Journal of EuCornea 3 (2019) 13–21

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Journal of EuCornea
journal homepage: www.elsevier.com/locate/xjec

Modified crosslinking in the treatment of purulent keratitis and corneal ulcers T

ARTICLE INFO ABSTRACT

Keywords: Purpose: To evaluate the efficacy of modified crosslinking (M-CXL) in the treatment of purulent corneal ulcers,
Purulent corneal ulcer including those of mixed etiology.
Infectious keratitis Methods: The M-CXL method consists of simultaneous cross-linking and frequent instillations (FI) of anti-in-
Mixed keratitis fective solutions. We observed 36 patients (37 eyes) with purulent corneal ulcers (PCU) of various etiologies. The
Frequent instillations
test group included 24 patients (24 eyes) who received 1–2 sessions of M-CXL with active conservative therapy.
Crosslinking
In the control group (12 patients, 13 eyes), only active conservative therapy was performed.
Results: Complete reduction of the purulent process was achieved in 18 (75%) eyes in 29.6 ± 9.38 days in the
test group; and in 8 eyes (61.5%) in 50.4 ± 15.9 days in the control group. The efficiency of M-CXL ranged from
100% to 66.6% depending on depth and width (square area) of the infiltration in question. In cases where
infiltration affected the entire stromal thickness, the M-CXL efficacy sharply decreased to 66.6%, even with its
small (< 6 mm) area. In cases where infiltrations extended to the Descemet’s membrane with an overall
area > 7 mm, the clinical effect of M-CXL was absent or insufficient.
Conclusion: In 75% cases, M-CXL showed complete reduction of PCU. Comparing with control groups, the
duration of treatment in the test group decreased 42% (P less than 0.05). In infiltrations over a wide area
affecting all the layers up to the Descemet’s membrane, resorbtion of the purulent focus was not achieved.
However, it’s spread and purulent fusion were sufficiently suspended, thereby allowing therapeutic penetrating
keratoplasty to be performed with a smaller graft diameter.

1. Introduction stilled in the postoperative period [10,11].

To date, the problem of the treatment of purulent keratitis (PK) and
purulent corneal ulcers (PCU) in an advanced stage and corneal abscess
has a great and growing importance in ophthalmology. PK is a major
cause of preventable monocular blindess [1].
Today one of the methods for the treatment of PCU and keratitis is
corneal collagen cross-linking [2–5]. The effects of cross-linking (CXL)
on corneal tissue (increased biomechanical strength and resistance to
enzymes) can potentially provide a useful therapeutic effect in in-
flammatory diseases of the cornea [6,7]. However, the most important
impact of CXL in the treatment of infectious keratitis is the anti-
microbial effect that occurs due to the interaction of ultraviolet A
(UVA) radiation with riboflavin, which leads to damage to micro-
organisms, as well as the direct bactericidal effect of ultraviolet radia-
tion [8].
The disadvantages of CXL include limited penetration of UVA into
tissues: the greatest effect is achieved in the surface and middle layers
of the cornea at a depth of approximately 300 μm [9]. Therefore, UV
radiation may not reach any purulent infiltration that affects the deeper
layers of the cornea. In addition, unlike the transparent stroma of a
healthy cornea, in dense opaque purulent infiltrates, the penetration
depth of UV radiation can significantly decrease and thus reduce the
efficacy of CXL in the treatment of deep-seated purulent infiltration
It is also known that corneal permeability after CXL decreases by
16–28%, an effect that reduces the efficacy of anti-infective agents in-
One of the methods of therapeutic treatment of PK and PCU is fre-
quent instillations (FI) of solutions of anti-infective agents [12]. The FI
of solutions of antimicrobial drugs create and maintain a consistently
high therapeutic concentration of the substance in the cornea and
aqueous humor, which permits the achievement of a greater ther-
apeutic effect [13,14]. FI have proven clinical efficacy and are included
in the algorithms for the treatment of PCU and PK [13–16].
Based on the above, we modified the CXL and supplemented it with
FI of anti-infective agents (antibiotics, antiseptics, or antifungal agents)
during the procedure. This combination created a synergistic effect.
1.1. Aim
To evaluate the clinical efficacy of modified CXL (M-CXL) in the
treatment of PCU.
2. Materials and methods
The M-CXL method consists of simultaneous CXL and FI of anti-in-
fective agents (once every 3–5 min for an hour), which allows the use of
the synergistic effect of cross-linking and anti-infective therapy.
The study included patients with PCU. M-CXL was not performed in
patients with significant stromal thinning (over 50%), descemetocele
and corneal perforation, as well as in those with keratitis without sec-
ondary purulent infection.

https://doi.org/10.1016/j.xjec.2019.12.001
Received 29 July 2019; Received in revised form 12 November 2019; Accepted 3 December 2019
Available online 05 December 2019
2452-4034/ © 2019 Published by Elsevier Inc. on behalf of European Society of Cornea & Ocular Surface Disease Specialists. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
 Journal of EuCornea 3 (2019) 13–21

Table 1 We observed 36 patients (37 eyes) with PCU of various causes; all
Distribution of patients in the test group by etiology of PK. corneal ulcers affected no more than 50% of the stromal thickness. Of
Group by etiology: Number of patients these, 22 were women and 14 men. The age of the patients ranged from
18 to 80 years (49.0 ± 14.6).
Bacterial 4 In addition to taking detailed medical histories, we conducted the
Fungal 6
following examinations in all patients: visual acuity measurement,
Mixed In the presence of HSV + bacteria 14 10 4
HSV HSV + fungi 6
biomicroscopy, culture from the surface of purulent infiltrate or corneal
In the presence of acanthamoeba + bacteria 4 2 ulcers, and optical coherence tomography (OCT) of the cornea. To ex-
acanthamoeba acanthamoeba + fungi 2 clude local foci of infection, all patients with PCU underwent tear duct
Total 24 rinsing, X-ray examination of the paranasal sinuses and of the roots of
the teeth. When infected foci were detected, we referred those patients
to dentists and otolaryngologists for teatment.
In case of suspicion of preexisting herpetic keratitis (history of re-
Table 2 current keratitis or previous episodes of herpetic keratitis), we ex-
Distribution of patients in the test group by severity of PI. amined conjunctival scrapes with fluorescent antibodies method. The
test was considered positive if the presence of fluorescent luminescence
Subgroup (of main Depth of damage Diameter of the Total number of
group) by the depth of (% of corneal damage, mm. patients in of the nucleus (antigen-antibody complex) of the 2nd degree was de-
the damage caused by stromal thickness) subgroup tected.
PI Acanthameba keratitis was suspected as an underlying cause of as-
sociated with the patient’s PCU if he/she was using contact lenses, or if
I Less than 50% 4–7 7
II 50–70% Less than 5 3
the patient sustained severe pain at the outset of the disease, had an
III 50–70% More than 5 7 annular corneal infiltrate, or if a lack of effect from previous anti-
IV Less than 90% Less than 6 3 bacterial and anti-herpes therapy was observed. These patients under-
V 100% More than 7 4 went corneal confocal biomicroscopy.
Total 24
The test group consisted of 24 patients who underwent M-CXL
sessions in combination with subsequent active conservative therapy
(FI of solutions of antibacterial or antifungal agents – from 10 to 16

Fig. 1. (a) A purulent corneal ulcer which developed after LASIK, multiple purulent corneal infiltrates before M-CXL. (b) After 2 sessions of M-CXL, complete
resorption of purulent infiltrates, and gentle opacification of the cornea in the center. Visual acuity with correction – 0.6.

14

Fig. 2. (a) Keratitis of mixed etiology (fungi + HSV). (b) 28 days after the second session of M-CXL. Purulent infiltration was completely resorbed. Opacification of
the cornea. Visual acuity – 0.5 not correctable.
times per day, periocular injections and systemic anti-infective
therapy). In the control group (12 patients, 13 eyes), only active con-
servative therapy analogous to that used in the test group was ad-
ministered.
Infiltrates were most often localized in the central and paracentral
zones of the cornea, which led to a sharp decrease in visual acuity: from
0.5 to 0.01 (decimal system) with correction.
In the test group, PCU of bacterial etiology was noted in 4 eyes,
fungal etiologydy in 6 eyes, PCU of mixed etiology in 14 eyes (herpes
simplex virus (HSV) + bacteria in 4 eyes, HSV + fungi in 6 eyes;
acanthameba + bacteria in 2 eyes, and acanthameba + fungi in 2 eyes)
(Table 1).
In the test group, 5 subgroups (subgroup I-V) were distinguished
according to the depth and area of purulent infiltration (PI) in the
corneal stroma (Table 2).
Of the 12 patients (13 eyes) in the control group, purulent in-
filtration affected up to half the stromal depth in 4 patients (5 eyes),
more than half (but not more than 70% of the stromal depth) in 4
patients and all layers up to Descemet’s membrane in 4 patients.
Diameter of the damage less than 3 mm was noted in 4 eyes, from 3 to 6
mm in 3 patients (4 eyes), and over 6 mm in 3 eyes.
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Journal of EuCornea 3 (2019) 13–21
In the control group, PCU of bacterial etiology was noted in 2 eyes,
fungal etiology in 4, PCU of mixed etiology in 7 eyes : HSV + bacteria
in 2 eyes, HSV + fungi in 4 eyes, and acanthameba + fungi in 1 eye.
M-CXL included de-epithelialization of the cornea over the purulent
infiltrate area with an inclusion of 3 mm of the transparent cornea
around it, alternate instillations of a 0.1% riboflavin solution and anti-
infective solutions (eye drops of tobramycin 0.3%, levofloxacin 0.5%,
or fluconazole solution 2 mg/ml (off-label) or chlorhexidine 0.02% –
depending on the type of pathogen causing PCU) and implementation
of CXL. The duration riboflavin solution instillation and solutions of
anti-infective agents was 60 min; the frequency of riboflavin instillation
was every 2 min, the frequency of therapeutic eye drops every 3–5 min
(invention patent in the Russian Federation “Method for the treatment
of purulent corneal ulce” No. 2635454 with priority from 13.11.2017).
The toxicity of high-frequency instillation of antibiotic eye drops
has been ruled out in our animal experiments [12]. All patients signed a
voluntary informed consent form to receive M-CXL. This procedure has
been approved by the ethical committee of FGBNU NII GB [Federal State
Budgetary Scientific Institution Research Institute of Eye Diseases].
Below we present a detailed regimen for intensive conservative
treatment by etiology and clinical picture of PCU. In mixed keratitis, a
 Journal of EuCornea 3 (2019) 13–21

Fig. 3. (a) Purulent corneal ulcer (fungi + HSV) before M-CXL. Purulent infiltration affects more than 50% of the stroma. (b) 47 days after M-CXL and covering the
defect with a corneoscleral flap. Reduction of purulent infiltration with the formation of opacification. Acuity is 0.5, with correction sph – 2.0, cyl – 3.0, axis 5° = 0.9.

combination of the below regimens were used.
• Antibacterial therapy: FI of solutions of 0,3% tobramycin and 0.5%
levofloxacin eye drops, tetracycline or colbiacin ointment overnight,
gentamicin periocularly; enteral or parenteral levofloxacin.
• Antifungal therapy: FI of fluconazole 2 mg/ml, amphotericin B (off
label) 0.15%, and 0.02% chlorhexidine solutions; oral fluconazole
or itraconazole 200 mg/day).
• Antiamebic therapy: instillations of 0.02% chlorhexidine, flucona-
zole, polyhexamethylene biguanide and oral fluconazole 150 mg/
day.
• Antiherpetic therapy: inducer Interferon drops and periocular in-
jections, oral valacyclovir 1000–1500 mg/day.
3. Results
The criteria for assessing the efficacy of the method were full re-
sorption of purulent infiltrate of the cornea, reduction of the corneal
syndrome (pain, increased lacrimation, photophobia and reflective
spasm of the eyelids), and epithelialization.
Pathogenic microflora was isolated by the cultivation method in 13
cases (pseudomonas aeruginosa – 2, staphylococcus – 7, streptococcus –

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 Journal of EuCornea 3 (2019) 13–21

Fig. 4. (a) Purulent corneal ulcer of mixed etiology (fungi + HSV) before M-CXL. (b) Before M-CXL, the cornea is edematous, purulent infiltrate affects up to 50% of
the stromal thickness. (c) 19 days after M-CXL, opacification of the cornea. (d) 3 months after M-CXL. Visual acuity is 0.1, with correction sph – 3.0, cyl – 3.5, axis
140° = 1.0. (e) The cornea is calm, forming a scar, and the epithelium is well healed.

2, fungi – 2), acanthameba cysts were detected in 2 patients using
corneal confocal biomicroscopy. In 2 patients, acanthameba cysts and
fungi were detected by a pathomorphological study of discs of removed
corneas after therapeutic keratoplasty, in the laboratory by examination
of semithin sections. In other cases, the results of bacteriological cul-
tures and smear examinations from the surface of purulent infiltrates
and ulcers were negative, and the diagnosis was made on the basis of
medical history, biomicroscopic images, clinical assessment and re-
sponse to treatment.
In 18 out of 24 (75%) patients (all patients from subgroups I-II, 6
patients from subgroup III, and 2 patients from subgroup IV), a com-
plete resolution of the purulent process was achieved in
29.6 ± 9.38 days after the implementation of M-CXL in combination
with anti-infective therapy. In 8 patients high visual acuity was
achieved (0.5–1.0 with correction) after M-CXL (Figs. 1–6).
In one patient (subgroup V) with a PCU of mixed etiology (acan-
thameba + fungi), where extensive (11 mm) purulent infiltration af-
fected all layers of the cornea up to Descemet’s membrane, a partial
effect was noted in the form of a 1.5 mm reduction of the area of in-
filtrate and cessation of corneal melting, She underwent a planned
penetrating therapeutic optical keratoplasty. In the remaining 5 (21%)
patients (1 patient from subgroup IV and all patients from subgroup V),
no effect of M-CXL was observed; they underwent therapeutic pene-
trating keratoplasty (Fig. 7).
The average recovery time for subgroup I was 22.1 ± 4.48 days;
for subgroup II 32.6 ± 4.89 days; for subgroup III 34.5 ± 7.0 days;
for subgroup IV 36 ± 4.0 days; in subgroup V, treatment was in-
effective in all patients (Table 3).

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Fig. 5. Abscess of a cornea with hypopyon and neovascularization, which developed on penetrating graft. (a) Before M-CXL, abscess affects the entire thickness of the
stroma. (b) After 2 sessions of M-CXL, the purulent process was reduced, diffuse opacification of the graft.
A complete resolution of the purulent process in patients with PCU
of bacterial etiology was observed in 4 eyes (100%), of fungal etiology
in 5 eyes (83%), and of mixed etiology in 9 eyes (64%). The results are
presented in Table 4.
15 patients underwent 2 sessions of M-CXL with an interval of
1 week due to insufficient effect after one session. In 9 patients, the
effect was achieved after 1 session of M-CXL.
In the control group, recovery on average was achieved in
50.4 ± 15.9 days; complete resolution of the purulent process was
observed in 8 eyes (61.5%); due to the ineffectiveness of the con-
servative therapy 5 (38.5%) patients underwent therapeutic kerato-
plasty.
Comparing the test and control groups, the duration of treatment in
the test group decreased 42% (the difference is significant).
Due to the high risk of exacerbation of herpes infection after CXL
[17,18], in patients, who developed PCU in the presence of herpetic
keratitis, oral valacyclovir in dosages from 1000 to 1500 mg per day
was administered before and after M-CXL. In the postoperative period
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Journal of EuCornea 3 (2019) 13–21
we also administered active anti-infective therapy (antibiotics, anti-
septics, or antifungal agents) combined with instillations and periocular
injections and eye drops of endogenous Interferon inducer. The treat-
ment course after M-CXL varied from 14 to 40 days. In 3 cases with
delayed epithelialization, we used a corneoscleral flap as a therapeutic
corneal cover. All patients with a history of recurrent herpetic keratitis
received antiherpetic vaccination (every six months for the next
3 years) in order to avoid recurrence.
In addition to treatment with antibiotic or antifungal agents, PCU
that developed in the presence of acanthameba infections was treated
with FI of two antiseptic agents of biguanide type (“Comfort Drops” and
0.025% solution of chlorhexidine bigluconate), the antifungal agent
fluconazole2 mg/ml solution and 150 mg orally over a course of
21–30 days.
In view of the long persistence of acanthameba cysts in the corneal
tissue, treatment was continued for 6–20 months after clinical recovery.

4. Discussion
CXL is a new method for the treatment of PK and PCU today. In our
experience it has a significant therapeutic efficacy for superficial and
anterior stromal forms of PCU.
Several authors [19–21] report that photodynamic therapy com-
bined with antibiotic therapy showed significant anti-bacterial effect.
Kilic et al. [21] has shown that topical antibiotics and CXL enhance
each other’s effects in the treatment of resistant bacterial keratitis. This
phenomenon supports our idea of combining CXL with intraoperative
anti-infective therapy (FI of eye drops) in patients with PCU. Since both
methods have well documented antimicrobial action, uniting them, in
our opinion can bring synergic effect.
Our results proved this to be correct. M-CXL showed a significant
therapeutic effect – complete resolution of PCU in 75% of patients. The
same result was obtained in only 50% in the control group. The re-
covery time after M-CXL was 42% shorter than in the control group.
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Journal of EuCornea 3 (2019) 13–21
Fig. 6. Developed purulent corneal ulcer on
the eye with keratotomy incisions. (a)
Purulent infiltration of the cornea that has
spread to the periphery and affected the
limbus. In the area of keratotomy incisions:
purulent fusion of the stroma. Visual acuity
OS is 0.01. (b) 9 days after first session of M-
CXL. A significant reduction in the area of
purulent infiltration, lysis of the stroma in
the area of incisions reduced, residual
purulent infiltration in the center. (c) After 2
sessions of M-CXL: almost complete resorp-
tion of purulent infiltrate. Intense opacifi-
cation with thinning of the corneal tissue in
the periphery and thickening in the center.
(d) 10 months after short-stay hospitaliza-
tion. (e) 3 years after short-stay hospitali-
zation. Transparent engraftment. Visual
acuity OS = 0.1 sph – 2.0 = 0.4; with a
scleral contact lens, visual acuity – 0.9.
The frequency of urgent keratoplasty is less in the test group than in the
control group (Table 5).
The necessity of intensive anti-infective agents FI during and after
M-CXL is explained by the fact of corneal permeability reduction after
CXL. According to the authors [10,11] it decreases by 16-28%. That in
turn reduces the efficacy of anti-infective agents instilled in the post-
operative period. Therefore, FI during M- CXL procedure help to
achieve and maintain consistently high therapeutic concentrations of
anti-infective agents in corneal tissue.
The main potential complications of CXL are endothelial damage
and/or corneal melting. However, judging by existing scientific data
they are quite rare [22–25]] and we did not observe them in any of our
cases. We believe that the potential risk of even 2 courses of M-CXL is
much less than the potential risk of purulent keratitis progression that
requires urgent therapeutic keratoplasty.
In conclusion, based on our studies, we consider M-CXL to be a low-
risk procedure and a viable treatment option for PK and PCU.
 Journal of EuCornea 3 (2019) 13–21

Fig. 7. PK of mixed etiology (fungi + acanthameba) (a) extensive purulent infiltration affecting all layers of the cornea up to Descemet’s membrane (b) disc of the
removed cornea after therapeutic keratoplasty. Fungi of the genus Candida (arrow) in the corneal stroma in combination with an acanthameba infection. Semi-thin
section. Toluidine blue dye. Zoom x200. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 3
Clinical result of M-CXL by area and depth of damage to the cornea, test group.
Subgroup (of test group) by depth of damage to the Total number of patients in Number of patients who experienced Efficacy Average recovery time (days)
PK subgroup recovery

I 7 7 100% 22.1 ± 4.48

II 3 3 100% 32.6 ± 4.89
III 7 6 85.7% 34.5 ± 7.0
IV 3 2 66.6% 36 ± 4.0
V 4 0 – –
Total 24 18 75.0% 29.6 ± 9.38

Table 4
Clinical efficacy of M-CXL in the test group by etiology of infectious process.
Subgroup (of the test group) by etiology of PK Total number of patients in subgroup Number of patients who experienced recovery Efficacy %

Bacterial 4 4 100
Fungal 6 5 83
Mixed In the presence of HSV HSV + bacteria 14 10 4 9 7 4 64 70 100
HSV + fungi 6 3 50
In the presence of acanthameba acanthameba + bacteria 4 2 2 2 50 100
acanthameba + fungi 2 0 –

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Table 5
Comparison of the results of treatment of PK and PCU with the use of M-CXL and without it.
Main group Control group
Efficacy Average recovery time number of emergency therapeutic Efficacy
(days) keratoplasty
18 (75%) 29.65 ± 9.38 5 (20.8%) 8 (61.5%)
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Evgeniya A. Kasparovaa, Anatoly A. Fedorova, Elizaveta A. Kasparovab,
Biao Yanga,
⁎
a
FSBI “Research Institute of Eye Diseases”, Rossolimo 11A, Moscow
119021, Russian Federation
b
Clinic for Eye Diseases, Zoologicheskaya Ulitsa, 22, Moscow,109240.
Russian Federation
E-mail address: 411619457@qq.com (B. Yang).