ophthalmology volume 120 issue 6 2013 doi 10.1016 j.ophtha.2012.11.013 sharma namrata goel manik...

7/25/2019 Ophthalmology Volume 120 Issue 6 2013 Doi 10.1016 j.ophtha.2012.11.013 Sharma Namrata Goel Manik Bansal

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Evaluation of Moxifloxacin 0.5% in

Treatment of Nonperforated Bacterial

Corneal Ulcers

A Randomized Controlled Trial

Namrata Sharma, MD,1Manik Goel, MD,

1Shubha Bansal, DNB,

1Prakashchand Aar!al, MD,

1"ee!an S#

Titi$al, MD,1Ashish D# %&adh$a$a, MSc,

'Rasik B# (a)&a$ee, *RCS+d, *RANC-

1,.

Purpose: To compare the equivalence of moxifloxacin 0.5% with a combination of fortified cefazolin sodium 5%

and tobramycin sulfate 1.3% eye drops in the treatment of moderate bacterial corneal ulcers.

Design: andomized! controlled! equivalence clinical trial.

Participants and Controls: "icrobiolo#ically proven cases of bacterial corneal ulcers were enrolled in thestudyand were allocated randomly to 1 of the $ treatment #roups.

Intervention: roup & was #iven combination therapy 'fortified cefazolin sodium 5% and tobramycinsulfate(

and #roup ) was #iven monotherapy 'moxifloxacin 0.5%(.

Main Outcome Measures: The primary outcome variable for the study was percenta#e of the ulcershealed at 3

months. The secondary outcome variables were best*corrected visual acuity and resolution of infiltrates.

Results: +f a total of $$, patients with bacterial -eratitis! 11, patients were randomized to #roup &! whereas

110 patients were randomized to #roup ). The mean standard deviation ulcer size in #roups & and ) were ,.$ $

and ,.,1 1.5 mm! respectively. The prevalence of coa#ulase*ne#ative Staphylococcus',0.% in #roup & and

,/.$% in #roup )( was similar in both the study #roups. & complete resolution of -eratitis and healin# of ulcers

occurred in 0 patients '/1./%( in #roup & and // patients '/1.,%( in #roup ) at 3 months. The observed

percenta#e of healin# at 3 months was less than the equivalence mar#in of $0%. orsenin# of ulcer was seen

in 1/.$% cases in #roup & and in 1/.5% cases in #roup ). "ean time to epithelialization was similar! and there

was no si#nificant difference in the $ #roups 'P0.05(. 2o serious events attributable to therapy were reported.


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Conclusions: orneal healin# usin# 0.5% moxifloxacin monotherapy is equivalent to that of combination

therapy usin# fortified cefazolin and tobramycin in the treatment of moderate bacterial corneal ulcers.

Financial Disclosure(s): The author's( have no proprietary or commercial interest in any materials discussedin

this article. Ophthalmology 2013;120:11731178 2013 by the America Aca!emy o" Ophthalmology#

Microbial keratitis is an ophthalmic emergency and requires

meticulous management to prevent sight-threatening com-

plications.13

Bacterial keratitis accounts for a significant

proportion of infectious keratitis worldwide4,5

and may have

diverse clinical presentation depending on the geo-graphical

location and climatic conditions.6Gram-positive bacteria such

as coagulase-negative Staphylococcus, Staph-ylococcusaureus, andStreptococcus species account formost the

organisms isolated.79

The protocol for the management of bacterial keratitis ideally

involves collection of corneal scraping material for smear and

culture and starting empirical intensive antimi-crobial therapy

until culture and antibiotic sensitivity re-ports are available.

However, at some centers, presumed bacterial infiltrates with

an overlying epithelial defect may be treated empiricallywithout microbiologic studies. The regimens of empirical

therapy practiced across the world are either monotherapy

with a broad-spectrum antibiotic10 14

or

2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

a combination of 2 antibacterial drugs to cover both gram-

negative and gram-positive organisms.1517

This prospective, randomized study was conducted to

evaluate and compare the efficacy and safety of combina-

tion therapy of fortified 5% cefazolin sodium and 1.3%

tobramycin sulphate eye drops versus monotherapy with

0.5% moxifloxacin hydrochloride eye drops in patients

with bacterial corneal ulcers.

Patients and Methods

tud! "esi#n

A randomized, prospective study was conducted in which 224

patients with proven bacterial corneal ulcers were enrolled from

the cornea services of our center. They were assigned randomly

into 1 of the 2 groups using a computer-generated random number

table. One eye of each patient was enrolled. The clinical trial was

registered at http://www.controlled-trials.com(no.

ISSN 0161-6420/13/$see front matter 11/.

http://dx.doi.org/10.1016/j.ophtha.2012.11.013


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Ophthalmology (olume 1'0, Number , "une'01.

ISRCTN10323655/11/08/201

0). Bacterial corneal ulcers

measur-ing 2 to 8 mm were

identified as well as the

presence of infiltrate, for

which a diagnostic scraping

had been performed and that

showed a significant presence

of bacteria on corneal

scraping or culture. Group A

received topical fortified

cefazolin sodium (50 mg/ml)

and fortified tobramycin

sulphate (14 mg/ml) eye

drops, whereas group B

received topical moxifloxacin

hydrochloride (0.5%;Vigamox; Alcon

Laboratories, Inc., Fort

Worth, TX). The drug was

dispensed by an independent

investigator. The study was

approved by the ethics

committee of the All India

Institute of Medical Sciences,

New Delhi, India, and written

informed consent was

obtained from all the patients

included in the study.

Patients with suspected

fungal, viral, or

acanthamoeba ulcers and

patients with known allergy

to fluoroquinolones,

aminoglyco-sides, penicillins,

or cephalosporins were

excluded from the study.

Pregnant and lactating womenand patients younger than 12

years also were excluded

from the study.

tud! Protocol

Patients were examined by a

single investigator (N.S.) who

was masked to the study

medication. The study

medications were dispensed

by another investigator who

was unaware of the clinical

findings and investigations.

All patients underwent a

meticulous history taking,

which included the

demographic profile, duration

and type of symptoms, and

risk factors. A complete

initial ocular examination

including record of best-

corrected visual acuity; slit-

lamp biomicroscopy to assess

the size, depth, and location

of the ulcer; anterior chamber

reaction; and presence and

height of hy-popyon was

undertaken. Anterior segmentphotographs were ob-tained

from all patients at each

clinical visit. A standard

protocol was used for the

initial microbiologic

investigation of all patients

with keratitis. At presentation,

corneal scrapings were

collected from the base and

edges of the ulcer and

examined with grams stain

and potassium hydroxide wetmount. Any patients who

demonstrated hyphae or

acanthamoeba cyst on

potassium hydrox-ide mount

were excluded from the study.

Corneal scrapings were plated

directly on culture plates of

blood agar, chocolate agar,

Sabourauds dextrose agar,

and thioglycolate broth.

Growth in culture media was

considered significant if the

same organism was isolated

on more than 1 culture

medium with direct

microscopy of corneal scrapes

revealing bacterial

morphologic features

consistent with those of

bacteria isolated on culture.

Suscepti-bility of the isolates

to antimicrobials was

assessed by the Kirby-Bauerdisk diffusion method.


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Dosage Schedule. The

dosage schedule was as

follows. For thefirst 72

hours, antibiotics were given

every hour, day and night.

After 72 hours, the same

medications were

administered every 2 hours

for next 7 days, then tapered

according to the clinical

response. The additional

supportive treatment included

cycloplegic and antiglaucoma

therapy if required.

The examination findings

were recorded on days 1, 4, 7,14, and 21 and at 3 months.

Slit-lamp biomicroscopy with

fluorescein staining was

carried out at each visit to

assess the size, depth, and

location of the ulcer; anterior

chamber reaction; and

presence and height of

hypopyon. To distinguish

between stromal infiltrates

and corneal scarring,

fluorescein staining wasperformed at each follow-up

visit. Stromal infiltrate is

yellowish and shows evidence

of staining, whereas a scar is

whitish and does not stain

with fluorescein. Moreover, a

scar is associated with corneal

thinning, whereas a stromal

infiltrate demonstrates

corneal edema in the

surrounding area along with

cellular invasion and necrosis.

The above-mentioned

parameters were evaluated at

each visit. Any change of

protocol, adverse event, or

surgical intervention was

documented. Healing was

defined as closure of the

epithelial defect with

disappearance of the stromal

infiltrates at or before 3

months. Clinical response to

medication was poor if the

ulcer size remained the same

or increased for 72 hours. If

the pa-tients keratitis

worsened, the treatment code

was broken, and the patient

was administered a treatment

regimen deemed fit by the

investigator.

"ata $nal!sis and

tatistical Methods

Sample size for the study was

computed for the healing rate at

3 months as the primary

outcome in a 2-group

equivalence trial. Considering

85% as the healing rate at the

end of 3 months in the fortified

antibiotics group and 80% in

the moxifloxacin group, to

detect an equivalence margin of

up to 20% with 80% power and

95% confidence level, the

required number of patients

was 80 in each group. Taking

losing patients to follow-up into

consideration, a minimum of100 patients were to be enrolled

in the study.

Comparison between the 2

treatment groups of the

distribution of the baseline

characteristics was carried out

using the chi-square test or

Fisher exact test for

categorical variables.Proportion tests and the

analysis of covariance was

used to assess the difference

(95% confidence interval

[CI]) and adjusted difference

(95% CI) between the healing

of the 2 groups at 3 months.

The data were analyzed

according to the protocol.

Cure was defined as no evi-

dence of active bacterial

infection, complete wound

healing (re-epithelialization),


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and resolved signs of

inflammation. The inves-

tigator who noted the findings

and the person who dispensed

the medicines were blinded to

each other.

esults

Of a total of 224 patients with

bacterial keratitis enrolled in

the study, 114 patients were

randomized to the fortified

tobramycin and cefazolin

group (group A) and 110patients were randomized to

the moxifloxacin group

(group B). Four patients were

lost to follow-up in group A

(2 patients at day 7 and 2

patients at day 14), and 2

patients were lost to follow-

up in group B (both patients

at day 7), so that 110 patients

in group A and 108 patients

in group B were analyzed. An

independent investigatorfollowed up with the patients,

who were blinded to the study

medications. There were no

statistically significant

differences between the 2

groups for any demographic

or baseline characteristics. No

statistically significant

difference was seen in the

prestudy pathologic features

associated with predisposition

of corneal ulcers in the 2

groups (Table 1).

Micro&iolo#ic $nal!sis

Among 218 gram-stain

specimens analyzed, 60

(27.5%) were gram-positive

cocci and 13 (5.9%) were

gram-negative bacilli.

Positive bacterial culture

results were obtained in 175

patients (80.7%), and no

growth was seen in 42 cases

(19.4%) (Table 2). Among the

bacterial isolates, coagulase-

negative Staphylococcus

(40.9% in group A and 48.2%

in group B) was seen most

com-monly in both groups,followed by Staphylococcus

aureus(19.1% in group A and

21.3% in group B).

Pseudomonas aeruginosawas

isolated in 5.4% in group A

and in 4.6% in group B. There

was no significant difference

in the organisms isolated in

either group (Table 3).

The antibiotic sensitivity of the

isolated organisms was ana-

lyzed by the Kirby-Bauer disk

diffusion method. The isolates

were considered resistant,

intermediate, or susceptible to

an antibiotic based on the zone

of inhibition (HiMedia

Laboratories Pvt. Ltd.,

Bombay, India). It showed that

100% samples of

Staphylococcus, Streptococcus,

andPseudomonas species were

sensitive to moxi-

11/2


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Sharma et al Moxifloxacin 0.5% in Nonperforated Bacterial Corneal Ulcers

Table 1. Demographic and Baseline

Characteristics

'roup $(

P

)ortified

'roup B(

$nti&iotics

Moxifloxacin

*alue

No. enrolled

110

108

Age (yrs)

!

"

(1.8)

#0

($.8)

#0%"!

"1

(#$.#)

"&

("1.$)

0.##


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&0%'!

##

(#0)

$

(&)

$0%!0

1

(10.!)

0'

(&.')

ye

ight

&0

("&.&)

"

(#8.!)

0.#

*e+t

'0

(&".&)

''

('1.1)

,ocioeconomic stat-s

-ral

&"

("!.1)

#0

($.8)

,emi-rban

$

(".&)

##

(#0.')

0.00"


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rban

!

('.")

"&

("1.$)

,ystemic +actor

Absent

10"

(!".&)

81

($&)

0.00

/resent

0'

(&.&)

$

(&)

Type o+ admission

npatient

1&

(1#.')

1'

(1".8)

0.80

O-tpatient

!&

(8'.")

!

(8&.)

pithelial de+ect sie

(diameter in mm)


9/26

2ean

".

"."1 1.&

0.

ange

0.&%8

1.&%$.

/rest-dy pathologic +eat-res

Tra-ma

&!

(.')

"

(.)

Contact lens -se

#'

(#.$)

"8

("".")

ye r-bbing

0

1

(11.1)

3ome4based medication

!

(8.)

!

(8.##)

0.00

*agophthalmos

#

(.$)

!

(8.##)


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Corneal gra+ts

0

'

(&.')

/re4e5isting 6iral 7eratitis

#

(.$)

0

,D standard de6iation.

floxacin. All the isolates of Pseudomonas

species, Proteus mira-bilis, andKlebsiella

species were sensitive to tobramycin. In

comparison, sensitivity to cefazolin was seen

in 90.6% isolates of coagulase-negative

Staphylococcus, 76.6% isolates of S aureus,

and 45.5% isolates of P aeruginosa(Table 4).

Table #. Organism solated +rom the

Corneal lcer (n 1$$)

'roup $(

)ortified

'roup B(

P

$nti&iotics

Moxifloxacin

Total

+r#anism

,n -/

,n 1/

,n 22/

*alue

Sta&h$lococcus e&idermidis

"&


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("0.!)

&

("8.)

!$

Sta&h$lococcus aureus

1

(1!.1)

#

(1.#)

""

Pseudomonas aeruinosa

0'

(&."&)

0&

(".')

11

0."

Stre&tococcus &neumoniae

01

(0.!1)

00

(0)

01

3lebsiella species

0"

(#.')

01

(0.!)

0&

Proteus mirabilis

1"

(1.$)

0&

(".')

1!

The n-mbers in the brac7ets indicate the

percentage o+ the cases.

similar, and there was no significant

difference in the 2 groups (P0.065). No

serious events directly attributable to therapywere reported during the study. Percentage

healing difference was calculated to be 0.33

(95% CI, 10.04 to 10.7) and adjusted

percentage difference (adjusted for

socioeconomic status, prestudy pathologic

features, and presence of systemic factor) was

found to be 1.58 (95% CI, 9.66 to 12.83) at 3

months. It was found to be statistically

insignificant (Table 5and Fig 1).

The mean logarithm of the minimum angle of

resolution best-corrected visual acuities in

group A and group B at the time of

presentation were 1.59 0.44 and 1.55 0.46,

respectively (P0.50). At the end of 3 months,

the mean logarithm of the minimum angle of

resolution best-corrected visual acuities were

comparable in the 2 groups, that is, 1.3 0.51

in group A and 1.34 0.53 in group B (P0.88).

Twenty cases each in both the groups

worsened (P0.78). There was no difference


12/26

in terms of mean age (P0.29) or

socioeconomic status (P0.52) in the

worsened cases between the 2 groups. All

ulcers that worsened with therapy in group A

and 80% (16/20) of ulcers in group B

extended deeper than the mid stroma, and

most of these ulcers demonstrated negative

culture results (14/20 in group A and 16/20 in

group B). However, a change in therapy

guided by repeat microbiologic examination

led to resolution of ulcers in these cases, so

that therapeutic keratoplasty was required in

2 cases in group A and in 1 case in group B.

+utcome

A complete resolution of keratitis and healing

of ulcer occurred in 178 (81.6%) patients at 3

months. Of these, 90 patients (81.8%) were in

group A and 88 patients (81.4%) were in

group B. Worsening of ulcer was seen in

18.2% of cases in group A and in 18.5% of

cases in group B. Mean time to

epithelialization was

Table . 2icrobiologic Analysis o+

Corneal ,craping ,amples

'roup $(

)ortified

'roup B(

P

$nti&iotics

Moxifloxacin

Total

'ram stain

,n 0/

,n 0/

,n 3/

*alue

ram4positi6e cocci

$

(".&)

##

(#0.')

'0

($.&)


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ram4negati6e bacilli

0$

('.")

0'

(&.')

1#

(&.!)

0.'

Total stain negati6e

$'

('!.1)

'!

('#.!)

1"&

(''.&)

9al-es pro6ided as n (:).

"iscussion

The standard treatment of microbial

keratitis consists of a combination of

fortified topical antibiotics or fluoroquino-

lones. It generally is advocated that for

nonsevere ulcers that are not threatening

the visual axis, fluoroquinolones are

preferred over combination therapy,

whereas in cases of severe bacterial ulcers

threatening the visual axis, combination

ther-apy with fortified antibiotics is

preferred. There are factors favoring

monotherapy, such as ease of procurement

of medi-cine, simplicity of application and

storage, and less chance of toxicity.10

With

the advent of newer fourth-generation

fluoro-quinolones with enhanced gram-

positive coverage while re-taining efficacy

against gram-negative organisms, there has

been a renewed interest in newer-

generation fluoroquinolone monotherapy

for bacterial keratitis.18 23

This has been

ac-complished by substitution of the

methoxy group at position 8 of thequinolone ring, which helps in

simultaneous inhi-bition of both DNA

gyrase and topoisomerase 4 in gram-

11/4


14/26

Ophthalmology (olume 1'0, Number , "une '01.

Table ". n 9itro Antibiotic ,ensiti6ity o+ Bacteria solated +rom C-lt-re ,amples

T!pe of +r#anism

Cefa4olin

To&ram!cin

Moxifloxacin

Ciprofloxacin

+floxacin

'atifloxacin

Sta&h$lococcus e&idermidis

8$;!'

(!0.':)

!";!'

(!$.!:)

!';!'

(100:)

!#;!&


15/26

(!$.8:)

!;!'

(!&.8:)

!";!'

(!$.!:)

Sta&h$lococcus aureus

##;"#

($'.$:)

";"#

(!$.$:)

"#;"#

(100:)

"0;"

(!&.:)

#!;"#

(!0.$:)

#!;"#

(!0.$:)

Pseudomonas aeruinosa

&;11

("&.&:)

11;11

(100:)

11;11

(100:)

!;11

(81.8:)

8;11

($.$:)

!;11

(81.8:)

Proteus mirabilis

1;&

(0:)

&;&


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(100:)

";&

(80:)

";&

(80:)

";&

(80:)

&;&

(100:)

3lebsiella species

1;1

(100:)

1;1

(100:)

1;1

(100:)

1;1

(100:)

1;1

(100:)

1;1

(100:)

Stre&tococcus &neumonia

1#;18

($.:)

1$;18

(!".":)

18;18

(100:)

1';1$

(!".11:)

1$;18

(!".":)

1$;18

(!".":)


17/26

positive bacteria. This not only increases the efficacy of the

action of moxifloxacin and gatifloxacin but also reduces

the risk of resistance because concomitant mutations in

both genes are less likely to occur than the single mutation

required for developing resistance to older fluoroquinolo-

nes. This structural modification also decreases the suscep-

tibility to efflux the drug from the bacterial cell, thereby

reducing risk of resistance development.19 23

The points supporting combination fortified antibiotic

therapy are better coverage of gram-positive and gram-

negative organisms and less chance of development of

antibiotic resistance. Fortified antibiotics have the

disadvan-tage that they need to be prepared under sterile

conditions at a pharmacy for use. Concerns have been

expressed about their shelf life, appropriate method of

storage, and the duration for which they can be used safely

before replace-ment.24 27

Fortified drops also have the

theoretical risk of the first drug being washed away if both

the medicines are applied simultaneously. Using 2 drugs as

a combina-tion may enhance ocular toxicity and may

prevent re-epithelialization.28 30

Monotherapy with ciprofloxacin and ofloxacin were studied in

the past and were found to be equally effec-tive.10 14

In a

study by Gangopadhyay et al,29

monotherapy with

fluoroquinolone eye drops led to shorter duration of intensive

therapy and a shorter hospital stay compared with combined

forties therapy (tobramycin and cefazolin). How-ever, seriouscomplications were encountered more com-monly in the

fluoroquinolone group, such as corneal perfo-ration,

evisceration, or enucleation of the affected eye. The limitation

of this study was that it was retrospective.29

There are only 2

prospective, randomized, controlled clinical trials comparing

the efficacy of moxifloxacin with combination fortified

therapy in bacterial keratitis.31,32

In a pilot prospective study comparing moxifloxacin(0.5%), gatifloxacin (0.3%), and fortified tobramycin

(1.33%) plus cefazolin (5%) with 20 patients with corneal

ulcers in each group, similar outcomes were seen.31

How-

ever, the sample size of this study was small and the power

of the study was only 32%. The only other randomized,

controlled clinical trial comparing moxifloxacin and com-

bination therapy was carried out by Constantinou et al.32

They

compared moxifloxacin (1%), ofloxacin (0.3%), and fortified

tobramycin (1.33%) plus cefazolin (5%) and found similar


18/26

rates of healing of corneal ulcers. There were 3 differences in

the study protocol compared with the present study. The

present study used commercially available moxi-floxacin

hydrochloride 0.5% (Vigamox; Alcon), unlike the study by

Constatinou et al, in which 1% moxifloxacin that was

reconstituted at a pharmacy was used; the availability of this

commercial preparation obviates the need for a hos-pital

pharmacy to prepare the drug. In the study by Con-statinou et

al, the initial therapy was ceased at 1 week and a preservative-free prophylactic antibiotic such as chloram-phenicol ointment

was used subsequently, if required. How-ever, in the present

study, because preservative-free moxi-floxacin was being

used, it was continued until complete healing occurred.

Furthermore, in this study, no topical corticosteroids were

used, which were used in the study by Constatinou et al as the

ulcer was resolving. It has been demonstrated amply in the

available randomized clinical trials that topical corticosteroids

may not help in enhancing the rate of healing in cases of

resolving keratitis.33,34

The argument against fluoroquinolone monotherapy is that

although these agents are considered very effective and safe,

resistance is bound to occur if they are used indiscrim-inately,

and a few cases of moxifloxacin and gatifloxacin resistance

already are emerging, especially in cases of in-fectious

keratitis occurring after refractive surgery35 40

; however, their

judicious use in an appropriate setting may be justified.

Furthermore, poor patients from rural areas often are

uneducated and have poor access to tertiary care hospitals or

pharmacy. They may not be able to store the fortified

medication at a cool temperature to maintain its shelf life. The

combination therapy may enhance the cost of treat-ment as

well. It may be difficult to explain the method of sequential

application of fortified topical medication to uned-ucated

patients, and inappropriate application may nullify the

Table &. O-tcomes o+ /atients


19/26

Not healed at # mos

0 (18.)

0 (18.&)

0.## ( 10.0" to 10.$)

1.&8 ( !.'' to 1.8#)

3ealed at # mos

!0 (81.8)

88 (81.")

=Ad>-sting +or socioeconomic stat-s? ris7 +actors? and systemic +actors.

11/


20/26

Sharma et al Moxifloxacin 0.5% in Nonperforated Bacterial Corneal Ulcers

)i#ure . Graph showing the unadjusted and

adjusted percentage differ-ence in healing !5%

confidence inter"al# $etween patients recei"ing

oxifloxacin and those recei"ing fortified

anti$iotics.

advantage of combination therapy.

Compliance also is difficult to maintain withmore medications and confusing regimens.

To conclude, this study demonstrated

that monotherapy with commercially

available 0.5% moxifloxacin hydrochlo-

ride may be as effective as a combination

therapy of forti-fied cefazolin and

tobramycin in cases of nonperforated

bacterial keratitis. Moxifloxacin 0.5%

may be continued during the entire

treatment course because, beingpreserva-tive free, it is not significantly

epitheliotoxic. Further studies are

required to evaluate the role of

moxifloxacin 0.5% in perforated corneal

ulcers.

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Polack S, Brooker S, Kuper H, et al. Mapping

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Asbell P, Stenson S. Ulcerative keratitis:survey of 30 years laboratory experience.

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Liesegang TJ, Forster RK. Spectrum of

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Baum JL. Initial therapy of suspected

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)ootnotes and )inancial "isclosures

Originally received: April 16,

2012.

Final revision: October 14, 2012.

Accepted: November 8, 2012.

Available online: February 15,

2013. Manuscript no. 2012-

546.

Rajendra Prasad Centre for

Ophthalmic Sciences, All IndiaInstitute of Medical Sciences,

New Delhi, India.

Department of Biostatistics, All

India Institute of Medical

Sciences, New Delhi, India.

Centre for Eye Research

Australia, University of

Melbourne, Royal Victorian Eye

and Ear Hospital, Melbourne,

Australia.

Financial Disclosure(s):

The author(s) have no proprietary

or commercial interest in any

materials discussed in this article.

Supported by the All India

Institute of Medical Sciences,

New Delhi, India.

Correspondence:

Namrata Sharma, MD, Rajendra

Prasad Centre for Ophthalmic

Sciences, All India Institute of

Medical Sciences, New Delhi

110029, India. E-mail:

[email protected].


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