FUNGAL CORNEAL ULCER. Arundhati Dvivedi final year p.g Dept.of Ophthalmology 2018/7/31

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1 FUNGAL CORNEAL ULCER Arundhati Dvivedi final year p.g Dept.of Ophthalmology

2 Introduction: Fungal Keratitis is one of the most difficult forms of microbial keratitis to diagnose & to treat successfully Constitute 44% of all corneal ulcers in India Fungi are eukaryotic, heterotrophic organisms & typically forms reproductive spores. Fungus may be a part of normal external ocular flora. (3-28% of normal eyes)

3 CLASSIFICATION Filamentous Septate Fungi (Non Pigmented): 1.Fusarium 2.Aspergillus Filamentous Septate Fungi(Pigmented): 1.Alternaria 2.Curvularia Filamentous Non Septate: 1.Mucor 2.Rhizopus Yeasts: 1.Candida 2.Cryptococus Dimorphic fungi: 1.Histoplasma 2.Coccidioides and 3.Blastomyces

4 Overall incidence is low- 6-20% EPIDEMIOLOGY Aspergillus most common organism worldwide. Incidence varies geographically: Western countries: Candida, Aspergillus, Fusarium In India: Aspergillus (27-64%) Fusarium (6-32%) Penicillium (2-29%) Rural>urban years, males Monsoon,early winter due to humidity & during harvest seasons However, in colder climates, where Candida infections predominate

5 OCULAR : RISK FACTORS Trauma (M/C)-veg matter,mud, animal matter most common Contact lens use: Cosmetic Lens- filamentous Therapeutic Lens- Yeast Indiscriminate use of Topical Medications- Corticosteroids and Broad Spectrum Antibiotics Corneal Sx- Penetrating Keratoplasty, LASIK. Chronic Keratitis- Herpes Simplex, Herpes Zoster,Vernal/allergic keratitis

6 SYSTEMIC: Immunocompromised State- HIV, Leprosy Patients on immunosuppressives, Diabetes Mellitus, ICU patients

7 PATHOGENESIS Fungi are saprophytic pathogenic organisms. Fungi gain entry into stroma through a defect in epithelial barrier. release toxins and proteolytic enzymes Host response-pmns at the site of defect from tears & limbal vessels Release of cytokines & interleukins Necrosis & sloughing of epithelium, Bowman s membrane & stroma Progressive invasion of cornea & increase in size of ulcer A saucer shaped defect with projecting walls above the normal surface due to swelling of tissue resulting from fluid imbibition by corneal stroma with grey zone of infiltration

8 CLINICAL FEATURES Symptoms: Foreign body Sensation Slow onset increasing pain Watering Photophobia Clinical signs are more severe than symptoms. Signs: Conjunctival injection Epithelial defect Anterior chamber reaction

Curvularia) Hypopyon ( non Sterile, thick &

9 Specific: Feathery edges with fluffy margins Infiltrate Elevated edges Satellite lesions Endothelial plaque Grey/brown Pigmentation( s/o dermaticeous fungi like Curvularia) Hypopyon ( non Sterile, thick & immobile) Yellow line of demarcation Immune Ring (Wesseley)

10 Yeast: A collar button configuration is typical of the keratitis associated with a small ulceration and an expanding discrete stromal infiltrate Confocal microscopy is rarely available, but may permit identification of organisms in vivo.

11 Evaluation Visual acuity Slit lamp examination KOH mount IOP measurement with tonopen B scan Culture and senitivity. Systemic investigations- 1. Blood sugar levels 2. Complete blood picture 3. Liver function tests 4. Renal function tests

12 scrapings of corneal ulcers are obtained, from the most active regions. The eye is anesthetized with topical anesthetic A heat-sterilized platinum spatula or blade no.15 or 11,is used to firmly scrape the leading edges of the ulcer. Multiple areas of a large ulcer should be sampled. care must be exercised not to precipitate perforation. calcium alginate swab moistened with soy broth can be used. Scrapings should be placed on a slide for staining and directly applied to culture media, such as plates and broth, to maximize the chance of recovery. Multiple C streaks should be used on agar plates, because it is often difficult to identify an organism recovered in culture as the offending pathogen, and growth outside of the C streak might indicate contamination.

13 KOH mount Potassium hydroxide (KOH) preparation is used for the rapid detection of fungal elements in clinical specimen KOH is a strong alkali. When specimen is mixed with 20% w/v KOH, it softens, digests and clears the tissues, surrounding the fungi so that the hyphae and conidia (spores) of fungi can be seen under microscope.

14 Procedure for KOH mount The scrapings are placed directly onto a microscope slide and are covered with 10% or 20% potassium hydroxide. The slide is left to stand until clear, normally between five and fifteen minutes, in order to dissolve cells and debris. To enhance clearing dimethyl sulfoxide can be added to the slide. To make the fungi easier to see lactophenol cotton blue stain can be added. The slide is gently heated to speed up the action of the KOH. Adding calcofluor-white stain to the slide will cause the fungi to become fluorescent, making them easier to identify under a fluorescent microscope. Place the slide under a microscope to read.

15 KOH mount

16 Stains: Gram Stain Giemsa Stain Gomorie Methenamine Silver PAS Stain lectins Fluoroscent Microscopy: Acridine Orange Calcoflour white Potassium Hydroxide Wet Mount (10-20%w/v)

17 Lactophenol cotton blue-for quick evaluation of fungi, stains chitin in the cell wall of fungi. PAS- stains polysaccharide in the cellwall of fungi. Gomori methenamine Silver nitrate outlines fungi in black due to silver precipitating on the fungal cell wall.

18 SDA with Chloramphenicol -inhibits bacterial growth Cycloheximide to inhibit saprophytic fungi and some yeasts(including C.neoformans) Cycloheximide will prevent the growth of opportunistic pathogens - Aspergillus

19 Culture Media Blood Agar Chocolate Agar Sabouraud s dextrose Agar Thioglycollate Broth Brain Heart Infusion Broth / Solid Media Positive culture expected in 90% cases, within 72 hrs in 83% cases within 1 week in 97% cases Increasing Humidity of medium by placing inoculated agar plates in Plastic bags enhance fungal growth.

21 Candida on SDA

22 Candida albicans grows rapidly in culture, reaching maturity in as little as three days. Colonies are cream coloured, raised, entire, smooth & butyrous.

Newer Methods Electron Microscopy Polymerase Chain Reaction SCRAPING Advantage: Provide initial debridement of organisms- reduce the fungal load

23 Newer Methods Electron Microscopy Polymerase Chain Reaction SCRAPING Advantage: Provide initial debridement of organisms- reduce the fungal load Improve penetration of drugs Methods: Surgical Blade 26 gauge needle Diamond tipped motorized burr Diagnostic Superficial Keratectomy/Corneal Biopsy

24 Corneal biopsy: Done in Minor OT with Topical Anaesthesia 2-3 mm dermatologic trephine on anterior corneal stroma incorporating both clinically infected & adjacent clear cornea.(avoiding Visual Axis) Anterior Chamber Tap: Hypopyon or Endothelial Plaque

25 COMPLICATIONS: 1. Scleritis 2. Impending perforation 3. Endophthalmitis 4. Glaucoma

26 TREATMENT MEDICAL Topical: Natamycin5% Amphotericin B 0.15% Cycloplegics Antibiotics IOP lowering medication SYSTEMIC: Fluconazole Voriconazole SURGICAL 1. Debridement 2.Therapeutic Penetrating Keratoplasty 3.Conjunctival Flap 4.Flap + Keratectomy 5.Flap + Penetrating Graft 6.Lamellar Graft 7.Cryotherapy ( In Kerato scleritis)

27 Anti fungals POLYENES: Amphotericin B, Natamycin Binds to ergosterol in fungal cell membrane & cause the membrane to become leaky. AZOLES: Ketoconazole Fluconazole Voriconazole Inhibits CYP P a demethylase enzyme involved in conversion of lanosterol to ergosterol

28 PYRIMIDINES: Flucytosine Causes Faulty RNA Synthesis & non competitive inhibitor of Thymidylate Synthesis ALLYLAMINES: Terbinafine Ergosterol Biosynthesis inhibitor ECHINOCANDINS: Cell wall Synthesis inhibition by D-glucan synthesis inhibition Capsofungin, Micafungin

29 Topical Natamycin 5% is Initial drug of choice. Topical Amphotericin B 0.15% added in c/o worsening, candida & aspergillus oral or Topical Azole added in c/o Fusarium Indication for Systemic antifungals:( voriconazole 1st choice) Severe deep keratitis Scleritis Endophthalmitis Prophylactic t/t after Penetrating Keratoplasty for Fungal Keratitis Virulent Fungus

30 Topical : initially 5% Natamycin- hrly :day time n 2 hrly : night :+ fluoroquinolones for 2⁰ bacterial infections. Bd eye checkups under slitlamp Resolving -give Natamycin 2 hrly ->2 wks worsening -topical Amphotericin B 0.15%/fluconazole 2% is given. CandidiaI - Ampho B 0.15%/ fluconazole 0.3% 1st choice Echinocandins, Ampho: not effective against fusarium Nata 5% = econazole1% = voriconazole0.5 μg/ml.

31 VORICONAZOLE- derived from Fluconazole wider spectrum of activity against Candida, Aspergillus and Fusarium exerts its effect from inhibition of cytochrome P450 dependant 14 alpha sterol demethylase, an enzyme involved in the ergosterol biosynthetic pathway.

32 Intracameral therapy In severe keratomycosis not responding to topical natamycin It ensures adequate drug delivery into AC and avoid surgical intervention in the acute stage of the disease. performed under strict aseptic conditions. If the infection involves the anterior capsule of the lens, care should be taken to avoid injury to the lens. 5 μg ampho B in 0.1 ml 5% dextrose through a paracentesis Injections repeated in case of inadequate response

33 Length of treatment is based on clinical response of individual. If toxicity is suspected and if adequate t/t has been given for 4-6 weeks treatment should be discontinued & patient is observed for reccurence in follow up. Subconjunctival injections: reserved in cases of scleritis, severe keratitis, endophthalmitis Miconazole (preferred) as is least toxic and best toleratedx(5 to 10 mg of 10mg/ml )suspension

34 INTRACORNEAL THERAPY for non healing fungal corneal ulcers Amphotericin B injection μg, given near to stromal site of growth. raise the local concentration of the antifungal agent enough to be effective in the eradication of the deep corneal infection total elimination repeated after 48 to 72 hours

35 SIGNS OF IMPROVEMENT Decreased pain Decreased size of infiltrate. Disappeared satellite lesions Rounding of feathery margins DURATION OF TREATMENT :4-6 WKS only due to toxicity

36 Synergism: Amphotericin B & flucytosine Natamycin & Ketoconazole Antagonism: Amphotericin B & Imidazoles Antibiotics with Antifungal Property: Chloramphenicol -fusarium, Aspergillus Moxifloxacin & tobramycin - Fusarium Chlorhexidine Povidone Iodine.

37 SURGICAL MANAGEMENT 1. Debridement 2.Therapeutic Penetrating Keratoplasty 3.Conjunctival Flap 4.Flap + Keratectomy 5.Flap + Penetrating Graft 6.Lamellar Graft 7.Cryotherapy ( In Keratoscleritis)

38 Debridement: Done every hrs under topical anaesthesia Debulks necrotic material & organisms Enhances penetration of topical drugs Penetrating Keratoplasty Indication: Infectious process progress to limbus or sclera Failure of medical t/t Recurrence of infection To delay or prevent the need for corneal transplant with severe thinning or perforation is managed with TISSUE ADHESIVE(N - BUTYL CYANOACRYLATE) BANDAGE CONTACT LENS

39 Technique for Penetrating Keratoplasty : Size of trephination should leave mm clear zone of clinically uninvolved cornea to reduce residual fungus. Interrupted sutures with slight longer bites should be used to avoid cheese wiring Irrigation of Anterior chamber with antifungals Affected intraocular structures like iris, lens,& vitreous should be excised, the lens should be left untouched to prevent the spread of infection in the posterior segment The specimens -mcirobiology and pathology for culture and fixed section examination.

40 If involvement of intraocular structures or endophthalmitis is suspected, an antifungal agents :amphotericin B (5μg/0.1ml) or miconazole (25μg/0.1ml)

43 Fungal hyphae usually lie parallel to the cornea to the corneal surface and lamellae. A vertical or perpendicular arrangement of fungal hyphae in the corneal stroma: increased virulence and in patients on topical corticosteroid therapy. Surgical instruments should be changed to sterile ones once infected tissue removed to avoid recontamination.

44 If endophthalmitis is suspected: Intraocular Antifungal injected at the time of keratoplasty. ( Preferably AmphotericinB) After Penetrating keratoplasty: Topical antifungals continued to prevent recurrence. If pathology reports are negative for organism at edge of corneal specimen STOP antifungals after 2 weeks and follow up patient for recurrence. If Pathology reports are positive t/t continued for 6-8 weeks.

45 PROGNOSIS: Factors associated with Treatment Failure: Large ulcer size (greater than 14mm square) Presence of Hypopyon Aspergillus as causative organism

Mycotic Keratitis in Patients Attending a Tertiary Care Hospital

Mycotic Keratitis in Patients Attending a Tertiary Care Hospital International Journal of Current Microbiology and Applied Sciences ISSN: 2319-7706 Volume 6 Number 10 (20) pp. 1665-1670 Journal homepage: http://www.ijcmas.com Original Research Article https://doi.org/10.20546/ijcmas.20.610.201