Comparison of antibiotic-only and antibioticsteroid

combination treatment in corneal ulcer patients: double-blinded

randomized clinical trial
Jason Blair,* MD; William Hodge,{ MD, PhD, FRCSC; Saeed Al-Ghamdi,* MD, FRCSC; Rita Balabanian,* BSc;
Beth Lowcock,* MSc; Yi Irene Pan{; Hesham Sherif,* MD, FRCSC; Tahra AlMahmoud,* MD, FRCSC;
Dean Fergusson,{ PhD; Allan Slomovic, MD, FRCSC
ABSTRACT N RESUME
Objective: To determine the benefit of early addition of corticosteroids to antibiotics in the treatment of corneal ulcers.
Design: Randomized clinical trial.
Participants: Thirty eyes of 30 patients, over the age of 12 years, with bacterial corneal ulcer confirmed by culture.
Methods: Patients were randomized before enrollment; 15 were treated with gatifloxacin (Zymar) and a masked placebo and the other 15 were
treated with gatifloxacin and masked dexamethasone 0.1% (Maxidex). Primary outcome was residual ulcer size at 10 weeks based on
digital photographs. Secondary outcomes included residual ulcer area by clinician estimate, visual acuity, VF-14 score, and time to healing.
Results: All subjects (n 5 30) demonstrated a reduction in ulcer size over the study period. There was no significant difference between the
2 groups in terms of the primary outcome. There was a significant difference between the 2 groups in 1 of the secondary outcomes. The
mean residual ulcer size compared with the baseline by clinician estimate (slit-lamp) was 20.789 mm2 for the antibiotic-only group and
24.206 mm2 for the antibioticsteroid group (p 5 0.05). Among the other secondary outcomes there were no significant differences
between the 2 groups.
Conclusions: No benefit was demonstrated in our primary outcome for using steroids in combination with antibiotic therapy in treatment of
corneal ulcers. This study suggests that the early addition of steroids to the antibiotic treatment of corneal ulcers does not seem to be
harmful when employed in a closely monitored clinical setting.
Objet : Etablir lavantage de lajout rapide des corticosterodes aux antibiotiques dans le traitement des ulce`res corneens.
Nature : Essais cliniques randomises.
Participants : Trente yeux de 30 patients de plus de 12 ans, ayant un ulce`re bacterien de la cornee, confirme par culture.
Methodes : Les patients ont ete randomises avant linscription; 15 ont ete traites la gatifloxacine (Zymar) avec placebo masque et 15 autres
le furent avec gatifloxacine et dexamethasone masquee 0,1 % (Maxidex). Le premier resultat a porte sur la taille residuelle de lulce`re
apre`s 10 semaines selon les photographies numeriques. Les resultats secondaires ont porte sur laire residuelle de lulce`re selon
lestimation du clinicien, lacuite visuelle, le score VF-14 et le delai de guerison.
Resultats : Tous les sujets (n 5 30) ont montre une reduction de la taille de lulce`re pendant letude. Il ny eut pas decart significatif entre les 2
groupes quant au premier resultat. Les seconds resultats ont presente un ecart important entre les 2 groupes au niveau dun des
resultats. La taille residuelle moyenne comparativement lestimation de base du clinicien (biomicroscopie) etait 20,789 mm2 pour le
groupe antibiotique seulement et 24,206 mm2 pour le groupe antibiotique sterode (p 5 0,05). Quant aux autres resultats secondaires,
il ny eut pas decarts significatifs entre les 2 groupes.
Conclusions : Nos premiers resultats nont pas demontre quil etait avantageux dutiliser des sterodes en combinaison avec la therapie
antibiotique pour traiter les ulce`res de la cornee. Cette etude sugge`re que lajout rapide de sterodes au traitement antibiotique des
ulce`res corneens ne semble pas nuire dans un encadrement clinique suivi de pre`s.

Infectious ulcerative keratitis (corneal ulcer) is an increasingly common sight-threatening condition and is of
significant concern to public health. Between 1950 and
1988 the incidence of corneal ulcers increased by 435%
in the United States.1 This increase has largely been attributed to the increased use of contact lenses. Prior to 1980,
ocular trauma was the main predisposing factor for corneal
ulceration, while today more than half of all ulcers are
related to contact lens wear.2,3 With the change in risk
factors for ulceration there was also a shift in the demographic profile of affected individuals;4 the number of

cases in young, working-aged patients increased substantially over the past few years.1,4 This emphasizes that
ulcers, while a cause of vision loss, now also contribute to
the total years of vision lost because they often affect young
people. Identifying corneal ulcers is a common ocular task
for primary-care physicians and optometrists, and treating
corneal ulcers is currently one of the most common tasks
for general ophthalmologists and cornea specialists. Prompt
and effective treatment is necessary to preserve sight. The
standard treatment for corneal ulcers is broad-spectrum topical antibiotic coverage, but controversy exists in other areas

From *the Department of Ophthalmology, University of Ottawa, Ottawa,

Ont.; {the Ivey Eye Institute, Schulich School of Medicine, University of
Western Ontario, London, Ont.; {Clinical Epidemiology Unit, Ottawa
Health Research Institute, Ottawa, Ont.; and University Health Network,
Faculty of Medicine, University of Toronto, Toronto, Ont.

Correspondence to William Hodge, MD, Ivey Eye Institute, St Josephs

Hospital, 268 Grosvenor St., London, Ont. N6A 4V2;
William.Hodge@sjhc.london.on.ca

Originally received July 8, 2009. Final revision Mar. 15, 2010

Accepted Mar. 24, 2010
Available online Jan. 31, 2011

Presented at the Canadian Ophthalmological Society Annual Meeting,

Whistler, B.C., June 13, 2008. Canadian Ophthalmological Society Research
Award winner.
Can J Ophthalmol 2011;46:405

doi:10.3129/i10-054

40

CAN J OPHTHALMOLVOL. 46, NO. 1, FEBRUARY 2011

Comparison of antibiotic-only and antibioticsteroid combination treatmentBlair et al.

of management. For example, even with effective antibiotic
treatment scar tissue usually develops on the cornea and
decreases vision. Treatments to decrease this scar formation
would be a logical option. An obvious, but controversial,
method would be the use of topical corticosteroids.
Published reports5,6 have shown worsening of the ulcer
and (or) vision loss after steroid use. On the other hand, 16
bacterial ulcer patients were treated with high dose topical
corticosteroids with favourable results.7 Nearly half of these
patients achieved a final visual acuity (VA) of . 20/60 or
equivalent. The degree of therapeutic success achieved was
largely dependent on the severity of the initial ulcer.
Analytic studies have also been inconclusive. To date,
the only randomized clinical trial (RCT) to explore the use
of topical corticosteroids in conjunction with antibiotic
treatment was carried out in the 1980s by Carmichael
et al.8 No significant difference in healing rate was observed
between the 2 groups, nor was there any difference in final
vision. Despite a lack of statistical significance, both mean
healing rate and final VA were better in the steroid group.
Similar complications were observed in the 2 groups.
Coster and Badenoch,9 in a review of 77 cases, reported
a success rate of 78% when bacterial ulcers were treated
with antibiotics alone and 69% when antibiotics and corticosteroids were combined. However, infection recurred
in 13% of individuals treated with steroids versus no infection in those not receiving steroids.
In trials carried out by the Ciprofloxacin Bacterial Keratitis Study Group1012 to investigate the efficacy of treating
bacterial corneal ulcers with ciprofloxacin, topical corticosteroids were used at the discretion of the treating investigator. Participants receiving antibiotic plus steroid treatment were as likely to improve and cure as participants
receiving just antibiotics. There was no difference in time
to cure or final VA. This result may be biased because the
more severe ulcers were treated with steroids. This bias
highlights the need for randomized controlled trials in
which the ulcer severity is varied.
The value of corticosteroids in the treatment of bacterial corneal ulcers has been discussed.13,14 A recent heterogeneous meta-analysis of analytic studies abstracted
from the literature was inconclusive as to the effect of using
topical corticosteroids following the onset of a bacterial
corneal ulcer.14
This RCT was designed to study the benefits and risks
of using steroids in treating corneal ulcers. The residual
ulcer size (difference between the ulcer size at beginning of
treatment and that at the end of treatment) and other
treatment outcomes between the steroid and non-steroid
groups were compared.

METHODS
Research ethics board approvals (Ottawa Hospital,
Ottawa, Ont. and University Health Network, Toronto,
Ont.) were obtained for this prospective, randomized,

double-blinded, parallel-armed clinical trial. A sample size

was calculated based on previous data8 using the method
of Blackwelder and Chang15 for parallel-armed RCTs.
In order to detect a difference of 4 mm2 between groups
with a standard deviation of 3.3 mm, a type I error of 0.05,
and a power of 0.08, a crude sample size (2N) of 54
was calculated.
Patients were recruited from the hospital-based, clinical
practice of one of the investigators in Ottawa, Ont.
(W.H.). Later, a second hospital-based recruitment site
in Toronto, Ont. was added (A.S.). All participants signed
a written consent form before enrollment. After being
asked to participate, patients had until day 3 of treatment
to agree to participate in the study, as the treatment was the
same for either group on days 1 and 2.
Stratified block randomization in blocks of 6 was used to
force a reasonably equal number of eyes in the 2 groups.
Randomization was stratified by ulcer size (, 2 mm greatest diameter, 24 mm greatest diameter, or . 4 mm greatest diameter) as ulcer size is an important confounder in
this study. The allocation schedule was generated by a
central office using a computer algorithm from the uniform distribution (STATA Corp, College Station, Tex.).
The generator of the random allocation did not participate
in executing the intervention and the executors did not
participate in generating the schedule. Both the investigators and the patients were blinded to the treatment allocation. Medications were prepared by the hospital pharmacy
and packaged identically. On days 21 and 42, the patients
and the examiners were asked their opinions of their treatment groups, and resulting data were compared against a
binomial distribution with a probability of 0.5. These
results verified masking for both patients (p 5 0.84) and
examiners (p 5 0.79).
Inclusion criteria were (i) bacterial corneal ulcer (defined
as corneal epithelial defect and stromal inflammation of
presumed bacterial origin) that was confirmed by culture
or by bacteria seen on gram stain, (ii) involvement of only
1 eye, and (iii) patients over the age of 12 years.
Exclusion criteria were (i) fungal, viral, or amoebic keratitis, (ii) known sensitivity or allergy to trial drugs, (iii)
perforated ulcer, (iv) involvement of the only functional
eye, with best corrected VA worse than 20/200 in the
uninfected eye, and (v) use of topical or systemic steroids
concurrently or within the past 2 months.
Patients were randomly assigned to receive either gatifloxacin (Zymar, Allergan Inc, Irvine, Calif.) and a masked
placebo, or gatifloxacin and masked dexamethasone 0.1%
(Maxidex, Alcon Inc, Fort Worth, Tex.). They were instructed to take the antibiotic every hour they were awake
for days 1 and 2. On day 3, the patients reduced the antibiotic dose to every 2 hours and began the steroid or placebo 4 times daily. There was a 2-day delay from antibiotic
start to steroid start as per the recommendation of the
Ottawa Hospital ethics review board that at least some
antibiotic be taken before steroids were begun. On day 7,
CAN J OPHTHALMOLVOL. 46, NO. 1, FEBRUARY 2011

41

Comparison of antibiotic-only and antibioticsteroid combination treatmentBlair et al.

patients were instructed to reduce the antibiotic to
4 times daily. The dose schedule thereafter is provided
in Table 1.
If the treating physician felt fortified antibiotics were
necessary, the option of topical cefazolin 50 mg/ml and
tobramycin 14 mg/ml, in place of gatifloxacin, was allowed.
The primary outcome was residual ulcer size at
10 weeks compared with the baseline size using photographic measurement. Ulcer dimensions were also documented using digital slit-lamp corneal surface photography
(Nikon 500, Nikon, Tokyo, Japan) by a technician following a specific protocol at each visit. Subsequently, 2
trained observers independently measured ulcer dimensions using Image J software (NIH, Bethesda, Md.).
Secondary outcomes included residual ulcer area by
clinician estimate, VA with a standard protocol illuminated ETDRS chart, VF-14 score, and time to healing.
Adverse events, such as re-infection, allergy to study medications, corneal thinning, and perforation were also measured and recorded.
Primary analysis was performed based on an intent-totreat scenario regardless of compliance or protocol deviations. A univariate analysis with percentage of change in
corneal ulcer size from baseline as the primary outcome
between groups was used. The eye, not the patient, was the
unit of analysis. Secondary analyses were multivariate.
Baseline characteristics between the 2 treatment groups
were compared using an unpaired t test for continuous
variables after checking for normality using an inverse normal plot and the ShapiroWilk test. Binary and ordinal
variables were compared using the x2 test with the Yates
correction when appropriate. We included any difference
in covariates of 30% or more with a p value of 0.20 in
the multivariate model. These covariates as well as the
predictor variable (antibiotic-only vs antibioticsteroid)
and the primary outcome (percentage change in residual
ulcer size) were used in the multiple linear regression model
as residual ulcer size is a continuous outcome.
Secondary linear outcomes were examined in the same
way. Ordinal outcomes were examined with multiple
logistic regressions. Effect modification was analyzed in
the model in a multiplicative method with a p value of
0.05 used for the conjoint term. A time-to-event analysis
was carried out to compare the time to healing of the
2 groups.

RESULTS
Fifty-one patients were recruited and 21 of these did
not meet eligibility criteria because of either a negative
Table 1Daily dosage schedule post surgery

Antibiotic
Steroid/Placebo

42

Days
713

Days
1420

Days
2127

Days
2834

Days
3542

4
4

4
4

4
2

0
1

0
0

CAN J OPHTHALMOLVOL. 46, NO. 1, FEBRUARY 2011

gram-stain and negative cultures, or recent prior use of

steroids. Thirty patients were enrolled and were randomized equally between the antibiotic-only group (n 5 15)
and the antibioticsteroid group (n 5 15). One patient in
the antibiotic-only group and 3 patients in the antibiotic
steroid group were lost to follow-up (Fig. 1).
Randomization resulted in similar baseline characteristics in each treatment group. There were no significant
differences except for baseline mean intraocular pressure
(antibiotic-only 5 13.9 mmHg [SD 2.53]; antibiotic
steroid 5 18.2 mmHg [SD 5.44]; p 5 0.0089) (Table 2).
There were 31 bacterial isolates cultured in the study,
12 were coagulase-negative staphylococcal species, 4 were
Staphylococcus auereus, 2 were other staphylococcal species,
5 were Pseudomonas aeuroginosa isolates, and 2 were streptococcal species. All other species isolated were singular
isolates (e.g., no other species was isolated more than once).
There was no significant difference between the
2 groups in terms of the primary outcome. Mean residual
ulcer size at 10 weeks was compared with the baseline by
photographic measurement (Fig. 2). The mean difference
in ulcer area in the antibiotic group was less than that in the
steroid group (21.919 mm2 in the antibiotic group vs
24.388 mm2 in the antibioticsteroid group); however,
this was not statistically significant (p 5 0.56) (Table 2).
Multivariate analysis showed no significant predictor of
change in ulcer area for this outcome.
There was a significant difference between the 2 groups
in 1 of the secondary outcomes (Table 3). The mean residual ulcer size at 10 weeks compared with the baseline by
clinician estimate (slit-lamp) was 20.789 mm2 for the
antibiotic-only group compared with 24.206 mm2 for
the antibioticsteroid group (p 5 0.05). Multivariate analysis revealed that change in ulcer area from the baseline
was only significantly predicted by baseline ulcer size for
this outcome (p 5 0.03).
There were no significant differences in other secondary
outcomes between the 2 groups. Mean change in VA
(logMAR) was 20.18 for the antibiotic-only group compared with 20.31 for the antibioticsteroid group
(p 5 0.5178) (Table 4). Mean change in quality of life, as
represented by the VF-14 score, was 6.2 for the antibioticonly group compared with 9.7 for the antibioticsteroid
group (p 5 0.4156). A KaplanMeier time to healing analysis (Fig. 3) showed no difference in healing rate between
the antibiotic-only group and the antibioticsteroid group.
Median healing times were 8 weeks in the antibiotic-only
group versus 6 weeks in the antibioticsteroid group.
Two patients experienced adverse events. One patient in
the antibioticsteroid group experienced a possible recurrence of the ulcer at week 10 (5 weeks after stopping all
medications); however, repeat culture was negative. One
patient in the control group experienced a second corneal
ulcer that was confirmed by culture. They were treated
with topical antibiotics and a partial tarsorrhaphy because
of the nature of their underlying condition.

Comparison of antibiotic-only and antibioticsteroid combination treatmentBlair et al.

DISCUSSION
One of the difficulties in interpreting the results of this
study is that patient enrollment was lower than expected.
Many of the recruited patients had sterile ulcers and thus
did not meet the inclusion criteria. Nevertheless, a substantial number of patients participated in this analytical study,
adding to the limited body of evidence on the subject of
steroid use in treating corneal ulcers.

Measurement methodology and its conflicting results

relating to change in ulcer size is worthy of discussion.
While the primary outcome of photographic measurement
of ulcer size did not detect a difference, the secondary outcome of clinician estimate of ulcer size showed a significant
benefit for those treated with antibioticsteroid. The trend
in the photographic data was also for more improvement in
the steroid group thus suggesting that a larger sample size
would have yielded a statistically significant result.

Fig. 1CONSORT flow diagram.

Table 2Baseline subject characteristics

Sex (M:F)
Study eye (OS:OD)
Ulcer size (small:medium:large){
Contact lens user (yes:no)
Ulcer location (peripheral:paracentral:central){
Ulcer area (mm2) by slit-lamp
Ulcer area (mm2) by clinical photo
History of ulcer (yes:no)
History of cataract (yes:no)
Central corneal thickness (mm; mean [SD])
Intraocular pressure (mmHg; mean [SD])
Visual acuity (logMAR)
Age (years; mean [SD])
Presence of hypopyon (yes:no)
Density of lesion (mild:moderate:severe)"
Limbal conjunctival injection (% clockwise seen)
Corneal vascularization (% clockwise seen)

Antibiotic-only n515

Antibiotic + steroid n515

p value

6:9
8:7
7:3:5
7:8
6:5:4
4.596
5.483
3:12
0:15
722.1 (125.02)
13.9 (2.53)
0.53
40.7 (21.12)
1:6
0:3:11
96%
14%

4:11
9:6
6:3:6
8:6
6:5:4
8.302
8.802
0:14
3:11
665.7 (154.47)
18.2 (5.44)
0.90
48.7 (19.88)
1:2
0:6:8
92%
0%

0.439*
0.713*
0.920*
0.573*
1.000*
0.300
0.854
0.077*
0.058*
0.5796
0.0089
0.718
0.295I
0.346*
0.225*

*Chi-square test.
{
Small, greatest diameter , 2 mm; medium, greatest diameter 24 mm; large, greatest diameter . 4 mm.
{
Peripheral, completely outside central 3 mm of pupil; paracentral, partially overlaps central 3 mm of pupil; central,completely within central 3 mm of pupil.

KruskalWallis test.
I
Students t test.
"
Mild, iris detail easily visible; moderate, iris detail partly blurred; severe iris detail completely blurred.

CAN J OPHTHALMOLVOL. 46, NO. 1, FEBRUARY 2011

43

Comparison of antibiotic-only and antibioticsteroid combination treatmentBlair et al.

The primary outcome of change in ulcer size, as measured from photographic documentation, should be the
most robust method of data capture. Two independent
and blinded observers used validated software to precisely
map ulcer areas. Theoretically, photographic measurement
should be quite accurate.
Conversely, the photographic measurements may have
been prone to error. A measurement bias may have been
introduced during photo analysis as the photos were analyzed sequentially over a short period of time. As such,
there may have been a tendency for the observers to trace
ulcer margins similar to those they drew on the first photo
(i.e., visit 1) in a series. This would result in the under
detection of any change in ulcer size. Other errors may
have been introduced related to photo quality and differences in observer interpretation.
Though the clinicians estimate of ulcer size at the slitlamp showed a benefit to those treated with the antibiotic
and steroid, these results should be interpreted with
caution. Multivariate analysis shows that baseline ulcer
size was the biggest predictor of change in ulcer size for
this outcome. Although not statistically significant, the

antibioticsteroid group did have a larger baseline ulcer

size compared with that of the antibiotic-only group. This
secondary outcome was the only positive outcome of all the
outcomes that we measured.
The data showed no significant difference in healing rate
and final VA which is consistent with the findings from the
Carmichael et al.8 randomized control trial. If there had
been a larger sample size, subgroup analysis could have
been performed on VA in centrally located ulcers. This is
an important analysis to include in future studies.
In reviewing adverse events, there was no increased
harm in employing steroid drops early in treatment when
used in combination with antibiotic drops. This finding
is similar to Carmichael et al.,8 who reported similar complications in their 2 groups. That this RCT has also reported no increase in harm with antibioticsteroid treatment is important because some case reports and series
have suggested that this treatment could lead to higher
rates of reinfection.5,6
This RCT looked at all ulcers: central, peripheral, and
from any culture-proven bacterial cause. The most common isolate was coagulase negative Staphylococcus found
mostly in small peripheral ulcers (27% were in contact
lens wearers).
Based on most of the outcomes measured, there was no
benefit to using steroids in combination with antibiotic
therapy in the treatment of corneal ulcers. Only 1 of our
secondary outcomes, clinician measurement of ulcer size,
showed benefit from the use of steroids. This study suggests
that antibioticsteroid combination treatment does not
seem to be harmful when employed in a closely monitored
clinical setting and may be beneficial. A larger RCT is
needed to confirm the role of early steroids in the treatment
of corneal ulcers.

Fig. 2Photo depicting use of Image J software to determine ulcer

area.

Table 3Mean residual area (mm2) by treatment group

By photo
Antibiotic-only
Antibiotic + steroid
By slit-lamp
Antibiotic-only
Antibiotic + steroid

Baseline

Final

Difference

p value*

5.483
8.802

3.090
4.412

21.919
24.388

0.56

4.596
8.302

3.712
4.263

20.789
24.206

0.05

*p values were calculated using the KruskalWallis test.

Table 4Mean change in visual acuity (logMAR) between treatment groups

Antibiotic-only
Antibiotic + steroid

Baseline

Final

Difference

p value*

0.53
0.90

0.18
0.60

20.18
20.31

0.52

*p values were calculated using the KruskalWallis test.

44

CAN J OPHTHALMOLVOL. 46, NO. 1, FEBRUARY 2011

Fig. 3Time to healing analysis by treatment group. Total observation n 5 30. Censored (lost to follow-up) n 5 4. Not healed n 5 2.
Successfully healed (events) n 5 24. No difference in healing rate
(p 5 0.5135): antibiotic-only (96.10%) vs antibiotic plus steroid
(94.99%). Median healing times were 8 weeks (antibiotic-only) vs
6 weeks (antibioticsteroid). Total follow-up time slightly longer in
antibiotic-only group (104 weeks) vs antibiotic plus steroid group
(78.14 weeks).

Comparison of antibiotic-only and antibioticsteroid combination treatmentBlair et al.

Acknowledgement: The authors thank Shawn Aaron, MD, MSc,
FRCPC, Ottawa Health Research Institute, for his input on the
study design. We also thank Francie Si, MD, MSc, Ivey Eye Institute, University of Western Ontario, for manuscript reviewing,
proofreading, collection of authorship forms, and submission.
Disclosure: The authors have no proprietary or commercial interest
in any materials discussed in this article.
Support: This study was funded by The Physicians Services Incorporation Foundation, North York, Ont.
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