit of a less-frequent dosing regimen.
context within which to consider these trials. We searched Also relevant is that at high shear stress, such as when
for unpublished material by searching online trials databases dispensed from a bottle tip, the azithromycin 1% in DuraSite®
(http://clinicaltrials.gov/and http://www.controlled-trials. flows and spreads over the ocular surface. When the shear
com/). stress is removed the polymer returns to a gel state, which,
in contrast with conventional aqueous drops, limits its loss
Results through reflex tearing and naso-lacrimal drainage. This
We found reports of six randomized controlled trials23–28 results in a sustained level of medication on the conjunctiva,
enrolling a total of 2933 patients. Two of these were as yet which makes the formulation useful for treatment of ocular
unpublished in their full form.24,26 There were three reports23–25 surface infections.29
focusing on clinical effectiveness: two 23,24 comparing Azithromycin 1% in DuraSite®’s persistence on the eye’s
azithromycin 1% in DuraSite® with placebo (vehicle) and a surface means that it needs to be administered only twice
randomized controlled trial25 comparing azithromycin 1% in daily for the first two days, and then only once a day for
DuraSite® with tobramycin 0.3%, all in patients with clinically days 3–5 to complete the course. The full treatment course,
diagnosed conjunctivitis. The searches of the online trial data- comprising of a total of only seven doses, is thus potentially
bases listed details of one planned and one ongoing study of very convenient for patients. This is in contrast to drugs such
azithromycin 1% in DuraSite® and 0.1% dexamethasone for as tobramycin which require dosing four times a day.
blepharo-conjunctivitis. An azithromycin 2% in DuraSite ® delivery system
In total, three reports26–28 included details of safety and has been evaluated in rabbits and its pharmacokinetic/
tolerability: one26 comparing 1% azithromycin in DuraSite® pharmacodynamic profile suggests that it may have efficacy
with vehicle, another27 comparing it with 0.3% tobramycin against common bacteria with just one dose per day for three
and finally a comparison with 0.5% moxifloxacin.28 days. Again, it is hoped that such a dosing regimen will, when
made available for humans, improve concordance.30
Formulation
The studies on formulations give insight into how this Mode of action
new preparation is thought to work.29,30 Azithromycin is Azithromycin is a macrolide antibiotic derived from
hydrophobic and is sparingly soluble in water at neutral erythromycin. It has better stability than erythromycin in acidic
pH. Aqueous preparations of azithromycin for topical environments. Azithromycin works by binding the 50s subunit of
a dministration to the eye are therefore labile at room the 70s bacterial ribosome, thereby inhibiting RNA-dependent
temperature and can degrade. The most stable pH for protein synthesis and preventing bacterial growth.31
azithromycin in solution is 6.3 and a range of 6.3 ± 0.3 has
therefore been set for the manufacture of the solution. This Kinetic properties
is within the range commonly used for ophthalmic solutions. Pharmacokinetics (ie, absorption, distribution, metabolism,
Azithromycin 1% in DuraSite® has been shown to be stable and elimination) are predictive of the concentration and time-
in formulation for at least 24 months at refrigerated storage course of the drug in the body, but do not necessarily correlate
temperatures (∼5°C). Stored at room temperature for six with expected antibacterial effect. The regimen of once-a-day
months, ocular formulation samples maintained 93%–98% dosing for five days demonstrated that peak concentrations
of their azithromycin content.30 of 150–200 µg/g and trough concentrations of 40 µg/g were
DuraSite® is a polycarbophil (polymer of polyacrylic sustained during a 24 hour period. These concentrations are
acid) bio-adhesive support matrix, which facilitates topical higher than the minimum inhibitory concentrations (MICs)
delivery of azithromycin.29 It binds neutral, cationic and needed to combat eye surface infections.31 In vitro stud-
anionic small molecules and then releases these over a period ies have confirmed that once-a-day dosing is adequate to
of time in a controlled fashion. The cross-linked polymer provide antibiotics at a level high enough to counter typical
chains form hydrogen bonds with glycosaminoglycans in conjunctival pathogens.
Patient Preference and Adherence 2010:4 submit your manuscript | www.dovepress.com

71
Dovepress
There are some caveats to this advantage to consider, ophthalmic fourth-generation fluoroquinolones, such
however. As azithromycin is used less frequently than other as moxifloxacin, as better options for the treatment of
topical antibiotic preparations, each dose represents a greater conjunctivitis.33
percentage of the total dose and this means that missing a We found no studies assessing the cost-effectiveness of
dose has greater significance. When doses are missed, the azithromycin 1% in DuraSite®.
infection can take longer to resolve and there is the theoretical
possibility that resistance is more likely to arise when trough Safety and tolerability
concentrations fall below the MIC for prolonged periods. Three reports 26–28 (Table 2) pertain to the safety and
tolerability of azithromycin 1% eye drops in DuraSite®.
Clinical effectiveness Heller et al conducted a large trial with 685 participants
Table 1 summarizes key data from trials assessing the and found the rate of adverse events to be approximately
effectiveness of azithromycin 1% in DuraSite®. There are 12% in both the azithromycin 1% in DuraSite® arm and the
two studies23,24 comparing azithromycin 1% in DuraSite® vehicle arm in patients with bacterial conjunctivitis. Protzko
with vehicle, both of which have used an appropriate et al27 randomized 743 patients and compared azithromycin
randomization technique. The patients and clinicians who 1% in DuraSite® with tobramycin 0.3%. Adverse events
were rating the clinical and bacterial cure levels were observed in the azithromycin group in the Protzko trial,
blinded to the allocation of the patients. Overall, these included eye irritation (1.9%), conjunctival hyperemia (1.1%)
studies appear to have been of moderate to good quality. and worsening bacterial conjunctivitis (1.1%). Finally, the
The Abelson-controlled Phase III clinical trial27 for bacte- third study,28 which was conducted in healthy volunteers,
rial conjunctivitis was performed with 316 randomized tested azithromycin 1% in DuraSite® in comparison with
participants aged 1–96 years. A five-day regimen of 1% moxifloxacin 0.5%. A much higher rate of ocular adverse
azithromycin in DuraSite® was compared with a five-day events was found in the azithromycin 1% in DuraSite® arm:
regimen of 0.3% tobramycin eye drops administered four 17.3% of patients’ eyes experienced ocular adverse events
times a day. Twenty drops of masked study medication were including redness, irritation, stinging, burning, dryness,
given to all participants. In the azithromycin in DuraSite® itching or chemosis; whereas only 1% of eyes receiving
arm, subjects received active drug in a twice-daily load- moxifloxacin experienced similar adverse events. This
ing dose on days 1 and 2 and once daily on days 3–5 and is a considerable difference and has implications when
vehicle drops were administered at other times. On day 6, considering whether a prescription of azithromycin 1% in
clinical resolution rates of 1% azithromycin in DuraSite® DuraSite® should be continued for its full course by any
were found to be equivalent to 0.3% tobramycin (79.9% vs patient who experiences these effects.
78.3%; P = 0.78). Bacterial eradication was defined as the
absence of detectable levels of new pathogens in cultures Patient perspectives
taken at study exit. Bacterial eradication with azithromycin As nonadherence is an important consideration in bacterial
1% in DuraSite® was reported as being as effective as with resistance, we now consider the patients’ perspectives. This
0.3% tobramycin (88.1% vs 94.3%; P = 0.07). includes what affects their decision to consult and their
Lichtenstein and Granet28,32 have, however, been criti- expectations of the treatment.
cal of this study. They argue that the addition of twice There are a variety of possible reasons for patient
daily vehicle drops to the azithromycin 1% in DuraSite ® nonadherence with eye drops including: poor motivation
drops constituted a possible additional therapeutic effect. (stemming from lack of understanding of the function
That is, that the vehicle drops possibly diluted the infec- of the medication); inability to use eye drops properly
tion and washed it out of the eye giving the azithromycin (eg, difficulty aiming the drop, inability to squeeze the
1% in DuraSite ® arm of the trial an artificially enhanced container well enough, blinking, inability to see the tip of
appearance of effectiveness. They argue that the azithro- the container, physical difficulties such as arthritis); and
mycin 1% in DuraSite® arm does not represent a true once patients’ reluctance to admit that they have problems with
daily regimen due to this “washout” effect of the vehicle the process.9,33
drops. When Lichtenstein and Granet considered all Indirect evidence on the importance of patient preferences
factors related to therapy (ie, bacterial resistance, blurri- comes from a study by Jampel et al34 who performed a
ness, dosing compliance, and comfort) they recommend willingness-to-pay analysis on subjects taking eye drops

Dovepress
Table 1 Randomized controlled trials assessing the clinical effectiveness of azithromycin 1% in DuraSite®
Author, Number of Azithromycin Comparator Result Quality
references patients/
patient age
Abelson26 N = 279 1% in DuraSite® dosed Vehicle with same Clinical resolution with Prospective
Age 1–96 twice daily on days 1–2 dosing schedule; azithromycin in DuraSite® randomized
and once daily on vehicle was identically was statistically improved vehicle-controlled,
days 3–5 supplied and compared with that of double-masked
formulated except vehicle P = 0.03 study. Randomiza-
that it contained no tion protocol not
azithromycin. explained in
study. Allocation
concealment appears
to be adequate
during enrolment.
Possible problem as
“data monitoring
committee” was not
blinded, although
these team mem-
bers did not have
any contact with
study participants.
Abelson27 N = 685 1% in DuraSite® dosed Vehicle with same Clinical resolution and Unpublished study,
npublished
U Age not available twice daily for days 1–2 dosing schedule. bacterial eradication double–masked
and four times a day for significantly better in and randomized,
days 3–5 the azithromycin group but insufficient
than in the vehicle information to
group P  0.05. determine quality.
Abelson29 N = 316 1% in DuraSite® dosed Tobramycin 0.3% Clinical resolution was Although the study
Age 1–83 twice a day with active four times a day 79.9% in azithromycin states that it was
drug on days 1–2 and group and 78.3% in the randomized there
once daily days 3–5, tobramycin group. The is no explanation of
other doses difference in clinical sequence gen-
were vehicle. resolution between the eration or alloca-
two groups was not tion concealment
statistically significant during enrolment.
(P = 0.78). Patients could not
have been blinded
to their treatment
as the viscosity of
the drops would be
different. The results
may also be affected
by incomplete
outcome data (ie, 17
patient withdraw-
als due to adverse
events, 16 patients
lost to follow-up,
withdrawn consent
or lack of efficacy).
for glaucoma. They found that patients preferred drops such side effects. Willingness-to-pay analysis may be useful
that did not produce blurring, drowsiness or inhibit sexual when adapted for investigating the preferred characteristics
performance. If such drops were available, then patients of antibiotic eye drops in a population of subjects with
would be willing to pay more for them than for drops with conjunctivitis.34

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Table 2 Randomized controlled trials assessing safety and tolerability of azithromycin 1% in DuraSite®
Author, Number of Azithromycin Comparator Result Quality
references patients/
patient age
Heller27 N = 685 1% in DuraSite® twice Vehicle with same 12% of patients Unpublished study
Age 1–96 daily for 2 days then dosing schedule. experienced at from Cochrane
four times a day for days least one adverse register of
3–5 in adults and event in both the trials. Double-masked
children. Azasite (azithromycin and randomized. No
1% in DuraSite®) and summary statistics
vehicle groups. No reported.
drug-related serious
adverse events.
Protzko28 N = 743 1% in DuraSite® dosed 0.3% Tobramycin Both medications Prospective
Age 1–93 twice a day with active four times a day well-tolerated. randomized
drug on days 1 and 2 for 5 days. A reported 3% of active-controlled
and once daily days azithromycin group double masked
3–5; other doses were and 5.6% of study, but no details
vehicle. tobramycin group had of randomization
treatment-related protocol given in
adverse events. study. The medication
Rates of microbial was masked. No odds
eradication and ratios reported.
bacterial infection
recurrence were the
same in both groups.
Granet28 N = 125 1% azithromycin in Tears Natural II® Ocular adverse events This study was
34 adults and DuraSite® or moxifloxacin were observed in 17% supported by Alcon
50 children received 0.5% in of participants and used Alcon’s
moxifloxacin and contralateral receiving azithromycin preparation of
contralateral eyes. 1% in DuraSite® and moxifloxacin. No
azithromycin; 11 1% receiving summary statistics
adults and 10 children moxifloxacin. were reported.
received moxifloxacin and Moxifloxacin was
contralateral placebo significantly more
tolerable in
healthy eyes.
Further research treatments most commonly used in other parts of the world
The willingness-to-pay study design discussed above could are also needed to inform local prescribing decisions. Such
be used to determine whether patients would be prepared to trials should focus on patient-reported outcome measures and
pay more for the convenient dosing schedule of azithromycin should also assess cost-effectiveness considerations.
1% in DuraSite®.
We did not find studies comparing azithromycin 1% in Conclusion
DuraSite® to chloramphenicol ointment/drops or to fusidic Based on the evidence of the Cochrane review and Everitt
acid drops. Since these are the two antibiotics most commonly et al’s randomized controlled trial incorporating a delayed
prescribed in the UK, a comparison of their effectiveness and treatment arm, we believe there is a strong argument for not
costs would be particularly useful. This is also relevant because prescribing antibiotics for the treatment of acute bacterial
chloramphenicol has an inconvenient dosing schedule (ie, conjunctivitis as this is, in the majority of cases, a relatively
every two hours), which can result in doses being missed or minor self-limiting illness. Furthermore, treatment may also
delayed. Fusidic acid drops are administered twice a day and increase the risk of development of antibiotic resistance in
so are more comparable with azithromycin 1% in DuraSite®. the community and also runs the risk of unnecessary medi-
Research needs to be carried out before a recommendation calization of this problem.
of the place of azithromycin in the UK can be made. Studies If, however, a decision to prescribe antibiotics is made,
comparing azithromycin 1% in DuraSite® with the topical the available evidence suggests that azithromycin 1% in

Dovepress
DuraSite® (Box 135) is likely to be as effective as other topical 10. Friedlaender MH, Protzko E. Clinical development of 1% azithromycin
in DuraSite, a topical azalide anti-infective for ocular surface therapy.
antibiotics. Its main advantage is a convenient once-a-day Clin Ophthalmol. 2007;1(1):3–10.
dosing schedule, which may aid concordance. This benefit 11. Buznach N, Dagan R, Greenberg D. Clinical and bacterial characteristics
may be offset however by a relatively high risk (compared of acute bacterial conjunctivitis in children in the antibiotic resistance
era. Pediatr Infect Dis J. 2005;24:823–828.
with tobramycin and moxifloxacin) of minor side effects. 12. Friedlaender MH, Protzko E. Response to correspondence from
We did not find data formally assessing cost-effectiveness Lichtenstein and Granet Re: Fluoroquinolones compared to 1%
azithromycin in DuraSite for bacterial conjunctivitis. Clin Ophthalmol.
considerations. 2008;2(1):242–244.
In summary, we suggest that the preferred course of 13. McCracken G. Microbiologic activity of the newer macrolide antibiotics.
Pediatr Infect Dis J. 1997;16:432–437.
action is not to prescribe antibiotics for the management of
14. Ohnsman C, Ritterband D, O’Brien T, Girgis D, Kabat A. Comparison
acute bacterial conjunctivitis, with the delayed prescription of azithromycin and moxifloxacin against bacterial isolates causing
strategy being a proven alternative approach. In the minor- conjunctivitis. Curr Med Res Opin. 2007;23:2241–2249.
15. Gigliotti F, Hendley J, Morgan J, Michaels R, Dickens M, Lohr J. Effi-
ity of patients who may need to be given an antibiotic, this cacy of topical antibiotic therapy in acute conjunctivitis in children.
needs to be prescribed by the physician after considering the J Pediatr. 1984;104:623–626.
16. Leibowitz H. Antibacterial effectiveness of ciprofloxacin 0.3%
patient’s preferences regarding convenience, side effects,
ophthalmic solution in the treatment of bacterial conjunctivitis. Am
safety, effectiveness, and cost. J Ophthalmol. 1991;112:295–33S.
17. Miller I, Wittreich H, Vogel R, Cook T. The safety and efficacy of topical
Acknowledgments norfloxacin compared with placebo in the treatment of acute bacterial
conjunctivitis. Eur J Ophthlamol. 1992;258–266.
We are grateful to Vicky Hammersley, Dr Allison Worth 18. Rietveld R, Tiet Gd, Bindels P, Bink D, Sloos J, Weert HV. The treatment
and James McLean for their helpful comments on an earlier of acute infectious conjunctivitis with fusidic acid: a randomized con-
trolled trial. Br J Gen Pract. 2005;559(924–930).
draft of this paper. 19. Everitt H, Little P, Smith P. A randomized controlled trial of management
strategies for acute infective conjunctivitis in general practice. BMJ.
2006;333:321.
Box 1 Key considerations for prescribing azithromycin 1% in DuraSite 20. Leibovici L, Lievre M. Medicalization: peering from the inside. BMJ.
• Licensed for use in those aged over 1 year 2002;324:866.
21. Sheikh A. Delayed prescribing of antibiotics is an effective strategy in
• Use in pregnancy only if clearly needed, as some animal data have
managing acute conjunctivitis; J Pediatr. 2007;150:114–115.
shown maternal toxicity
22. Little P, Gould C, Williamson I, Warner G, Ganrley M, Kinmonth A.
• Exercise caution in breast-feeding mothers as it is not known Reattendance and complications in a randomized trial of prescribing
whether it is excreted in breast milk strategies for sore throat: the medicalizing effect of prescribing
• Dosing twice a day for 2 days then once a day for 3 days antibiotics. BMJ. 1997;314:177–182.
• The most common adverse reaction reported in patients is eye 23. Abelson M, Heller W, Shapiero A, et al. clinical cure of bac-
irritation (in 1%–2% of patients). terial conjunctivitis with azithromycin1%: vehicle-controlled
double-masked clinical trial. Am J Ophthalmol. 2008;145:
959–965.
Disclosures 24. Abelson M, Heller W. Efficacy of azithromycin 1% eye drops vs
The authors report no conflicts of interest in this work. vehicle as first line therapy for bacterial conjunctivitis. Unpublished
study the Cochrane Register of Controlled Trials (CENTRAL). 2006;ID
CN00634804.
References 25. Abelson M, Protzko E, Shapiero A, Garces–Soldana A, Bowman L. A
1. Dart J. Eye disease at a community health centre. BMJ. 1986;293: randomized trial assessing the clinical efficacy and microbial eradica-
1477–1480. tion of 1% azithromycin ophthalmic solution vs tobramycin in adult and
2. McDonnell P. How do general practitioners manage eye disease in the pediatric subjects with bacterial conjunctivitis Clin Ophthalmol. 2007;1:
community? Br J Opthalmol. 1998;72:733–376. 177–182.
3. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial conjuncti- 26. Heller W, Abelson M, Group TAS. Safety and tolerabiltiy of azithromycin
vitis: a systematic review. Br J Gen Pract. 2001;51:473–477. 1% eye drops as anti-infective therapy for bacteria conjunctivitis.
4. Sheikh A, Hurwitz B. Antibiotics versus placebo for acute bacterial Unpublished study for the Cochrane Register of Controlled Trials
conjunctivitis. Cochrane Database Syst Rev. 2006;2:CD001211. (CENTRAL). Study ID CN 00634521.
5. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial 27. Protzko E, Bowman L, Abelson M, Shapiero A, Group TACS.
conjunctivitis: Cochrane systematic review and meta-analysis update. Phase 3 safety comparisons for 1% azithromycin in polymeric muco-
Br J Gen Pract. 2005;55:962–964. adhesive eye drops versus 0.3% tobramycin eye drops for bacterial
6. Rose P, Harnden A, Brueggemann A, Perera, Sheikh A, Crook D, et al. conjunctivitis. Invest Ophthalmol Vis Sci. 2007;48(3425–3429).
Chloramphenicol treatment for acute infective conjunctivitis in children 28. Granet D, Lichtenstan SJ, Onofney B, Katz JA. An assessment of the
in primary care: a randomized double-blind placebo-controlled trial. tolerability of moxifloxacin 0.5% compared to azithromycin 1.0% in
Lancet. 2005;366:37–43. durasite. Clin Ophthalmol. 2007;1:133–139.
7. West S. Azithromycin for control of trachoma. Community Eye Health. 29. Bowman L, Si E, Pang J, Archibad R, Friedlaender M. Development of
1999;12:55–56. a topical polymeric mucoadhesive ocular delivery system for azithro-
8. Everitt H, Little P. How do GPs diagnose and manage acute infective mycin. J Ocul Pharmacol Ther.2009;2:133–139.
conjunctivitis? A GP survey. Fam Pract. 1999;12:55–56. 30. Si PC, Bowman L, Hosseini K. Ocular pharmacokinetics of Azasite
9. Perry H, Donnenfeld D. Issues in the use of preservative-free topicals Xtra – 2% azithromycin formulated in a Durasite delivery system. Curr
Manag Care. 2003;12 Suppl:39–42. Eye Res. 2009;34:485–491.

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31. Dorfman M, Wagner R, Jamison T, Bell B, Stroman DW. The phar- 34. Jampel H, Schwartz G, Robin A. Patient preference for eye drop
macodynamic properties of azithromycin in a kinetics of kill model characteristics: a willingness to pay analysis. Arch Ophthalmol.
and implications for bacterial conjunctivitis treatment. Adv Ther. 2003;121:540–546.
2008;25:208–217. 35. FDA. Patient information leaflet NDA 50-810. Revised 5/2007. Avail-
32. Lichtenstein S, Granet D. Fluoroquinolones compared to 1% able from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.
azithromycin in durasite for bacterial conjunctivitis Clin Ophthalmol. cfm?fuseaction=Search. [Label Approval History] Accessed December
2007;1:519–525. 7, 2009.
33. Winfield A, Jessiman D, Silliams A. A study of the causes of non-
compliance by patients prescribed eyedrops. Br J Opthalmol. 1990;74:
477–480.
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Clinical Ophthalmology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/doph20
Besifloxacin: a novel anti-infective for the

treatment of bacterial conjunctivitis
Timothy L Comstock, Paul M Karpecki, Timothy W Morris & Jin-Zhong Zhang
To cite this article: Timothy L Comstock, Paul M Karpecki, Timothy W Morris & Jin-Zhong Zhang
(2010) Besifloxacin: a novel anti-infective for the treatment of bacterial conjunctivitis, Clinical
Ophthalmology, , 215-225, DOI: 10.2147/opth.s9604
To link to this article: https://doi.org/10.2147/opth.s9604
© 2010 Comstock et al, publisher and

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Open Access Full Text Article review
Besifloxacin: a novel anti-infective for the

treatment of bacterial conjunctivitis
This article was published in the following Dove Press journal:

Clinical Ophthalmology
26 March 2010
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Timothy L Comstock 1 Abstract: Bacterial conjunctivitis, commonly known as pink eye, is demographically unbiased
Paul M Karpecki 2 in its prevalence and can be caused by a variety of aerobic and anaerobic bacteria. Timely
Timothy W Morris 3 empiric treatment with a broad-spectrum anti-infective, such as a topical fluoroquinolone, is
Jin-Zhong Zhang 4 critical in preventing potentially irreversible ocular damage. However, the rise in ocular methi-
cillin-resistant Staphylococcus aureus isolates and the patterns of fluoroquinolone resistance
1
Global Medical Affairs,
Pharmaceuticals, Bausch and Lomb, for patients with other ocular bacterial infections mandate the need for new agents targeted for
Inc., Rochester, NY, USA; 2Koffler ocular use. Besifloxacin, a novel broad-spectrum fluoroquinolone, is approved for the treat-
Vision Group, Lexington, KY, ment of bacterial conjunctivitis. It has a uniquely balanced dual-targeting activity that inhibits
USA; 3Research and Development
Microbiology and Sterilization both DNA gyrase and topoisomerase IV and is associated with a lower incidence of resistance
Sciences, Bausch and Lomb, Inc., development. Besifloxacin is not marketed in other formulations, ensuring that its exposure is
Rochester, NY, USA; 4Global limited to bacterial populations in and around the eye. This specifically precludes any bacte-
Preclinical Development, Bausch and
Lomb, Inc., Rochester, NY, USA rial exposure to besifloxacin resulting from systemic use, which further reduces the likelihood
of emergence of bacterial resistance. In vitro, besifloxacin has demonstrated equivalent or
superior activity compared with other commonly used topical antibiotics. In clinical trials,
besifloxacin has consistently demonstrated efficacy and safety in the treatment of patients with
bacterial conjunctivitis. Besifloxacin is considered safe and is well tolerated with no observed
contraindications.
Keywords: conjunctivitis, fluoroquinolones, besifloxacin, besivance, bacterial conjunctivitis
Introduction
Conjunctivitis, commonly known as red eye or pink eye, is frequently the result of a
bacterial infection but can also be caused by viruses or fungi or result from noninfectious
origins, such as allergens, toxins, or the extended use of contact lenses.1–3 Bacterial con-
junctivitis is a contagious infection of the conjunctiva, the mucous membrane that lines
the inner surface of the eyelids and extends over the sclera.1,4 Empiric broad-spectrum
topical antibacterials are the usual course of therapy for bacterial conjunctivitis. Timely
treatment of ocular infections is important, but, clinically, early recognition and treat-
ment of bacterial conjunctivitis is especially significant because of its ability to progress
rapidly and potentially cause irreversible ocular damage, including, in rare cases, loss of
vision.2,5 For example, development of bacterial conjunctivitis after glaucoma-filtering
Correspondence: Timothy L Comstock surgery has been reported to increase the patient’s risk of developing endophthalmitis.1
Global Medical Affairs, Pharmaceuticals,
Bausch and Lomb, Inc., 1400 N. Goodman Broad-spectrum empiric antibiotic therapy for bacterial conjunctivitis has been associ-
St., Rochester, NY 14609 USA ated with substantially improved rates of clinical and microbiological remission.6
Tel +1 (585) 338-6631
Fax +1 (585) 338-0273
Although empiric antibiotic therapy is administered to prevent spread, speed
Email tcomstock@bausch.com recovery, alleviate patient discomfort, and avoid potentially serious complications
submit your manuscript | www.dovepress.com Clinical Ophthalmology 2010:4 215–225 215

Dovepress © 2010 Comstock et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
Comstock et al Dovepress
such as keratitis, this treatment approach is not without its it is initiated before causative pathogens are identified.3
own potential concerns. As the use of a particular antibiotic In these cases, treatment is based on the patient’s age,
increases, the pathogens targeted by that agent tend to evolve environment, and any related ocular observations. Broad-
and develop resistance, decreasing the treatment’s effective- spectrum topical antibiotics, usually eyedrops, effectively
ness over time.7 The growing concern regarding antibiotic treat common cases of acute bacterial conjunctivitis and may
resistance related to the overuse of empiric antibiotic therapy be given as preventative treatment of a secondary infection in
has led to the search for newer therapies designed to address cases of viral conjunctivitis. The antibacterial agent should
the development of resistance through innovative or more- have activity against H. influenzae, S. pneumoniae, S. aureus,
focused targeting approaches that restrict nonocular exposure and S. epidermidis.9 Although acute bacterial conjunctivitis
to the antibiotic by limiting systemic availability. This paper may be self-limiting, effective treatment, such as antibacte-
will review besifloxacin, a potent new fluoroquinolone anti- rial drops, can hasten clinical and microbiological recovery,
bacterial that has proven efficacy against the most common prevent spread and transmission of the infection, reduce the
pathogens of bacterial conjunctivitis, has a uniquely balanced chance of recurrence, and prevent the rare but potentially
dual-targeting mechanism of action associated with decreased serious complications associated with bacterial conjuncti-
spontaneous resistance development, and was developed vitis. Additional preventative measures for acute bacterial
exclusively for topical ocular use. conjunctivitis center around good hygienic practices, includ-
ing frequent hand washing, avoiding direct contact with the
Bacterial conjunctivitis eyes, appropriate handling and cleaning of contact lenses, and
Bacterial conjunctivitis results from infections caused by a regular replacement of eye cosmetics. It is also recommended
variety of aerobic and anaerobic bacteria. Aerobic bacteria that pillowcases be changed frequently and towels and hand-
tend to predominate and most commonly include Haemophilus kerchiefs not be shared.1,3
influenzae, Streptococcus pneumoniae, other streptococci,
Staphylococcus aureus, Staphylococcus epidermidis, and Fluoroquinolones
Moraxella species. Other, less common bacteria include Neis- Fluoroquinolones, a class of broad-spectrum synthetic anti-
seria gonorrhoeae, Neisseria meningitides, Pseudomonas infective agents, were introduced in the late 1980s and are
species, Proteus species, and Corynebacterium species.2 the most commonly used anti-infectives for the treatment
Acute bacterial conjunctivitis is demographically unbiased of acute bacterial conjunctivitis.9 In the United States,
in its prevalence. It affects individuals of both genders, all 6 fluoroquinolones are now marketed for ophthalmic use
ages, and all races. Acute or mucopurulent bacterial conjunc- in the treatment of acute bacterial conjunctivitis. They
tivitis is characterized by mucopurulent or purulent discharge, include ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin,
irritation, and diffuse conjunctival hyperemia. Preauricular moxifloxacin, and besifloxacin. Besifloxacin is the newest
lymphadenopathy is usually not present in acute bacterial fluoroquinolone approved for topical ophthalmic treatment;
conjunctivitis. The acute form of the infection is caused by a however, it has unique chemical, structural, and biological
variety of microbial pathogens; however, infections caused by features that differentiate it from others in its class.4
Haemophilus species, S. pneumoniae, S. aureus, or S. epider- Fluoroquinolones act, with varying selectivities, through
midis tend to be more common.1 Bacterial conjunctivitis tends inhibition of the essential bacterial enzymes DNA gyrase
to be transmitted by eye-hand contact and therefore initially and topoisomerase IV.11 In other words, they inhibit bac-
presents as a unilateral infection. However, over the course of terial type II topoisomerases, leading to nonrepairable
a few days, the second eye may become infected.8 Because of double-stranded DNA breaks and death of bacterial cells.
its high incidence rate and broad, nonselective demographics, DNA gyrase, a topoisomerase found in all types of bacte-
the treatment of acute bacterial conjunctivitis has been a focus ria, is the primary target for gatifloxacin and moxifloxacin
in the development of pharmaceutical therapy. in most Gram-negative bacteria such as Escherichia coli,
and, to a much lesser extent, in the Gram-positive species
Traditional treatment options S. pneumoniae. On the other hand, topoisomerase IV is
Ideally, acute bacterial conjunctivitis should be treated usually the primary target for most fluoroquinolones in the
with an antimicrobial agent that targets the causative pathogen, majority of Gram-positive pathogens, particularly against
especially in the hospital setting. However, in clinical practice, prevalent conjunctivitis pathogens such as S. aureus and S.
outpatient treatment of conjunctivitis is often empiric because epidermidis.7,12
216 submit your manuscript | www.dovepress.com Clinical Ophthalmology 2010:4

Dovepress
Dovepress Besifloxacin for the treatment of bacterial conjunctivitis
Topical fluoroquinolones approved for ocular use are all S. aureus, S. pneumoniae, and H. influenzae.7 Ocular isolates
considered safe. However, the question of efficacy is ever of S. pneumoniae demonstrated susceptibility to all the fluo-
changing based on the patterns of developing resistance. roquinolones tested, with the exception of 10.2% showing
Newer anti-infective agents with enhanced activity and novel intermediate resistance to ciprofloxacin, one of the oldest fluo-
targeting mechanisms may be less prone to resistance and roquinolones. However, 22.4% of the isolates were resistant
may help address this situation. to trimethoprim, and 65.3% to tobramycin. Susceptibility of
methicillin-susceptible S. aureus (MSSA) isolates was high
Dealing with resistance among all the fluoroquinolones tested – ciprofloxacin (79.9%),
Rates of antibiotic resistance continue to rise in both nosoco- levofloxacin (81.1%), gatifloxacin (81.1%), and moxifloxacin
mial and community settings.7 Susceptibility of S. pneumoniae (81.1%) – and the aminoglycoside tobramycin (92.7%). How-
and S. aureus, two of the most common pathogens found in ever, susceptibility of MSSA to azithromycin was low (54.3%).
acute bacterial conjunctivitis, to many commonly employed Susceptibility of MRSA was low among all the antibacterial
antibacterial medications have demonstrated dramatic agents tested (15.2% for ciprofloxacin, levofloxacin, gatifloxa-
declines over the past decade. A recent study on S. aureus cin, and moxifloxacin; 6.1% for azithromycin; and 36.4% for
that summarized data submitted by more than 200 clinical tobramycin) except trimethoprim (93.9%). As a result, it has
laboratories across the United States showed that the propor- been suggested that the use of older, or earlier-generation,
tion of methicillin-resistance S. aureus (MRSA) isolates from topical fluoroquinolones as first-line empiric therapy in ocular
ocular infections increased by 12.1%, from 29.5% to 41.6% infections is supported, given that the causative pathogen has
between 2000 and 2005.13 A significant percentage (∼80%) generally not been MRSA,7 although the above data indicate
of ocular MRSA isolates demonstrated in vitro resistance to that this may be changing. Because treatment of bacterial
ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, and conjunctivitis is usually empiric, the question then remains,
the aminoglycoside tobramycin.7 Patterns of fluoroquinolone which broad-spectrum topical antibacterial agent would be the
resistance for patients with bacterial keratitis have also shown most sensible choice for empiric outpatient therapy?
significant increases in resistance of S. aureus to ciprofloxacin
(from 5.8% to 35.0%; P  0.001) and ofloxacin (from 4.7% Enhanced technologies and
to 35.0%; P  0.001) between 1993 and 1997.14 improved therapeutics – besifloxacin
The Ocular Tracking Resistance in the United States The continuous hurdle of emerging resistance, including
Today (Ocular TRUST) study evaluated susceptibility resistance toward older fluoroquinolones, has resulted
patterns to ciprofloxacin, gatifloxacin, levofloxacin, moxi- in a recent focus on newer fluoroquinolones that exhibit
floxacin, azithromycin, tobramycin, and trimethoprim in enhanced activity against Gram-positive bacteria, namely
prospectively collected and archived ocular isolates of S. pneumoniae and staphylococci.12 This has led most recently
to the development of a new fluoroquinolone that may help
address the problem with a dual-targeted mechanism of
O
action that is relatively well balanced and has shown reduced
development of spontaneous resistance in vitro. Besifloxacin
F COOH
[(+)-7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolone-
3-carboxylic acid hydrochloride] is a synthetic fluoroqui-
N N • HCl nolone (Figure 1) indicated for topical use in patients aged
1 year or older for the treatment of bacterial conjunctivitis
Cl caused by susceptible isolates of CDC coryneform group G,
Corynebacterium pseudodiphtheriticum*, Corynebacterium
striatum*, H. influenzae, Moraxella lacunata*, S. aureus,
NH2
S. epidermidis, Staphylococcus hominis*, Staphylococcus
C19H21ClFN3O3 HCl • lugdunensis*, Streptococcus mitis group, Streptococcus
Molecular Weight 430.30

Figure 1 Structure of besifloxacin hydrochloride. *Efficacy for these organisms was studied in fewer than 10 infections.
Clinical Ophthalmology 2010:4 submit your manuscript | www.dovepress.com

217
Dovepress
oralis, S. pneumoniae, or Streptococcus salivarius.*15 Unlike Mechanism of action

other fluoroquinolones, besifloxacin is not marketed in other Whereas older fluoroquinolones have a preference for
formulations for systemic use.4 This ensures that exposure either DNA gyrase or topoisomerase IV, besifloxacin has
of besifloxacin is limited to the bacterial populations in a more balanced targeting of both type II topoisomerases
and around the eye. The exclusive topical ophthalmic use (Figure 2).12 The structure of besifloxacin contains the
of besifloxacin precludes any bacterial exposure resulting N-cyclopropyl group, which is associated with broad-spectrum
from systemic use, which reduces the likelihood of resis- activity of other fluoroquinolones, such as gatifloxacin and
tance development. Besifloxacin ophthalmic suspension moxifloxacin. In laboratory studies investigating the target
0.6% is formulated in a mucoadhesive polymer (DuraSite®; selectivity for besifloxacin against S. pneumoniae, S. aureus,
InSite Vision, Inc., Alameda, CA), designed to prolong the and E. coli, the last as a reference pathogen, DNA gyrase
drug’s residence time on the ocular surface.16 The suspension and topoisomerase IV were both shown to be targeted by
includes 0.01% benzalkonium chloride as a preservative. besifloxacin at nearly equal concentrations. Specifically,
Benzalkonium chloride has been shown in vitro to have some besifloxacin had similar activity against S. pneumoniae
bacteriostatic and bactericidal activities.17,18 gyrase and topoisomerase IV. Besifloxacin was equally
potent against S. pneumoniae and E. coli gyrases, which
Pharmacokinetics/pharmacodynamics was not the case for ciprofloxacin or moxifloxacin. Based
In animal studies, besifloxacin demonstrated good ocular on the inhibitory activity of the antibacterial agents tested,
penetration, with rapid absorption. A half-life of 5 to 14 hours besifloxacin was 5-fold more potent than was ciprofloxa-
was seen following a single topical dose, with an average cin and 2-fold more potent than was moxifloxacin against
Cmax of 6.43 µg/g in conjunctiva, 2.10 µg/g in cornea, and S. pneumoniae topoisomerase IV. The MICs determined for
0.796 µg/g in aqueous humor of monkeys.19 In rabbits, S. aureus mutants with defined topoisomerase mutations
besifloxacin demonstrated a mean residence time of more were also consistently lower for besifloxacin than for either
than 7 hours for tears, conjunctiva, and aqueous humor.20 ciprofloxacin or moxifloxacin. In contrast to the older fluo-
Conjunctival concentrations were in excess of the minimum roquinolone comparators, there were no resistant mutants
inhibitory concentration required to inhibit the growth of 90% recovered for either S. aureus or S. pneumoniae at 4-fold
of organisms (MIC90) for at least 12 hours after a single dose MIC90s for besifloxacin.12
for most Gram-negative and Gram-positive organisms and for The molecular structure of besifloxacin also contains
nonresistant ophthalmic isolates. Plasma exposure following a an 8-chloro and a 7-azepinyl substituent, which apparently
single dose was long lived at very low concentrations (10 ng/ further enhance potency against both type II topoisomerases
mL), demonstrating minimum systemic exposure.20 found in bacteria.12,20,21 This dual targeting theoretically
Plasma protein binding of besifloxacin was low makes besifloxacin less prone to spontaneous resistance
and unvaried across a wide concentration range (10– development. This is because the simultaneous occurrence
10,000 ng/mL) in rat and human plasma.20 In humans, the of fluoroquinolone-resistant mutations in both DNA gyrase
peak concentration (Cmax) of besifloxacin in tears following a and topoisomerase IV is a highly improbable event, although
single topical ocular dose was 610 µg/g (±540 µg/g), decreas- single-step mutations in genes encoding either of the 2 type II
ing to 1.6 µg/g at 24 hours.19 The Cmax/MIC90 ratios for besi- topoisomerases have been frequently reported.22 Addition
floxacin in human tears following once-daily, twice-daily, and of the 8-chloro and 7-azepinyl substituents present in the
3-times-daily dosing regimens were 1220 or greater, and the molecular structure of besifloxacin has also been associated
area under the concentration versus time curve from time 0 to with enhanced potency and more balanced targeting of both
24 hours (AUC0–24)/MIC90 ratios were 2500 or greater against essential type II bacterial topoisomerases, particularly in
S. pneumoniae (0.125 µg/mL MIC90), S aureus (0.25 µg/mL Gram-positive bacteria.10 This results in the potent activity of
MIC90), S. epidermidis (0.5 µg/mL MIC90), and H. influenzae besifloxacin against Gram-positive bacteria (Table 1),21,23–25
(0.06 µg/mL MIC90). In patients with clinically diagnosed Gram-negative bacteria (Table 2),21,25 and anaerobic bacteria
bacterial conjunctivitis, the Cmax of besifloxacin in plasma (Table 3).21
was less than 0.5 ng/mL on average, following 5 days of
repeated 3-times-daily ocular administration. Besifloxacin Spectrum of activity
was eliminated from human tears with an estimated half-life Besifloxacin has demonstrated potent broad-spectrum in
of 3.4 hours.19 vitro activity against aerobic and anaerobic, Gram-positive

Dovepress
DNA gyrase
Relaxed DNA Besifloxacin Supercoiled DNA
Topoisomerase IV
Catenated DNA Decatenated DNA
Figure 2 Dual-targeted mechanism of action for besifloxacin.

Besifloxacin binds to and inhibits 2 enzymes that are essential for maintaining bacterial DNA in the proper conformation required for DNA transcription into RNA, DNA
replication, and bacterial cell division.
Table 1 Activities of besifloxacin and other antibiotics against Gram-positive bacteria21

Species (no. of test isolates) and test drug MICa (µg/mL)
Range 50% 90%
Staphylococcus aureus (n = 19; CIP-S ; 21.1% MRSA )
b c
Besifloxacin 0.015–0.25 0.015 0.12

Moxifloxacin 0.015–0.06 0.03 0.06
Gatifloxacin 0.03–1 0.06 0.25
Ciprofloxacin 0.12–0.5 0.25 0.5
Levofloxacin 0.06–2 0.12 0.25
Azithromycin 0.5 to 8 1 8
Tobramycin 0.12–8 0.5 1
Oxacillin 0.12 to 8 0.25 8
S. aureus (n = 11; CIP-NSd; 63.6% MRSA)
Besifloxacin 0.03–4 0.5 4
Moxifloxacin 0.06 to 8 4 8
Gatifloxacin 0.12 to 8 4 8
Ciprofloxacin 2 to 8 8 8
Levofloxacin 0.25 to 8 8 8
Azithromycin 0.5 to 8 8 8
Tobramycin 0.25 to 32 1 32
Oxacillin 0.12 to 8 8 8
Staphylococcus epidermidis (n = 9; CIP-S; 44.4% MRSEe)
Besifloxacin 0.015–0.03 0.03 NAf
Moxifloxacin 0.03–0.06 0.06 NA
Gatifloxacin 0.06–0.06 0.06 NA
Ciprofloxacin 0.12–0.12 0.12 NA
Levofloxacin 0.12–0.12 0.12 NA
Azithromycin 0.25 to 8 8 NA
Tobramycin 0.008–8 0.03 NA
Oxacillin 0.06–2 0.12 NA
S. epidermidis (n = 6; CIP-NS; 83.3% MRSE)
Besifloxacin 0.25–4 0.25 NA
Moxifloxacin 1 to 8 2 NA
(Continued)

219
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Table 1 (Continued)
Range 50% 90%
Gatifloxacin 1 to 8 1 NA
Ciprofloxacin 2 to 8 8 NA
Levofloxacin 2 to 8 8 NA
Azithromycin 0.12 to 8 8 NA
Tobramycin 0.06–16 2 NA
Oxacillin 0.12–4 1 NA
Staphylococcus haemolyticus (n = 101)
Moxifloxacin 0.015 to 8 1 8
Gatifloxacin 0.03 to 8 2 8
Ciprofloxacin 0.06 to 8 8 8
Levofloxacin 0.06 to 8 4 8
Azithromycin 0.25 to 8 8 8
Tobramycin 0.015 to 32 2 32
Oxacillin 0.06 to 8 8 8
Streptococcus agalactiae (n = 100)
Besifloxacin 0.03–0.12 0.06 0.06
Moxifloxacin 0.06–1 0.12 0.25
Gatifloxacin 0.12–1 0.25 0.25
Ciprofloxacin 0.5–8 0.5 1
Levofloxacin 0.25–4 0.5 1
Azithromycin 0.015 to 8 0.06 8
Tobramycin 8 to 128 32 64
Penicillin 0.015–0.06 0.03 0.06
Streptococcus pneumoniae (n = 16; LVX-Sg)
Besifloxacin 0.015–0.25 0.03 0.06
Ciprofloxacin 0.12–8 0.5 2
Azithromycin 0.03 to 64 0.06 64
Tobramycin 4–32 8 16
Penicillin 0.06–2 0.06 0.5
S. pneumoniae (n = 85; LVX-NSh)
Besifloxacin 0.008–1 0.5 0.5
Moxifloxacin 0.25–8 2 4
Ciprofloxacin 1–64 32 64
Levofloxacin 4–32 16 16
Azithromycin 0.03 to 64 4 64
Penicillin 0.06–2 0.12 2
Streptococcus pyogenes (n = 101)
Besifloxacin 0.03–0.06 0.03 0.06
Moxifloxacin 0.06–0.5 0.12 0.25
Gatifloxacin 0.06–0.5 0.12 0.25
Ciprofloxacin 0.12–2 0.5 0.5
Azithromycin 0.03 to 8 0.06 8
Penicillin 0.015–0.06 0.015 0.015
a
Minimum inhibitory concentration; Ciprofloxacin susceptible; Methicillin-resistant Staphylococcus aureus; Ciprofloxacin nonsusceptible; Methicillin-resistant Staphylococcus
b c d e
epidermidis; fNot available; gLevofloxacin susceptible; hLevofloxacin nonsusceptible.

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Table 2 Activities of besifloxacin and other antibiotics against Gram-negative bacteria21

Range 50% 90%
Haemophilus influenzae (n = 15; CIP-Sb)
Besifloxacin 0.008–0.25 0.015 0.03
Moxifloxacin 0.015–0.05 0.015 0.06
Ciprofloxacin 0.008–1 0.008 0.015
Levofloxacin 0.008–1 0.015 0.015
Azithromycin 0.12–2 2 2
Penicillin 0.25 to 4 0.5 4
H. influenzae (n = 11; CIP-NSc)
Besifloxacin 0.015–2 2 2
Moxifloxacin 1–16 8 16
Ciprofloxacin 2–64 16 64
Levofloxacin 1–32 8 16
Azithromycin 0.5–8 1 8
Penicillin 0.5 to 4 1 2
Moraxella catarrhalis (n = 101)
Besifloxacin 0.015–0.12 0.03 0.03
Moxifloxacin 0.015–0.12 0.03 0.03
Gatifloxacin 0.008–0.25 0.015 0.015
Ciprofloxacin 0.008–0.25 0.015 0.015
Levofloxacin 0.015–0.5 0.015 0.03
Azithromycin 0.015–0.06 0.03 0.03
Tobramycin 0.03–0.5 0.25 0.25
Penicillin 0.25 to 8 4 8
Neisseria meningitides (n = 20)
Besifloxacin 0.004–0.03 0.008 0.015
Moxifloxacin 0.004–0.015 0.008 0.008
Ciprofloxacin 0.002–0.015 0.004 0.004
Levofloxacin 0.004–0.03 0.008 0.015
Azithromycin 0.03–0.12 0.06 0.06
Penicillin 0.06–0.25 0.06 0.12
Proteus mirabilis (n = 50)
Moxifloxacin 0.06–128 0.25 16
Ciprofloxacin 0.015 to 128 0.03 32
Imipenem 0.06–4 1 2
Tobramycin 0.25–32 1 4
Ceftazidime 0.03–16 0.03 0.06
Proteus vulgaris (n = 50)
Besifloxacin 0.06–1 0.12 0.25
Ciprofloxacin 0.008–0.12 0.015 0.03
Levofloxacin 0.015–0.25 0.03 0.06
Imipenem 0.25–4 1 4
Tobramycin 0.25–64 1 2
Ceftazidime 0.03–2 0.06 0.12
Pseudomonas aeruginosa (n = 105; CIP-S)
Besifloxacin 0.5–8 1 4
Moxifloxacin 0.5–16 2 4
Ciprofloxacin 0.03–1 0.12 0.5
(Continued)

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Table 2 (Continued )
Range 50% 90%
Imipenem 0.5 to 8 2 2
Tobramycin 0.25 to 64 0.5 1
Ceftazidime 0.5 to 16 2 8
P. aeruginosa (n = 96; CIP-NS)
Besifloxacin 2–128 16 64
Moxifloxacin 2 to 128 64 128
Ciprofloxacin 2 to 128 16 64
Levofloxacin 2 to 128 16 64
Imipenem 0.25 to 8 8 8
Tobramycin 0.25 to 64 1 64
Ceftazidime 0.25 to 16 4 16
Minimum inhibitory concentration; bCiprofloxacin susceptible; cCiprofloxacin nonsusceptible.
a
Table 3 Activities of besifloxacin and other antibiotics against and Gram-negative bacteria, including H. influenzae,
anaerobic bacteria21 S. pneumoniae, S. aureus, and S. epidermidis, relative
Species (no of test isolates) MICa (µg/mL) to that of other fluoroquinolones.12,21 Besifloxacin, along
and test drug
with nadifloxacin, ofloxacin, and sparfloxacin, was tested
Range 50% 90%
in vitro against isolates of Gram-negative, Gram-positive,
Clostridium perfringens (n = 21)
and anaerobic bacteria.21 No substantial differences in
Besifloxacin 0.12–0.25 0.25 0.25
MIC values were observed across the 4 fluoroquinolones
Moxifloxacin 0.25–0.5 0.5 0.5
for the Gram-negative organisms. For Gram-positive
Gatifloxacin 0.5–1 1 1
bacteria, which included a variety of Staphylococcus
Clindamycin 0.06–4 2 4
species (including MRSA) and Streptococcus species,
Metronidazole 1–4 2 4
besifloxacin demonstrated notably more potent inhibi-
Fusobacterium species (n = 21)
tion than did ofloxacin. Besifloxacin also demonstrated
4.5-fold more potent inhibition than nadifloxacin and
Moxifloxacin 0.25 to 16 1 2
4.4-fold more potent inhibition than sparfloxacin against
Gatifloxacin 0.5 to 16 1 4
Gram-positive bacteria and similar activity to the 2 agents
Clindamycin 0.06–8 0.06 2
against MRSA. Finally, besifloxacin was significantly more
Metronidazole 0.12–2 0.25 1
potent against anaerobic bacteria than was either ofloxacin
Peptostreptococcus species (n = 52) or nadifloxacin.20
Besifloxacin 0.06–2 0.25 0.5 In a recent laboratory analysis evaluating the broad-
Moxifloxacin 0.25–4 0.25 0.5 spectrum activity of besifloxacin, 2690 clinical isolates,
Ciprofloxacin 0.5 to 8 2 4
including 34 aerobic and 6 anaerobic bacterial species, were
Clindamycin 0.06 to 8 0.25 8 tested for susceptibility to besifloxacin and a wide range of
Metronidazole 0.03 to 16 0.5 1 other commonly used antibacterial agents, including other
Propionibacterium acnes (n = 21) fluoroquinolones.21 The in vitro activity of besifloxacin
Besifloxacin 0.12–0.25 0.25 0.25 against isolates of Gram-negative, Gram-positive, and
Moxifloxacin 0.25–0.25 0.25 0.25 anaerobic bacteria was generally equivalent or superior to
Gatifloxacin 0.25–0.5 0.25 0.5 that of topical antibacterial agents commonly used to treat
Clindamycin 0.03–2 0.06 0.12 ocular infections. Agents tested included ciprofloxacin,
Metronidazole 16 to 16 16 16 moxifloxacin, levofloxacin, gatifloxacin, azithromycin, and
Minimum inhibitory concentration.
a tobramycin, among others. In particular, besifloxacin was

Dovepress
markedly more potent against non–ciprofloxacin-susceptible was noninferior to moxifloxacin for clinical resolution
S. aureus than were all other ophthalmic fluoroquinolones on day 5 (58.3% vs 59.4%, respectively; 95% confidence
(MIC90 4 µg/mL vs 8 µg/mL, respectively). Besifloxacin interval [CI], -9.48 to 7.29) and on day 8 (84.5% vs 84.0%,
was also far more potent than were other fluoroquinolones respectively; 95% CI, -5.67 to 6.75).25 Besifloxacin was
against staphylococcal isolates that were both methicillin- also noninferior to moxifloxacin for microbial eradication
and fluoroquinolone-resistant. In short, the activity of besi- on day 5 (93.3% vs 91.1%, respectively; 95% CI, -2.44
floxacin against staphylococci was substantially improved to 6.74) and on day 8 (87.3% vs 84.7%, respectively; 95%
compared with the activities observed for azithromycin, CI, -3.32 to 8.53).
tobramycin, and all other fluoroquinolone comparators. Besi-
floxacin activity was generally comparable to that of other Safety and tolerability
fluoroquinolones against ciprofloxacin-susceptible isolates Besifloxacin is considered safe and is well tolerated with
of Gram-negative aerobes. Finally, besifloxacin and moxi- no observed contraindications. In clinical trials, the most
floxacin were the most active of the agents tested against common adverse event reported was conjunctival redness,
anaerobic bacteria. Overall, besifloxacin demonstrated occurring in approximately 2% of patients. 15 Tables 426
potent activity against Gram-positive bacteria that were and 527 highlight the most common treatment-emergent
resistant to other fluoroquinolones. See Tables 1 through 3 ocular adverse events observed across the above-mentioned
for detailed results.21 3 clinical studies for study eyes and for all treated eyes
(patients with bilateral conjunctivitis had both the study eye
Clinical efficacy and fellow eye treated), respectively.
In clinical trials, besifloxacin has demonstrated efficacy Data drawn from phase 1 studies demonstrated that topi-
and safety in the treatment of patients with bacterial cal ocular administration of besifloxacin resulted in negligible
conjunctivitis. In a phase 3 randomized, multicenter, systemic exposure, with no changes in corneal endothelial
double-masked, vehicle-controlled trial of 390 patients cell density.27 In a vehicle-controlled trial of 957 adult patients
with culture-confirmed bacterial conjunctivitis, besifloxacin with bacterial conjunctivitis, a greater percentage of eyes
demonstrated significant efficacy in clinical resolution and treated with vehicle experienced adverse effects than did
microbial eradication compared with vehicle.23 At day 5, those treated with besifloxacin (13.9% vs 9.2%, respectively;
clinical resolution was 45.2% for besifloxacin, compared P = 0.0047).23 In another randomized, vehicle-controlled
with 33.0% for vehicle (P = 0.0084). Microbial eradica- trial of 118 patients, there was no significant difference of
tion was 91.5% vs 59.7%, respectively (P  0.0001). On cumulative adverse events between placebo and besifloxacin
day 8, clinical resolution was 84.4% vs 69.1%, respectively groups.24 Finally, in a randomized trial of 1161 patients
(P = 0.0011), and microbial eradication was 88.4% vs 71.7%, treated with either besifloxacin or moxifloxacin, both drugs
respectively (P  0.0001). were well tolerated.25 Patients treated with moxifloxacin
In another multicenter, prospective, randomized, vehicle-
controlled trial (N = 118 culture-confirmed cases of acute Table 4 Pooled analysis: treatment-emergent ocular adverse events
bacterial conjunctivitis), patients receiving besifloxacin (AEs) in 1.0% of all treated study eyes in any treatment group26
(n = 60) had a significantly higher rate of clinical resolution Patients, n (%)
Besifloxacin Vehicle Moxifloxacin P valuea
of baseline symptoms at day 8 than did patients receiving
(n = 1192) (n = 616) (n = 579)
vehicle (n = 58) (73.3% vs 43.1%, respectively; P  0.001).24
Total no. of AEs 191 146 81
Besifloxacin also had a significantly higher rate of bacterial
Patients with 139 (11.7) 101 54 (9.3) 0.0055
eradication than did vehicle at this visit (88.3% vs 60.3%, 1 AE (16.4)
respectively; P  0.001). This trial demonstrated that besi- Vision blurred 25 (2.1) 24 (3.9) 3 (0.5) 0.0318
floxacin (ophthalmic suspension 0.6%) 3 times daily for Eye irritation 17 (1.4) 18 (2.9) 8 (1.4) 0.0457
5 days is effective in attaining clinical resolution of symptoms Eye pain 22 (1.8) 11 (1.8) 7 (1.2) 0.9999
associated with bacterial conjunctivitis and in eradicating the Conjunctivitis 14 (1.2) 15 (2.4) 5 (0.9) 0.0492
bacteria that cause the disease. Eye pruritus 13 (1.1) 10 (1.6) 2 (0.3) 0.3777
Finally, in a multicenter, randomized, double-masked, Conjunctivitis, 7 (0.6) 9 (1.5) 2 (0.3) 0.0678
active-controlled noninferiority study of 1161 patients (533 bacterial
with culture-confirmed bacterial conjunctivitis), besifloxacin P values were based on Fisher’s exact test comparing besifloxacin with vehicle.
a

223
Dovepress
Table 5 Pooled analysis: treatment-emergent ocular adverse events complexity of dosing.30 The convenience of besifloxacin is
(AEs) in 1% of all treated eyesa in any treatment group (safety further enhanced by the recommended intervals between
population)27
doses, which can range from 4 to 12 hours, adding a degree
Besifloxacin Vehicle Vigamox P valueb
(n = 1810) (n = 961) (n = 855)
of flexibility.15
n (%) n (%) n (%) Besifloxacin is supplied as an ophthalmic suspension with
Total no of 327 258 153 benzalkonium chloride as a preservative, and the closed bottle
ocular AEs should be inverted and shaken once prior to use.
Eyes with 249 (13.8) 190 (19.8) 120 (14.0) 0.0001
1 AE
Conjunctivitis 47 (2.6) 41 (4.3) 33 (3.9) 0.0223
Conclusions
Vision blurred 38 (2.1) 39 (4.1) 4 (0.5) 0.0035
Besifloxacin is a novel synthetic, broad-spectrum fluoroqui-
Conjunctivitis, 32 (1.8) 27 (2.8) 22 (2.6) 0.0736 nolone recently approved for the treatment of bacterial con-
bacterial junctivitis. Clinical trials have demonstrated superior efficacy
Eye irritation 26 (1.4) 27 (2.8) 12 (1.4) 0.0187 of besifloxacin to that of vehicle and clinical equivalence
Eye pain 28 (1.5) 17 (1.8) 9 (1.1) 0.6396 (noninferiority) to that of moxifloxacin. In vitro, besifloxacin
Eye pruritus 18 (1.0) 18 (1.9) 3 (0.4) 0.0761 has demonstrated potent activity often superior to that of other
Treated eyes, including study and fellow eyes; P values for besifloxacin compared
a b commonly used topical anti-infectives. Besifloxacin has a
with vehicle (Fisher’s exact test). uniquely balanced dual-targeting activity that inhibits both
DNA gyrase and topoisomerase IV and potentially hinders
did have a significantly higher incidence of eye irritation the rise of resistance. Unlike other fluoroquinolones, besi-
(1.4% vs 0.3% for besifloxacin; P = 0.0201); however, all floxacin has highly selective usage. It is formulated only for
other adverse events occurred with similar frequency between ocular use and is neither marketed nor in development in for-
both agents. mulations for systemic administration. The reduced exposure
A subanalysis of adverse events among patients less of besifloxacin to bacterial populations will presumably limit
than 6 years of age from the above studies demonstrated the the likelihood of the emergence of bacterial resistance result-
safety and efficacy of besifloxacin ophthalmic suspension ing from any nonocular exposure to the drug, although cross-
0.6% in this population.28 The most common adverse events resistance from other fluoroquinolones has been observed.
reported in patients less than 6 years of age were conjunc- Taking into account the changing susceptibility profiles of
tivitis (2.1%, 7/331), bacterial conjunctivitis (1.8%, 6/331), the major causative pathogens, the first-line use of a potent
conjunctival hemorrhage (1.2%, 4/331), viral conjunctivitis new ophthalmic fluoroquinolone with a lower potential for
(1.2%, 4/331), and eye pain (1.2%, 4/331). As an adverse resistance development may result in an improved resistance
event, conjunctivitis was reported less frequently in patients development profile relative to that of the other ophthalmic
receiving besifloxacin than in patients receiving vehicle. fluoroquinolones, all of which have also been used for more
Finally, in a rabbit wound-healing model using dexa- than 10 years in a broad variety of nonophthalmic health
methasone as a positive control, planimetry measurements care – and community-associated infection settings.
showed that besifloxacin did not impede corneal reepitheli-
alization compared with saline at 72 hours.29 Disclosures
TLC, TWM, JZ disclose being employees of Bausch and
Dosing Lomb, Inc.
The recommended dosage of besifloxacin is 1 drop of the PMK discloses that he is a paid consultant for AMO,
besifloxacin ophthalmic suspension 0.6% in the affected Allergan Inc., Bausch and Lomb, Inc., Cyanacon Ocusoft,
eye 3 times a day, at intervals of 4 to 12 hours, for a total Eyemaginations, Focus Laboratories, Inspire Pharmaceu-
of 7 days. 15 The dosing frequency for besifloxacin is ticals, Pixel Optics, Odyssey Medical, Office Mate/VSP,
similar to that for moxifloxacin, whereas other ophthalmic Rapid Pathogen Screening, Science Based Health, Sirion
fluoroquinolones are administered more frequently,4 possibly Therapeutics, VMax. Advisor for LCA Vision-LASIK Plus,
leading to compliance issues, an important consideration in OcuSense/TearLab and share holder for Inspire Pharmaceu-
the fight against emerging microbial resistance. Compliance ticals, OcuSense/TearLab and VMax.
has been shown to be inversely related to frequency and Editorial support was provided by Phocus Inc.

Dovepress
18. Blondeau JM, Borsos S, Hesje CK. Antimicrobial efficacy of gatifloxa-

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Schuster AK, Harder BC, Schlichtenbrede FC, Jarczok MN, Tesarz J
Schuster AK, Harder BC, Schlichtenbrede FC, Jarczok MN, Tesarz J.

Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients.
Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD011503.
DOI: 10.1002/14651858.CD011503.pub2.
www.cochranelibrary.com
Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients
(Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 5
OBJECTIVES.................................................................................................................................................................................................. 5
METHODS..................................................................................................................................................................................................... 6
RESULTS........................................................................................................................................................................................................ 8
Figure 1.................................................................................................................................................................................................. 9
Figure 2.................................................................................................................................................................................................. 10
DISCUSSION.................................................................................................................................................................................................. 11
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 12
ACKNOWLEDGEMENTS................................................................................................................................................................................ 12
REFERENCES................................................................................................................................................................................................ 13
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 15
DATA AND ANALYSES.................................................................................................................................................................................... 17
Analysis 1.1. Comparison 1 Valacyclovir versus acyclovir, Outcome 1 Ocular involvement............................................................. 18
Analysis 1.2. Comparison 1 Valacyclovir versus acyclovir, Outcome 2 Pain at week 24 (self-reported; yes).................................... 18
Analysis 1.3. Comparison 1 Valacyclovir versus acyclovir, Outcome 3 Adverse effects.................................................................... 18
ADDITIONAL TABLES.................................................................................................................................................................................... 19
APPENDICES................................................................................................................................................................................................. 21
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 23
DECLARATIONS OF INTEREST..................................................................................................................................................................... 23
SOURCES OF SUPPORT............................................................................................................................................................................... 23
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 24
INDEX TERMS............................................................................................................................................................................................... 24
Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients (Review) i
Informed decisions.
[Intervention Review]
Valacyclovir versus acyclovir for the treatment of herpes zoster

ophthalmicus in immunocompetent patients
Alexander K Schuster1, Björn C Harder2, Frank C Schlichtenbrede2, Marc N Jarczok3, Jonas Tesarz4
1Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany. 2Department of Ophthalmology, Medical Faculty
Mannheim, Heidelberg University, Mannheim, Germany. 3Heidelberg University, Heidelberg, Germany. 4Department of General Internal
Medicine and Psychosomatics, Medical Hospital, Heidelberg University, Heidelberg, Germany
Contact: Alexander K Schuster, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, Mainz, 55131,
Germany. alexander.k.schuster@gmx.de.
Editorial group: Cochrane Eyes and Vision Group.

Publication status and date: New, published in Issue 11, 2016.
Citation: Schuster AK, Harder BC, Schlichtenbrede FC, Jarczok MN, Tesarz J. Valacyclovir versus acyclovir for the treatment of herpes
zoster ophthalmicus in immunocompetent patients. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD011503. DOI:
10.1002/14651858.CD011503.pub2.
ABSTRACT
Background
Herpes zoster ophthalmicus affects the eye and vision, and is caused by the reactivation of the varicella zoster virus in the distribution of the
first division of the trigeminal nerve. An aggressive management of acute herpes zoster ophthalmicus with systemic antiviral medication
is generally recommended as the standard first-line treatment for herpes zoster ophthalmicus infections. Both acyclovir and its prodrug
valacyclovir are medications that are approved for the systemic treatment of herpes zoster. Although it is known that valacyclovir has an
improved bioavailability and steadier plasma concentration, it is currently unclear as to whether this leads to better treatment results and
less ocular complications.
Objectives
To assess the effects of valacyclovir versus acyclovir for the systemic antiviral treatment of herpes zoster ophthalmicus in
immunocompetent patients.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process
and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June
2016), Web of Science Conference Proceedings Citation Index-Science (CPCI-S; January 1990 to June 2016), BIOSIS Previews (January
1969 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World
Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date
or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016.
Selection criteria
We considered all randomised controlled trials (RCTs) in which systemic valacyclovir was compared to systemic acyclovir medication for
treatment of herpes zoster ophthalmicus. There were no language restrictions.
Data collection and analysis

Two review authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data. We did
not conduct a meta-analysis, as only one study was included. We assessed the certainty of the evidence for the selected outcomes using
the GRADE approach.
Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients (Review) 1
Informed decisions.
Main results
One study fulfilled the inclusion criteria. In this multicentre, randomised double-masked study carried out in France, 110
immunocompetent people with herpes zoster ophthalmicus, diagnosed within 72 hours of skin eruption, were treated, with 56 participants
allocated to the valacyclovir group and 54 to the acyclovir group. The study was poorly reported and we judged it to be unclear risk of
bias for most domains.
Persistent ocular lesions after 6 months were observed in 2/56 people in the valacyclovir group compared with 1/54 people in the acyclovir
group (risk ratio (RR) 1.93 (95% CI 0.18 to 20.65); very low certainty evidence. Dendritic ulcer appeared in 3/56 patients treated with
valacyclovir, while 1/54 suffered in the acyclovir group (RR 2.89; 95% confidence interval (CI) 0.31 to 26.96); very low certainty evidence),
uveitis in 7/56 people in the valacyclovir group compared with 9/54 in the acyclovir group (RR 0.96; 95% CI 0.36 to 2.57); very low certainty
evidence). Similarly, there was uncertainty as to the comparative effects of these two treatments on post-herpetic pain, and side effects
(vomiting, eyelid or facial edema, disseminated zoster). Due to concerns about imprecision (small number of events and large confidence
intervals) and study limitations, the certainty of evidence using the GRADE approach was rated as low to very low for the use of valacyclovir
compared to acyclovir.
Authors' conclusions
This review included data from only one study, which had methodological limitations. As such, our results indicated uncertainty of the
relative benefits and harms of valacyclovir over acyclovir in herpes zoster ophthalmicus, despite its widespread use for this condition.
Further well-designed and adequately powered trials are needed. These trials should include outcomes important to patients, including
compliance.
PLAIN LANGUAGE SUMMARY
Valacyclovir compared with acyclovir for the treatment of herpes zoster ophthalmicus in people with an otherwise normal immune
system
What is the aim of this review?

The aim of this Cochrane Review was to find out if valacyclovir performs better than acyclovir in the treatment of a painful itchy rash
caused by the chickenpox virus (herpes zoster ophthalmicus). Cochrane researchers collected and analysed all relevant studies to answer
this question and found one study.
Key messages
There is uncertainty as to the benefits and harms of valacyclovir compared with acyclovir for the treatment of herpes zoster ophthalmicus.
What was studied in the review?

Herpes zoster ophthalmicus is a painful itchy rash that appears on one side of the forehead. If the rash reaches the eye it may lead to
visual impairment. This is because the infection can damage the front of the eye. Herpes zoster is caused by the chickenpox virus, which
can remain in the body for many years after the original chickenpox infection, and may get reactivated. Doctors can treat herpes zoster
ophthalmicus with acyclovir. This is an antiviral medication that kills the chickenpox virus. Valacyclovir is a modified version of acyclovir
that may need to be taken less frequently as it is better absorbed by the body.
What are the main results of the review?

The review authors found one relevant study from France. This study compared valacyclovir 1000 mg taken three times a day for seven
days with acyclovir 800 mg taken five times a day for seven days. The company that makes valacyclovir (Glaxo) funded the study.
The review authors are uncertain whether valacyclovir has any benefit over acyclovir in the treatment of herpes zoster ophthalmicus. They
judged the certainty of the evidence to be very low because the study was small and there were some problems with the way it was reported.
How up-to-date is this review?

The Cochrane researchers searched for studies that had been published up to June 2016.
Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients (Review)
SUMMARY OF FINDINGS
Summary of findings for the main comparison.
Library
Cochrane
Valacyclovir compared with acyclovir for the systemic treatment of herpes zoster ophthalmicus in immunocompetent patients
Patient or population: Adult immunocompetent patients with herpes zoster ophthalmicus

Setting: No restriction on the type or location of the health service (primary, secondary and tertiary care)
Better health.
Informed decisions.
Trusted evidence.
Intervention: Systemic valacyclovir
Comparison: Systemic acyclovir
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of Partici- Certainty of the Comments
(95% CI) pants evidence
Risk with acy- Risk with valacyclovir (studies) (GRADE)
clovir
Occurrence of ocular involve- 19 per 1000 36 per 1000 RR 1.93 (0.18 to 20.65) 110 ⊕⊝⊝⊝ Data were on-
ment (3 to 382) (1 RCT) VERY LOW1 2 ly available on
persistent ocu-
lar lesions after
6 months.
Ocular involvement - Dendritic 19 per 1000 54 per 1000 RR 2.89 110 ⊕⊝⊝⊝ -
ulcer (6 to 49) (0.31 to 26.96) (1 RCT) VERY LOW1 2
Ocular involvement - Uveitis 167 per 1000 125 per 1000 RR 0.96 110 ⊕⊝⊝⊝ -
(50 to 312) (0.36 to 2.57) (1 RCT) VERY LOW1 2
Pain at week 24 (self-reported; 56 per 1000 53 per 1000 RR 0.96 110 ⊕⊝⊝⊝ -
yes) (11 to 254) (0.20 to 4.57) (1 RCT) VERY LOW1 2

Adverse effects - Vomiting 37 per 1000 54 per 1000 RR 1.45 110 ⊕⊝⊝⊝ -
(9 to 308) (0.25 to 8.32) (1 RCT) VERY LOW1 2
Adverse effects - Eyelid or facial 56 per 1000 18 per 1000 RR 0.32 110 ⊕⊝⊝⊝ -
oedema (2 to 167) (0.03 to 3.00) (1 RCT) VERY LOW 1 2
Adverse effects - Disseminated 19 per 1000 6 per 1000 RR 0.32 110 ⊕⊝⊝⊝ -
zoster (0 to 143) (0.01 to 7.73) (1 RCT) VERY LOW 1 2
* The risk in the intervention group (valacyclovir) (and its 95% confidence interval) is based on the assumed risk in the comparison group (acyclovir treatment) and the
relative effect of the intervention (and its 95% CI).
3
Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients (Review)
CI: Confidence interval; RR: Risk Ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence
Library
Cochrane
High certainty: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: We are very uncertain about the estimate.
1 We downgraded 1 level for risk of bias, as the authors did not report on random sequence generation, allocation concealment and masking of staff, and the extent to which
Better health.
Informed decisions.
Trusted evidence.
bias had been avoided was largely unclear (-1).
2 We downgraded 2 levels for imprecision as there were few events and very wide confidence intervals.

4
Informed decisions.
BACKGROUND How the intervention might work
Description of the condition Antiviral medication is integral to most current treatment

guidelines and represents an important pillar in the treatment of
Herpes zoster is the result of reactivation of a prior varicella herpes zoster ophthalmicus (Dworkin 2007; Gross 2003). Acyclovir
zoster virus infection. Herpes zoster ophthalmicus arises when (standard dose for herpes zoster ophthalmicus: 800 mg five
a latent infection of the trigeminal ganglion is reactivated and times daily for seven to 10 days) and valacyclovir (standard
involves the ophthalmic division of the trigeminal nerve (Arvin dose for herpes zoster ophthalmicus: 1000 mg three times daily
1996). Approximately 10% to 20% of herpes zoster infections for seven days) have both been approved for the treatment
have an ophthalmic involvement, 20% to 70% of which end with of herpes zoster, and are widely used (Dworkin 2007). Both
ocular involvement (Ragozzino 1982; Womack 1983). Accordingly, acyclovir and valacyclovir work by stopping the herpes zoster
effective treatment for the prevention of ocular involvement is virus from reproducing and infecting more cells. Inside the cells
necessary, as ocular involvement can lead to debilitating chronic of the body, acyclovir is phosphorylated specifically by the viral
pain and severe vision impairment. thymidine kinases, and thus selectively activated in those cells
that are infected with herpes zoster. After being activated by
Herpes zoster itself typically presents as an itchy and painful rash of the addition of phosphate groups, acyclovir is incorporated into
limited duration. In the case of acute herpes zoster ophthalmicus, the viral deoxyribonucleic acid (DNA) strand by the enzyme DNA
the dermatome of the ophthalmic division of the trigeminal nerve polymerase. Once incorporated, acyclovir acts as a DNA chain
is affected. However, some patients suffer further complications terminator. By blocking the action of the viral DNA polymerase,
and have a long lasting and severe course. In particular, the ocular acyclovir prevents the herpes zoster virus from multiplying. This
complications of herpes zoster ophthalmicus, such as scleritis, controls the infection and helps the immune system to deal with it.
uveitis, vasculitis, and especially acute retinal necrosis, represent
high risk for the patient to develop significant vision loss (Kanski Valacyclovir is the esterified version of acyclovir and hence, an
2008). In addition, patients with herpes zoster ophthalmicus are at acyclovir prodrug. It is characterised by greater bioavailability
greater risk of developing postherpetic neuralgia and of developing than acyclovir. This higher oral bioavailability is mediated by
persistent neuropathic pain that lasts long after the initial rash has a carrier-mediated intestinal absorption (the human intestinal
healed (Gross 2003). peptide transporter (Gou 1999)), followed by a rapid conversion
into its active form, acyclovir, by ester hydrolysis in the small
Description of the intervention intestine (De Clercq 2006). During this rapid first-pass metabolism,
An aggressive management of acute herpes zoster with antiviral valacyclovir is split into acyclovir and the essential amino acid
medication can reduce the duration and severity of the acute valine (Perry 1996). The steady-state plasma concentration of
zoster manifestation, and in particular, in the case of herpes zoster acyclovir after oral doses of valacyclovir (1 gram three times daily)
ophthalmicus, may prevent more serious complications (Gross is described to be similar to those after intravenous acyclovir (three
2003). Accordingly, an aggressive management of acute herpes times daily) application (Ormrod 2000). Similarly, the vitreous
zoster ophthalmicus with potent antiviral medication is integral to penetration of orally administrated valacyclovir is comparable to
most current treatment guidelines (Dworkin 2007; Gross 2003). that of intravenous acyclovir, at least in non-inflamed eyes (Huynh
2008). Therefore, valacyclovir might be equal to intravenous
As one of the most commonly used antiviral drugs, acyclovir acyclovir administration and possibly superior to oral acyclovir
represents the mainstay of antiviral herpes zoster treatment. administration, resulting in less complications in patients with
However, its poor bioavailability and need for frequent daily dosing herpes zoster ophthalmicus.
prompted the development of later generation antiviral agents
with improved pharmacokinetics and lower dosing frequency. Why it is important to do this review
Valacyclovir is a modified product of acyclovir (l-valyl ester of Although it is known that valacyclovir has an improved
acyclovir). After oral administration, it is rapidly converted to bioavailability and steadier plasma concentrations, it is currently
acyclovir in the gastrointestinal tract and liver. Thus, the plasma unclear whether this finally leads to comparable treatment results
levels of acyclovir are three to five times greater after the oral and less ocular complications. Therefore, an up-to-date systematic
intake of valacyclovir compared to the direct oral intake of review is warranted to compare the effects of valacyclovir versus
acyclovir. Simplified and shortened medication regime should acyclovir for the systemic antiviral treatment of herpes zoster
improve compliance and therefore, might also improve efficacy. ophthalmicus.
Accordingly, in recent years, there has been an increasing amount
of literature on the use of valacyclovir as an antiviral agent for the OBJECTIVES
treatment of herpes zoster, and it is now considered a promising
alternative to conventional acyclovir regimes. To assess the effects of valacyclovir versus acyclovir for the
systemic antiviral treatment of herpes zoster ophthalmicus in
In common ophthalmic literature, acyclovir and other oral antiviral immunocompetent patients.
medication (valacyclovir, famciclovir, brivudin) are reported as
similar in efficiency (Cohen 2013; Kanski 2008; Pavan-Langston
2008). Nevertheless, one trial showed an improved effect in
immunocompetent adults having herpes zoster (Beutner 1995),
while another reported no difference in patients with herpes zoster
ophthalmicus (Colin 2000). Both focused on the properties of
valacyclovir in comparison to acyclovir.
Informed decisions.
METHODS • Occurrence of severe ocular manifestation (Intraocular

involvement: e.g. scleritis, uveitis, vasculitis, optic neuritis,
Criteria for considering studies for this review chorioretinitis, acute retinal necrosis; time point: 12 months
after infection).
Types of studies
• Occurrence of simple ocular manifestation (primary superficial
This review was conducted according to our published Cochrane ocular affection: e.g. conjunctivitis, superficial keratitis,
protocol (Schuster 2015). We included randomised controlled trials episcleritis, stromal keratitis, dendritic ulcer; time point: 12
(RCTs) only. We did not use sample size, language, or publication months after infection).
status to determine whether or not a study was included. • Occurrence of vision loss (best corrected visual acuity of 6/60 or
less; time point: 12 months after infection).
Types of participants
• Occurrence and severity (pain intensity) of postherpetic
Immunocompetent adults of both sexes, with a clinical diagnosis of neuralgia (time point: 12 months after infection).
herpes zoster affecting the ophthalmic part of the trigeminal nerve. • Second eye involvement in ocular manifestation of herpes
We excluded studies with participants who had a compromised zoster ophthalmicus (time point: more than 12 months after
immune system, such as patients with acquired immune deficiency infection).
syndrome (AIDS), or patients treated with immunosuppressive
• Quality of life (if assessed by standardised questionnaire;
drugs. We included studies that included subsets of relevant
time points: under antiviral medication, three months after
participants if the data for the relevant subsets were reported
treatment and 12 months after treatment).
separately (in such cases, we only included the data for the relevant
subsets). Adverse effects
Types of interventions • Adverse effects (diarrhoea, vomiting, constipation, dizziness,

headache, death, others) were also recorded within 12 months
We considered any trial where systemic valacyclovir was compared
after infection.
to systemic acyclovir medication, at any dose, for the treatment
of herpes zoster ophthalmicus. There was no restriction to any Search methods for identification of studies
type or location of the health service (primary, secondary and
tertiary care). We included studies regardless of the time of onset of Electronic searches
intervention after first symptoms. We searched CENTRAL (which contains the Cochrane Eyes
Types of outcome measures and Vision Trials Register (2016, Issue 5)), Ovid MEDLINE,
Ovid MEDLINE In-Process and Other Non-Indexed Citations,
From each trial, we selected the measure considered to be most Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June
appropriate for each of the pre-defined outcomes of this review. If 2016), Embase (January 1980 to June 2016), Web of Science
an outcome had been reported in several different ways, preference Conference Proceedings Citation Index-Science (CPCI-S) (January
was given to the outcome measure that was used and documented 1990 to June 2016), BIOSIS Previews (January 1969 to June
frequently in the field, as opposed to a novel or not validated 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch),
measure. The time point of most outcome measures was defined as ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health
12 months after primary infection, defined as a period of six to 18 Organization (WHO) International Clinical Trials Registry Platform
months. Time points for occurrence are meant as any occurrence (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or
up to this time point and do not mean persistent occurrence up to language restrictions in the electronic searches for trials. We last
this time point. In cases in which time points of outcome measures searched the electronic databases on 13 June 2016.
were only available at other points of time, data were not included
in the primary analyses, but reported descriptively. See: Appendices for details of search strategies for CENTRAL
(Appendix 1), MEDLINE (Appendix 2), Embase (Appendix 3), CPCI-
While the primary outcome summarizes any occurrence of S (Appendix 4), BIOSIS (Appendix 5), ISRCTN (Appendix 6),
ocular involvement during the disease, secondary outcomes did ClinicalTrials.gov (Appendix 7) and the ICTRP (Appendix 8).
differentiate ocular manifestation into intraocular involvement
(defined as severe manifestation due to risk of blindness) Searching other resources
and superficial ocular affection (defined as simple ocular In addition, we searched the reference lists of all included studies
manifestation). and current reviews and guidelines for the management of herpes
Primary outcomes zoster ophthalmicus, and contacted corresponding authors of
guidelines for management of herpes zoster. We also contacted
The primary outcome measure was the companies selling valacyclovir currently to the European and
US market, and asked whether there were additional studies
• Occurence of ocular involvement (time point: 12 months after comparing valacyclovir to acyclovir for the treatment of herpes
infection), defined as signs of any ocular manifestations (e.g. zoster ophthalmicus.
conjunctivitis, superficial keratitis, stromal keratitis, dendritic
ulcer, scleritis, uveitis, vasculitis, optic neuritis, chorioretinitis, Data collection and analysis
acute retinal necrosis)
Selection of studies
Secondary outcomes
Two review authors (AKS, JT) independently assessed titles and
Secondary outcome measures included: abstracts from the search results and scanned them against the
Informed decisions.
inclusion criteria. Initially, a list was made for included and We calculated risk ratios (RR) for dichotomous data (occurrence of
excluded studies, as well as for studies assessed as unsure. The two postherpetic neuropathy, occurrence of simple and severe ocular
review authors (AKS, JT) then discussed these lists. For potentially manifestations, occurrence of adverse effects). We calculated the
relevant studies, the two review authors independently read the 95% confidence intervals (CIs) for all outcomes. We reported
full-text articles to determine whether the articles met the pre- categorical data descriptively.
specified selection criteria. They discussed disagreements in order
to make a final decision; if agreement between the two authors was Unit of analysis issues
not achieved, a third review author (BCH) was contacted to reach As the chosen medication was administered systemically, we
final consent. analysed participants based on their randomisation to treatment
type, and not on individual eyes. This is in accordance with the
Data extraction and management
outcomes defined for this review that relate to participants and not
Two review authors (AKS, JT) independently extracted the data to eyes. Bilateral herpes zoster ophthalmicus is infrequent except in
of the identified studies (study characteristics, study results and patients with acute retinal necrosis syndrome (which is a rare major
assessments of the risk of bias), using a pre-specified data ocular complication), so we anticipated that one eye per person
extraction form. The review authors (AKS, JT) met to double-check would be reported.
all discrepancies; if agreement between them was not achieved, a
third review author (BCH) was contacted to reach final consent. Dealing with missing data
Due to the low number of studies, we abstained from combining
If a publication required translation, the two review authors
studies in a meta-analysis and reported the results descriptively
independently extracted relevant data from the translated article
instead. Nevertheless, if outcome data (loss to follow-up data
and sought further quality checks from the translator. If there were
or non-reporting outcome data) were missing or incomplete, we
missing or unclear data, we contacted the corresponding authors
contacted the corresponding authors twice, at least three months
twice, at least three months apart, for further information (Beutner
apart, for further information.
1995, Colin 2000).
Assessment of heterogeneity
We collected demographic data of participants, and if mentioned,
previous ophthalmic diseases, interventions or operations, Due to the low number of studies, we abstained from combining
and follow-up intervals for all primary outcomes and their studies in a meta-analysis and reported the results descriptively
corresponding findings. instead. We had prespecified that heterogeneity among enough
trials would be assessed using the heterogeneity statistics Chi2
In the description of study characteristics, we presented data as and I2, complemented by visual exploration of forest plots. We
reported in the original publications. had planned to consider I2 values above 50% as substantial
heterogeneity (Higgins 2002). For testing the significance of
All data were entered into Review Manager 5.3 (RevMan 2014) by
heterogeneity, we would have considered the Chi2 statistic; P = 0.1
one review author (AKS); another review author (JT) then compared
or less would indicate significant heterogeneity.
the entered data against the data extraction forms.
Assessment of reporting biases
Assessment of risk of bias in included studies
We used Cochrane's 'risk of bias' tool as described in Chapter 8 of
the Cochrane Handbook for Systematic Reviews and Interventions
instead. If we had included 10 or more studies in the review, we
(Higgins 2011). For missing information about study design, we
had planned to assess potential publication bias using a funnel
contacted the corresponding authors twice (at least three months
plot. Funnel plots with fewer than 10 trials should be avoided, as
apart) for further information. Two review authors (AKS, JT)
the power of both visual inspection and regular testing is small
independently performed 'risk of bias' assessment; disagreements
when fewer than 10 trials are plotted (Sterne 2011). In addition, we
were solved in a meeting. If necessary, a third review author (BCH)
had planed to assess selective outcome reporting bias by using an
was contacted to reach final consent.
outcome reporting matrix (the ORBIT classification), as previously
Measures of treatment effect described by others (Kirkham 2010).
Due to the low number of studies, we abstained from combining Data synthesis
instead, by calculating measures of treatment effect for the
included study. If we would have found more studies, we had
instead. We assessed the certainty of the level of evidence for the
planned to calculate effect measures as mean differences (MD) for
selected outcomes using the GRADE approach (GRADEpro 2014).
continuous data (time point of becoming acute pain free, time point
of skin healing, severity of postherpetic neuropathy and quality We had planned to compare and combine studies using a
of life. Data in publications only allowed us to report proportion DerSimonian-Laird random-effects model to calculate pooled
of persistent ocular lesions and persistent pain six months estimates with 95% CIs (DerSimonian 1986). A random-effects
after treatment. When assessment procedures varied in scale model was chosen because we expected that studies would
or principle of measuring method, we would have summarised differ in the nature of patients (e.g. Caucasian, Asian etc), age,
continuous outcomes as standardized mean differences. and gender (the ratio of women to men). We had planned to
further analyse any results with I2 values over 50% for sources
Informed decisions.
of clinical heterogeneity and methodological differences. If no evidence using GRADE (GRADEpro 2014). GRADE considers the
methodological or clinical reasons could be found to explain strong following criteria: study limitations, indirectness, imprecision,
statistical heterogeneity,we would not have proceeded with the inconsistency, and publication bias.
meta-analysis. If only a very small number of trials had met the
inclusion criteria, we had planned to report the results descriptively We included the following outcomes in the summary of findings
and not perform a meta-analysis. All secondary outcomes were table.
analysed in an explorative way.
1. Occurrence of ocular involvement
Subgroup analysis and investigation of heterogeneity 2. Ocular involvement - dendritic ulcer
Due to the low number of studies, we abstained from performing 3. Ocular involvement - uveitis
subgroup analyses or analyses of heterogeneity. 4. Pain at week 24 (self-reported; yes)
5. Adverse effects - vomiting
Had we included more studies, we had planned to perform 6. Adverse effects - eyelid or facial oedema
subgroup analyses and investigate heterogeneity for:
7. Adverse effects - disseminated herpes zoster
• Starting point of therapy: comparing participants with initial
treatment (up to and including 72 hours) to participants with Time point for analysis was defined as 12 months, and if data were
delayed start of treatment (longer than 72 hours). not available, the closest time point to 12 months in the time span
of six to 18 months.
• Dosage regime: comparing standard dosage regime
(valacyclovir: 1000 mg three times daily for at least seven days, RESULTS
oral acyclovir: 800 mg five times daily for at least seven days,
intravenous acyclovir: concentration of 15 mg per kilogram Description of studies
bodyweight per day for seven days) to other dosage regimes.
◦ Additional use of topical medication. Results of the search
◦ Time point of outcome observation after treatment. The electronic searches yielded a total of 2072 references (Figure
1). The Cochrane Information Specialist (CIS) scanned the search
Sensitivity analysis results, removed 344 duplicates and then removed 1034 references
Due to the low number of studies, we did not perform any which were not relevant to the scope of the review. We screened
sensitivity analyses. We had planned to conduct sensitivity the remaining 694 reports and obtained the following 19 full-text
analyses to determine the impact of excluding industry-funded reports for further assessment: Anonymous 1996; Barsic 2004; Bell
studies (industry-funded studies versus industry-independent 1996; Beutner 1995; Carrington 1994; Chen 2006; Cochener 1997;
studies), unpublished studies (full reports versus abstracts or Colin 1997; Colin 2000; Desmond 2002; Grant 1997; Grose 1997;
unpublished), and studies with missing data. Jubelt 2002; Li 1999; Lin 2001; Liu 2000; Wood 1998; Xu 2000; Yan
1999). This search resulted finally in three references meeting the
Summary of findings table prespecified inclusion criteria (Cochener 1997; Colin 1997; Colin
2000). These three references, however, related to the same study
In an amendment to our published protocol, we prepared a
(publication: Colin 2000 and two meeting abstracts: Cochener 1997;
'summary of findings' table and graded the certainty of the
Colin 1997).
Informed decisions.
Figure 1. Study flow diagram.
Informed decisions.
Included studies reporting incidence and types of adverse effects descriptively. This
study only reported extractable data for time point 6 months.
We included one study in this review, which reported on a
comparison of valacyclovir to acyclovir in patients with herpes Excluded studies
zoster ophthalmicus (Colin 2000).
We excluded 16 studies after reviewing the full-text copies. Reasons
Colin 2000 included 110 participants who had herpes zoster for excluding these studies can be found in the Characteristics of
ophthalmicus in a multicentre, randomised, double-masked study excluded studies table.
that compared valacyclovir 1000 mg three times daily for seven
days to acyclovir 800 mg five times daily for seven days. This Risk of bias in included studies
study was carried out in France. Main outcome measures were the
As described in the following sections in more detail (and shown in
frequency, severity, and duration of ocular complications, patient
Figure 2), the overall risk of bias, according to Higgins 2011 criteria,
reports of zoster-associated pain, and the healing progress of skin
was unclear. Despite repeated inquiries, missing information were
lesions. In addition, overall treatment tolerance was assessed,
not provided by the study authors of the original study.
Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.
Allocation Other potential sources of bias

Risk of selection bias was unclear as there was not sufficient Some of the study authors were sponsored by the pharmaceutical
information given by the authors. company marketing valacyclovir, and it was unclear whether a
conflict of interest existed.
Blinding
Masking of study medication was sufficiently described and carried
Effects of interventions
out, but the masking of observers was unclear. Further, success and See: Summary of findings for the main comparison
efficacy of masking was unclear.
As only one study was included in the review, we did not carry
Incomplete outcome data out a meta-analysis but report the findings of this single study
Participants withdrawing informed consent was explained in detail. descriptively.
In addition, the authors used an intention-to-treat analysis. Thus Colin 2000 reported similar incidence of ocular complications
there was low risk of attrition bias. between the two study groups being treated with either
Selective reporting valacyclovir or acyclovir. At enrolment, 13% (7/56) of the
participants in the valacyclovir group and 7% (4/54) in the
Selective reporting bias could not be safely ruled out as an a acyclovir group already had ocular involvement. Primary ocular
priori published protocol of the study was not available. When complications in the observation time (up to six months) were:
comparing the publication Colin 2000 with the two published conjunctivitis in 54% (30/56) of the valacyclovir group and 52%
abstracts Colin 2000, we did not find differences with respect to (28/54) of the acyclovir group (relative risk (RR) 1.03; 95%
reported outcomes. confidence interval (CI 0.72 to 1.47)), punctate keratitis in 39%
(22/56) and 48% (26/54), respectively (RR 0.82 (95% CI 0.53 to 1.25),
and dendritic keratitis in 11% (6/56 and 6/54) of each group (RR
0.96 (95% CI 0.33 to 2.81); Analysis 1.1; Table 1). The total number
Informed decisions.
of participants with dendritic ulcer (3/56 and 1/54, respectively) Nevertheless, treatment with valacyclovir might be efficacious in
and episcleritis (4/56 and 1/54, respectively) were small and did these conditions.
not show a statistical difference between the two groups (Analysis
1.1). Participants with ocular complications of scleritis, vasculitis, Summary of main results
optic neuritis, chorioretinitis, or acute retinal necrosis were not
One study fulfilled the inclusion criteria and compared valacyclovir
reported in the included publication (Colin 2000) and therefore
to acyclovir in immunocompetent patients with herpes zoster
these complications could not be analysed. Persistent ocular
ophthalmicus. In this multicentre, randomised double-masked
lesions after six months were reported in 2/56 in the valacyclovir
study, 110 participants with herpes zoster ophthalmicus,
group and 1/54 in the acyclovir group (RR 1.93 (95% CI 0.18 to
diagnosed within 72 hour of skin eruption, were treated. The
20.65)) (Analysis 1.1).
most frequent ocular complications noted in each group were
Zoster-associated pain was comparable between the two study conjunctivitis (54% valacyclovir and 52% acyclovir), superficial
groups at all examined time points (valacyclovir versus acyclovir; keratitis (39% and 48%, respectively), and dendritic keratitis
presentation: 51/56 versus 47/54, week four: 14/56 versus 17/54, (11% in each group). Further, post-herpetic pain, tolerability of
week eight: 8/56 versus 10/54, week 16: 3/56 versus 6/54, week medication, and side-effect profiles were equivalent between the
24: 3/56 versus 3/54; Table 2; Analysis 1.2). Healing of skin lesions two groups, indicating that both medications were efficacious for
was comparable in both groups. The incidence of adverse effects the treatment of herpes zoster ophthalmicus.
was similar in both groups. The most frequent adverse effects were
Overall completeness and applicability of evidence
vomiting (5% versus 3%; RR 1.45 (95% CI 0.25 to 8.32; Analysis 1.3),
and eyelid or facial oedema (2% versus 5%; RR 0.32 (95% CI 0.03 As there was only one randomised controlled trial included in this
to 2.00; Analysis 1.3; Table 2). Three serious adverse events were systematic review, there was only limited evidence for the use of
observed, two in the valacyclovir group (rectorrhagia, kidney stone; valacyclovir compared to acyclovir in herpes zoster ophthalmicus.
Analysis 1.3; Table 2) and one in the acyclovir group (disseminated Treatment for other patient groups, such as patients with HIV
zoster; Analysis 1.3). infection, is currently under investigation and for this purpose, a
Cochrane protocol has been published (Olusanya 2010). Arora et
We downgraded the certainty of the evidence due to concerns al. reported that the use of valacyclovir in two dosages were safe
about study limitations (downgraded one level) and precision of and efficacious therapies for reduction of zoster-associated pain
the effect estimates (downgraded one or two levels) (Summary of and zoster-associated abnormal sensation in patients who were
findings for the main comparison). immunocompromised (Arora 2008).
Individual data were not provided in a way which would have Quality of the evidence
allowed stratification into any occurrence of ocular involvement,
or occurrence of simple or severe ocular manifestations. Therefore Due to concerns about imprecision (due to small number
we reported the different diseases descriptively and not the initially of events and large confidence intervals) and relevant study
intended classification into simple and severe manifestation. limitations (random sequence generation, allocation concealment
and masking of staff), the certainty of evidence was downgraded
DISCUSSION from high to low and very low. The included study reported a
similar incidence of ocular complications, and comparable zoster-
The present study analysed whether the occurrence of associated pain and rate of healing of skin lesions between the two
complications for herpes zoster ophthalmicus differed when study groups being treated with either valacyclovir or acyclovir. For
treated with valacyclovir compared to acyclovir. The most obvious adverse events, similar frequencies were reported. When analysing
finding to emerge from this review was that available data for the reported adverse events, it remains unclear whether eyelid and
use of valacyclovir in the treatment of herpes zoster ophthalmicus facial oedema is the consequence of therapy or rather reflects
in immunocompetent people were sparse. Our systematic search insufficient therapy.
of the scientific literature revealed that, thus far, only one study
was specifically tailored to examine whether the well-established Potential biases in the review process
and widely applied treatment approach with valacyclovir was
comparable to the standard treatment regimen using acyclovir. As we could only include one study in this review, there might
Thus, we concluded that there was currently only weak clinical trial be a risk of publication bias regarding other conducted but
evidence for the use of systemic valacyclovir in the treatment of not registered or published studies. We systematically searched
herpes zoster ophthalmicus in immunocompetent people. available clinical trial registrations, but registration of a clinical trial
was not available in the 1990s.
This was especially the case for severe complications, which
however, were considered to be the most relevant reason for using Agreements and disagreements with other studies or
aggressive antiviral medication in this condition. Thus far, there reviews
was only one single comparative study that included a total of Similar results as in the included study were reported by another
110 participants. Therefore, based on the generally low prevalence study that provided a subgroup analysis of participants with
of severe complications in immunocompetent people, the total herpes zoster ophthalmicus based on the primary inclusion criteria
number of participants with dendritic ulcer and episcleritis in this of herpes zoster (Beutner 1995). This study was conducted as
study was too small to draw any conclusion about differences a multicentre, randomised, three-arm, double-masked, double-
between acyclovir and valacyclovir in this condition. Furthermore, dummy study. In a subgroup analysis, Beutner and colleagues
participants with scleritis, vasculitis, optic neuritis, chorioretinitis, included 119 participants with herpes zoster ophthalmicus, which
or acute retinal necrosis did not present in this study at all.
Informed decisions.
were randomised to either valacyclovir 1000 mg three times herpes zoster, including ophthalmicus, but did not further evaluate
daily for seven days, to valacyclovir 1000 mg three times daily ophthalmic complications (McDonald 2012).
for 14 days, or to acyclovir 800 mg five times daily for seven
days. They demonstrated comparable duration of pain, similar AUTHORS' CONCLUSIONS
duration of abnormal sensations, comparable time to cessation
of new lesion formation, and similar time to development of Implications for practice
at least 50% crusting or healing of the rash between the three Based on the one included study, there is uncertainty in evidence
study groups. Ocular involvement was present in 34 (29%) that valacyclovir as systemic treatment option for herpes zoster
participants with ophthalmic herpes zoster at presentation. During ophthalmicus is different or comparable to acyclovir. Valacyclovir
the observation period, an additional 17 participants presented may offer theoretical advantages, especially in cases in which the
with ocular involvement. Twenty-three participants had serious patient's compliance is not consistent. In such cases, the greater
ocular involvement (keratitis, uveitis, iritis, corneal, or scleral bioavailability and simplified dosing regimen of valacyclovir may
involvement), while 28 participants had minor ocular involvement allow for improved compliance rates (De Clercq 2006).
(conjunctivitis, 'red eye', or excessive lacrimation). In more than
90% of these participants, the ocular involvement resolved within Implications for research
five weeks.
As there is only one randomised controlled trial comparing
There are severe ocular involvements stated to be related to systemic valacyclovir to acyclovir in patients with herpes
herpetic diseases. Two case reports described sufficient therapies zoster ophthalmicus, further well-designed RCTs are needed
using oral valacyclovir in patients with acute retinal necrosis to investigate valacyclovir in the treatment of herpes zoster
(Emerson 2006; Taylor 2012). Taking into account the low number ophthalmicus. Sample size should be calculated to meet rare
of events for severe complications overall, it must be assumed complications, such as severe intraocular complications; the
that the statistical power to detect differences was insufficient, and follow-up period should be at least six months to investigate
further research should be undertaken to investigate the effects of permanent post-herpetic neuralgia.
valacyclovir on the occurrence of rare but clinically relevant ocular
complications. ACKNOWLEDGEMENTS
However, the uncertainty of evidence in our review does not We acknowledge assistance from the Cochrane Eyes and Vision
necessarily indicate that valacyclovir is less efficacious. A recent (CEV) for creating and executing the electronic search strategies.
systematic review showed that oral treatment with valacyclovir We thank Catey Bunce, Simon Taylor, and Stephanie Watson for
compared to acyclovir resulted in a significant reduction in risk of their comments on the protocol and review and Jennifer Evans and
herpes zoster-associated pain up to 112 days in participants with Anupa Shah for their assistance throughout the review process.
Informed decisions.
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Jubelt B. Valacyclovir and famciclovir therapy in herpes zoster.
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Lin 2001 {published data only}
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Lin WR, Lin HH, Lee SS, Tsai HC, Huang CK, Wann SR, et al.
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Liu C, Shi XM, Ji MK. A randomised controlled trial of valaciclovir
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Colin 2000
Methods Multicentre, randomised, double-masked study that was conducted in France between 1 July 1994 and
16 October 1995.
Participants Immunocompetent patients aged 18 years or older with herpes zoster ophthalmicus, diagnosed within
72 hours of skin eruption, were eligible for this study.
People with other pre-existing ocular disorders, renal failure, immune dysfunction, or diseases neces-
sitating cytotoxic or immunosuppressive treatment, liver failure, or intolerance or hypersensitivity to
acyclovir were ineligible.
Women of childbearing age who were not using effective contraceptions or who were pregnant or
breast-feeding were excluded.
Interventions Participants were randomly allocated to either valacyclovir (1 g three times daily for 7 days) or acy-
clovir (800 mg five times daily for 7 days), the other tablets of the five-times daily regime were substitut-
ed with placebo tablets.
Outcomes The aim was to compare efficacy and safety of valacyclovir and acyclovir. Ocular symptoms, ocular
movement, pupil diameter and reflexes, conjunctivae, sclera and episclera, cornea, anterior chamber,
ocular tension, and retina were investigated. The ophthalmic examination focused on the frequency,
severity and duration of ocular complications. Participants assessed ocular pain severity on a 4-point
scale (0 to 3) and on a visual analogue scale. Sensorineural disorders and healing of skin lesions were
assessed at each visit. Tolerance was assessed on the basis of adverse effects and changes in laborato-
ry parameters on days 1 (inclusion) and 7.
Notes The study was supported by Glaxo Wellcome, France. There was no declaration of interest among the
primary researchers.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Sufficient information is not given by the authors.
tion (selection bias)
Allocation concealment Unclear risk Sufficient information is not given by the authors.
(selection bias)
Informed decisions.
Colin 2000 (Continued)
Blinding of participants Unclear risk Sufficient information is not given by the authors.
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Sufficient information is not given by the authors.
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Participants withdrawing informed consent is explained in detail.
(attrition bias)
All outcomes
Selective reporting (re- Low risk Reported outcomes of the two abstracts and the main publication did not dif-
porting bias) fer.
Other bias Unclear risk Some of the study authors were sponsored by the pharmaceutical company
marketing valacyclovir and it is unclear whether a conflict of interest exists.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Anonymous 1996 Review article without primary data.
Barsic 2004 Participants did not have herpes zoster ophthalmicus, but genital herpes or varicella zoster virus
infections.
Bell 1996 Review article without primary data.
Beutner 1995 Randomisation was performed without regard to localisation of herpes zoster. Frequency of ocu-
lar complications was reported overall and not separately for valacyclovir or acyclovir. We were not
able to get in contact with the authors.
Carrington 1994 Review article without primary data.
Chen 2006 No subgroup of participants with herpes zoster ophthalmicus was reported.
Desmond 2002 Model building based on data of other primary studies. No primary participant data.
Grant 1997 Cost-consequence model based on data of other primary studies. No primary participant data.
Grose 1997 Review article. No primary participant data.
Jubelt 2002 Secondary report of a study comparing valacyclovir to famciclovir. No control group with acyclovir.
Li 1999 No subgroup of participants with herpes zoster ophthalmicus was reported.
Lin 2001 No subgroup of participants with herpes zoster ophthalmicus was reported.
Liu 2000 No subgroup of participants with herpes zoster ophthalmicus was reported.
Wood 1998 Secondary data analysis based on data of two primary studies. No primary participant data.
Informed decisions.
Study Reason for exclusion
Xu 2000 No treatment with valacyclovir in the treatment group.
Yan 1999 We were unable to obtain a copy of this paper.
DATA AND ANALYSES
Comparison 1. Valacyclovir versus acyclovir
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1 Ocular involvement 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
1.1 Conjunctivitis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 Punctate keratitis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.3 Dendritic keratitis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.4 Dendritic ulcer 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.5 Stromal keratitis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.6 Uveitis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.7 Episcleritis 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.8 Elevated intraocular 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
pressure
1.9 Persistent ocular lesions 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
2 Pain at week 24 (self-re- 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
ported; yes)
3 Adverse effects 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3.1 Vomitting 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.2 Eyelid or facial oedema 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.3 Rectorrhagia 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.4 Kidney stone 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.5 Disseminated zoster 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Informed decisions.
Analysis 1.1. Comparison 1 Valacyclovir versus acyclovir, Outcome 1 Ocular involvement.

Study or subgroup Valacyclovir Acyclovir Risk Ratio Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
1.1.1 Conjunctivitis
Colin 2000 30/56 28/54 1.03[0.72,1.47]
1.1.2 Punctate keratitis

Colin 2000 22/56 26/54 0.82[0.53,1.25]
1.1.3 Dendritic keratitis

Colin 2000 6/56 6/54 0.96[0.33,2.81]
1.1.4 Dendritic ulcer

Colin 2000 3/56 1/54 2.89[0.31,26.96]
1.1.5 Stromal keratitis

Colin 2000 7/56 7/54 0.96[0.36,2.57]
1.1.6 Uveitis
Colin 2000 7/56 9/54 0.75[0.3,1.87]
1.1.7 Episcleritis
Colin 2000 4/56 1/54 3.86[0.45,33.42]
1.1.8 Elevated intraocular pressure

Colin 2000 8/56 7/54 1.1[0.43,2.83]
1.1.9 Persistent ocular lesions

Colin 2000 2/56 1/54 1.93[0.18,20.65]
Favours valacyclovir 0.01 0.1 1 10 100 Favours acyclovir
Analysis 1.2. Comparison 1 Valacyclovir versus acyclovir, Outcome 2 Pain at week 24 (self-reported; yes).
Colin 2000 3/56 3/54 0.96[0.2,4.57]
Favours valacyclovir 0.1 0.2 0.5 1 2 5 10 Favours acyclovir
Analysis 1.3. Comparison 1 Valacyclovir versus acyclovir, Outcome 3 Adverse effects.

1.3.1 Vomitting
Colin 2000 3/56 2/54 1.45[0.25,8.32]
1.3.2 Eyelid or facial oedema

Colin 2000 1/56 3/54 0.32[0.03,3]
Informed decisions.

1.3.3 Rectorrhagia
Colin 2000 1/56 0/54 2.89[0.12,69.55]
1.3.4 Kidney stone

Colin 2000 1/56 0/54 2.89[0.12,69.55]
1.3.5 Disseminated zoster

Colin 2000 0/56 1/54 0.32[0.01,7.73]
ADDITIONAL TABLES
Table 1. Ocular involvement

Valacyclovir versus acyclovir in the systemic treatment of herpes zoster ophthalmicus in immunocompetent patients to re-
duce ocular involvement

Outcomes Anticipated absolute effects* Relative effect № of par- Certainty of Comments

(95% CI) (95% CI) ticipants the evidence
(studies) (GRADE)
Risk with Risk with Valacy-
acyclovir clovir
Development of conjunc- 519 per 534 per 1000 RR 1.03 110 ⊕⊕⊝⊝ -
tivitis 1000 (373 to 762) (0.72 to 1.47) (1 RCT) LOW 1 2
Development of punc- 481 per 395 per 1000 RR 0.82 110 ⊕⊕⊝⊝ -
tate keratitis 1000 (255 to 602) (0.53 to 1.25) (1 RCT) LOW 1 2
Development of dendrit- 111 per 107 per 1000 RR 0.96 110 ⊕⊝⊝⊝ -
ic keratitis 1000 (37 to 312) (0.33 to 2.81) (1 RCT) VERY LOW 1 3
Development of dendrit- 19 per 1000 54 per 1000 RR 2.89 110 ⊕⊝⊝⊝ -

ic ulcer (6 to 499) (0.31 to 26.96) (1 RCT) VERY LOW 1 3
Development of stromal 130 per 124 per 1000 RR 0.96 110 ⊕⊝⊝⊝ -
keratitis 1000 (47 to 333) (0.36 to 2.57) (1 RCT) VERY LOW 1 3
Development of uveitis 167 per 125 per 1000 RR 0.75 110 ⊕⊝⊝⊝ -
1000 (50 to 312) (0.30 to 1.87) (1 RCT) VERY LOW 1 3
Development of episcle- 19 per 1000 71 per 1000 RR 3.86 110 ⊕⊝⊝⊝ -

ritis (8 to 619) (0.45 to 33.42) (1 RCT) VERY LOW 1 3
Development of elevated 130 per 143 per 1000 RR 1.10 110 ⊕⊝⊝⊝ -
intraocular pressure 1000 (56 to 367) (0.43 to 2.83) (1 RCT) VERY LOW 1 3
Informed decisions.
Table 1. Ocular involvement (Continued)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the
relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; RCT: randomised controlled trial.

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the ef-
fect, but there is a possibility that it is substantially different.
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the
effect.
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the
estimate of effect.
1 We downgraded 1 level for risk of bias, as the authors did not report on random sequence generation, allocation concealment and masking
of staff, and the extent to which bias had been avoided was largely unclear (-1).
2 We downgraded 1 level for imprecision as confidence intervals were wide and compatible with both benefit or harm.
3 We downgraded 2 levels for imprecision as there were few events and very wide confidence intervals.
Table 2. Adverse effects

Valacyclovir versus acyclovir in the systemic treatment of herpes zoster ophthalmicus in immunocompetent patients - an
analysis of adverse effects

Outcomes Anticipated absolute effects* (95% CI) Relative effect № of partici- Certainty of the Comments
(95% CI) pants evidence
Risk with Risk with Valacyclovir (studies) (GRADE)
acyclovir
Vomiting 37 per 1000 54 per 1000 RR 1.45 110 ⊕⊝⊝⊝ -

(9 to 308) (0.25 to 8.32) (1 RCT) VERY LOW 1 2
Eyelid or fa- 56 per 1000 18 per 1000 RR 0.32 110 ⊕⊝⊝⊝ -

cial oede- (2 to 167) (0.03 to 3.00) (1 RCT) VERY LOW 1 2
ma
Rectorrha- 0 per 1000 0 per 1000 RR 2.89 110 ⊕⊝⊝⊝ -

gia (0 to 0) (0.12 to 69.55) (1 RCT) VERY LOW 1 2
Kidney 0 per 1000 0 per 1000 RR 2.89 110 ⊕⊝⊝⊝ -

stone (0 to 0) (0.12 to 69.55) (1 RCT) VERY LOW 1 2
Disseminat- 19 per 1000 6 per 1000 RR 0.32 110 ⊕⊝⊝⊝ -

ed zoster (0 to 143) (0.01 to 7.73) (1 RCT) VERY LOW 1 2
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the
relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; RCT: randomised controlled trial.

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the ef-
fect, but there is a possibility that it is substantially different.
Informed decisions.
Table 2. Adverse effects (Continued)

Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the
effect.
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the
estimate of effect.
1 We downgraded 1 level for risk of bias, as the authors did not report on random sequence generation, allocation concealment and masking
of staff, and the extent to which bias had been avoided was largely unclear (-1).
2 We downgraded 2 levels for imprecision as there were few events and very wide confidence intervals
APPENDICES
Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Herpes Zoster Ophthalmicus] this term only
#2 MeSH descriptor: [Herpes Zoster] this term only
#3 MeSH descriptor: [Herpesvirus 3, Human] this term only
#4 human herpesvirus 3 or human herpes virus 3
#5 (herpes or varicella) near/2 zoster*
#6 MeSH descriptor: [Chickenpox] this term only
#7 chicken pox or chickenpox
#8 shingles
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 MeSH descriptor: [Acyclovir] this term only
#11 acyclovir or aciclovir
#12 #10 or #11
#13 valacyclovir or valaciclovir or valciclovir or valcyclor or valcyclovir
#14 #9 and #12 and #13
Appendix 2. MEDLINE (Ovid) search strategy

1. randomised controlled trial.pt.
2. (randomised or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. exp animals/
10. exp humans/
11. 9 not (9 and 10)
12. 8 not 11
13. Herpes Zoster Ophthalmicus/
14. Herpes Zoster/
15. Herpesvirus 3, Human/
16. (human herpesvirus 3 or human herpes virus 3).tw.
17. ((herpes or varicella) adj2 zoster$).tw.
18. Chickenpox/
19. (chicken pox or chickenpox).tw.
20. shingles.tw.
21. or/13-20
22. Acyclovir/
23. (acyclovir or aciclovir).tw.
24. or/22-23
25. (valacyclovir or valaciclovir or valciclovir or valcyclor or valcyclovir).tw.
26. or/13-21
27. 21 and 24 and 26
28. 12 and 27
Informed decisions.
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.
Appendix 3. Embase (Ovid) search strategy

1. exp randomised controlled trial/
2. exp randomization/
3. exp double blind procedure/
4. exp single blind procedure/
5. random$.tw.
6. or/1-5
7. (animal or animal experiment).sh.
8. human.sh.
9. 7 and 8
10. 7 not 9
11. 6 not 10
12. exp clinical trial/
13. (clin$ adj3 trial$).tw.
14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15. exp placebo/
16. placebo$.tw.
17. random$.tw.
18. exp experimental design/
19. exp crossover procedure/
20. exp control group/
21. exp latin square design/
22. or/12-21
23. 22 not 10
24. 23 not 11
25. exp comparative study/
26. exp evaluation/
27. exp prospective study/
28. (control$ or prospectiv$ or volunteer$).tw.
29. or/25-28
30. 29 not 10
31. 30 not (11 or 23)
32. 11 or 24 or 31
33. Herpes Zoster Ophthalmicus/
34. Herpes Zoster/
35. Varicella Zoster Virus/
36. (human herpesvirus 3 or human herpes virus 3).tw.
37. ((herpes or varicella) adj2 zoster$).tw.
38. Chickenpox/
39. (chicken pox or chickenpox).tw.
40. shingles.tw.
41. or/33-40
42. Aciclovir/
43. (acyclovir or aciclovir).tw.
44. or/42-43
45. valaciclovir/
46. (valacyclovir or valaciclovir or valciclovir or valcyclor or valcyclovir).tw.
47. or/45-46
48. 41 and 44 and 47
49. 32 and 48
Appendix 4. Web of Science Conference Proceedings Citation Index - Science (CPCI-S) search strategy
#11 #8 AND #9 AND #10
#10 TS=(valacyclovir or valaciclovir or valciclovir or valcyclor or valcyclovir)
#9 TS=(acyclovir or aciclovir)
#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7
#7 TS=shingles
#6 TS=(chicken pox OR chickenpox)
#5 TS=varicella zoster
Informed decisions.
#4 TS= (human herpesvirus 3 OR human herpes virus 3)

#3 TS=Herpesvirus 3, Human
#2 TS= Herpes Zoster
#1 TS=Herpes Zoster Ophthalmicus
Appendix 5. BIOSIS search strategy

#11 #8 AND #9 AND #10
#10 TS=(valacyclovir or valaciclovir or valciclovir or valcyclor or valcyclovir)
#9 TS=(acyclovir or aciclovir)
#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7
#7 TS=shingles
#6 TS=(chicken pox OR chickenpox)
#5 TS=varicella zoster
#4 TS= (human herpesvirus 3 OR human herpes virus 3)
#3 TS=Herpesvirus 3, Human
#2 TS= Herpes Zoster
#1 TS=Herpes Zoster Ophthalmicus
Appendix 6. ISRCTN search strategy

(herpes zoster OR varicella zoster OR herpesvirus OR chicken pox OR chickenpox OR shingles) AND (acyclovir OR aciclovir) AND (valacyclovir
OR valaciclovir OR valciclovir OR valcyclor OR valcyclovir) AND (eye OR ophthalmic OR ophthalmicus OR ocular)
Appendix 7. ClinicalTrials.gov search strategy

(herpes zoster OR varicella zoster OR herpesvirus OR chicken pox OR chickenpox OR shingles) AND (acyclovir OR aciclovir) AND (valacyclovir
OR valaciclovir OR valciclovir OR valcyclor OR valcyclovir) AND (eye OR ophthalmic OR ophthalmicus OR ocular)
Appendix 8. ICTRP search strategy

herpes zoster OR varicella zoster OR herpesvirus OR chicken pox OR chickenpox OR shingles = Condition AND acyclovir OR aciclovir =
Intervention
CONTRIBUTIONS OF AUTHORS
The review was written by AK Schuster (AKS), J Tesarz (JT), MN Jarczok (MNJ), BC Harder (BCH), and FC Schlichtenbrede (FCS). AKS and JT
developed the first draft of the protocol, MNJ made corrections and contributions to the statistical section, BCH and FCS gave clinical advice
on its importance, the selection of outcomes, their measurement, and the subgroup analysis. They made corrections and contributions to
these paragraphs. All authors approved the final review.
DECLARATIONS OF INTEREST
AKS: None known.
BCH: None known.
FCS: None known.
MNJ: None known.
JT: None known.
SOURCES OF SUPPORT
Internal sources
• No sources of support supplied
External sources
• National Institute for Health Research (NIHR), UK.
◦ Richard Wormald, Co-ordinating Editor for the Cochrane Eyes and Vision (CEV) acknowledges financial support for his CEV research
sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye
Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.
◦ The NIHR also funds the CEV Editorial Base in London.
The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS, or the Department of Health.
Informed decisions.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

According to the prespecified protocol, an estimation of distribution for non-continuous data as suggested by Altman 1996 was originally
planned, as well as a transformation of data if necessary (Schuster 2015). However, due to the low number of studies, we abstained from
performing any meta-analytic analyses, but reported data descriptively.
As the primary outcome "occurrence of ocular involvement" could not be determined based on the study reports, we included "persistent
ocular lesions" as outcome. This outcome summarizes ocular involvements being persistent till the end of the study (six months).
INDEX TERMS
Medical Subject Headings (MeSH)

*Immunocompetence; Acyclovir [adverse effects] [*analogs & derivatives] [*therapeutic use]; Antiviral Agents [adverse effects]
[*therapeutic use]; Herpes Zoster Ophthalmicus [*drug therapy] [immunology]; Randomized Controlled Trials as Topic; Valacyclovir;
Valine [adverse effects] [*analogs & derivatives] [therapeutic use]
MeSH check words

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