Photoactivated Chromophore for Moderate to
Severe Infectious Keratitis as an Adjunct
Therapy: A Randomized Controlled Trial
NGAMJIT KASETSUWAN, USANEE REINPRAYOON, AND VANNARUT SATITPITAKUL

PURPOSE: To evaluate the efficacy of photoactivated
chromophore for infectious keratitis (PACK-CXL) in
the treatment of patients with moderate to severe infec-
tious keratitis as adjunct therapy to the topical medication
treatment.

DESIGN: Randomized clinical trial.

METHODS: Thirty eyes from 30 patients with moderate
to severe infectious keratitis were randomized to receive
either standard treatment plus PACK-CXL (n [ 15) or
standard treatment alone (control group, n [ 15). The
primary outcome was the sizes of stromal infiltrates
measured on slit-lamp photographs 30 days after treat-
ment. The secondary outcomes were the sizes of epithelial
defects, the complication rates, and best pinhole-
corrected visual acuity (BPVA).

RESULTS: The median (interquartile range [IQR]) sizes
of stromal infiltrates at day 30 were 5.0 mm2
(0–23.0 mm2) in the PACK-CXL group and 10.6 mm2
(1.1–16.3 mm2) in the control group (median difference
0, 95% CI L7.0 to 0, P [ .66). The median (IQR) sizes
of epithelial defects were 0.7 mm2 (0–6.3 mm2) and
4.6 mm2 (0–10.2 mm2) in the PACK-CXL group and
control group, respectively (median difference L3.0,
95% CI L0.8 to 0, P [ .41). The complication rates
and BPVA after treatment were comparable between
groups.

CONCLUSIONS: Standard treatment combined with
PACK-CXL did not provide any advantageous effect
over standard treatment alone in moderate to severe in-
fectious keratitis over a 30-day period. (Am J
Ophthalmol 2016;165:94–99. Ó 2016 Elsevier Inc. All
rights reserved.)
I
NFECTIOUS KERATITIS IS A LEADING CAUSE OF RAPID
and devastating visual loss worldwide, especially in
developing countries. Despite topical broad-spectrum
medical therapies being used initially, infectious keratitis
Supplemental Material available at AJO.com.
Accepted for publication Feb 24, 2016.
From the Department of Ophthalmology, Faculty of Medicine,
Chulalongkorn University, and King Chulalongkorn Memorial Hospital,
Bangkok, Thailand.
Inquiries to Vannarut Satitpitakul, Department of Ophthalmology,
Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road
Pathuwan, Bangkok, Thailand 10330; e-mail: vannaruts@gmail.com
94 Ó 2016 ELSEVIER INC. ALL
leading to corneal perforation or endophthalmitis is not
uncommon. A new paradigm-changing treatment able to
enhance microbial eradication and improve treatment out-
comes with fewer side effects needs to be established.
Corneal collagen cross-linking is a procedure in which
the photosensitizer riboflavin and ultraviolet A (UVA)
irradiation are used. This procedure preliminarily aims to
strengthen the corneal stroma, thereby improving the
corneal biomechanics in ectatic corneal disorders.1 Soon
after the acceptance of this concept, corneal cross-linking
was proposed to be effective for treating infectious keratitis
based on the disinfectant properties of photoactivated
chromophore. The possible mechanisms include inhibition
of microbial replication, intercalation of the chromophore
with microbial nucleic acid,2 direct damage to the path-
ogen cell walls by reactive oxygen free radicals,3,4
increased resistance of the cross-linked cornea to enzymatic
damage, and changing of the ocular surface environment.5
However, the clinical evidence in terms of collagen cross-
linking efficacy for keratitis is still inconclusive.6–9
In this study, we evaluated the efficacy of photoactivated
chromophore for infectious keratitis (PACK-CXL) as an
adjunct to medical treatment for patients with moderate
to severe infectious keratitis.
METHODS
THE INSTITUTIONAL REVIEW BOARD, FACULTY OF MEDI-
cine, Chulalongkorn University approved and monitored
this randomized controlled trial, which adhered to the te-
nets of the Declaration of Helsinki. The trial was registered
with clinicaltrials.gov (NCT01831206). The sample size
for the study was calculated using a superiority design for-
mula with power of 0.8 and a 2-tailed significance level
of .05 to detect 7 mm2 difference in areas of stromal infiltra-
tion with standard deviation of 6. This provided a sample
size of 15 patients per group. Written informed consent
was obtained from all participants.
The participants were recruited from the Department of
Ophthalmology, King Chulalongkorn Memorial Hospital,
Bangkok, Thailand from March 2013 to December 2014.
All patients presenting with infectious keratitis underwent
ophthalmic examination including best pinhole-corrected
visual acuity (BPVA), slit-lamp biomicroscopy, anterior
RIGHTS RESERVED. 0002-9394/$36.00
http://dx.doi.org/10.1016/j.ajo.2016.02.030
 TABLE 1. Baseline Characteristics of Participants With Moderate to Severe Infectious Keratitis in the Medical Therapy Plus
Photoactivated Chromophore Group and Medical Therapy Group

Parameter PACK-CXL Group (n ¼ 15) Control Group (n ¼ 15)

Mean age (range), y 44.60 (17–73) 53.93 (15–84)

Male-to-female ratio 11:4 10:5
Moderate to severe infectious 2:13 4:11
keratitis ratio
Median size of epithelial defect 31.29 (13.48–41.61) 31.11 (19.13–45.94)
(IQR), mm2
Median size of stromal infiltration 31.89 (28.52–62.78) 31.07 (17.93–54.88)
(IQR), mm2
Hypopyon 9/15 (60%) 7/15 (46.67%)
Mean initial BPVA (logMAR) 1.75 6 0.22 1.68 6 0.32
Etiologic organisms
- Bacteria 7/15 (46.67%) 5/15 (33.33%)
- 1 Pseudomonas spp - 4 Pseudomonas spp
- 1 Enterobacter spp - 1 negative laboratory result
- 5 negative laboratory results
- Fungus 8/15 (53.33%) 10/15 (66.77%)
- 2 Fusarium spp - 5 unidentified septate hyphae
- 1 Aspergillus spp - 1 unidentified budding yeast
- 1 Purpureocillium spp - 1 Pythium spp
- 1 Pythium spp - 3 negative laboratory results
- 2 negative laboratory results

BPVA ¼ best pinhole-corrected visual acuity; IQR ¼ interquartile range.

PACK-CXL group ¼ medical therapy plus photoactivated chromophore; Control group ¼ medical therapy alone.

segment photography, and posterior segment ultrasonogra-
phy. The severity of keratitis was graded by slit-lamp bio-
microscopy using a modification of Jones’s grading.10
Ulcers that were 2-6 mm in size and infiltration that
involved the mid stroma but not beyond the posterior
one third of the corneal stroma were graded as moderate in-
fectious keratitis. Ulcers either involving the posterior one
third of the cornea or that were more than 6 mm in size
were graded as severe infectious keratitis.
Consecutive cases of patients aged older than 6 years
with moderate to severe infectious keratitis were enrolled
in the study. Pregnant patients or patients with a history
or evidence of herpetic keratitis, parasitic keratitis, corneal
perforation, autoimmune diseases, endophthalmitis, or
corneal thickness less than 400 mm by ultrasound pachy-
metry were excluded.
After enrollment, participants were randomized to
receive standard treatment with or without PACK-CXL us-
ing simple randomization. Sealed envelopes, used to
conceal the randomization, were opened after enrollment
of each participant. A microbiological evaluation included
Gram stain, KOH preparation, and cultures; the samples
were obtained by corneal scraping in all participants.
Participants randomized to standard treatment received
standard medical therapy according to the patient’s history,
clinical findings, and initial laboratory results. The primary
medical therapy for bacterial keratitis included hourly instil-
lation of fortified cefazolin (50 mg/mL; BIOLAB, Samutpra-
karn, Thailand) and fortified amikacin (20 mg/mL; Atlantic
Lab, Bangkok, Thailand); the primary medical therapy for
fungal keratitis included hourly topical application of
amphotericin B (1.0 mg/mL; Bharat Serums and Vaccines,
Maharashtra, India) and topical natamycin (50 mg/mL;
Alcon, Bangkok, Thailand). In case of positive clinical
response, the medications were tapered based on the judg-
ment of 1 clinician (N.K.). However, if the ulcers
progressed, the regimens were changed according to the re-
sults of the microbiological evaluation. All participants were
treated as inpatients until the medications were tapered to
applications of fewer than 4 times a day. No topical or sys-
temic corticosteroids were used during the study period.
For the participants randomized to PACK-CXL, corneal
collagen cross-linking with UVA and riboflavin was
performed under topical anesthesia on the first day of pre-
sentation. The corneal limbus was shielded by a Merocel
ring (Medtronic, Inc, Dublin, Ireland). Riboflavin (Medio-
CROSS [Peschke Meditrade GmbH, Germany] 0.1% ribo-
flavin/20% dextran solution) was administered to the
cornea every 2 minutes for an initial period of 30 minutes
and then every 5 minutes for a further 30 minutes during
UVA illumination. The epithelium was not removed as
there were epithelial defects overlying the ulcers. The

VOL. 165 PHOTOACTIVATED CHROMOPHORE FOR INFECTIOUS KERATITIS 95

 UV-X lamp (Peschke Meditrade GmbH, Hünenberg,
Switzerland) was used to deliver UVA (365 nm with 3.0

P Valuea

.62

.87
TABLE 2. Areas of Stromal Infiltration in Participants With Moderate to Severe Infectious Keratitis at Day 7 and Day 30 After Treating With Medical Therapy Plus Photoactivated
mW/cm2) for 30 minutes. After the PACK-CXL treat-
ment, the participants received standard medical treatment

1.1 (16.9 to 0)
Median Difference
as described previously.
Fungal Keratitis Cases (Median, IQR; mm2)

6.0 (12.4
The results of measurement of the BPVA, slit-lamp ex-

(95% CI)

to 10.4)
amination, and anterior segment photography with and
without fluorescein staining were recorded at the initial
presentation and on day 7 and day 30. The logarithm of
the minimal angle of resolution visual acuity values equal
Control Group

40.5 (12.5
to 59.7)

to 23.9)
(n ¼ 10)

12.6 (4.4
to or below the counting fingers level were recorded as fol-
lows: counting fingers, 1.7; hand movements, 1.8; light
perception, 1.9; and no light perception, 2.0. All anterior
9.1 (0 to 27.4)

segment photography was masked and 1 investigator

Group (n ¼ 8)
PACK-CXL

(V.S.) randomly assessed the images for the sizes of stromal

30.2 (19.9
to 64.8)

infiltrates and epithelial defects using Image-Pro version

7.0 (Media Cybernetics, Rockville, Maryland, USA).
The primary outcome was the size of the stromal infiltrates;
P Valuea

the secondary outcomes were the sizes of the epithelial de-

.42

.75

fects, the complication rates after treatment, and BPVA at

day 30. The results were compared between the 2 groups us-
0.73 (7.8 to 4.6)
Chromophore Compared to Medical Therapy Alone

Median Difference
Bacterial Keratitis Cases (Median, IQR; mm2)

ing Mann-Whitney U test for both the sizes of the stromal

(95% CI)

infiltrates and epithelial defects; the unpaired t test was

10.3 (3.6
to 17.1)

PACK-CXL group ¼ medical therapy plus photoactivated chromophore; Control group ¼ medical therapy alone.

used for the complication rates and BPVA (IBM SPSS sta-
tistics, Version 22.0; IBM Corp, Armonk, New York,
USA). An alpha value of 0.05 was considered significant.
21.7 (8.1 to 25.4)

8.6 (0 to 14.9)
Control Group
(n ¼ 5)

RESULTS
Group (n ¼ 7)

18.1 (13.6
PACK-CXL

to 44.6)

to 19.1)
0.8 (0.3

THIRTY PARTICIPANTS WITH INFECTIOUS KERATITIS WERE

enrolled in this study. The ulcers in all participants
involved the visual axis. The baseline characteristics
P Valuea

were comparable in both groups (Table 1). The clinical

.50

.66

pictures suggested that 7 patients in the PACK-CXL group

and 5 patients in the control group had bacterial keratitis.
0 (7.0 to 0)
Median Difference

Eight and 10 cases, respectively, in the PACK-CXL group

4.76 (0.74
(95% CI)

to 6.36)

and control group were treated for fungal keratitis. Five of

All Cases (Median, IQR; mm2)

the 15 participants (33.33%) in each group had a history of

contact lens wear. Seven (46.67%) and 8 (53.33%) partic-
ipants in the PACK-CXL and control groups, respectively,
25.4 (10.3 to 48.6)

10.6 (1.1 to 16.3)

had a history of infection with a vegetative origin. Both

Control Group
(n ¼ 15)

participants with a Pythium infection had been exposed

to contaminated water. The microbiological laboratory re-
sults are shown in Table 1.
The median sizes of stromal infiltrates in the PACK-
Mann-Whitney U test.

CXL group at days 7 and 30 were 22.1 mm2 (interquartile

5.0 (0 to 23.0)
Group (n ¼ 15)
PACK-CXL

range [IQR], 16.0–53.6 mm2) and 5.0 mm2 (IQR,

22.1 (16.0
to 53.6)

0–23.0 mm2) and those in the control group were

25.4 mm2 (IQR, 10.3–48.6 mm2) and 10.6 mm2 (IQR,
1.1–16.3 mm2), respectively. There was no significant
Day 30

(P ¼ .50 and P ¼ .66) differences between the groups. Sub-

Day 7

group analysis in the bacterial and fungal keratitis samples

also showed no significant differences (Table 2).

96 AMERICAN JOURNAL OF OPHTHALMOLOGY MAY 2016

 The median sizes of the epithelial defects at days 7 and
30 in the PACK-CXL group were 23.0 mm2 (IQR, 13.5–

P Valuea

.50

.83
41.6 mm2) and 0.7 mm2 (IQR, 0–6.3 mm2), respectively;
TABLE 3. Areas of Epithelial Defect in Participants With Moderate to Severe Infectious Keratitis at Day 7 and Day 30 After Treating With Medical Therapy Plus Photoactivated the median sizes of the epithelial defects in the control

1.48 (33.7 to 0)
group were 16.9 mm2 (IQR, 6.3–39.5 mm2) and 4.6 mm2

Median Difference
Fungal Keratitis Cases (Median, IQR; mm2)
(IQR, 0–10.2 mm2), respectively. However, there were

5.3 (12.2
(95% CI)

to 0.62)
no significant (P ¼ .68 and P ¼ .41) differences between
the 2 groups. Subgroup analysis regarding etiology also
showed no significant differences (Table 3).
Therapeutic keratoplasty was performed in 2 cases in the
Control Group

34.4 (6.6

3.8 (0.7
to 47.1)

to 22.8)
(n ¼ 10)

PACK-CXL group and 3 cases in the control group owing

to uncontrolled infection with corneal perforation. One
case in the control group underwent evisceration owing
1.42 (0 to 13.6)

to endophthalmitis. Recurrent stromal infiltrates into the

Group (n ¼ 8)
PACK-CXL

corneal graft with development of endophthalmitis

to 31.8)
23.7 (9.8

occurred in 1 case in the PACK-CXL group and the eye

was eviscerated.
Among cases without further intervention, the BPVA at
P Valuea

.75

.52

day 30 improved from baseline in 8 of 12 cases (66.7%) in

the PACK-CXL group and 7 of 11 cases (63.6%) in the
4.2 (13.2 to 7.3)

control group. The mean BPVAs was 1.48 6 0.64 in the

Chromophore Compared to Medical Therapy Alone

Median Difference

0 (0 to 2.9) 7.7 (0 to 9.9) 8.0 (6.5 to 0)

Bacterial Keratitis Cases (Median, IQR; mm2)

standard treatment plus PACK-CXL group and 1.20 6

(95% CI)

0.67 in the standard treatment group. There was no signif-

PACK-CXL group ¼ medical therapy plus photoactivated chromophore; Control group ¼ medical therapy alone.

icant difference in the mean BPVAs on day 30 after treat-

ment (P ¼ .32, 95% CI 0.29 to 0.85).
Control Group

to 16.87)
12.4 (7.23
(n ¼ 5)

DISCUSSION
Group (n ¼ 7)
PACK-CXL

to 44.23)
31.3 (14.1

COLLAGEN CROSS-LINKING IS A NEW THERAPEUTIC MODAL-

ity to treat infectious keratitis through various proposed
mechanisms.2–5 Moreover, the microbial eradicating
property of PACK-CXL against Pseudomonas aeruginosa,
P Valuea

.68

.41

Staphylococcus aureus, Staphylococcus epidermidis, Strepto-

coccus pneumoniae, Candida albicans, Fusarium spp, and
Aspergillus fumigatus including multidrug-resistant strains
1.3 (10.0 to 0.8)
Median Difference

was also verified by various in vitro studies.11–16

3.0 (8.0 to 0)
(95% CI)

In the current randomized controlled trial, we compared

All Cases (Median, IQR; mm2)

the exact sizes of stromal infiltrates in patients treated with

medical treatment with or without PACK-CXL in the early
period after cross-linking. Primary medical therapies were
chosen according to the common isolated microorganisms,
16.9 (6.3 to 39.5)

Day 30 0.7 (0 to 6.3) 4.6 (0 to 10.2)

Control Group

which were P aeruginosa, S pneumoniae, Fusarium spp,

(n ¼ 15)

Aspergillus spp and Curvularia spp.17,18

Initially, we believed that PACK-CXL treatment that
induced massive and simultaneous death of microorgan-
Mann-Whitney U test.

isms might debulk the infectious load. This could be used

Group (n ¼ 15)

as a 1-time adjunctive treatment to hasten the resolution

PACK-CXL

23.0 (13.5
to 41.6)

of moderate to severe infectious keratitis. The antimicro-

bial efficacy of PACK-CXL is shown in many case series.
Systematic reviews and meta-analysis of reported cases sug-
gested that from the pooled results of 12 articles, CXL had a
Day 7

favorable effect on the blocking of corneal melting in 85%

of eyes (77%–91%), with very few complications.6

VOL. 165 PHOTOACTIVATED CHROMOPHORE FOR INFECTIOUS KERATITIS 97

 As far as we know, the current study is the first to report a
randomized, single-masked, controlled trial. We compared
the exact areas of corneal infiltrate changes 30 days after
PACK-CXL and we found that the adjunctive PACK-
CXL with standard medical treatment did not speed up
healing of the infiltrate sizes. The complication rates and
BPVA after treatment were comparable between groups.
Re-infection after therapeutic keratoplasty was found in 1
of 3 cases in the PACK-CXL group, which was approxi-
mately the same as reported previously in patients not
treated with PACK-CXL.19
The current results agreed with those from a randomized
study of advance infectious keratitis with coexisting corneal
melting by Said and associates.7,20 They concluded that
PACK-CXL did not shorten the healing time in advance in-
fectious keratitis with corneal melting. The study also
showed a clear but nonsignificant trend in decreasing the
rate of corneal perforation and recurrent infection. In
contrast, the randomized study of Uddaraju and associates9
on recalcitrant deep stromal fungal keratitis and after the
initial 2 weeks of topical antifungal therapy, the study was
stopped before complete enrollment because of a signifi-
cantly higher rate of corneal perforation in the PACK-
CXL group vs the no treatment group. However, the authors
suggested that further studies be undertaken in which the
fungal keratitis is limited only to the anterior stroma.
Until now, only 1 randomized study has reported the ad-
vantages of PACK-CXL in patients with moderate bacterial
keratitis. Bamdad and associates8 reported that PACK-CXL
helped to shorten the healing time regarding epithelializa-
tion and areas of infiltration on days 7 and 14 after treatment.
Compare to our study, the studies of Said and associates,7
Uddaraju and associates,9 and Bamdad and associates8 were
unmasked and the corneal epithelial tissue was removed
before PACK-CXL treatment. Epithelium removal itself
might enhance topical drug penetration and enlarged the
initial sizes of epithelial defects in the PACK-CXL group
only. Therapeutic contact lens wear after PACK-CXL in
the study of Bamdad and associates8 also confounded the
epithelium healing rate.
To the best of our knowledge, the current study is the
first to report a case of Pythium insidiosum keratitis
managed with PACK-CXL. P insidiosum, a pathologic
FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NO
financial disclosures: Ngamjit Kasetsuwan, Usanee Reinprayoon, and Vannarut Satitpitakul. All authors attest that they meet the current ICMJE criteria
for authorship.
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