Clinical science
Re-appraisal of topical 1% voriconazole and 5%
1
L V Prasad Eye Institute,
Bhubaneswar, Odisha, India
2
L V Prasad Eye Institute, Brien
Holden Eye Research Center,
Hyderabad, Andhra Pradesh,
India
3
L V Prasad Eye Institute,
Visakhapatnam, Andhra
Pradesh, India
Correspondence to
Dr Savitri Sharma, L V Prasad
Eye Institute, KAR campus,
Road No. 2, Banjara Hills,
Hyderabad, AP 500034, India;
savitri@lvpei.org
Received 3 December 2014
Revised 5 February 2015
Accepted 15 February 2015
To cite: Sharma S, Das S,
Virdi A, et al. Br J
Ophthalmol Published
Online First: [ please
include Day Month Year]
doi:10.1136/bjophthalmol-
2014-306485
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
natamycin in the treatment of fungal keratitis
in a randomised trial
Savitri Sharma,1,2 Sujata Das,1 Ajoy Virdi,1 Merle Fernandes,3 Srikant K Sahu,1
Nagendra Kumar Koday,3 Md Hasnat Ali,2 Prashant Garg,2 Swapna R Motukupally2
ABSTRACT
Purpose To compare the efficacy of topical 1%
voriconazole vs 5% natamycin for the treatment of fungal
keratitis.
Methods In a prospective, double-masked, randomised,
controlled, registered clinical trial, 118 patients with
fungal keratitis were treated using identical dosage
schedule with either voriconazole (58) or natamycin (60)
as inpatients for 7 days and followed up weekly. The
outcome measures were percentage of patients with
healed or resolving ulcer and final visual acuity at last
follow-up ( primary) and on day 7 (secondary) in each
group.
Results More patients ( p=0.005) on natamycin (50/56,
89.2%) had healed or resolving ulcer compared with
voriconazole (34/51, 66.6%) at last follow-up. The
improvement in vision was marginally greater in patients
in the natamycin group compared with the voriconazole
group at day 7 ( p=0.04) and significantly greater at final
visit ( p=0.01). In univariate analysis, drug, age and mean
size of corneal infiltrate and epithelial defect had a
significant effect on the final visual outcome. In
multivariate analysis, the effect of drug (voriconazole vs
natamycin, adjusted coefficient 0.27 (−0.04 to 0.57),
p=0.09) was marginal while the effect of age and
epithelial defect was significant ( p<0.001 for both). In
the group treated with natamycin, the final visual acuity
was significantly better ( p=0.005, Wilcoxon signed-rank
test) in patients with Fusarium keratitis but not with
Aspergillus keratitis ( p=0.714, paired t test).
Conclusions When compared with voriconazole,
natamycin was more effective in the treatment of fungal
keratitis, especially Fusarium keratitis.
Trial registration number: Clinical Trial Registry India
(2010/091/003041).
INTRODUCTION
Fungi are responsible for 20–44% of keratitis in
India.1 The prevalence of fungal pathogens in micro-
bial keratitis has been reported to be 38% in Ghana,
36% in Bangladesh, 35% in southern Florida and
17% in Nepal.1 Currently, fungal infections of the
cornea are difficult to eradicate as fungi often resist
treatment. Amphotericin B and the azoles, ketocona-
zole and fluconazole, are generally not very effective
against Fusarium and Aspergillus. Although natamy-
cin is a good drug to treat fungal keratitis, treatment
failures have been reported by several authors and
the search for a better broad spectrum antifungal
drug to treat fungal keratitis continues.2 In recent
times, topical 1% voriconazole with or without oral
administration has been shown to be effective in the
Sharma S, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306485
treatment of refractory fungal keratitis caused by
yeast as well as filamentous fungi.2 One of the advan-
tages of topical voriconazole is its diffusion into the
aqueous humour (0.61–3.30 mg/L after 1 h of
topical administration).3 This level was above the
minimum inhibitory concentration for Aspergillus
fumigatus and Candida albicans.3 In most parts, the
current literature suggests a promising role of vorico-
nazole in the treatment of fungal keratitis, and given
its better penetration, this drug is purported to be a
superior alternative to natamycin. However, recently
published clinical trials have reported equal or infer-
ior efficacy of 1% voriconazole (reconstituted from
injection vial) compared with 5% natamycin eye
drops in fungal keratitis.45 These results are contra-
dictory to experimental and in vitro data.6 7
Moreover, commercial 1% voriconazole eye drop has
come into the Indian market recently and the avail-
ability of another potent topical antifungal drug in
the market has its own benefits. The purpose of this
study was to revisit the comparison of the efficacy of
1% voriconazole eye drops to 5% natamycin eye
drops, in a randomised, masked, controlled trial, for
the treatment of small-to-medium-sized fungal
corneal ulcers with the hypothesis that subjects
treated with voriconazole eye drops will have a non-
inferior outcome compared with subjects treated
with natamycin.
MATERIALS AND METHODS
The study was conducted at three tertiary centres
of L V Prasad Eye Institute located in three differ-
ent cities of India—Hyderabad, Bhubaneswar and
Visakhapatnam—between November 2010 and
December 2012. The study coordinator (SS) pro-
vided common protocol, case record forms and
randomisation list to all study centres. Each centre
had an ophthalmologist, microbiologist, pharmacist
and study nurse to execute the study. All patients
with suspected microbial keratitis seen in the
cornea clinic of these hospitals were considered for
inclusion in the study. The trial was stopped when
the required number of patients was recruited.
Inclusion and exclusion criteria
Patients with age ≥18 years, able to understand and
sign the informed consent form, and either men or
women with duration of complaints not more than
the past 14 days before presentation to the study
centre were included in the study. All included
patients were required to have the presence of a
corneal epithelial defect with stromal infiltrate or
exudate, clinically suggestive of fungal ulcer with
1
 Clinical science
or without hypopyon. The widest diameter of the ulcer needed
to be between 2 and 6 mm as long as there was no scleral
involvement. It was mandatory that only patients with corneal
scraping positive for fungal filaments in direct smear examin-
ation by any one or more of the methods used be recruited. At
the time of recruitment, either none or inadequate prior treat-
ment with antifungal eye drop (less than six times per day) and
absence of foreign body on the cornea was required. If present,
the subject was enrolled after the foreign body was totally
removed and the other enrolment criteria were met.
Patients having history of allergy to voriconazole or natamycin
were excluded from the study. Other exclusion criteria included
patients with impending or actual corneal perforation, presence
of scleral involvement or involvement of posterior one-third
stroma, legally blind unaffected eye, presence of dacryocystitis,
presence of other comorbidities such as corneal anaesthesia,
exposure or dry eye and patients who received/required topical
or systemic steroids or other immunosuppressants (unless discon-
tinued before randomisation). Patients who were known to be
HIV-positive or diabetic, whose corneal infiltrate extended into
the posterior one-third of the stroma, whose initial corneal
culture showed significant growth of bacteria (>10 colonies) or
who were on any topical antifungal agent that had been used in
adequate dosage (four hourly) within the past one week or those
who had bilateral infection, were excluded.
Laboratory investigations
Corneal scrapings were collected using blade no. 15 on Bard
Parker handle, under topical anaesthesia on the slit lamp and
smeared on glass slides and inoculated on culture media in the
clinic and brought to microbiology laboratory. The smears were
stained with Gram stain and 10% potassium hydroxide with
0.1% calcofluor white for direct microscopy. Table 1 shows the
culture media inoculated and the incubation conditions. Any
bacterial growth was identified using API system (bioMérieux,
France) and fungal identification was based on colony character-
istics and microscopic features. All media were held for 2 weeks
in case of no growth before declaring the sample as sterile. Only
unequivocal or significant culture results were considered as
described earlier.8
Masking, randomisation and treatment
The treating ophthalmologist, microbiologist and patients
were masked to the drug by using similar vials. The study
pharmacist provided the drugs. The patients were randomised
(by SS) using computer-generated randomisation blocks (http://
www.randomization.com) into one group receiving 1% vorico-
nazole eye drop (Aurolab, Madurai, India) and the other group
receiving 5% natamycin ophthalmic suspension eye drop (USP
5% Natamet, M.J. Pharmaceuticals, Mumbai, India). No sys-
temic antifungals were given, and the subjects were hospitalised
Table 1 Culture media inoculated and the incubation conditions for the processing of corneal scrapings
Culture media Incubation condition
5% sheep blood agar Aerobic
5% sheep blood chocolate agar 5% CO2
Brain heart infusion broth Aerobic
Thioglycollate broth Aerobic
Sabouraud dextrose agar with chloramphenicol Aerobic
Non-nutrient agar with Escherichia coli overlay Aerobic
2 Sharma S, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306485
for 7 days and discharged on the same randomised medication
that they were assigned while hospitalised. They were asked to
follow-up weekly.
The dosing schedule of both medications was identical—day
1–3: one drop topical medication every hour round the clock;
day 4: one drop hourly while awake, every three hours when
asleep; and day 5 and after: one drop every two hours while
awake until cured.
Sample size
Sixty subjects in each of the two treatment arms were required
with 80% probability that the study would detect a one-sided
0.05 significance level if the true difference between the treat-
ments was 5.0 units.
Outcome measures
Assessed at the end of 1 week and at last follow-up visit, the
outcome measures were response to medical treatment in the
form of healed keratitis, resolving keratitis or worsening keratitis
and visual acuity (logarithm of the minimum angle of resolution
(logMAR)). An ulcer was defined healed if epithelial defect diam-
eter reduced to ≤1 mm associated with the complete absence of
stromal infiltrate, plaque and satellite lesions. A corneal ulcer
characterised by reduction of size of stromal infiltrate size by at
least 1 mm and/or density of infiltrate and/or decrease in endo-
thelial plaque or satellite lesions was classified as resolving kerati-
tis. An ulcer was deemed to demonstrate no response or
worsening if there was lack of improvement or worsening in
inflammatory sign scores or stromal infiltrate dimensions or
corneal melt and deterioration in any clinical examination factor.
Best-corrected visual acuity was recorded at the follow-up visits.
Patients requiring surgical interventions such as tissue adhesive
for impending perforation, superficial keratectomy, penetrating
keratoplasty and evisceration were considered as treatment
failure.
Statistical analyses
All statistical analyses were performed using the R software
(V.2.12). Means with SDs were reported for normally distribu-
ted continuous variables and median with IQR were reported
for non-parametric data. The χ2 tests were used to compare cat-
egorical data and t test and Wilcoxon rank-sum and Wilcoxon
signed-rank tests were used to compare continuous data. Visual
acuity at three time points for patients in both groups were com-
pared by multiple comparisons of means from a mixed effect
model with Dunnett contrasts. Adjusted p value was obtained
by Bonferroni method.
A univariate linear regression was carried out to evaluate the
relationship between the final visual acuity ( primary outcome
measure) with regard to fungal species, drug, follow-up, age,
gender, mean corneal infiltrate size and mean size of corneal
Incubation temperature (°C) Incubation period (weeks)
37 2
37 2
37 2
37 2
27 2
37 1
 Clinical science

Table 2 Comparison of baseline clinical and microbiological parameters between the patients recruited in the voriconazole and natamycin
groups
Voriconazole Natamycin
Parameters (n=58) (n=60) p Value

Mean age (years) 42 (32.25 to 54.75) 40 (28.75 to 51) 0.22

Men 43/58 42/60 0.77
Women 15/58 18/60 0.77
Mean corneal infiltrate size* (day 1) 2.619 (2 to 3.76) 2.75 (2 to 3.6) 0.86
Mean corneal epithelial defect size* 2.5±1.37 2.77±2.8 0.98
Presenting visual acuity (logMAR) 0.9 (0.3 to 2) 0.6 (0.3 to 1.5) 0.20
Aspergillus sp. in culture 7/58 8/60 1.0
Fusarium sp. in culture 13/58 16/60 0.74
No growth in culture 14/58 14/60 1.0
Other species in culture 24/58 22/60 0.73
Corneal scraping was positive for septate fungal filaments in all 118 patients.
*Mean of length plus width of ulcer in millimetre.
logMAR, logarithm of the minimum angle of resolution.

epithelial defect. A multivariate linear regression model with group, the visual improvement compared with baseline was sig-
stepwise elimination using Akaike information criteria (AIC) nificant at day 7 ( p value 0.01) as well as at the final visit
was used to assess the association between the final visual acuity ( p value 0.02). On the other hand, initial insignificant improve-
and the independent variables. ment at day 7 ( p value 0.16) became highly significant at the
final visit ( p=0.001) in the natamycin group (figure 2).
RESULTS
The total number of patients in the voriconazole group was 58
while 60 patients received natamycin.
A comparison of baseline clinical and microbiological findings Table 3 Fungal species grown from corneal scrapings of 44
of the two groups is given in table 2. The type of fungi isolated fungus culture-positive patients in the voriconazole group and 46
from patients in both groups is shown in table 3. culture-positive patients in the natamycin group
There was no significant difference between the groups in Serial no. Type of fungus Voriconazole Natamycin
terms of mean age, gender, mean presenting infiltrate size, pre-
senting visual acuity and type of fungal species grown. Mean Hyaline filamentous fungi
follow-up was 26 (15 to 38.5) and 21 (10.33) days in the nata- 1 Fusarium solani 7 9
mycin and voriconazole groups, respectively. Despite the fre- 2 Fusarium sp. 6 6
quency of healed or resolving ulcers being similar on day 7 3 Fusarium roseum 0 1
(natamycin 35/54, 65%; voriconazole 34/50, 68%), at the final 4 Aspergillus flavus 3 4
visit the percentage of patients who had healed corneal ulcer 5 Aspergillus fumigatus 3 2
were significantly higher in the group treated with natamycin 6 Aspergillus niger 0 1
(50/56, 89.2% vs 34/51, 66.6%; p=0.005). 7 Aspergillus terrreus 1 1
Out of the 18 patients who worsened in the voriconazole 8 Acremonium sp. 2 3
group, 11 were switched over to natamycin (figure 1). The 9 Trichoderma sp. 1 0
ulcers healed in 10 of 11 patients, with 1 patient proceeding to 10 Cylindrocarpon sp. 1 0
penetrating keratoplasty. All remaining patients required surgical 11 Penicillium sp. 0 1
intervention ( penetrating keratoplasty in three, superficial kera- 12 Colletotrichum dematium 1 0
tectomy in one and evisceration in one) and two patients were 13 Colletotrichum coccodes 1 1
lost to follow-up. There was no difference between the groups 14 Unidentified hyaline 4 5
in the number of patients who either did not improve or mar- Dematiaceous filamentous fungi
ginally worsened on day 7 (natamycin 19/54, 35%; voricona- 1 Curvularia lunata 3 3
zole 18/50, 36%). Patients on natamycin were continued on 2 Alternaria sp. 1 0
natamycin. While the ulcer healed or was resolving in 15 3 Lasiodiplodia theobromae 0 1
patients, 2 patients required keratoplasty and 2 were lost to 4 Cladosporium sp 0 1
follow-up. 5 Phialophora verrucosa 0 1
Figure 2 compares the visual acuity of the patients in the 6 Bipolaris sp. 0 1
two study groups at baseline, day 7 and final follow-up visit. 7 Unidentified dematiaceous 8 4
Using Wilcoxon signed-rank and Wilcoxon rank-sum tests for Yeast-like fungi
non-parametric data, the visual acuity was compared between 1 Candida glabrata 1 0
the two drugs at the three time points. There was no difference 2 Candida sp. 1 0
in the baseline visual acuity ( p=0.19) of the patients in the 3 Candida parapsilosis 0 1
two groups; however, the improvement in vision was margin- Total 44 46
ally greater in patients in the natamycin group compared with Fungus culture-negative patients: voriconazole group 14; natamycin group 14.
Only bacterial growth in one patient each of the voriconazole group (Staphylococcus
the voriconazole group at day 7 ( p=0.04) and significantly aureus) and the natamycin (Acinetobacter baumannii) group.
greater at the final visit ( p value 0.01). Within the voriconazole
Sharma S, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306485 3
 Clinical science
Figure 1 Flow chart depicting the
outcome of all patients included in the
study. LTFU, lost to follow-up.
On univariate analysis (table 4), the following factors were
associated with significantly better visual acuity: drug, age, mean
corneal infiltrate size and mean size of corneal epithelial defect.
The lesser the age, the better the visual outcome ( p<0.001).
Similarly, the lesser the mean corneal infiltrate and epithelial
defect size, the better the vision ( p<0.001 and <0.001,
respectively).
In multivariate regression analysis (table 4), we built a model
with the independent factors (fungal species, drug, follow-up, age,
sex, mean corneal infiltrate size and mean size of corneal epithelial
defect) followed by stepwise elimination using the AIC. The final
model retained drug, age and epithelial defect size as significant
factors affecting visual outcome in fungal keratitis. After adjusting
with other cofactors, the natamycin group showed a marginally
better outcome ( p=0.09) compared with voriconazole. Similarly,
with final visual acuity as a dependent variable and drug, age and
Figure 2 Comparison of best-corrected visual acuity of baseline, day
7 and final follow-up visit of patients in the voriconazole and
natamycin study groups. logMAR, logarithm of the minimum angle of
resolution; VA, visual acuity.
4 Sharma S, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306485
epithelial defect as the independent variables, the latter two
remained significant ( p<0.001 for both).
In a subanalysis of the group treated with natamycin, the final
visual acuity was significantly better than pretreatment visual
acuity ( p=0.005, Wilcoxon signed-rank test) in patients with
Fusarium keratitis. Although the numbers were small, such a dif-
ference was not seen in patients with Aspergillus keratitis
( p=0.714, paired t test).
DISCUSSION
This study reiterates the findings of two previous studies pub-
lished in 2010 and 2013 from India.4 5 The former study
found no difference in visual acuity, scar size and perforations
between the two fungal keratitis groups treated with voricona-
zole and natamycin. The latter study reported significant
better clinical and microbiological outcomes in the natamycin-
treated group compared with voriconazole, with difference
specifically seen in patients with Fusarium keratitis. Both
studies used reconstituted parenteral preparation of 1% vori-
conazole and commercially available 5% natamycin eye drop.
We evaluated a commercial eye drop of 1% voriconazole
against a commercial eye drop of 5% natamycin with results
similar to the former study in multivariate analysis and similar
to the latter study in univariate analysis. Our study reaffirms
the results obtained in the previous studies that go in favour
of natamycin. In addition to analysing visual outcome at day
7 and final visit, we also analysed the change in corneal infil-
trate size at day 7 and final visit. It was interesting to note
that after 7 days of therapy there was no difference (voricona-
zole 18/50, 36%; natamycin 19/54, 35%) in the number of
patients whose corneal ulcer either did not respond or wor-
sened on medical treatment. However, as per the protocol, on
worsening, 11 patients in the voriconazole group were
switched over to natamycin. Although the visual acuity at day
7 had initially improved in marginally greater number of
patients on voriconazole, it plateaued thereafter and the visual
improvement was significantly higher in the natamycin group
(figure 2). On the same lines, surgical intervention was more
often required (voriconazole in six and natamycin in two) in
patients treated with voriconazole.

Table 4 Regression table showing association of various factors with final visual acuity in multivariate and univariate analyses (n=118)
Univariate analysis
Coefficient (95% CI)
Reference: Aspergillus sp.
Fusarium spp. 0.06 (−0.54 to 0.66)
No growth 0.17 (−0.45 to 0.79)
Other fungal species 0.09 (−0.48 to 0.65)
Drug: voriconazole vs natamycin 0.36 (0.02 to 0.71)
Follow-up (continuous variable) 0 (0 to 0)
Age (continuous variable) 0.02 (0.01 to 0.03)
Gender: male vs female −0.26 (−0.65 to 0.12)
Mean infiltrate size (continuous variable) 0.27 (0.12 to 0.41)
Mean epithelial defect (continuous variable) 0.23 (0.11 to 0.35)
Statistical significance: p<0.05.
Significant p values are in bold.
Response to natamycin topical therapy was significantly better
in patients with Fusarium keratitis, a finding similar to Prajna
et al.5 We could not show such a response in patients with
Aspergillus keratitis but are unable to accept this as true effect
due to the smaller number of isolates in each group (natamycin
in eight and voriconazole in seven). Contradictory reports exist
in the literature regarding the response of Fusarium and
Aspergillus keratitis to monotherapy with 5% natamycin.9 10
While Prajna et al found Aspergillus infection to be a predictor
of poorer outcome,9 Jones10 reported Fusarium to be more
destructive. However, compared with Aspergillus spp., in vitro
susceptibility of Fusarium spp. to natamycin is indeed reported
to be better and this may reflect in the in vivo response. In the
face of the argument that factors other than susceptibility of the
fungus contribute to the outcome in fungal keratitis,11 12 we
would like to submit that this study had reasonably good
control of the confounding factors such as duration of symp-
toms, age, gender, baseline visual acuity, size of corneal infiltrate
and size of corneal epithelial defect, and we believe that the
superior effect of natamycin is acceptable, especially in
Fusarium keratitis. Apart from final visual acuity, using the
measure of efficacy of a drug as reduction in size of corneal
infiltrate and healed ulcer at last follow-up, this study found sig-
nificantly better results with natamycin.
Despite strict implementation of inclusion criteria and inten-
sive medical therapy under supervision for at least one week,
two patients in the natamycin group required keratoplasty. This
outcome reiterates the fact that medical treatment of fungal ker-
atitis needs further research to find effective antifungal drugs.
Until then it seems that natamycin is the drug of choice for the
treatment of filamentous fungal keratitis, leaving the choice of
voriconazole as the second best.
There is increasing trend of using topical, stromal, as well
as oral voriconazole in the treatment of fungal keratitis, and
given its excellent penetration in the cornea, it is considered
superior to natamycin by many.13–19 With the current avail-
ability of commercial voriconazole eye drops, it is likely to be
used more often, especially because it is only marginally more
expensive than natamycin (250.00 rupees vs 118.00 rupees).
A survey published in 2009 indicated that physicians would
prefer to use voriconazole over natamycin if it were to be
commercially available.20 Unpublished reports of high efficacy
of intrastromal injection in deep-seated corneal infiltrates in
fungal keratitis are often presented in meetings, although a
recent study did not find it particularly useful.19 The study,
Sharma S, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306485
Clinical science
Multivariate analysis
p Value Adjusted coefficient (95% CI) p Value
0.835
0.593
0.762
0.03 0.27 (−0.04 to 0.57) 0.09
0.456
<0.001 0.02 (0.01 to 0.03) <0.001
0.176
<0.001
<0.001 0.21 (0.10 to 0.33) <0.001
however, recommends topical voriconazole to be used as an
adjunct therapy along with natamycin in the face of no
response to monotherapy with natamycin.19 Synergistic action
of natamycin and voriconazole is an interesting aspect to
explore in future studies.
Contributors SS: concept, design, data analysis, microbiology investigation,
manuscript preparation and final approval of manuscript. SD, MF, SKS and PG:
patient treatment, data collection, surgery and final approval of manuscript.
AV: data collection, data analysis and final approval of manuscript. NKK and SRM:
microbiology investigation, data collection and final approval of manuscript.
MHA: statistical analysis.
Funding Hyderabad Eye Research Foundation (HERF), Hyderabad and Aurolab,
Madurai. While HERF provided the infrastructure and financial support, Aurolab
provided the voriconazole eye drops.
Competing interests None.
Patient consent Obtained.
Ethics approval Institutional Review Board of L V Prasad Eye Institute, Hyderabad
Eye Research Foundation.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All clinical and microbiology raw data pertaining to all
subjects included in the study are available with the corresponding author (SS). Final
format of all data used for statistical analysis and all comparisons are available with
the biostatistician (MHA).
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6 Sharma S, et al. Br J Ophthalmol 2015;0:1–6. doi:10.1136/bjophthalmol-2014-306485

 Re-appraisal of topical 1% voriconazole and
5% natamycin in the treatment of fungal
keratitis in a randomised trial
Savitri Sharma, Sujata Das, Ajoy Virdi, Merle Fernandes, Srikant K Sahu,
Nagendra Kumar Koday, Md Hasnat Ali, Prashant Garg and Swapna R
Motukupally

Br J Ophthalmol published online March 4, 2015

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Collections Cornea (469)
Ocular surface (559)
Eye (globe) (636)

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