Infectious keratitisA.KhalilianM.D

Natural eye defense

Eyelids, blinking

Tear film ( Ig, complement, enzymes)

Corneal epithelium

Normal ocular flora

MALT in conjectiva

Intact corneal sensation

Predisposing factors Contact lens (most common. 10 fold risk)

Trauma

Contaminated ocular med

Impaired defense mechanisms( Sj ,ocp,…)

Tap water, eyewash solutions

Chronic anesthetics abuse

Malnutrition,DM, collagen vascular dis

Contact lens induced ulcer

EW > RGP = daily wear Overnight lens use; major RF ( 15)

Apkakia, corneal graft, chronic keratopathy,fail to practice lens care regiment,worn CL

Pseudomonas sp ; most common

Corneal abrasion, epith thining, epith mitosis, anerobic metabolism, hypoxia

pathogenesis

Adhesions

S areus: use adhesins to bind collagen/fibronectin of bowman layer

P aeruginosa : directly binds (pili) to receptors exposed of injured epith

CED,abrasion S.areus- S.pnemoniaeS.aeruginosa

Pathogenesis( cont…)Invasion

LPS are the major mediators of inflm

Local production of cytokins/chemokins

Migration of neutrophils from limbus

Enzyme released by PMN

Activation of MMPs

Microbial proteas: destroy stroma

Invasion through intact epithelium

N gonorrhoeae

N meningitidis

Corynebacterium diphtheriae

Haemophilus aegyptius

Listeria monocyrogenes

Clinical presentation

Bacterial corneal ulcer shows:

I. Sharp epith demarcation

II. underlying dense supporative stromal inflm with indinstinct edges

III. surrounded by stromal edema

Clinical examination

Good Hx (traum,HSV, CL ,Sx …) General/ facial appearance/ lid closure NLD regurgitation, corneal sensation

On slit lampLid margin: MGD,ulcer, eyelash abNLTear filmConj, sclera: scar, discharge,membrane or pseudo m, thining

Clinical examination (cont…)Cornea Location (central) Density, size,depth

Shape : ring, satellite lesions Character of infiltrate margin

(feathery,crystalline, soft, necrotic)

Endothelium plaque AC reaction, hypopyon,fibrin

The most common pathogenic organism identified in bacterial keratitis include:

Pseudomonas

Staphylococci

streptococci

Pseudomonas.aeruginosaIncreasing prevalence due to soft CL usage

>2/3 cosmetic CL induced ulcers

dense stromal inflt , necrosis shaggy surface adherent mucupurulent exudate endo inflmm plaque AC reaction/ hypopyon Descemetocele , corneal perforation

Pseudomonas(cont…) despite Rx, may progress to deep abscess Sometimes ring infiltrate

Staphylococci NL ocular flora More in compromised cornea like:

bullous keratopathychronic HSV keratitisK-conj siccaocular rosaceaAKC

Nonaureus staph most frequently organism isolated from corneal ulcers

Staphylococci

streptococciS pneumoniae usually occurs after

corneal trauma Dacryocystitis Flitering beleb infection

Ulcer is acute, purulent,rapidly progressive,deepstromal abscess, severe marked hypopyon,retrocorneal fibrin,

Perforation is common

Ulcer is acute, purulent, rapidly progressiveDeep stromal abscess, Severe marked hypopyonRetrocorneal fibrin

Atypical mycobacteria

Slow growing,fastidious organismslike mycobacteria or anaerobes may have

a non-supp infiltate & intact epith

Keratitis from non-tuberculous mycobacteria

Delayed onset (2-8 week), slowly progressive Feathery, indistinc margin, craked windsheild After LASIK, corneal F.B or trauma Lack of response to conventional Abs

Teratment of nontuberculous mycobacteria

Oral or topical Clarithromycin +/-Amikacin

Fluoroquinolone(moxifloxacin,gatifloxacin)

Imipenem co-trimoxazole

Infectious crystalline keratopathy

Most commonly: streptococcus alpha-hemolytic Densly packed,white branching aggregates of

organism in the absence of host inflm response

No CED, mild stromal inflm GC use,CL wear , PKP, anesthetic abuse

nocardia

Indolent ulcer, waxes ana wane pattern Minor trauma, especially contaminated soil Characteristic feature:

Raised, superfacial, chalky white infl in a wreath likePattern with multifocal satellite lesions

Indications for smear & culture

Large Corneal infiltrate(> 2mm)

Infiltrate extending to the middle deep stroma

Chronic ulcer Unresponsive to broad-spectrum Abs

Suspecious to fungal,amoebic,mycobacterium

culture

By Slit lamp magnification

Proparacaine 0.5% (not tetracaine )

Scrape corneal tissue from the advancing border

With wet sterile cotton swab, NO 15 blade

Muliple samples from advancing edges Corneal specimens should be inoculated directly

onto media in C streaks

culture

Culture of CL, lense case & solutions maybe useful:suspecious to acanthamoebanegative cultures

Before being reported as no-growth Aerobic cultures should be held for 1 week Anaerobic cultures should be held for 1-2 weeks Mycobacterial & fungal for 4-6 weeks

stains

Gram stain

Best for bacteria

Rapid(5 min) Sensivity 55-79% Distinguish bacteria from fungi/acanthomoeba

Geram positives : bluish purpule

Geram negatives: Pink

Stains(cont…)

GimsaBacteria, fungi, chlamydia,acanthomoeba

Acridine orange:Rapid(2min)Accurately predicts culture results in 71-84%More sensitive than gram stainRequires epi-fluorescence microscope

Other stains

Calcofluor white :fungi,acanthomoebaRequires epi-fluorescence microscope

Acid fast (Ziehl-Neelsen):mycobacteria, nocardia

Corneal biopsy

1. Unresponsice ulcer2. Negative culture3. Infiltrate in mid or deep stroma with intact

overlynig tissue

Specimen 1-2 mm

Healing effect of Bx due to debulking or debridment of necrotic tissue

Alternative to Bx:pass a sterile silk suture through the inflt>> culture

Confocal microscopy

Non invasive, in vivo diagnostic tool Real time veiwing of structures

in the living cornea at cellular level

Acanthomoeba cysts Fungal hyphae

Rxcephalosporins

CefazolinExellent activity against Gram+ Minimal toxicityUsage in combination with other anti,Gram – agents

CeftazidimeAnti pseudomonal activityUsed in pseudomona keratitis not responding to AG or FLQ

Rxglycopeptides

Vancomycin

Active against many Gram+ bacteria

One of most potent AB against methiciline-R S.areus & coagulase negative Staph

It should be reserved for cephalosporin –R staph

Rx

Aminoglycosides

Bacericidal effect against Gram -, aerobics

For severe pseudomona ulcers may be combined with Cephalosporins

Amikacin is the drug of choice for nocardia

Less pseudomonas resistancy to Amikacin,ratherthan gentamicin & tobramicin

RxMacrolides

Erythromycin has a relativley activity againstmost Gram +some Gram –most viridans & anaerobic Streptococcimost strains of Neisseria( gonorrhoeae,meningitides)majority of aerobic Gram – bacilli are resistant

limited role for bacterial ulcer( poor corneal penetration)

RxMacrolides

Newr macrolides: Azithromycin Clarithromycin Roxithromycin

Favorable for treating:Chlamidia.t Nontuberculous mycobacteria

RxFluoroquinolones

Ciprofloxacin,ofloxacin (2nd)

Caverage most Gram - & some Gram+

Moxi, gati, levo and besifloxacin(3rd&4 )have improved Gram+ and atypic mycobacterium coverage ,but limmited activity against MRSA

RxFluoroquinolones

Similar efficacy compared to FF Abs for common ocular pathogens(small, non central, not severe ulcer)

Lesser topical side effects than FFABs

Higher risk of perforation than FF Abs

Increasing resistance: P.aeruginosa Staphylococcus(MRSA) Streptococcus

Initial management FF loading dose: evey 5-15 min for 1 hour then

every 15min –hourly

Cycloplegics : synechia & pain, c.spasm

Sub conj AB:imminent scleral spread/ perforationpoor compliance

Sys AB: Scleral / intraocular extensionimpending/frank corneal perforation

Strategies for initial treatment

1- Culture guided approach:smear& culture of all ulcersstart Rx based on clinical & epidemiologic datamodify Rx by smear/culture results

Disadvantages:1- cost2-positive cultures only 60% 3-discrepancy between in vitro sensivity and

clinical response

Strategies for initial treatment (cont…)

2-Emprical approach

based on pre-existing culture sensivityuse broad spectrum ABcefazolin or vanco for Gram+ tubramycin or ceftazidime for Gram –

Failed Rx culture appropriate Rx

Strategies for initial treatment (cont…)

3- case based approachsmear/culture before Rx only in1-involving visual axis2-large, deep ulcer3-keratitis associated with trauma,contamination by vegetation material or unsantizied water

Small, peripheral ulcers: no culture, empirical RXCentral. Large,deep,unusual ulcer: culture based Rx

Ulcer at presentation

Small/peripheral

No microbiologic work-up

Broad spectrum AB

Central/ multiple/ deep

Microbiologicwork-up

Specific AB for causal organism

Initial evaluation

(48 hr after treatment)Stable

improve

Cont RX

Sig progression

Poor compliance

Alternative treatment

Good compliance

No initial microbiolog

ic w/u

Stop treatment for 24 hr

Then microbiological

w/u

Had microbiologic

w/u

Check culture results/ mofify

treatment

clinical features suggestive of positive response to AB

1. Pain reduction2. Consolidiation & sharper edges of stromal inflt3. Decreased density of stromal inflt4. Reduction of stromal edema & endo plaque5. Reduction of AC reaction6. Re-epith

The clinical response is best assessed after 48 hr

Treatment (cont…)

Most bacterial ulcers will be culture negative after 48-72 hr of treatment

But FF Abs should be continued untill substantial control of infection is seen.

There after, a prophylactic AB (not a FF) may be given at a theraputic dose,untill CED is healed

Corticosterois therapy

GC therapy in bacterial keratitis is still contraversial

Potential advantage:supression of inflmmreduction of corneal scar

Potential adverse effects:1-enhancment of bacterial growth2-Impairment of phagocytosis3-Inhibition of collagen synthesis4-Cataract,glaucoma

Corticosterois therapy( cont…)

There is no different between pts treated with or without steroid therapy in terms of:

time to cure Final VA Complications

Corticosteroids is contraindicated in:1-sig corneal thining2- impending to perforation3-absence of appropriate AB therapy

Corticosterois therapy (cont…)

The goal of using GC is reduction of inflmm ation & scarring and morbidity.

In cases where the corneal infiltrate & scaring Compromises the visual axis, topical steroid may be added to regimen, following at least 2-3 days of progressive improvement with topical Abs.

If the patient shows no adverese effect after 1-2 day,the frequency of steroid may be adjusted

Cyanoacrylate tissue adhesive

Tectonic support Bacteriostatic effect Stopping keratolysis by blocking proteases

Can be used for perforations up to 2-3 mm

Necrotic tissue& debris should be removed Use the minimmun amount of glue BCL

Surgical management

Conj flapBring vessels to infected are,promote healing,stable surface covering

Conj flap is contraindicated in necrotic area with active infection!

Conj flap is best useful in cases of non-healing preipheral ulcer

Surgical management

Emergency theraputic PKP:I. Uncontrolled progression of infiltrateII. Limbal involvment/impending scleritisIII. Corneal perforation/descematocele

Interrupted sutures, PI,circumscribe all infected areas

Intensive Abs should be administered for 48hr before surgery

Defer the PKP as late as you can

Fungal keratitisA.khalilianM.D

Fungal keratitis

FilamentousNon septated

FilamentousSeptated

Pig hyphea

Filamentous septatedNon pig hyphae

Yeast

MucorRhizopus

AlternariaCurvularia

FusariumAspergillusAcremonium

CandidaCryptococcus

Fungal keratitis epidemiology

Fungi as a NL flora( 3-28%) in conjetival sac

More common in rural setting

Aspergillus is the most common cause worldwide

In the largest case series from India:Aspergillus(27-64%)Pencillium (2-29%)Fusarium (6-32%)

Fungal keratitis

Risk factors:

Trauma (plant) major RF Soft CL (cosmetic > theraputic) Topical steroid/anesthetic Sys immunosuppression (DM,HIV,leprosy)Corneal surgery (PK,LASIK,RK)Chronic keratitis (HSV,VKC) >> candida

Fungal keratitis clinical features Slow onset Fewer inflmm sign,symp initially May have littile or no conj inj initially

Pain can be out of proportion to the relatively uninflamed cornea.

Occasionally,fungus may invade the iris,PC and leads to pupillary ACG.

Fungal keratitis

Special signs: Elevated area Hypate(branching) ulcer Irrigular feathery marginDry rough texture Satellite lesion Brown pig( curvularia ) Invasive to AC Intact epith+deep stromal inflt

Fungal keratitis

Fungal keratitis

Laboratory diagnosis

Smear with Gram/Gimsa/Gomori stains are helpful(27-43%)Positive cultures in 90% of cases(wait 1 week)

Blood agar,chocolate agarSabouraud,thioglycolate,brain-heart infusion

Others: immunfluorescence staining,electronmicroscopy,PCR

Fungal keratitis

Laboratory diagnosis(cont...)

Corneal biopsy (lamellar keratectomy) is superior to scraping for recovering fungi in cases with negative smear/culture

AC tap

Confocal microscopy is promising

Classification of antifungals

othersPyrimidinesAzolePolyenes

BetadinNystatin 5%PHMBchlorhexidn

5-FCClotrimazolKetoconazolFluconazolvoriconazol

Amphotericin B(0.15%)

Natamycin (5%)

AspergillusCandidafusarium

?Almost allExceptfusarium

Almost allfungi

Fungal keratitis treatment

Natamycin 5% is recommended for initial treatment of most cases of filamentous(Fusarium)fungal ulcer

topical amphotericin B(0.15%- 0.30%) is the most effectice agent agianst Yeast keratitis &Aspergillus

Topical voriconazole(1%) is useful in some cases of refractory fungal keratitis( increasing resistance!)

Principles of Fungal keratitis treatment

1-Epith debridment especially early (every 1-2 day)*significantly enhance the topical antifungal penetration

2-Start with natamycin(every 5 min for 1 hour loading dose)If worsening of keratitis continues: in candida keratitis add amph-B 0.15% In aspergillus keratitis add an azole(fluconazole2%)

Don use amph-B and imidazole (antagonist)

Principles of Fungal keratitis treatment (cont…)

Treatmen lengh: 4-6 weeks(based on clinical response)

Sys antifungal or sub conj antifungals indicated in:1-Severe deep keratitis, 2-scleritis, 3- endophthalmitis

Sys voriconazole(200-400 mg),posaconazole has the better corneal penetration

intrastromal/intracameral Amph-B(5-10 mcg/0.1 cc) or voriconazole(50-100 mcg/0.1cc) are becoming more widely validated

Principles of Fungal keratitis treatment (cont…)

Corticosteroids can be used after 2 weeks of treatment & clear clinical evidence of inf control

The steroid drop is used in conjuction with antifungal and never without

Newer modalities of fungal keratitis Rx: Collagen sheilds impregnated with Ampho-B Excimer laser (surface infec ablation) Intra-cameral Ampho-B Cryotherapy(keratoscleritis)

Principles of Fungal keratitis treatment surgical therapy

Progression of keratitis despite med Rx = PK

Post pk regimen: Sys azole+ topical antifungalfor 2weeks (negative edge pathology report)for 6-8 weeks (positive edge or intraocular infection)

Instead of steroids cyclosporin A is used because of dual action(anti-inflmm + anti-fungal effect)