This document discusses fungal corneal ulcers. It begins by describing the signs and symptoms of fungal ulcers, including pain, redness, defective vision, lid edema, and corneal opacity staining with fluorescein. Diagnosis involves smears, cultures and microscopy to identify causative fungi. Common fungi include Fusarium, Aspergillus, and Candida. Treatment involves topical natamycin or voriconazole drops. Prognosis includes potential complications like scar formation, astigmatism, perforation and fistula formation. Close monitoring is needed due to the difficulty treating fungal infections.

1. Dr. K. Vasantha M.S., F.R.C.S., Edin
Director RIO Chennai (Rtd)

2.  Watering, pain and redness usually following injury with
vegetative matter
 Defective vision. More if the ulcer is in the center
 Lid edema, muco purulent discharge
 Circum corneal congestion, sometimes conjunctival
congestion also. Chemosis if there is severe
inflammation
 Signs will be more than the symptoms

3.  Opacity in the cornea which will take up fluorescein stain
as the epithelium will be abraded.
 Pupil will be constricted and sluggishly reactive due to
irritation to the iris.
 This toxic reaction can produce hypopyon which will be
sterile in bacterial ulcer.
 In fungal ulcer fungal hyphae may be present.

4.  Stage of progressive infiltration
 Stage of active ulceration
 Stage of regression
 Stage of cicatrization

5. When you see an ulcer the following tests must done to
find the causative organism
 Smear
 KOH suspension
 Culture
 Detection of antigens, antibodies and endotoxins
 Immunoglobulins
 PCR
 Confocal microscopy

6.  Gram stain: for bacteria, yeasts, cysts of Acanthamoeba.
Can detect 60 – 70% of bacteriae. Fungal hyphae are
Gram negative or faintly stained walls with unstained
protoplasm
 Giemsa: viral and Chlamydia inclusion bodies,
polymorphs and mononuclear cells besides the above
microbes
 Ziehl-Neilson: Mycobacteria and Nocardia

7.  Acridine orange: bacteria, fungi and Acanthamoeba
cysts
 Calco flour white: fungi and Acanthamoeba will appear
bright white
 Need a fluorescent microscope
 Gomori Methenamine silver: best for fungi. Cell wall and
septa stain black against green background

9.  KOH suspension: use of KOH suspension is to remove
the other fibers leaving the fungal elements which are
resistant. Very useful as it can be done quickly and
treatment can be started if fungal ulcer is present
 Can detect fungus, Nocardia, Pythium and
Acanthamoeba cysts
 Ink and Lacto Phenol cotton blue also can be used to see
the fungal elements

10. Many branching septate fungal filaments are seen in
KOH

11.  Lactophenol cotton blue preparations of slide cultures of
Aspergillus fumigatus Curvularia species

12. Trophozoite Cyst

13.  Apply topical anesthetic and wait for 3 – 5 mins for the
anesthetic to drain off
 Use a Kimura’s spatula or a surgical blade to take the
sample. This is preferably done under a slit lamp. The
spatula can be sterilized with flame or 70% alcohol.
Contamination by eye lashes is avoided by using a
speculum

14.  Chocolate agar: Haemophilus
 Thioglycollate broth: both aerobic and anaerobic
 Non nutrient agar with E. coli – Acanthamoeba
 Thayer Martin agar: to isolate Neisseria
 Lowenstein Jenson for Mycobacteria

15.  Sabouraud’s Dextrose Agar (SDA) (25°C)
 Blood Agar : for aerobic bacteriae and fungi esp.
Fusarium
 Brain-heart infusion medium(37°C) filamentous fungi and
Yeast
 It might grow within 24 hrs also,
 Usually 2-3 days
 Fungal medium should be retained for a week to declare
negative result

16.  Confocal microscopy for Acanthamoeba cysts (10 to 20
microns), fungi (>200 microns), Pythium, some bacteria
and Microsporidia
 Aspergillus antigen can be detected by using Aspergillus
kit

17. In the following slides you will see the typical
characteristics of fungal ulcers with
 Dry ulcer
 Hyphate margins
 Satellite lesions
 Thick cheesy hypopyon which is immobile and has a
convex surface
 Pigmentation – dematiacious fungi
 Endothelial plaques

29. It is difficult to treat a fungal ulcer as
 Only few drugs are freely available
 Penetration of the drugs is very poor
 Poor bio availability of the drugs due to the poor
penetration
 Toxicity of the systemic drugs
 Drug sensitivity cannot be determined

30.  Atropine eye drops are given to cause dilatation and
cycloplegia. This will reduce pain as ciliary spasm which
is the cause for the pain is relieved
 Dilatation will break any synechiae and also prevent
synechiae from forming
 Atropine reduces the tear secretion and there by
increases the lysozomal content of the tears
 It also separates the corneal lamellae and helps in
penetration of the drops applied

31.  If chronic dacryocystitis is present sac excision has to
be done
 As diabetes may predispose to infection and delay
healing, this must be checked for
 History must be taken regarding use of
immunodepressants and immunosuppression

32.  Natamycin 5% suspension hourly for 2 days and then 2
hourly. Dosage is then adjusted depending up on the
response. Administration of the drug during the night
should be insisted.
 Econazole 2%, Fluconazole 0.3%, Voriconazole 1% or
Amphotericin 0.1 to 0.25% can also be used

33.  Amphotericin B 5 to 10 micro grams/0.1ml in 5%
dextrose can be injected in to the anterior chamber esp.
for Aspergillus
 Can be repeated after 3 days
 Removing the cheesy hypopyon and the aqueous humor
will also help. Fresh aqueous will have more lysozymes
which will help in healing.
 Can be given intra stromal 0.02mg/ml. Not for Fusarium

34.  Complications: cataract, hyphema, corneal edema, iritis
due to suppression of T suppressor cells and activation
of pro inflammatory cells
 There is also the danger of breaching the natural barrier
there by spreading the infection to deeper tissues
 Glaucoma
 Endothelial damage

35.  If the ulcer is not healing with above measures VCZ can
be injected in to the stroma around the ulcer.
 50 to 100 micro grams/0.1ml
 This has to be divided in to 5 doses and injected in to the
stroma around and close to the ulcer
 Used for recalcitrant cases, deep stromal ulcer, after
DSEK for inter face infection, Infection after PRK
 Natamycin also has been tried. Not effective and causes
increased vascularization

37. Mycotic ulcer treatment study MUTT found
 No advantage of topical Voriconazole over Natamycin
 MUTT II found - Oral Voriconazole as add on therapy to
topical anti fungal drugs did not show any benefit. In
Fusarium keratitis there was less incidence of
perforation, but it was not significant.
 Oral Ketoconazole also did not show much benefit
 Between oral VCZ and Ketoconazole, Voriconazole was
found to be better

38.  Scleral or limbal involvement
 Pediatric cases
 Peripheral ulcer
 Recalcitrant cases
 Post keratoplasty
 Endophthalmitis

39.  Polyenes
 Azoles
 Pyrimidines
 Allyl amines
 Echinocandins
 Heterocyclic benzofurans

40.  Polyenes are fungicidal.
 Interacts with ergosterol present in the fungal cell wall
and leads on to extrusion of vital contents of the cell,
causing death.
 Natamycin acts by inhibiting the amino acid and glucose
transport. This causes a reversible and ergosterol
specific action without altering the permeability
 Large polyenes : Nystatin, Amphotericin B
 Small polyene : Natamycin

41.  Fungi static at low concentration, fungicidal at high
concentration
 14 alpha – sterol demethylase inhibitor
 Inhibits ergosterol synthesis, causing increased cell
membrane permeability and lysis
 Imidazoles: miconazole, clotrimazole, econazole and
ketoconazole
 Triazole: voriconazole, posaconazole, fluconazole,
itraconazole, ravaconazole

42.  Pyrimidine: Interferes with pyrimidine metabolism as well
as RNA, DNA and protein synthesis. E.g.- 5-Flucytosine
 Allylamine: Squalene epoxidase inhibitor which inhibits
ergosterol synthesis – Terbinafine
 Echinocandins : fungicidal – inhibits the beta – 1,3 –d-
glucan synthase leading on to increased permeability
E.g. Caspofungin
 Heterocyclic benzofurans: fungi static – interferes with
microtubules - Griseofulvin

43.  Also called Pimaricin
 Produced by Streptomyces natalensis
 Has a broad spectrum for filamentous fungi like
Fusarium, Aspergillus, Curvularia
 Does not enter the anterior chamber
 Has to be applied every hour for initially. Reduced to 6 to
8 times later and continued as 4 times per day for 4
weeks after clinical healing of the ulcer
 Adverse effect: Particles remaining in the eye and
causing irritation

44.  1% solution is prepared from the parentral formulation
 Acts against Candida, Cryptococcus, Aspergillus
 Inhibits growth of Fusarium to some extent. For this
drops have to be applied every hour and not every two
hours which is used for other fungi
 It enters the a.c. and vitreous
 Should be given 1 hour before or 2 hours after meals as
acidic medium will reduce the absorption of drugs
 Best for recalcitrant cases not responding to Natamycin

45.  Inhibits cytochrome P 450 dependant 14 alpha sterol
demethylase an enzyme needed for synthesis of
ergosterol
 It has fungicidal action on Aspergillus
 It also induces release of tumor necrosis factor alpha in
monocytes

46.  Visual disturbances which starts 30 minutes after taking
the drugs and last for 30 minutes
 Photophobia and color vision changes
 Visual hallucinations
 Skin rash, contact dermatitis
 Steven Johnson’s
 Liver toxicity, bone toxicity
 Skin cancer and melanomas in long term use
 Teratogenic

47.  Produced by Streptomyces nodosus
 Broad spectrum, highly active against Cryptococcus and
Candida
 Poorly soluble in water. Photosensitive. Hence must be
stored in the dark and refrigerated at 2 – 8 degrees
 Topical 0.15%
 Intra vitreal liposomal AMB was found to be effective for
Candida endophthalmitis in animals
 Combination with Fluconazole gives good results

48.  Renal failure and electrolyte imbalance (avoided with IV
fluids)
 Hepatotoxicity
 Can be used during pregnancy

49.  An Imidazoles active against dermatophytes, yeasts,
molds. Limited action against filamentous fungi and
some bacteriae
 Dose 200-400 mg/day taken with meal as acidic medium
is needed for absorption. So if the patient is taking
antacids the absorption will be less
 CYP3A4 enzymes are needed for the metabolism of this
drug. So if CYP3A4 substrate drugs like dofetilide,
quinidine, cisapride are given serious adverse reactions
will occur due to accumulation

50.  No significant benefit seen if added to Natamycin
 It is hepatotoxic, renal toxic ,
 can cause hyperglycemia, hyperlipidemia, hypertension,
infertility
 QT prolongation
 Anaphylaxis
 Anorexia or increased appetite
 Insomnia and nervousness

51.  1% solution and ointment. Oral 200 mg/day for
Aspergillus
 Active against Candida, Aspergillus, and minimal action
against Fusarium and Mucorales
 Ocular concentration is low as it is protein bound
 Hepatotoxic, rash, headache, GI upset
 Teratogenic

52.  Broad spectrum – Candida, Aspergillus, Fusarium,
Mucorales
 Oral suspension is absorbed well with high fat meals
 Poor penetration as it is protein bound
 Oral 200mg/q.i.d with topical 10% prepared from oral
solution
 Fever, NVD, headache, hypokalaemia, rash, purpura,
uremic syndrome, pulmonary embolus, adrenal
insufficiency, hypersensitivity, ECG changes
 Teratogenic

53.  Echinocandins: Topical Caspofungin 0.5-1% helps in
Candida, Aspergillus and Alternaria. Used for refractory
cases
 Stable for 28 days if refrigerated
 Micafungin 0.1% - Candida and Alternaria
 Headache, GI upsets, hepatotoxic

54.  Fluconazole: for Candida 100-200mg/day
 Steven Johnsons’, headache, rash, gastritis, hepatotoxic
 Teratogenic
 Flucytosine: converted to 5 fluorouracil which inhibits
intracellular DNA synthesis
 Active against Candida and Cryptococcus, limited
against Aspergillus
 Poor penetrance. Fusarium is resistant

55.  Patient will feel better
 Reduction in chemosis and conjunctival congestion
 Lack of progression of the ulcer
 Rounding off of the edges. In fungal ulcer the feathery
margin will be blunted
 Reduction in the cellular infiltrate and hypopyon
 Reduction in edema of the cornea around the ulcer
 If hypopyon reappears secondary bacterial infection
should be suspected in a fungal ulcer

56.  Even when an ulcer heals a scar is produced which will
cause defective vision
 A small peripheral scar may not affect vision .
 If the scar is central mechanical obstruction to vision is
caused.
 A nebular opacity or a peripheral opacity especially one
with iris adherence can cause astigmatism and affect
vision

58.  Even when the ulcer heals there is a complication – scar
 When you see a leucoma one must look for adherence
 In the above slide if you see from the clear area above
you can see whether there is adherence and if any
cataract is there
 The pupil should be dilated and if there is clear cornea
on any one side of the scar, vision and fundus must be
checked
 Thinner scars can be macula or nebula

60.  An ulcer may perforate as the stroma dissolves due to
infection and by the action of neutrophils
 If the perforation is in the periphery the iris plugs the
leak and the ulcer may heal with an adherent leucoma
 If the perforation is in the center a fistula will form. When
this ulcer heals an anterior polar cataract may form
 Sometimes if a small ulcer perforates it may help in
healing as it acts like a paracentesis

61.  Before the ulcer perforates the Descemet’s membrane
will with stand for some time as it is elastic. This will
cause the membrane to bulge forward giving raise to
Descemetocoele
 At this stage and for small perforations glue with either
bandage or bandage contact lens can be used to seal the
perforation

63.  Disappearance of hypopyon may only mean reduction in
the secondary bacterial infection
 Therapeutic keratoplasty must be considered if the
infection is spreading fast.
 It should be tried before the peripheral cornea gets
involved as the wound will not heal well.
 Chances for rejection will be more as one has to choose
a large graft if the ulcer involves the periphery
 Sclero corneal graft do not have a good prognosis

64.  Compliance must be checked
 If Natamycin is used one can see the white granular
deposits on the ulcer and in the fornix
 Cleanliness of the periocular surface must be insisted
 If total ulcer or panophthalmitis ensues, evisceration
may have to be done