Recent trends in the management of corneal ulcer

RECENT TRENDS IN THE
MANAGEMENT OF
CORNEAL ULCER
Presenter – Dr. Jayant Ekka Moderator – Dr. Arup Deuri
3rd year PG Student Assistant Professor
RECENT TRENDS IN THE MANAGEMENT OF CORNEAL ULCER

OVERVIEW
 PRESENT SCENARIO
 CLINICAL EVALUATION
 INVESTIGATIONAL DIAGNOSTIC
MODALITIES
 OLDER TREATMENT MODALITIS
 CURRENT TREATMENT OPTIONS
 RECENT ADVANCES AND
FUTURE SCOPE

PRESENT SCENARIO
 Corneal ulcer is the second commonest cause of preventable blindness
next to cataract among people in Asia, Africa & in the Middle East.
 Corneal opacities due to infectious keratitis is the 4th leading cause of
blindness globally and are responsible for 10% of avoidable visual
impairment in developing countries.*
 An important cause of monocular vision loss worldwide but unfortunately
the clinical features do not always correlate to the classical textbook
description.
*World Health Organization. Causes of blindness and visual impairment. Available at: http://www.who.int/blindness/causes/en.

 In developing countries, fungal keratitis following trauma by vegetative
matter still contributes the majority.
 With the increase in contact lens use, contact lens associated corneal ulcer
is the most common type seen in developed countries.
 Improvement in diagnostic modalities leads to the isolation of less
common organism became more frequent.
 Also as the refractive surgeries are now a days commonly performed, the
atypical mycobacteria causing ulcer following refractive surgeries are
isolated more frequently.

CLINICAL EVALUATION
 Based on history and clinical examination.
 The classical symptoms of corneal ulceration include the presence of pain,
watering, discharge, photophobia, decrease in visual acuity and swelling of
lids.
 There are no pathognomonic sign for specific type of bacterial keratitis.
 Points in the favor of fungal keratitis – dry looking ulcer with feathery
margins, satellite lesions, relatively less symptoms, thick immobile
hypopyon
 These typical features not always present in fungal keratitis and then it is
difficult to differentiate with the bacterial ulcer.
 In viral keratitis – easy to diagnose

FALLACIES
 Pain will be more in early acanthamoeba keratitis, less in herpetic
dendritic ulcer and may be absent in neurotrophic ulcer.
 Bacterial keratitis - Sudden onset of symptoms with rapid progression.
 Certain bacteria like Moraxella, coagulase negative Staphylococcus,
Nocardia species and atypical Mycobacteria cause corneal ulcers that
present with gradual onset and have an indolent course.
 Acanthamoeba – variable.
 Clinical picture suggestive of common organism but not improving on
empirical treatment – always suspect of atypical mycobacteria /
acanthamoeba.

BACTERIAL CORNEAL ULCER

FUNGAL CORNEAL ULCER
ASPERGILLUS
CURVULARIACANDIDA
FUSARIUM

VIRAL ULCERATVE KERATITIS

ACANTHAMEBA KERATITIS

PERIPHERAL ULCERATIVE KERATITIS

MOOREN’S ULCER

CORNEAL SCRAPPINGS FOR SMEAR
EXAMINATION AND CULTURE
SMEAR
EXAMINATION
GRAM’S STAIN
KOH WET
MOUNT
CALCOFLUOR
WHITE
OTHERS

COLLECTION OF THE SAMPLE
 From the edge and the base.
 Kimura’ s spatula, 26-gauge needle, Bard Parker blade, hypodermic
needle, surgical blade no 15 and calcium alginate swab.
 Platinum spatula has been traditionally used. It is rapidly sterilized with a
Bunsen burner and cools rapidly between scrapings.
 Difficulties in Collection of Corneal Scrapings
1. Small corneal ulcers
2. Non suppurative keratitis
3. Advanced keratitis with severe thinning.

Chlorazol Black E Mounts
 sensitivity of 82% and a specificity of 98%**
**Thomas PA, Kaliamurthy J, Jesudasan CA, et al. Use of chlorazol black E mounts of corneal scrapes for diagnosis of
filamentous fungal keratitis. Am J Ophthalmol. 2008;145(6):971-6.

Culture on the standard media is the gold standard for the diagnosis
of microbial keratitis.
CULTURE

JONE’S CRITRERIA
 Clinical signs of infection plus
1. Isolation of bacteria (10 or more colonies) on one solid medium and one
additional medium, or
2. Isolation of fungi/bacteria (any detectable growth) on any solid two media
or
3. Isolation of bacteria/fungi in one medium in the presence of a positive
smear
 Aerobic cultures of the corneal specimens should be held for 7 days,
anaerobic cultures for 7 to 14 days and Mycobacterial and fungal cultures
for 4 to 6 weeks before being reported as no growth.

CORNEAL BIOPSY
 In case of deep mycotic keratitis/intrastromal abscess – staining &
culture comes negative.
 In such cases, a diagnostic corneal biopsy is necessary.
 Performed under topical anesthesia under operating microscope/slit lamp.
 A micro-trephine or 2-3 mm dermatological punch is advanced into the
anterior corneal stroma to incorporate both the infected & clinically
normal 1mm rim.
 Avoid visual axis.
 A crescent blade or bard parker knife is used to undermine the tissue,
which may then be cut with micro-scissors & the tissue excised
with fine tooth forceps.

NEWER TECHNIQUES
 CONFOCAL MICROSCOPY
 POLYMERASE CHAIN REACTION

IN-VIVO CONFOCAL MICROSCOPY
Figure(a-e) Representative
confocal photographs of
patients with fungal keratitis
– appear as high
reflective, double walled,
septate filaments Size 3 - 8 μ,
uniform width, irregular
branching.

Acanthamoeba cysts present as
highly reflective, double walled
round particles 10–20 µm in
diameter within the corneal
epithelium and stroma. The inner
wall has a hexagonal
configuration
Bacterial keratitis is
characterized by activated
keratocytes, with infiltration of
leucocytes, and Langerhans cells.
Bacteria typically not visualized

Viral keratitis is characterized by ovoid dendritic
cells at the level of sub epithelial cells which are
an indicator of disease activity which is often
over looked on slit lamp examination.

POLYMERASE CHAIN REACTION
 Rapid diagnosis within hours.
 PCR amplification and sequencing of bacterial genes encoding the small
subunit of ribosomal RNA (16s rDNA) without prior cultivation allow the
identification of fastidious or non-culturable bacteria.
 28s rRNA is the targeting molecule for fungal keratitis, which is present in
all fungus.
 For acanthamoeba targeting molecule is 18s rRNA.
 A reduced-sensitivity PCR can detect HSV DNA in tears from patients
with clinically diagnosed HSV epithelial keratitis.

CULTURE VS PCR
CULTURE PCR
TECHNIQUE STANDARD NEWER
REPORT DAYS TO WEEK HOURS
BEST RESULT UNTREATED ALL
PRIMER NOT REQUIRED REQUIRED
COST LESS MORE
CONTAMINATION POSSIBLE NOT
TEMP VARIED CONSTANT

OLDER MODALITIES IN TREATMENT
 Patching of the eye.
 Repeated debridement in viral keratitis.
 Cauterization of the base of the ulcer.
 Sub Conjunctival antibiotic
 The use of traditional eye medicines.

TREATMENT STRATEGIES OF NON-
VIRAL ULCER – EMPIRICAL
RECENT TRENDS IN THE MANAGEMENT OF CORNEAL ULCER SOURCE: WHO GUIDELINES
THIRD OR FOURTH GENERATION
FLUOROQUINOLONES MAY BE COMBINED WITH
CEFAZOLIN INSTEAD OF GENTAMYCIN

TREATMENT FREQUENCY, DURATION
AND FOLLOW-UP
BACTERIAL / NO ORGANISM
ON SMEAR
FUNGAL
SOURCE: WHO GUIDELINES

ADJUNCTIVE THERAPY
 CYCLOPLEGICS
 ANALGESICS
 ANTI-GLAUCOMA MEDICATION

Decision making algorithm in the management of
therapeutic failures in presumed bacterial
keratitis

SOURCE: WHO GUIDELINES
1. Search for causative factor
2. Repeat culture
3. If not possible corneal biopsy
4. Staining and culture on selective media
for uncommon organism

SHIFTING TRENDS TOWARDS FOURTH
GENERATION FLUOROQUINOLONES
MONOTHERAPY
 Good alternative to the conventional therapy and has demonstrated
encouraging results, documented by meta-analysis and randomized
controlled trials where both forms of treatment have shown comparable
results in terms of efficacy and safety.*
 Fluoroquinolones demonstrate added advantages over fortified antibiotics
in terms of better stability, longer shelf life and less epitheliotoxicity, with
the added advantage of not requiring refrigeration.#
*Hanet MS, Jamart J, Chaves AP. Fluoroquinolones or fortified antibiotics for treating bacterial keratitis: Systematic review and
meta-analysis of comparative studies. Can J Ophthalmol 2012;47:493-9.
#Gokhale NS. Medical management approach to infectious keratitis. Indian J Ophthalmol 2008;56:215-20.

 A more recent study in central India by Toppo et al.(march 2018) showed
that Besifloxacin 0.6% was effective in most of Gram positive and Gram
negative infections including pseudomonas to which cefazolin was found
to be resistant.*
 AT PRESENT FLUOROQUINOLONE MONOTHERAPY IS
INDICATED:
1. < 3mm in diameter,
2. peripheral location not involving visual axis and,
3. not associated with thinning.
 S. pneumoniae, which is the most common bacterial isolate in our country,
has variable susceptibility to fluoroquinolones. and hence
fluoroquinolones may not be the ideal antibiotic for monotherapy for gram
positive organisms in our country.
*Toppo et al. Comparative Study of Role of Newer Antibiotics on Bacterial Corneal Ulcer; International Journal of Contemporary Medical
Research; Volume 5 | Issue 3 | March 2018

TREATMENT OF FUNGAL KERATITIS
 For filamentous fungi- Topical Natamycin 5% suspension 1hrly during
day and 2 hrly during night.
 For yeast – Topical Amphotericin B 0.15% 1hrly during day and 2 hrly
during night. Nystatin 3.5% eye ointment 5 times a day
 A new azole antifungal agent, Voriconazole, is derived from Fluconazole
and exhibits a wider spectrum of activity against Candida, Aspergillus and
Fusarium.
 Tapered according to response.
 Should be continued 2 weeks after the infection is resolved in all cases.

 The results of the MUTT I (2013) show a benefit of natamycin over
voriconazole for topical treatment of fungal keratitis, and in particular for
Fusarium keratitis.*
 The MUTT II (2016) was a double masked, randomized, placebo-
controlled clinical trial investigating the effect of adjuvant oral
voriconazole versus oral placebo for smear-positive filamentous fungal
keratitis.**
 There was no difference in the primary outcome, rate of perforation, or
need for therapeutic penetrating keratoplasty.
 There were significantly more adverse events in the oral voriconazole
group, including elevations in aspartate aminotransferase or alanine
aminotransferase.
*Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs. voriconazole.
JAMA Ophthalmol. 2013;131:422-429.
**Prajna NV, Krishnan T, Rajaraman R, et al. Effect of oral voriconazole on fungal keratitis in the Mycotic Ulcer Treatment Trial II (MUTT
II): a randomized clinical trial. JAMA Ophthalmol. 2016;134:1365-1372.

 Natamycin is currently the best drug against both molds and yeast.
 Contrary to popular belief, Voriconazole was found to be inferior
especially against Fusarium.
 Oral Voriconazole use is associated with higher risk of adverse reactions.

 SYSTEMIC ANTIBACTERIAL
1. Gonococcal infections.
2. Young children with severe H. Influenzae or P. Aeruginosa keratitis.
3. Perforations and scleral involvement.

 Recommended in fungal ulcers, which are:
 Large and deep, or
 Perforating, or
 Have scleral involvement
 Systemic antifungal
1. Oral Fluconazole 200 mg OD
2. Oral Ketoconazole 200 mg TID
3. Oral Voriconazole 1g TID
 Continued for 2-3 weeks.

INTRACAMERALANTIBIOTICS
 Deep keratitis particularly those due to fungal etiology with
retrocorneal involvement or anterior chamber involvement.
 With the advent of the newer generation antibiotics such as
fluoroquinolones, which have excellent ocular penetration, the
intracameral mode of anti-bacterials is not used for corneal ulcer.
 Amphotericin B – constituted in 5% dextorse 10µg in 0.1ml.
 Repeat injections - based on the clinical response.
 Non-responding cases - a repeat injection may be considered after a
time interval of 1 to 5 days.

INTRASTROMALAMPHOTERICIN B
 For non healing fungal ulcer.
 5-7.5 μg in 0.1ml dosage, given in the vicinity of the stromal site of fungal
growth.
 Can be repeated after a period of 48 to 72 hours.

ROLE OF TOPICAL CORTICOSTEROIDS
 Controversial in bacterial keratitis. Double aged sword.
 The rationale for using steroids - to decrease tissue destruction in bacterial
keratitis.
 Should be started after 48 hours of commencement of antibiotic therapy if
there is evidence of response to antibiotic.
 Patient should be monitored at 24 & 48 hrs after initiation and response to
steroid is evaluated.
 Not recommended for fungal and acanthamoeba keratitis.
 The Steroids for Corneal Ulcers Trial (SCUT 2012) # – “Topical
steroids, when used as an adjunctive treatment under antibiotic cover, do
not provide any added benefit for bacterial keratitis.”
# Srinivasan M, Mascarenhas J, Rajaraman R, Ravindran M, Lalitha P, Glidden DV, et al. Corticosteroids for bacterial keratitis: The
Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol 2012;130:143-50.RECENT TRENDS IN THE MANAGEMENT OF CORNEAL ULCER

TREATMENT OF ULCERATIVE VIRAL
KERATITIS
 TOPICALANTIVIRAL
1. Trifluridine 1% drops - 2 hourly until ulcer heals then 4 hourly for 5
days.
low bioavailability and causes ocular surface toxicity
2. Aciclovir 3% ointment - 5 times a day x 3 weeks.
as effective as trifluridine with less ocular surface
toxicity
3. Ganciclovir 0.15% gel- 5 times a day until ulcer
heals and then 3 times a day for 5 days.
broad spectrum, active against HSV, HZV,CMV. As effective as
acyclovir, less ocular surface toxicity and less development of resistance.

 SYSTEMIC ANTIVIRAL
 Used in herpes zoster ophthalmicus
 Acyclovir 800 mg 5 times a day x 10-14 days or
 Valaciclovir 500 mg thrice a day x 10-14 days
 Recurrent cases of herpes simplex keratitis and necrotizing stromal
keratitis
 Acyclovir 400 mg 5 times a day x 10-14 days or
 Valaciclovir 500 mg twice a day x 10-14 days

HEDS
Do topical steroid treat stromal keratitis?? Yes. also decrease duration of
keratitis
Is oral acyclovir ( steroid+trifluridine) helpful in
stormal keratitis??
No
Is oral acyclovir helpful in HSV iritis?? Favoring use of oral acyclovir
Does oral acyclovir prevent epithelial to stormal
keratitis??
No
Does oral acyclovir decrease HSV recurrence?? Yes

TREATMENT OF ACANTHAMOEBA
KERATITIS
 Topical antiamoebic agents include:
1. Diamidines: Propamidine isethionate (0.1 %), and hexamidine (0.1%).
2. Biguanides: Polyhexamethylene biguanide (PHMB), 0.02% and
chlorhexidine, 0.02%.
3. Aminoglycosides: Neomycin and Paromycin
4. Imidazoles: Clotrimazole and miconazole.
 Multiple drug therapy is needed for a long time (3–4 months) for early
epithelial lesions and 6–12 months for stromal lesions.

 Any of the following combination may be chosen
1. Propamidine or hexamidine + PHMB or
2. Chlorhexidine + Neomycin or
3. Paromycin + clotrimazole or miconazole or
itraconazole.
 Frequency of instillation: hourly for a week, then taper slowly over 3–4
months for epithelial lesions and 6–12 months for stromal lesions.

TREATMENT OF METAHERPETIC
CORNEAL ULCER
 Elimination of toxic medications.
 Preservative free lubricants.
 Punctal occlusion.
 Soft bandage contact lens.
 Autologus serum.
 Conjunctival flap.
 Amniotic membrane transplantation.
 Tarsorrhaphy.

TREATMENT OF MOOREN’S ULCER
AND OTHER STERILE PUK
 Topical corticosteroids for Mooren’s ulcer.
 Used cautiously in patient with RA, Wegener’s granulomatosis and
polyarteritis nodosa.
 Conjunctival resection (peritomy).
 Severe thinning and small perforation – cyanoacrylate glue
 Large perforation – full thickness keratoplasty
 Non responding case may require – systemic immunosuppression.
 Treatment of the associated collagen vascular disease.

TREATMENT OF NEUROTROPHIC/
NEUROPRALYTIC/EXPOSURE KERATOPATHY
 Topical therapy - preservative free lubricants, antibiotics, cycloplegics.
 Lid taping.
 Autologous serum drops.
 Soft bandage contact lens.
 Lateral tarsorrhaphy.
 Topical nerve growth factor drops for neurotrophic ulcer.
Approval Date: 08/22/2018

EVIDENCE OF HEALING ULCER
 The signs and symptoms decreases.
 Visual acuity continues to improve.
 Size of the epithelial defect and hypopyon decreases.
 The stromal infiltrates consolidate.
 Anterior chamber reaction decreases.
 Vascularization occurs and following complete healing the vessels regress
completely but sometimes leave “ghost vessels”.
 Visible shrinking of the endothelial plaque.
 Epithelialization is completed and necrotic stroma is replaced by scar.

SURGICAL TREATMENT MODALITIES
 Glue application.
 Therapeutic patch graft.
 Therapeutic lamellar keratoplasty.
 Therapeutic penetrating keratoplasty.
 Phototherapeutic keratectomy.
 Corneal collagen cross-linking.

GLUE APPLICATION
 Indications:
1. Perforation < 2mm
2. Melting and thinning
3. Descematocele
 Cyanoacrylate glue is used
 Followed by BCL
 It has significant bacteriostatic activity against gram-positive organisms.
 Also decreases keratolysis by leukocytes.
 Helps in delaying surgery (PK/Patch graft) which can be performed as an
elective procedure later.

AMNIOTIC MEMBRANE TRANSPLANTATION

CONJUNCTIVAL FLAPAPPLICATION
 Presently used only for recalcitrant sterile corneal ulcer.
 Provide a smooth ocular surface and also help in tectonic support
and nutrition to a chronic, non-healing corneal ulcer.
 Indications –
1. Neurotrophic corneal ulcers
2. Neuroparalytic keratitis
3. Exposure keratitis
4. Peripheral ulcerative keratitis

 TYPES-
1. Partial Conjunctival flaps
A. Advancement flaps
B. Single pedicle flaps
C. Bi-pedicle flaps
2.
Total Conjunctival flap (GUNDERSON flap)

THERAPEUTIC PENETRATING KERATOPLASTY
 Indications
1. Perforation not amenable to glue application i.e ≥ 3 mm
2. Non healing and non responsive fungal ulcer despite maximum medical
therapy.
3. Severe melting due to herpes necrotizing stromal keratitis.
4. Progressive non responsive bacterial ulcer despite maximum medical
therapy.

Pic courtesy - Yokogawa H et al. Surgical therapies for corneal perforations: 10 years of cases in a tertiary referral hospital, 2014, Dove
press

THERAPEUTIC PATCH GRAFT
Pic courtesy - Yokogawa H et al. Surgical therapies for corneal perforations: 10 years of cases in a tertiary referral hospital, 2014, Dove
press

 Helps by the following methods:
1. Debulking or removing the infectious organism.
2. It maintains the integrity of the globe integrity.
3. It may also help in diagnosis of the infective pathology.

PHTOTHERAPEUTIC KERATECTOMY
 The ability of 193 nm excimer laser to treat microbial keratitis was
demonstrated initially by Serdaveric et al.
 It has been shown to be effective in early localized Fusarium,
Mycobacterium and Pseudomonas keratitis in animal models.
 Due to the ultraviolet radiation, tissue sterilization occurs and this effect is
further enhanced due to ablation or elimination of organisms and the
surrounding necrotic tissue.
 It also provides debulking effect and improves drug penetration.

 Collagen cross linking (CXL) of the cornea has been developed recently as
a new treatment for multidrug-resistant infectious keratitis, as documented
by several recent case reports.
 This technique has showed promising results specially in patients with
corneal melting and impending perforation.
 Corneal melting has been arrested and complete epithelialization achieved
in several cases.
 The success rate was higher for bacterial infections than fungal infections
 Although randomized controlled trials are needed, the available evidence
supports the use of CXL in the treatment of infectious keratitis.
COLLAGEN CROSS-LNKING**
**Alio JL, AbboudaA, Valle DD, Del Castillo JM, Fernandez JA. Corneal cross linking and infectious keratitis: A systematic review with
a meta-analysis of reported cases. J Ophthalmic Inflamm Infect 2013;3:47.

RECENT ADVANCES AND FUTURE
SCOPE
 NANO PARTICLES FOR SUSTAINED ANTI-FUNGAL DRUG
DELIVERY.
Cell-penetrating peptides (CPPs) – to transport molecules across the cell
membranes – to enhance extracellular and intracellular internalization of
biomolecules. Eg; NTM with CPP carrier – TAT Dimer
 PHOTOACTIVATED CHROMOPHORE FOR INFECTIOUS
KERATITIS (PACK)
direct antimicrobial effect and effect by halting the ongoing melting.
 ROSE BENGAL PHOTODYNAMIC THERAPY

SUMMARY
 While characteristic clinical features have been described for ulcers caused
by different microorganisms, it is difficult to confirm these, especially
after the disease has become well established.
 A very close clinical suspicion is required for the diagnosis of
acanthamoeba keratitis.
 Microbiological examination (smear and culture) still remains the gold
standard for the diagnosis of bacterial and fungal corneal ulcer.
 Viral ulcerative keratitis diagnosed solely on clinical findings.
 Newer diagnostic modalities like in-vivo confocal microscopy aid in
diagnosis of fungal and acanthamoeba keratitis.

 Fortified topical antibiotic combination therapy still remains the mainstay
of treatment of bacterial corneal ulcer however there is shifting trends
towards the monotherapy with commercially available 4th generation
fluoroquinolones.
 Emergence of resistance to fluoroquinolones is a great concern in recent
decade.
 The most important problem with treating fungal corneal ulcer is less
penetration and bioavailability of currently available anti fungal drugs.
 Recent development of sustained drug delivery system for the fungal ulcer
may revolutionize the management in near future.

Recent trends in the management of corneal ulcer

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