A Prospective, Randomized Trial of Povidone-
Iodine 0.6% and Dexamethasone 0.1%
Ophthalmic Suspension for Acute Bacterial
Conjunctivitis
CHRISTOPHER N. TA, MICHAEL B. RAIZMAN, ROBERT D. GROSS, SUNIR JOSHI, SUSHANTA MALLICK,
YUEMEI WANG, AND BRUCE SEGAL

PURPOSE: To evaluate the efficacy and safety of a
topical ophthalmic suspension combination of povidone-
iodine 0.6% (PVP-I) and dexamethasone 0.1% (DEX)
for infectious and inflammatory components of bacterial
conjunctivitis.

DESIGN: Randomized, double-masked, multicenter,
phase 3 clinical trial.

METHODS: Subjects of all ages (those <3 months had
to be full-term) with a diagnosis of bacterial conjunctivitis
were randomized 3:1:3 to either PVP-I/DEX, PVP-I
alone, or placebo. The primary endpoint was clinical res-
olution in the study eye, and the key secondary efficacy
endpoint was bacterial eradication, both at the day 5 visit.
Adverse events (AEs) were documented at all visits.

RESULTS: Overall, 753 subjects were randomized
(intent-to-treat [ITT] population; PVP-I/DEX [n [
324]; PVP-I [n [ 108]; placebo [n [ 321]); mean and
standard deviation (SD) age was 44.3 (22.9) years, and
most were female (61.2%) and white (78.1%). In all
treatment groups, mean treatment compliance was
>98%. The modified ITT population for the efficacy
analysis comprised 526 subjects. In the study eye at the
day 5 visit, clinical resolution was achieved by 50.5%
(111/220) subjects in the PVP-I/DEX group vs 42.8%
(95/222) in the placebo group (P [ .127), and bacterial
eradication was achieved by 43.3% (94/217) and 46.8%
(102/218), respectively (P [ .500). Treatment-
emergent AEs were experienced by 32.8% (106/323),
39.8% (43/108), and 19.0% (61/321) of subjects in the
safety population treated with PVP-I/DEX, PVP-I, and
placebo, respectively (most mild in severity).

CONCLUSION: In this study, PVP-I/DEX did not
demonstrate additional benefit in clinical efficacy
Accepted for publication Mar 17, 2020.
From the Stanford University School of Medicine (C.N.T.), Byers Eye
Institute at Stanford, Palo Alto, California; Tufts University School of
Medicine (M.B.R.), Boston, Massachusetts; Department of
Ophthalmology (R.D.G.), University of Texas Southwestern Medical
Center, Dallas, Texas; Pinnacle Research Institute (S.J.), Fort
Lauderdale, Florida; Shire (S.M., Y.W.), a Takeda company, Lexington,
Massachusetts; and private practice (B.S.), Delray Beach, Florida, USA.
Inquiries to Christopher N. Ta, Byers Eye Institute at Stanford, 2452
Watson Court, Palo Alto, CA 94303; e-mail: cta@stanford.edu
56 © 2020 THE AUTHOR(S). PUBLISHED
compared with placebo in subjects with bacterial
conjunctivitis. (Am J Ophthalmol 2020;215:56–65.
Ó 2020 The Author(s). Published by Elsevier Inc. This
is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.
0/).)
B
ACTERIAL CONJUNCTIVITIS IS A COMMON CONDI-
tion that is highly contagious and that typically pre-
sents with conjunctival inflammation and
mucopurulent discharge.1 The economic impact of bacte-
rial conjunctivitis is substantial, with an estimated annual
treatment cost of $377 million to $857 million in the
United States for 2005.2
Although bacterial conjunctivitis usually resolves within
10 days without treatment, clearance of infection can take
<
_3 weeks.3 Treatment of bacterial conjunctivitis with anti-
biotics helps to reduce the duration and transmission of the
infection and the risk of sight-threatening complica-
tions.4,5 Given the risk of antibiotic resistance and allergic
reaction, there is a need for additional topical treatments
with broad-spectrum antimicrobial activity, acceptable
tolerability, and low potential for promoting resistance.
Povidone-iodine or polyvinylpyrrolidone-iodine (PVP-I)
is an effective antiseptic used in general and ophthalmic
surgery for infection prophylaxis.6,7 Preclinical data indi-
cate that PVP-I has broad antimicrobial activity, including
against various Gram-positive and Gram-negative bacterial
isolates and adenoviruses.8–11 In a landmark prospective,
controlled, open-label, nonrandomized study involving
>8000 intraocular cases, the use of topical 5% PVP-I
resulted in significantly fewer patients developing endoph-
thalmitis after intraocular surgery vs silver protein solution
(0.06% vs 0.24%; P < .03).12 In a double-masked,
controlled, prospective, clinical trial of 459 children with
acute conjunctivitis, PVP-I 1.25% ophthalmic solution
instilled 4 times daily was as effective as neomycin-
polymyxin B-gramicidin in treating bacterial conjuncti-
vitis.13 Allergic skin reactions to topical ophthalmic
PVP-I are rare,14 and no cases of bacterial resistance
have been reported in clinical practice across many decades
of use.
BY ELSEVIER INC. 0002-9394
https://doi.org/10.1016/j.ajo.2020.03.018
FIGURE 1. Study design. DEX [ dexamethasone; PVP-I [ povidone-iodine.
Dexamethasone (DEX) is a corticosteroid routinely used
as a topical ophthalmic treatment of ocular inflammation
alone15 or in combination with anti-infective agents.16
Topical steroids have demonstrated utility in reducing
the adverse effects of inflammation in the treatment of in-
fections of the anterior segment of the eye.17–21
In this study, we evaluated the efficacy and safety of a
topical ophthalmic suspension combination of PVP-I
0.6% and DEX 0.1% to treat both the infectious and in-
flammatory components of bacterial conjunctivitis. In an
in vitro study, PVP-I 0.4%/DEX 0.1% killed 99.9% of com-
mon ocular pathogens (eg, methicillin-resistant Staphylo-
coccus aureus, Pseudomonas aeruginosa, Serratia marcescens,
and Candida albicans) within 15 seconds of exposure.22 In
addition, PVP-I 0.6%/DEX 0.1% has demonstrated efficacy
and tolerability in a phase 2 trial of acute adenoviral
conjunctivitis.21
METHODS

STUDY DESIGN: This was a multicenter, randomized,
double-masked, placebo-controlled study conducted at
121 centers in 14 countries. The study was compliant
with the International Conference on Harmonization, Eu-
ropean Union Directive 2001/20/EC and its updates, and
local ethical and legal requirements. It was registered at
ClinicalTrials.gov (NCT03004924). Written informed
consent, and assent where applicable, was obtained from
each subject and/or the subject’s legal representative or
parent, as applicable before any study-related procedures
including screening assessments. The study protocol and
its amendments, subject recruitment information, and the
informed consent form were reviewed and approved by
the institutional review board (IRB) or independent ethics
committee (Copernicus Group IRB, Cary, North Carolina;
Western Institutional Review Board, Puyallup, Washing-
ton; Washington University in St. Louis IRB, St. Louis,
Missouri; East Midlands - Nottingham 2 Research Ethics
Committee, Nottingham, United Kingdom; Ethikkommis-
sion der Medizinischen Universität Wien, Vienna, Austria;
VOL. 215 POVIDONE-IODINE/DEXAMETHASONE FOR BACTERIAL CONJUNCTIVITIS
Comitato Etico - Azienda Ospedaliera Universitaria Poli-
clinico Sant’Orsola Malpighi, Bologna, Italy; Tallinn Med-
ical Research Ethics Committee, Tallinn, Estonia; Ouest II
EC, Angers, France; Egeszsegugyi Tudomanyos Tanacs
Klinikai Farmakologiai Etikai Bizottsaga, Budapest,
Hungary; Komisja Bioetyczna przy Okregowej Izbie Lekar-
skiej w Krakowie, Krakow, Poland; CEIC Grupo HM Hos-
pital Universitario Madrid Monteprı́ncipe, Madrid, Spain;
Human Research Ethics Committee of the University of
the Sunshine Coast, Sippy Downs, Queensland, Australia;
Central Helsinki Committee of Clalit HS Hospitals,
Helsinki, Finland; University of Waterloo- Clinical
Research Ethics Committee, Waterloo, Ontario, Canada;
McGill University Health Center-Research Ethics Board,
Montreal, Quebec, Canada; Rambam Health Care Campus
Ethics Committee, Haifa, Israel; Shaare Zedek MC Ethics
Committee, Jerusalem, Israel; and Pharma Ethics, Pretoria,
South Africa).
Randomization was centralized across study centers and
stratified by age (<6 years, 6-<18 years, and > _18 years).
Subjects were randomized 3:1:3 to receive either PVP-I
0.6%/DEX 0.1%, PVP-I 0.6% alone, or placebo, respec-
tively, using dynamic balanced allocation to maintain the
randomization ratio within each stratum (Figure 1). A
3:1:3 (PVP-I/DEX:PVP-I:placebo) ratio was used to inves-
tigate the efficacy and safety of PVP-I/DEX vs placebo. The
relatively small sized PVP-I arm was exploratory to provide
data for potential future follow-up studies.
The first dose was administered by site staff on day 1, and
thereafter subjects were administered 1 drop into each eye 4
times a day for 7 days. Further study visits occurred on days
3 (visit 2), 5 (visit 3), 8 (visit 4), and 12 (visit 5). All
follow-up procedures were conducted at visit 5. The dura-
tion of the study was <
_13 days for each subject. The placebo
treatment had a similar formulation, including color, as the
PVP-I/DEX and PVP-I treatments without the active com-
ponents (PVP-I and DEX). Benzalkonium chloride 0.01%
was added to the placebo as a preservative but not included
in the PVP-I-DEX and PVP-I treatments, as PVP-I enables
them to be self-preserving. The packaging, appearance, and
labeling of the study treatments were identical. Subject
compliance was verified verbally during study visits.
57
 58

TABLE 1. Pathologic Threshold Criteria for Individual Bacterial Speciesa

Group I Threshold, 1 CFU/mL Group II Threshold, 10 CFU/mL Group III Threshold, 100 CFU/mL Group IV Threshold, 1000 CFU/mL

Streptococcus, group A, beta-hemolytic Staphylococcus aureus Staphylococcus epidermidis Corynebacterium (diphtheroids)

(Streptococcus pyogenes) Streptococcus group B (beta- or Other coagulase-negative Staphylococcus Actinobacteria (Gram-positive Bacillus
Streptococcus pneumoniae nonhemolytic) species species or coccobacillus species)
AMERICAN JOURNAL OF OPHTHALMOLOGY

Citrobacter species Streptococcus group C (alpha-, beta-, or Micrococcus species

Enterobacter species nonhemolytic) Bacillus species
Escherichia species Other Streptococcus (groups D, G; Actinobacteria (Gram-positive cocci
Klebsiella species nongrouped; viridans species species)
Proteus/Morganella species Moraxella (Branhamella) catarrhalis Firmicutes (Gram-positive species)
Serratia marcescens Clostridium perfringens
Other Enterobacteriaceae species
Neisseria gonorrhoeae
Other Neisseria species
Other Moraxella species
Acinetobacter species
Achromobacter species
Haemophilus species
Pseudomonas aeruginosa
Other Pseudomonas species
Bacillus anthracis
Proteobacteria (Gram-negative species)
Bacteroidetes species

CFU ¼ colony-forming unit.

a
Data from Leibowitz and associates.23
JULY 2020
FIGURE 2. Subject disposition. *One subject was randomized in error and therefore captured in the ITT population but not in the
safety population. DEX [ dexamethasone; ITT [ intent-to-treat; PVP-I [ povidone-iodine.

SUBJECTS: Eligible subjects with a diagnosis of bacterial
conjunctivitis based on clinical signs and symptoms were of
all ages (subjects <3 months of age had to be full-term) and
were required to have adenovirus infection ruled out with
an AdenoPlus test (Quidel, San Diego, California, USA;
which detects all serotypes of adenovirus) at baseline in
both eyes. They were also required to have best-corrected
visual acuity of 0.60 logarithm of the minimum angle of res-
olution, equivalent to 20/80 on the Snellen chart, or better,
in each eye; signs and/or symptoms of bacterial conjuncti-
vitis for <
_4 days before the study; and a score totaling > _1
consisting of ocular conjunctival discharge (0-3 scale;
0 ¼ absent to 3 ¼ severe) and bulbar conjunctival injection
(0-4 scale; 0 ¼ absent to 4 ¼ severe).
Individuals were excluded if they met any of the
following criteria: known sensitivity to any components
of the investigational treatments; presence or history of
ocular herpes; presence of ocular inflammation other
than bacterial conjunctivitis (eg, uveitis, iritis, or ulcera-
tive keratitis); intraocular pressure steroid responder or a
history or current diagnosis of glaucoma; history of recur-
rent corneal erosion syndrome, presence of corneal epithe-
lial defect or any significant corneal opacity; clinically
significant optic nerve defects; significant ocular disease
(eg, Sjögren syndrome); or any uncontrolled systemic dis-
ease or debilitating disease. The use of antibiotics or ste-
roids, either topical ophthalmic or systemic, were not
allowed during the study. Also prohibited during the study
were any topical ophthalmic products, including tear
substitutes.

EFFICACY ASSESSMENTS: The primary endpoint was
clinical resolution (absence of bulbar conjunctival injec-
tion and ocular conjunctival discharge [score ¼ 0]) in the
study eye at the day 5 visit. The key secondary efficacy
endpoint was bacterial eradication (absence of all bacterial
species present at or above pathologic threshold at base-
line) at the day 5 visit.
One swab sample from the inferior conjunctival cul de
sac of each eye was collected at all study visits for testing
by bacterial culture. An additional sample was collected
from each eye at visit 1 for qualitative detection of herpes
simplex virus (HSV) DNA. This sample was also used for
polymerase chain reaction qualitative detection of chla-
mydia and gonorrhea in subjects <2 months of age. Sub-
jects who tested positive for ocular HSV at baseline in

VOL. 215 POVIDONE-IODINE/DEXAMETHASONE FOR BACTERIAL CONJUNCTIVITIS 59

 TABLE 2. Demographic Characteristics (Intent-to-Treat Population)

PVP-I/DEX (n ¼ 324) PVP-I (n ¼ 108) Placebo (n ¼ 321) All Subjects (N ¼ 753)

Age, years, mean (SD) 44.2 (22.9) 43.1 (23.0) 44.7 (23.0) 44.3 (22.9)
Sex, n (%)
Male 133 (41.0) 37 (34.3) 122 (38.0) 292 (38.8)
Female 191 (59.0) 71 (65.7) 199 (62.0) 461 (61.2)
Ethnicity, n (%)
Hispanic or Latino 62 (19.1) 30 (27.8) 87 (27.1) 179 (23.8)
Not Hispanic or Latino 254 (78.4) 76 (70.4) 230 (71.7) 560 (74.4)
Not reported/unknown 8 (2.4) 2 (1.9) 4 (1.2) 14 (1.9)
Race, n (%)
Asian 12 (3.7) 0 8 (2.5) 20 (2.7)
Black or African American 54 (16.7) 18 (16.7) 54 (16.8) 126 (16.7)
White 250 (77.2) 88 (81.5) 250 (77.9) 588 (78.1)
Other 8 (2.5) 2 (1.8) 9 (2.8) 19 (2.5)

DEX ¼ dexamethasone; PVP-I ¼ povidone-iodine; SD ¼ standard deviation.

either eye had their study treatment discontinued and
received alternate appropriate treatment as needed based
on the investigator’s clinical judgment. These subjects
were followed up for the remaining duration of the study
at the scheduled visits, and all safety-related assessments
were completed.

BACTERIAL CULTURE: Pathologic threshold for individ-
ual bacterial species was based on colony-forming unit per
milliliter threshold levels, established by Cagle and modi-
fied by Leibowitz and associates23 for different ocular bacte-
rial species found in the specimens collected from each
subject. In addition, bacterial species that were not covered
by Leibowitz and associates23 were assigned threshold
criteria (Table 1). Bacterial species were identified by
matrix-assisted laser desorption/ionization-time of flight
mass spectrometry, using their unique protein patterns.

SAFETY ASSESSMENTS: Adverse events (AEs), slit-lamp
biomicroscopy, and best-corrected visual acuity were docu-
mented at all study visits. AEs were coded using Medical
Dictionary for Regulatory Activities, version 19.1.24
Treatment-emergent AEs (TEAEs) were defined as any
AE that occurred after the instillation of the first dose of
study medication. Best-corrected visual acuity was assessed
using an Early Treatment Diabetic Retinopathy Study
chart. Urine pregnancy test on all females of childbearing
potential and fundus examination were performed at visits
1 and 5. A nondilated fundus examination was performed
in all subjects except infants and uncooperative small chil-
dren during the study. If a nondilated fundus examination
was attempted and was not feasible, a dilated fundus exam-
ination was performed.

STATISTICAL ANALYSES: All efficacy analyses were
based on the modified intention-to-treat (mITT) popu-
lation unless stated otherwise. The mITT population
consisted of a subset of the ITT population (all ran-
domized subjects) who received > _1 dose of study medi-
cation and had a positive bacterial culture (presence of
>
_1 bacterial species at or above pathologic threshold) at
baseline in the study eye. The safety population
consisted of all subjects who received > _1 dose of study
medication.
The primary and key secondary endpoints were tested us-
ing Fisher exact test at the 2-sided 0.0499 significance
level. Missing postbaseline efficacy assessments were
imputed using last observation carried forward from postba-
seline values.
The study eye was an eligible eye, defined as an eye
with a score of > _1 for both ocular conjunctival discharge
and bulbar conjunctival redness at baseline. For subjects
with both eyes eligible and having either a positive or
non-positive bacterial culture at baseline, the study
eye was the one with the highest global clinical score
(sum of bulbar conjunctival injection and ocular
conjunctival discharge) at baseline. If both eyes had
the same global clinical score at baseline, then the study
eye was the right eye. For subjects with both eyes
eligible and a positive bacterial culture in 1 eye at base-
line, the study eye was the 1 with positive baseline bac-
terial culture. If subjects had only 1 eligible eye, this
was the study eye regardless of its baseline bacterial cul-
ture result.
The sample size was estimated for the primary compari-
son of clinical resolution using nQuery Advisor 7.0. A sam-
ple size of 504 subjects (PVP-I/DEX, n ¼ 216; PVP-I, n ¼
72; placebo, n ¼ 216) was estimated to ensure approxi-
mately 90% power to compare the PVP-I/DEX and placebo
treatment groups assuming 61% and 45% subjects with
clinical resolution, respectively, using Fisher exact test at
the 2-sided 0.05 significance level.

60 AMERICAN JOURNAL OF OPHTHALMOLOGY JULY 2020

 TABLE 3. Bacterial Species at or Above Pathologic Threshold in the Study Eye at Baseline (Modified Intent-to-Treat Population)

Species, n (%) PVP-I/DEX (n ¼ 223) PVP-I (n ¼ 76) Placebo (n ¼ 227) All Subjects (N ¼ 526)

Staphylococcus epidermidis 142 (63.7) 48 (63.2) 147 (64.8) 337 (64.1)

Staphylococcus aureus 23 (10.3) 12 (15.8) 44 (19.4) 79 (15.0)
Haemophilus influenza 37 (16.6) 12 (15.8) 23 (10.1) 72 (13.7)
Staphylococcus warneri 32 (14.3) 12 (15.8) 21 (9.3) 65 (12.4)
Staphylococcus hominis 16 (7.2) 10 (13.2) 18 (7.9) 44 (8.4)
Staphylococcus pasteuri 13 (5.8) 7 (9.2) 10 (4.4) 30 (5.7)
Staphylococcus haemolyticus 10 (4.5) 2 (2.6) 7 (3.1) 19 (3.6)
Staphylococcus mitis 9 (4.0) 4 (5.3) 6 (2.6) 19 (3.6)
Bacillus species 4 (1.8) 1 (1.3) 8 (3.5) 13 (2.5)
Enterococcus faecalis 5 (2.2) 2 (2.6) 4 (1.8) 11 (2.1)
Staphylococcus capitas 5 (2.2) 1 (1.3) 5 (2.2) 11 (2.1)
Staphylococcus lugdenensis 4 (1.8) 0 7 (3.1) 11 (2.1)
Acinetobacter baumanii complex 3 (1.3) 0 7 (3.1) 10 (1.9)
Other (strains affecting <10 patients overall) 67 (30.0) 30 (39.5) 59 (26.0) 156 (29.7)

DEX ¼ dexamethasone; PVP-I ¼ povidone-iodine.

EFFICACY FINDINGS: A numerically higher proportion

RESULTS

STUDY POPULATION: The study was conducted between
March 2017 and October 2018. From 1080 subjects
screened, 753 were randomized and included in the ITT
population; 752 subjects were dosed and included in the
safety population, while 526 were included in the mITT
population and analyzed for efficacy. A total of 684 subjects
completed the study (Figure 2).
The mean (SD) age across all subjects in the ITT popu-
lation was 44.3 (22.9) years. Most subjects were female
(61.2%) and white (78.1%, Table 2). Overall, mean treat-
ment compliance was >98% in all treatment groups.
Completion of 4 days of dosing by the day 5 visit with no
extra or missed dose was achieved by 88.5% of subjects in
the PVP-I/DEX group, 79.6% in the PVP-I group and
91.0% in the placebo group. The most frequent ocular med-
ical history conditions included cataracts (20.6%), dry eye
(10.8%), myopia (6.0%), and eyelid dermatochalasis
(5.6%). The most frequent non-ocular medical history con-
ditions across all subjects included hypertension (28.3%),
hypercholesterolemia (15.4%), type 2 diabetes mellitus
(10.5%), gastroesophageal reflux disease (10.0%), and hy-
pothyroidism (9.6%). There were no major differences in
ocular or non-ocular medical history across treatment
groups.
Overall, the incidence of bacterial species at or above
pathological threshold in the study eye present at baseline
was similar between treatment groups (Table 3). The bac-
terial species that were present in the highest number of
subjects at baseline in the mITT population were the
Gram-positive species Staphylococcus epidermidis in 64.1%
(n ¼ 337/526) of subjects and S. aureus in 15.0% (79/
526) of subjects and the Gram-negative species Haemophi-
lus influenzae in 13.7% (n ¼ 72/526) of subjects.
of subjects in the PVP-I/DEX group achieved the primary
endpoint of clinical resolution in the study eye at the day
5 visit with last observation carried forward (50.5% [111/
220] PVP-I/DEX; 42.8% [95/222] placebo; P ¼ .127,
Figure 3) vs the placebo group; this difference did not
meet the 2-sided .0499 significance level. Three planned
sensitivity analyses conducted on the primary endpoint
data gave similar results. For the last observation carried
forward analysis in the ITT population, clinical resolution
in the study eye was achieved in 49.8% (159/319) of sub-
jects in the PVP-I/DEX group and in 44.0% (139/316) of
subjects who received placebo (P ¼ .152). For the worst
observation carried forward analysis in the mITT popula-
tion, clinical resolution in the study eye was achieved in
49.8% (111/223) of subjects in the PVP-I/DEX group and
in 41.4% (94/227) of subjects in the placebo group (P ¼
.088). For the multiple imputation analysis in the mITT
population, the pooled proportion of subjects who achieved
clinical resolution in the study eye was 51.7% in the PVP-I/
DEX group and 42.5% in the placebo group (P ¼ .057).
There were no significant differences between the PVP-
I/DEX and placebo groups in the key secondary endpoint,
bacterial eradication in the study eye at the day 5 visit
(mITT population: PVP-I/DEX, 43.3% [94/217]; placebo,
46.8% [102/218]; P ¼ .500, Figure 3).

SAFETY FINDINGS: Overall, 32.8% (106/323) of subjects
in the PVP-I/DEX group experienced > _1 TEAE vs 39.8%
(43/108) in the PVP-I group and 19.0% of subjects (61/
321) in the placebo group. A similar pattern was reported
for subjects with >_1 treatment-related TEAE (Table 4).
No serious AEs or deaths were reported in this study.
Across all treatment groups, most ocular and nonocular
TEAEs were considered mild in severity, and few subjects

VOL. 215 POVIDONE-IODINE/DEXAMETHASONE FOR BACTERIAL CONJUNCTIVITIS 61

FIGURE 3. Clinical resolution (A) and bacterial eradication (B) at day 5 (plus 1-day window; modified intent-to-treat population
with last observation carried forward, study eye). Percentages are based on the number of subjects achieving clinical resolution or
bacterial eradication (n) in the modified intent-to-treat population with observed or imputed data in each treatment group (N). Values
inside bars [ n/N. D [ difference in proportion for clinical resolution or bacterial eradication; CI [ confidence interval; DEX [
dexamethasone; PVP-I [ povidone-iodine.

had severe ocular or nonocular TEAEs. The incidence of
TEAEs leading to discontinuation of treatment was low
in all groups (PVP-I/DEX, 1.9%; PVP-I, 4.6%; placebo,
3.1%; Table 4).
Instillation site pain was the most common treatment-
related ocular TEAE and was the most common ocular
TEAE leading to discontinuation, although this was infre-
quent (PVP-I/DEX, 0.9% [n ¼ 3/323]; PVP-I, 1.9% [n ¼ 2/
108]), 0 placebo). Most instillation site pain was reported as
mild to moderate in severity with 0.9% (n ¼ 3/323) and
1.9% (n ¼ 2/108) of subjects in the PVP-I/DEX and
PVP-I groups, respectively, reporting it as severe. The rates
of other administration site AEs were also low. For
example, instillation site irritation, which coded for the
verbatim terms of ocular irritation/stinging during or post-
instillation, was reported in 0.3% (PVP-I/DEX), 0.9%
(PVP-I), and 0.3% (placebo) of subjects. Instillation site
reaction, which coded for blurry/blurred vision or light
sensitivity during or postinstillation, was reported in
0.9% (PVP-I/DEX), 0.9% (PVP-I), and 0% (placebo) of
subjects. The incidence of corneal AEs was low, including
punctate keratitis (PVP-I/DEX, 0; PVP-I, 1.9%; placebo,
0.9%) and corneal infiltrates (PVP-I/DEX, 1 [0.3%] patient
had mild corneal infiltrates in both eyes; PVP-I, 0; placebo,
2 [0.6 %] patients, 1 with mild and 1 with moderate corneal
infiltrates in their study eyes, leading to treatment discon-
tinuation in 1 patient).
Nineteen subjects (PVP-I/DEX, n ¼ 11; PVP-I, n ¼ 2;
placebo, n ¼ 6) tested positive for ocular HSV at baseline
and discontinued treatment but were followed for safety for
the remainder of the study visits. Of these subjects, 3 (PVP-
I/DEX, 0; PVP-I, n ¼ 1; placebo, n ¼ 2) reported ocular
TEAEs, none of which was active HSV keratitis, and 3
(PVP-I/DEX, n ¼ 1; PVP-I, n ¼ 1; placebo, n ¼ 1) reported
nonocular TEAEs.
The most common nonocular TEAE related to study
medication was dysgeusia, reported in 1.5% (n ¼ 5/323)
of subjects in the PVP-I/DEX group, but dysgeusia was
not reported in the other treatment groups.
DISCUSSION
THIS PHASE 3 STUDY EVALUATED THE EFFICACY AND SAFETY
of PVP-I 0.6%/DEX 0.1% ophthalmic suspension
compared with placebo in the treatment of bacterial
conjunctivitis. To our knowledge, this is the first large,
multicenter, randomized controlled trial of a topical
ophthalmic treatment containing PVP-I for the treatment
of bacterial conjunctivitis. In this study, the primary
endpoint of clinical resolution in the study eye was not
met. Although a greater percentage of subjects demon-
strated clinical resolution at the day 5 visit in the PVP-I/
DEX group compared with placebo, the difference between
the treatment groups was not statistically significant. For
the key secondary endpoint, bacterial eradication after
5 days of treatment, there were no notable differences in ef-
ficacy between the PVP-I/DEX group and the placebo
group. PVP-I/DEX was well tolerated and there were no
safety concerns.
Results from previous early-stage studies provide support
for the use of topical ophthalmic PVP-I/DEX solution to
prevent or treat ocular bacterial infections. In studies in
which PVP-I 5.0% was instilled in the eye immediately af-
ter ophthalmic surgery25 or administered at doses of 1.25%
and 2.5% for 3 times a day for a week after surgery,26 PVP-I
was significantly more effective at preventing an increase in
conjunctival bacterial colony-forming units vs a control
group of untreated eyes. In a large, controlled clinical

62 AMERICAN JOURNAL OF OPHTHALMOLOGY JULY 2020

 TABLE 4. Summary of Treatment-Emergent Adverse Events (Safety Population)

TEAE Type, n (%) PVP-I/DEX (n ¼ 323) PVP-I (n ¼ 108) Placebo (n ¼ 321) All Subjects (N ¼ 752)

Any TEAE 106 (32.8) 43 (39.8) 61 (19.0) 210 (27.9)

Treatment-related TEAEs 72 (22.3) 29 (26.9) 20 (6.2) 121 (16.1)
Ocular TEAEs 86 (26.6) 36 (33.3) 48 (15.0) 170 (22.6)
Mild 76 (23.5) 29 (26.9) 40 (12.5) 145 (19.3)
Moderate 11 (3.4) 6 (5.6) 10 (3.1) 27 (3.6)
Severe 5 (1.5) 4 (3.7) 2 (0.6) 11 (1.5)
Nonocular TEAEs 36 (11.1) 14 (13.0) 19 (5.9) 69 (9.2)
Mild 29 (9.0) 9 (8.3) 13 (4.0) 51 (6.8)
Moderate 7 (2.2) 5 (4.6) 8 (2.5) 20 (2.7)
Severe 1 (0.3) 0 1 (0.3) 2 (0.3)
TEAEs resulting in discontinuation 6 (1.9) 5 (4.6) 10 (3.1) 21 (2.8)
Ocular TEAEs resulting in discontinuation 3 (0.9) 3 (2.8) 8 (2.5) 14 (1.9)
Most frequent (>5%) ocular TEAE
Instillation site pain 67 (20.7) 26 (24.1) 7 (2.2) 100 (13.3)

DEX ¼ dexamethasone; PVP-I ¼ povidone-iodine; TEAE ¼ treatment-emergent adverse event.

study,13 PVP-I 1.25% was shown to be as effective as
neomycin-polymyxin-B gramicidin for the treatment of
bacterial conjunctivitis as measured by time to cure.13
The PVP-I concentration in our study was lower than
that used in these studies. The rationale for the 0.6%
dose was based on data that release of the active moiety,
iodine, from the PVP-I complex as well as PVP-I bacteri-
cidal activity are optimal at aqueous concentrations be-
tween 0.1 and 1.0%.9,27,28 In addition, in clinical studies
of adenoviral conjunctivitis, clinical efficacy was achieved
with PVP-I/DEX suspensions containing PVP-I between
0.4% and 1.0%.19,21,29 However, although free iodine con-
centrations peak in this dose range, the cumulative antimi-
crobial effect may be short, because the available iodine is
quickly used up in the reaction with bacteria.30 This may
explain the lack of efficacy for PVP-I/DEX in the present
study.
Benzalkonium chloride 0.01% was added to the placebo
preparation as a preservative but was not included in the
PVP-I-DEX and PVP-I treatments because PVP-I itself is
a preservative. Benzalkonium chloride is the most
commonly used preservative in ophthalmic preparations31;
however, as an antimicrobial agent and a cationic surfac-
tant,32 it may itself have efficacy in the treatment of bacte-
rial conjunctivitis, thereby contributing to the lack of
difference in efficacy between the placebo and treatment
groups. Indeed, in a previous study benzalkonium chloride
inhibited growth and biofilm formation of ocular staphylo-
coccal isolates in vitro in a dose-dependent manner.33
While a similar efficacy between the benzalkonium
chloride–containing placebo group, and the PVP-I-DEX
and PVP-I treatment groups was observed, the use of
benzalkonium chloride as a low-cost topical antiseptic
agent has a number of disadvantages, including disruption
and damage to the corneal epithelium,34,35 fibrosis,36 dry
eye syndrome,37 and increased risk of failure of trabeculec-
tomy in glaucoma.38 The inclusion of this agent is a poten-
tial limitation of this study, and should be investigated in
future studies both in vitro and in vivo.
The requirement of a negative AdenoPlus test result for
inclusion in this study may also have affected the outcome.
According to the AdenoPlus product insert, this test has a
negative predictive value of 97%.39 However, low levels of
virus shedding in the early stages of the infection in sub-
jects with adenoviral conjunctivitis could have led to false
negative results. In addition, subjects with a negative
AdenoPlus test could still have been positive for other vi-
ruses, such as coxsackievirus or enterovirus. Another
consideration is that instillation of PVP-I drops may be a
suboptimal method of drug administration because the
drug may not reach the deep crypts of the conjunctival
fornices. In a study of patients undergoing anterior segment
intraocular surgery, irrigation of PVP-I was shown to be
more effective than the instillation of PVP-I drops.40
In this study, PVP-I/DEX appeared to be well tolerated.
Although the incidence of TEAEs was higher in subjects in
the PVP-I/DEX group, severe AEs and discontinuations
owing to TEAEs were infrequent and no serious AEs
were reported. Instillation site pain was the most frequent
ocular TEAE related to treatment, with 20.7% of subjects
in the PVP-I/DEX group experiencing this AE compared
with 2.2% in the placebo group. However, most instillation
site pain was reported as mild to moderate in severity, and
discontinuations arising from this AE occurred in only 3
PVP-I/DEX-treated subjects, representing 0.9% of this
treatment group. The rates of other administration site
AEs, such as instillation site irritation (ocular irritation/
stinging), were also low. Of note, there was no difference

VOL. 215 POVIDONE-IODINE/DEXAMETHASONE FOR BACTERIAL CONJUNCTIVITIS 63

in safety between enrolled children (<6 years [n ¼ 46], and
6 to <18 years [n ¼ 56]) in comparison with that in the
overall patient population (>_18 years [n ¼ 650]; data not
shown).
Cataract formation and increases in intraocular pressure
have been reported in previous studies in which corticoste-
roids have typically been administered for >_2 weeks.41–46 In
the present study, there were no increases in the incidence
of cataract development or glaucoma reported as AEs, and
none of the 19 patients with a positive conjunctival HSV
DNA at baseline developed active HSV keratitis during
the study.
The main limitation of this study is that it is possible that
randomized subjects had viral conjunctivitis that was not
caused by adenovirus. In addition, the posology of PVP-I
in the study combination may not have been appropriate.
Future dose-ranging studies are needed to determine the
optimal PVP-I concentration for use in bacterial conjunc-
tivitis. However, PVP-I concentrations >1.25% may
decrease tolerability.13,26
In conclusion, in this phase 3 study, PVP-I/DEX did not
demonstrate clinical efficacy compared with placebo in
subjects with bacterial conjunctivitis. The posology of
PVP-I in the study combination may have been subopti-
mal. PVP-I/DEX had a favorable safety profile and was
well tolerated.
CRediT AUTHORSHIP CONTRIBUTION
STATEMENT
CHRISTOPHER N. TA: FORMAL ANALYSIS, WRITING - RE-
view & editing. Michael B. Raizman: Formal analysis,
Writing - review & editing. Robert D. Gross: Formal anal-
ysis, Writing - review & editing. Sunir Joshi: Formal anal-
ysis, Writing - review & editing. Sushanta Mallick: Formal
analysis, Writing - review & editing. Yuemei Wang:
Formal analysis, Writing - review & editing. Bruce Segal:
Formal analysis, Writing - review & editing.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST.
Funding/Support: Funded by Shire, a Takeda company. Financial Disclosures: Dr Gross has been a consultant for Shire PLC. Dr Ta has been a consultant
for Shire PLC, and his contribution to this publication was not part of his Stanford University duties or responsibilities. Dr Joshi received research funding
from Shire, a Takeda company. Dr Raizman has been a consultant for Aerie, Alcon, Avedro, BlephEx, EyeGate, Kala, Ocular Therapeutix, Shire PLC, Sun
Pharma, and TearLab, and owns stock in Avedro and EyeGate. Drs Mallick and Wang are employees of and hold stock or stock options in Shire, a Takeda com-
pany. Dr Segal has no financial conflicts of interest. Under direction of the authors, Nasser Malik, an employee of Excel Scientific Solutions, provided writing
assistance. Writing and editorial support were funded by Shire, a Takeda company. All authors attest that they meet the current ICMJE criteria for authorship.

REFERENCES 10. Kawana R, Kitamura T, Nakagomi O, et al. Inactivation of

1. Azari AA, Barney NP. Conjunctivitis: a systematic review of
diagnosis and treatment. JAMA 2013;310(16):1721–1729.
2. Smith AF, Waycaster C. Estimate of the direct and indirect
annual cost of bacterial conjunctivitis in the United States.
BMC Ophthalmol 2009;9:13.
3. Patel PB, Diaz MC, Bennett JE, Attia MW. Clinical features
of bacterial conjunctivitis in children. Acad Emerg Med 2007;
14(1):1–5.
4. Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician
1998;57(4):735–746.
5. Sheikh A, Hurwitz B. Topical antibiotics for acute bacterial
conjunctivitis: a systematic review. Br J Gen Pract 2001;
51(467):473–477.
6. Koerner JC, George MJ, Meyer DR, Rosco MG, Habib MM.
Povidone-iodine concentration and dosing in cataract sur-
gery. Surv Ophthalmol 2018;63(6):862–868.
7. Lachapelle JM, Castel O, Casado AF, et al. Antiseptics in the
era of bacterial resistance: a focus on povidone iodine. Clin
Pract 2013;10(5):579–592.
8. Benevento WJ, Murray P, Reed CA, Pepose JS. The sensi-
tivity of Neisseria gonorrhoeae, Chlamydia trachomatis, and her-
pes simplex type II to disinfection with povidone-iodine. Am J
Ophthalmol 1990;109(3):329–333.
9. Berkelman RL, Holland BW, Anderson RL. Increased bacte-
ricidal activity of dilute preparations of povidone-iodine solu-
tions. J Clin Microbiol 1982;15(4):635–639.
human viruses by povidone-iodine in comparison with other
antiseptics. Dermatology 1997;195(suppl 2):29–35.
11. Sauerbrei A, Wutzler P. Virucidal efficacy of povidone-iodine-
containingdisinfectants.LettApplMicrobiol2010;51(2):158–163.
12. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis
with topical povidone-iodine. Ophthalmology 1991;98(12):
1769–1775.
13. Isenberg SJ, Apt L, Valenton M, et al. A controlled trial of
povidone-iodine to treat infectious conjunctivitis in children.
Am J Ophthalmol 2002;134(5):681–688.
14. Wykoff CC, Flynn HW Jr, Han DP. Allergy to povidone-
iodine and cephalosporins: the clinical dilemma in
ophthalmic use. Am J Ophthalmol 2011;151(1):4–6.
15. Laurell CG, Zetterstrom C. Effects of dexamethasone, diclo-
fenac, or placebo on the inflammatory response after cataract
surgery. Br J Ophthalmol 2002;86(12):1380–1384.
16. Notivol R, Amin D, Whitling A, et al. Prophylactic effective-
ness of tobramycin-dexamethasone eye drops compared with
tobramycin/vehicle eye drops in controlling post-surgical
inflammation in cataract patients: prospective, randomised,
double-masked, two-arm, parallel-group, placebo-controlled,
multicentre study. Clin Drug Investig 2004;24(9):523–533.
17. Holland EJ, Fingeret M, Mah FS. Use of topical steroids in
conjunctivitis: a review of the evidence. Cornea 2019;38(8):
1062–1067.
18. American Academy of Ophthalmology Cornea/External Dis-
ease PPP Panel. Preferred Practice Pattern Guidelines.

64 AMERICAN JOURNAL OF OPHTHALMOLOGY JULY 2020

 Conjunctivitis. American Academy of Ophthalmology.
Available at: https://www.aaojournal.org/article/S0161-6420
(18)32646-0/pdf. Accessed November 13, 2018.
19. Kovalyuk N, Kaiserman I, Mimouni M, et al. Treatment of
adenoviral keratoconjunctivitis with a combination of
povidone-iodine 1.0% and dexamethasone 0.1% drops: a
clinical prospective controlled randomized study. Acta
Ophthalmol 2017;95(8):e686–e692.
20. Mohan N, Gupta V, Tandon R, Gupta SK, Vajpayee RB.
Topical ciprofloxacin-dexamethasone combination therapy
after cataract surgery: randomized controlled clinical trial. J
Cataract Refract Surg 2001;27(12):1975–1978.
21. Pepose JS, Ahuja A, Liu W, Narvekar A, Haque R. Random-
ized, controlled, phase 2 trial of povidone-iodine/
dexamethasone ophthalmic suspension for treatment of
adenoviral conjunctivitis. Am J Ophthalmol 2018;194:7–15.
22. Pelletier JS, Miller D, Liang B, Capriotti JA. In vitro efficacy
of a povidone-iodine 0.4% and dexamethasone 0.1% suspen-
sion against ocular pathogens. J Cataract Refract Surg 2011;
37(4):763–766.
23. Leibowitz HM. Antibacterial effectiveness of ciprofloxacin
0.3% ophthalmic solution in the treatment of bacterial
conjunctivitis. Am J Ophthalmol 1991;112(4 suppl):29S–33S.
24. Medical Dictionary for Regulatory Activities. Introductory
guide MedDRA version 19.1. Available at: https://www.
meddra.org/sites/default/files/guidance/file/intguide_19_1_
english.pdf. Accessed April 4, 2020.
25. Apt L, Isenberg SJ, Yoshimori R, et al. The effect of
povidone-iodine solution applied at the conclusion of
ophthalmic surgery. Am J Ophthalmol 1995;119(6):701–705.
26. Isenberg SJ, Apt L, Yoshimori R, Pham C, Lam NK. Efficacy
of topical povidone-iodine during the first week after
ophthalmic surgery. Am J Ophthalmol 1997;124(1):31–35.
27. Zamora JL. Chemical and microbiologic characteristics and
toxicity of povidone-iodine solutions. Am J Surg 1986;
151(3):400–406.
28. Rackur H. New aspects of mechanism of action of povidone-
iodine. J Hosp Infect 1985;6(suppl A):13–23.
29. Pinto RD, Lira RP, Abe RY, et al. Dexamethasone/povidone
eye drops versus artificial tears for treatment of presumed viral
conjunctivitis: a randomized clinical trial. Curr Eye Res 2015;
40(9):870–877.
30. Shimada H, Nakashizuka H, Grzybowski A. Prevention and
treatment of postoperative endophthalmitis using povidone-
iodine. Curr Pharm Des 2017;23(4):574–585.
31. Kaur IP, Lal S, Rana C, Kakkar S, Singh H. Ocular preserva-
tives: associated risks and newer options. Cutan Ocul Toxicol
2009;28(3):93–103.
32. Kim YH, Jung JC, Jung SY, Yu S, Lee KW, Park YJ. Compar-
ison of the efficacy of fluorometholone with and without
benzalkonium chloride in ocular surface disease. Cornea
2016;35(2):234–242.
VOL. 215 POVIDONE-IODINE/DEXAMETHASONE FOR BACTERIAL CONJUNCTIVITIS
33. Wu EC, Kowalski RP, Romanowski EG, Mah FS,
Gordon YJ, Shanks RM. AzaSite(R) inhibits Staphylococcus
aureus and coagulase-negative Staphylococcus biofilm for-
mation in vitro. J Ocul Pharmacol Ther 2010;26(6):
557–562.
34. Burstein NL. Preservative cytotoxic threshold for benzal-
konium chloride and chlorhexidine digluconate in cat
and rabbit corneas. Invest Ophthalmol Vis Sci 1980;19(3):
308–313.
35. Burstein NL. The effects of topical drugs and preservatives on
the tears and corneal epithelium in dry eye. Trans Ophthalmol
Soc U K 1985;104(pt 4):402–409.
36. Goh CL. Contact sensitivity to topical antimicrobials. (II).
Sensitizing potentials of some topical antimicrobials. Contact
Dermatitis 1989;21(3):166–171.
37. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface in-
flammatory changes induced by topical antiglaucoma drugs:
human and animal studies. Ophthalmology 1999;106(3):
556–563.
38. Kuppens EV, de Jong CA, Stolwijk TR, de Keizer RJ, van
Best JA. Effect of timolol with and without preservative on
the basal tear turnover in glaucoma. Br J Ophthalmol 1995;
79(4):339–342.
39. Quidel. Procedural bulletin. Available at: https://www.quidel.
com/sites/default/files/product/documents/CL1337501EN00.
pdf. Accessed June 27, 2019.
40. Mino de Kaspar H, Chang RT, Singh K, Egbert PR,
Blumenkranz MS, Ta CN. Prospective randomized compari-
son of 2 different methods of 5% povidone-iodine applica-
tions for anterior segment intraocular surgery. Arch
Ophthalmol 2005;123(2):161–165.
41. Bartlett JD, Horwitz B, Laibovitz R, Howes JF. Intraocular
pressure response to loteprednol etabonate in known steroid
responders. J Ocul Pharmacol 1993;9(2):157–165.
42. Clark AF, Wilson K, de Kater AW, Allingham RR,
McCartney MD. Dexamethasone-induced ocular hyperten-
sion in perfusion-cultured human eyes. Invest Ophthalmol
Vis Sci 1995;36(2):478–489.
43. Leibowitz HM, Bartlett JD, Rich R, McQuirter H, Stewart R,
Assil K. Intraocular pressure-raising potential of 1.0% rimex-
olone in patients responding to corticosteroids. Arch Ophthal-
mol 1996;114(8):933–937.
44. Mindel JS, Tavitian HO, Smith H Jr, Walker EC. Compara-
tive ocular pressure elevation by medrysone, fluorometho-
lone, and dexamethasone phosphate. Arch Ophthalmol 1980;
98(9):1577–1578.
45. Costagliola C, Cati-Giovannelli B, Piccirillo A, Delfino M.
Cataracts associated with long-term topical steroids. Br J
Dermatol 1989;120(3):472–473.
46. McLean CJ, Lobo RF, Brazier DJ. Cataracts, glaucoma, and
femoral avascular necrosis caused by topical corticosteroid
ointment. Lancet 1995;345(8945):330.
65