Amd

POSTULATED RISK FACTORS FOR AMD

AgeingThe Framingham Eye study (1976) showed the prevalence65-74 years- 11%75-85 years- 28%

GenderBlue Mountains study (2002) suggests that 5-year incidence of neovascular AMD among women is double that of men.

Smoking The Beaver Dam Study (1992) disclosed a relationship between the development of exudative lesions and a history of current cigarette smoking.

Cardiovascular Risk factorsHypertension: Rotterdam study (2003) suggests positive correlation between high blood pressure and increased incidence of AMD.

LightInitially postulated hypothesis: UV-damage by photo-oxidative damage via reactive oxygen intermediates.The Blue Mountains Eye Study (2002) disclosed no relationship between light and AMD.


NutritionSeveral studies (including AREDS) have described the beneficial effects of dietary carotenoids, anti-oxidants, Zn and omega-3 fatty acid in slowing the course of the disease.

Exogenous Post Menopausal OestrogenThe use of exogenous supplements in post menopausal women lowered risk of AMD in a study performed by the Eye Case Control Study Group.


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GENETICSFamily history of macular degeneration:Autosomal dominant with variable penetrationIn first degree relative with macular degeneration, chances is about 2.5 times.

Macular Degeneration Gene:Few studies* have described the increased risk of AMD associated with polymorphisms of complement factor H (HF1/CFH)single nucleotide polymorphisms on 1q32, 6p21, and 10q26 are the risk for development of AMDThe odds of developing macular degeneration are increased by about 2.5 to 5.5 times if one has the CFH gene variant.

*Moshfeghi DM, Blumenkranz MS, Retina. 2007 Mar;27(3):269-75

AMD: SYMPTOMSInitial symptoms: Straight lines appear wavy Blurry vision Distorted vision Objects may appear as the wrong shape or size A dark empty area in the centre of vision

AMD: SYMPTOMSPatients ability to perform normal daily tasks such as reading, sewing, telling the time, driving are greatly impaired.

FoveolaFoveaMACULAPara-foveal zonePeri-foveal zoneMACULA: ANATOMYUmbo

RETINAL PIGMENT EPITHELIUMThe retinal pigment epithelium (RPE) is a single layer of hexagonally shaped cells & attached to the photoreceptor layer.

Functions - Maintain the photoreceptorsAbsorption of stray light Formation of the outer blood retinal barrierPhagocytosis and regeneration of visual pigment

Bruchs membrane separates the RPE from vascular choroid.

Function of Bruchs membrane is to provide support to the retina.

Choroid capillaries are a layer of fine blood vessels that nourishes the retina and provides O2.

DRY AMDAccounts for about 90% of all casesAlso called atrophic, non-exudative or drusenoid macular degeneration

Clinically , dry AMD may manifest- Stage of drusen and/or hyperpigmentation Stage of incipient atrophy (non geographic atrophy) Stage of geographic atrophy

DRY AMDDrusen

Insufficient oxygen and nutrients damages photoreceptor molecules

With ageing, the ability of RPE cells to digest these molecules decreases

Excessive accumulation of residual metabolic debris and hyaline material (drusen)

RPE membrane and cells degenerate and atrophy sets in and central vision is lostDRY AMD

Drusen:

Drusen are aggregation of hyaline material located between Bruchs membrane and RPE.

Drusen are composed of metabolic waste products from photoreceptors.

Hypo/hyper pigmentation of RPE may be present.DRY AMD

Types:Small: 125

Hard:generally small (63 ), pale yellow, ill defined, fluffy marginsHigh risk for neovascular AMD

Soft Drusen:Membranous:63-175 Pale, shallow appearing drusensGranular:About 250 Solid appearing drusensSerous:>500 Have pooled serous fluidblister like appearanceMay result in serous PED

HISTOPATHOLOGYDrusen appear as focal areas of the eosinophilic material between the basement membrane of RPE & BM.

Deposits on the internal side of RPE basement membrane called basal laminar deposits & on its external aspects called basal linear deposits.

Basal linear deposits are believed to form soft drusen with the passage of time & are more common in eyes effected by neo-vascular AMD.

Drusen

Diagnostic criteria*Degenerative disorder in persons >50 years, characterized by the presence of any of the following:Soft drusen (>63 )RPE abnormalities- areas of hypo/hyperpigmentation (excluding pigment surrounding small, hard drusen)Visual acuity (VA) is not a criterion for the diagnosis

*International Epidemiological Age-related Maculopathy study Group

DRY AMD

DRUSEN

GEOGRAPHIC ATROPHY

DRY AMD: COURSE AND VISUAL PROGNOSISPatients with only drusen not have much loss of vision, but require additional magnification of the text and more intense lighting to read small points.

Presence of large drusen (>63 microns in diameter) is associated with a risk of the late form of the disease like CNV.

Geographic atrophy- severest form of the dry AMD, RPE atrophy >175 microns with exposure of the underlying choroidal vessels.

EXUDATIVE MACULAR DEGENERATION( WET OR NEOVASCULAR AMD )

Accounts for about 10%

The pathology of neovascular AMD is choroidal neovascularisation with the formation of a subretinal/choroidal neovascular membrane (SRNVM/CNVM) The CNVM lead to haemorrhage and fibrovascular proferation and subsequent scarring.

Age related Bruchs membrane change may be especially important in exudative macular degeneration, this change includes thickening of Bruchs membrane, drusen and other metabolic accuminata such as lipids and loss of basal connections with the RPE.

Pigment epithelial detachment may occur in relation to Bruchs membrane change.

Photoreceptors and pigment epithelium send a distress signal to choriocapillaries to make new vessels

New vessels grow behind the macula

Breakdown in the Bruchs membrane

Blood vessels are fragile

Leak blood and fluid

Scarring of macula

WET AMDPotential for rapid and severe visual damage

WET AMD

Diagnostic criteria*persons >50 years, characterized by the presence of any of the following:choroidal neovascularizationserous retinal pigment epithelial detachmenthemorrhagic retinal pigment epithelial detachmentfibrotic scar in the maculaWET AMD*Takahashi K et al.Nihon Ganka Gakkai Zasshi. 2008 Dec;112(12):1076-84.

WET AMD

WET AMDCNV lesion is well demarcated & its location may be determined by closest point to the FAZ.Lesion location is classified angiograpically as follows:-Subfoveal: under the centre of FAZJuxtafoveal: 1-199 m from the centre of FAZExtrafoveal: >200 m &

CLASSIC CNV

OCCULT CNV (TYPE-I)

OCCULT CNV (TYPE-II)

RPE DETACHMENT (PED) PED (Pigment epithelium detachment)

Depending on cause, it is of many types:DrusenoidSerousFibro vascularHemorrhagic

RPE DETACHMENT (PED)

RPE TEARSpontaneously or on photocoagulation of CNV.

Visual acuity abruptly fall

Angiogram shows CNV in early & in late phase shows hypofluorescence corresponding to heaped-up RPE with hyperfluorescence over the torn area.

DISCIFORM SCAR

WET AMD: COURSE AND VISUAL PROGNOSISLeakage of blood or serum in CNV may occur precipitously and associated with the abrupt loss of vision.

Patients with CNV shows rapid decline in vision (20/200) within weeks.

Once CNV has developed in one eye, the other eye is at relatively high risk for the same change.

More frequently, visual acuity deteriorates more slowly and stabilizes within 3 years.

AREDS Categories:No AMD (AREDS category 1)No or a few small (

Visual acuityAmsler grid test: Assesses distorted or reduced vision and small irregularities in the central field of vision.Ophthalmoscopy: to detect drusen, as well as neovascularizationFluorescein and ICG angiography: Determines the presence and location of neovascularization. Aided by optical coherence tomography.

AMD: DIAGNOSTIC TOOLS

Role of Antioxidants:AREDS-1 study- use of high dose of multivitamins & antioxidants decreases the risk of progression of ARM in those with high risk characteristics.Combination of antioxidants and zinc (AREDS-1 Formula)-Vitamin C: 500 milligrams (mg)Vitamin E: 400 international units (IU)Beta carotene: 15 mg (equivalent to Vit.A 25000 IU)Zinc: 80 mgCopper (cupric oxide): 2 mg

AMD: MANAGEMENT

AREDS-2 Study:Lutein & zeaxanthin antioxidants micronutrients found in human macula.Diet rich in these give some protection against the disease.omega-3 fatty acids,docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have also been shown to help with AMD.AREDS-2 Formula-Vitamin C - 500 mgVitamin E - 400 IUBeta-Carotene - 15 mgZinc - 80 mgCopper - 2 mgLutein - 10 mgZeaxanthin - 2 mgDHA - 350 mgEPA - 650 mg

AMD: MANAGEMENT

Current treatment

Antiangiogenic drugs

Photodynamic therapy

Laser photocoagulation

AMD: MANAGEMENT

ANTI ANGIOGENICSAnti-VEGFs:reduce the growth of new blood vessels, decrease the leakage through them.

Bevacizumab (Avastin)Ranibizumab (Lucentis)Pegaptanib sodium (Macugen)Aflibercept (VEGF Trap-Eye)

Bevacizumab (Avastin)-

Full-length monoclonal antibody (150 kD)Binds all isoforms of VEGFHas FDA approval for i.v. use in metastatic colorectal, metastatic breast and non-small cell carcinoma of lungIs being used off-label for choroidal neovascularization based on results of short-term studiesDose- 1-1.25 mg, repeated 6-8 weekly.

Ranibizumab (Lucentis ) Recombinant humanized immunoglobulin G1, kappa isotype, antibody fragment (Fab) (48 kD)Binds to all isoforms of VEGF.Dose- First 3 injections of 0.5 mg (0.05 mL) four weekly & further on physician's assessment.Comparison of AMD Treatment Trials (CATT)Multicentre clinical trialCompare safety and efficacy of ranibizumab and bevacizumabCurrently under way

Pegaptanib sodium (Macugen)

28 base ribonucleotide aptamerBinds to Heparin-binding domain of VEGF-AInactivates VEGF-A 165,189 and 206 isoformsGiven 0.3 mg dose six weekly minimum for two years.VISION (VEGF Inhibition Study in Ocular Neovascularization) (2002) has shown that pegaptanib (6 weekly injections) is superior to sham injections and as effective as PDT in teatment of CNV.

Aflibercept (VEGF Trap-Eye)

a fusion protein of key binding domains of human VEGFR-1 and 2 combined with a human IgG Fc fragment blocks all isoforms of VEGF-AAlso blocks placental growth factors-1 and 2Two Phase III clinical trials (VIEW-1 and VIEW-2) comparing aflibercept to ranibizumab are currently ongoing.

COMPLICATIONS

Common-Raised intra-ocular pressureOccasionalCataract FormationIntra-ocular hemorrhageRareEndophthalmitisRetinal Detachment

Submacular excision of CNVMacular translocationRetinal rotationHomologous Iris/Retinal pigment epithelium transplantationAutologous RPE transplantationSURGICAL OPTIONS

EMERGING TREATMENTS FOR AMDRetaane (Anecortave acetate)modified steroid promising in reducing the risk of vision loss due to the growth of unhealthy blood vessels in wet AMD.

AdPEDF : Adenovirus-based Pigment Epithelium Derived Factora gene that leads to the production of the protein PEDF, which helps keep photoreceptors healthy, thereby preserving vision.

siRNA (Bevasiranib)silences the genes that lead to the growth of unhealthy, vision-robbing blood vessels under the retina. safety and efficacy established in a Phase II studyPhase III clinical trial is planned

ATG3 (mecamylamine)a topical formulation that inhibits the nicotinic acetylcholine receptors Currently undergoing phase II human study

EVIZON (squalamine lactate)aminosterol with antiangiogenic activity Derived from the liver of the dogfish shark, administered intravenously (no eye injection)in a Phase III human study for the treatment of wet AMD

OT-551 (antioxidant eye drops)supplement the eyes natural defense system against disease and injury.Protection against both cataract and dry AMDcurrently in a clinical study for geographic atrophy (advanced dry AMD)EMERGING TREATMENTS FOR AMD (Contd.)

Encapsulated Cell Technology (ECT)

Developed by Neurotech, tiny capsule (6 mm) implanted into the eye, contains retinal cells that produce a vision-preserving protein ,Ciliary Neurotrophic Factor (CNTF) keep photoreceptors alive and healthy, preserving vision.currently in a Phase II human clinical trial for people with dry AMD.

EMERGING TREATMENTS FOR AMD (Contd.)

REHABILATATIONLow vision aids-

Individual who experiences untreatable visual loss & effects the daily life.

Reading lamps & simple magnifiers may be beneficial.

Closed circuit television & scanning devises are also available to provide electronic magnification & contrast enhancement.

CLASSIFICATIONEndophthalmitis can be classified according to the

Infectivity Infective / non infective ( sterile)Mode of entry exogenous / endogenousType of etiological agent

Classification Infectious Sterile (Infectivity)

Exogenous Endogenous ( Mode of entry)

Post trauma Post-operative Blebitis(PEI-IOFB)

Fulminant Acute Chronic

Cont.Etiological agent*

BacterialFungalviralParasitic

Endophthalmitis

Gram positive bacteria 75%-85%Gram negative bacteria 10%-15%Fungi3%Staphylococcus epidemidis (43%)Pseudomonas (8%)AspergillusStreptococcus spp (20%) Proteus (5%)FusariumStaphylococcus aureus (15%)Haemophilus influenzae (1%) Cephalosporium spp.Propionibacterium acnesKlebsiella( 0-1%)Bacillus cereus (1%)Coliform spp (0-1%)

Exogenous EndophthalmitisVitreous and aqueous primary site of involvement

Retina and uvea secondary involvement

Basically 3 types 1) post operative 2) post traumatic 3) Blebitis

Source of infection is from exteriorMaily bacterial

1)Post-op Endophthalmitis

Incidence: 0.05%MC among all types: 49-76%

SurgeryBascom Palmer Eye Institute (1984-1994)Katten et al(1984-1989)ECCE with and without PCIOL0.08%0.072%Secondary PCIOL 0.37%0.3%PPV0.05%0.05%PK0.18%0.11%Glaucoma filtration surgery0.12%0.06%

Source of infectionAirborne respiratory origin, air condition in O.T Solution and medications irrigating solutions, drops and ointment skin antiseptic, viscoelastic and silicon oilTissue periocular skin ,lid margin and lashes conjuctival sac, Lacrimal sac nasal mucosa, corneal graftObjects and materials surgical instruments, gloves, masks, IOL

Clinical Importance- all causes are preventable

Risk FactorsPreoperative risk factors blepharitis , active conjunctivitis Lacrimal drainage system infection or obstruction , contaminated eye drops.

Operative risk factors wound abnormalities, PC rent ,vitreous loss ,prolonged surgery & contaminated irrigation solutions

Types Of Presentations

Fulminant Acute Chronic (4 weeks) -gram ve -staph.epidermidis -staph.aureus -coag.-ve cocci -streptococci delayed delayed entry onset bleb P.acne related fungi S.epidermids

2)Post traumaticIncidence-2-7%(unsterile conditions & contaminated objects)Contributes to 17-40% of all casesPenetrating ocular trauma is main culpritCausative organisms fulminant: acute: chronic: B. cereus S.epidermidis(MC) fungi: Streptococcus Gram.-ve fusarium

Bacillus cerus isolated in 50% of culture positive cases causes fulminante Endophthalmitis

Difficult to diagnose early.

Rapid worsening of symptoms and inflammation should be suspected as Endophthalmitis until proved otherwise.

Ring corneal infiltrate & ring abscess is typical of Bacillus. also assoc.with proptosis,chemosis & severe orbital pain in 24hrs

Commoner in rural setting due to retained IOFB.

Removal of IOFB with in 24 hr.reduces risk.

3)Bleb related endophthalmitis4-18% of all casesAfter glaucoma filtration surgeryMay occur at any time (months- years )after surgeryMost of the time through intact bleb via conjuctival floraPoor prognosis as org. are more virulentCausative organism streptococci(MC)-faecalis,viridans,pneumoniae H.influenzae staph. are rareClinical signs infected white bleb Vitritis Hypopyon

Risk factors: use of antimitotic agents,inferior blebs,conjunctivitis,contact lens,periocular infectionsShould be differentiated from BLEBITISBlebitis - low virulence organism - mild intraocular inflammation - no Vitritis

Endogenous(Metastatic) Endophthalmitis2-15% of all casesHematogenous spread of organism from distant source Retina and choroid primarily involved due to high vascularity.Fungi> bacteria Candida(MC)>AspergillusPredisposing factors - Diabetes - immunosuppresion(AIDS,malignancies medications) - recent major abdominal surgery - prolong indwelling catheter ( intravenous , TPN) - intravenous drug abuser - distant infection ( endocarditis, meningitis, septicemia etc)no structural defect in globe

Clinical ApproachSymptoms: Decreased or blurred vision ( sudden / severe acute) ( slowly / mildchronic)Pain Photophobia Redness of eyes Swollen eyelids Discharge White lesion in black part of the eyeFloatersFever

SignsInitial visual acuity ( prognostic significance)Ocular motility ( sign of orbital inflammation)Eyelid swollen , blepharospasm Conjunctiva hyperemia, chemosis, bleb examination if presentCornea edematous, opacification , DM folds keratic precipitate, infiltrates, occult penetrationAnterior chamber cells, flare , fibrinous exudates and HypopyonIris muddy,boggy,resistant to dilatation,post.synechiae

Pupil-absent or sluggish reaction to lightLens - Membrane , exudates around IOLVitreous - Vitritis , exudates , yellowish appearance Fundus examination Absent red reflex and no fundal view Amaurotic cats eye reflex Papilitis White lesion in retina and chorioid Retinal hemorrhage and periphlebitisIOP- usually low,may be high in early casesSigns of penetrating injury and Intraocular foreign bodyWound dehiscence

Cont.OCULAR MEDIA CLARITY (I/O) Grade 1- Media clarity, 6/12 view of the retina. Grade 2- Media clarity

Fungal EndophthalmitisCaused by Candida albicans, Aspergillus, Fusarium etc.Causes - delayed post-operative endophthalmitis - endogenous endophthalmitis in immunocompromised patients

Minimal pain, mild external ocular involvement

Progressive iridocyclitis, Vitritis ( string of pearl )

Yellow white choroidal lesion single or multiple

DiagnosisA) Clinically B) Laboratory AC Tap (0.1ml) Vitreous tap (0.2 ml) Standard Media Grams stain Blood agar ( most aerobic bacteria) Giemsa stain Chocolate (aerobic , Neisssseria , Haemophilus ) Culture Thioglycolate broth ( aerobic ,anaerobic bacteria) SDA ( fungi) Specialized Media Lowenstein Jensen ( mycobacterium , nocardia) Non- nutrient agar E.coli enriched PCR

Ancillary studies1) Ultrasound-vitreous membrane and opacities anatomical status of the retina extent of inflammation choroidal detachment IOFB presence and localization retained lens material

2) CT Scan not much useful to detect IOFB3) ERG grossly abnormal - poor prognosis slightly subnormal - slight better

For endogenous endoph.:Complete blood count ( signs of infection)ESR ( malignancy ,chronic infections, rheumatic diseases)Cultures ( for detection of source of infection) blood culture urine culture throat swab CSF stool indwelling catheters tipChest X-rayOther necessary investigation according to suspicion like HIV

TreatmentGOALS

1) Retention of useful vision.2) Minimize the infection with antimicrobial agents.3) Limit the inflammation. 4) Symptomatic relief.

For bacterial endoph.Prompt therapy is critical Modalities

MEDICAL 1) Antibiotics Intravitreal, periocular, topical , systemic 2) Anti-inflammatory (steroids) topical ,periocular , systemic ( not for chronic Endophthalmitis) 3) Supportive Cycloplegic,AGM

SURGICAL vitrectomy

Medical treatmentIntravitreal injection - preferred route in all types of endophthalmitis. - direct administration in vitreous - by passes Blood Ocular Barrier. Intravitreal injection Vancomycin ( 1.0 mg in 0.1 ml ) Amikacin ( 400ug in 0.1 ml) OrCeftazidime (2.25mg/0.1ml)Subconjunctival injections Vancomycin (25mg in 0.5ml)Amikacin (25mg in 0.5ml)

Systemic : 1) penetrating ocular injury from contaminated objects. 2) Endogenous bacterial endophthalmitis. For Post-Op Endophthalmitis: - no role due to MIC in vitreous -Quinolones ( ciprofloxacin) can be tried

Rapid bacterial proliferation make even the Quinolones concentration inadequate to prevent the growth of organisms. Ideal duration - at least 2-4 week

DrugsDosesVancomycin1 gm iv.12 hrly(10-30 mg/kg)Ceftazidime2 gm iv. BdAmikacin250 mg iv. Tid(15mg/kg)Gentamycin80 mg iv tid (3-5mg/kg)Ciprofloxacin750 mg po.bdOfloxacin200 mg 12 hrly

Role Of SteroidsIndications recent onset after rule out of fungus.Contraindication Late onset endophthalmitis fungal endophthalmitisMechanism- reduce inflammation clinically and histopathologicaly

limit ocular damage

Routes - Intravitreal(dexa400mgm in 0.1ml),systemic, sub-conjuctival(1 mg in 0.25ml), topical

Treatment in Fungal Endoph.

Indication of Intravitreal antifungal 1) pre-existing fungal keratitis endophthalmitis 2) fungal endogenous endophthalmitis ( culture +)

Commonly used medications intra-vitreal Amphotericin B- 5microgm/0.1ml oral fluconazole / ketoconazole ( better vitreal penetration)

Voriconazole Intravitreal -50 microgm/0.1ml oral- 200 mg bd intravenous- 6 mg/kg bd 2 doses

Steroids in any form C/I

Systemic antifungals

VitrectomyAdvantages ( DIAGNOSTIC / THERAPEUTIC)1) more material for culture esp. fungus.

2) removal of inflammatory mediators /organisms /toxins.

3) removal of source of infection.

4) better dispersion of antibiotics in the vitreous.5) clears the media and better posterior segment visualization

6) removes vitreous membrane which may be a source of late traction and subsequent detachment. guided by Endophthalmitis vitrectomy study (EVS)

Endophthalmitis Vitrectomy Study(EVS)Multicenter randomized trial carried out at 24 centres in U.S. (1990-1994)Purpose : To determine The role of IV antibiotics in the management of POERole of initial vitrectomy in management.Patients : N = 420 patients having clinical evidence of POE within 6 weeks of cataract surgeryInterventionRandom assignment to immediate vitrectomy (VIT) or vitreous biopsy (TAP). They were also randomly assigned to treatment with IV or no IV.

Study medications : After initial VIT or TAP, all patients received I/V injection of amikacin (0.4 mg) + vanco(1 mg)Vanco(25 mg in 0.5 ml), Ceftazidime (100 mg in 0.5 ml), Dexamethasone (6 mg in 0.25 ml) administered subconjunctivally. IV treatment: ceftazidime (2 g every 8 hrs) + amikacin (6mg/kg every 12 hrs) for 5-10 days

Main outcome measuresEvaluation of visual acuity and clarity of ocular media at 3, 9, 12 monthsNo difference in outcome between PPV followed by I/V group compared to vitreous tap and I/V if vision better than light perceptionNo difference in final visual acuity or media clarity whether or not EVS systemic antibiotic( Amikacin , Ceftazidime) were employedVision with light perception or worse ,much better results in immediate PPV

Limitations of EVS 1) only for acute post -operative endophthalmitis after cataract surgery 2) doesnt mention the outcome of vitrectomy in other forms of endophthalmitis like; - post traumatic -chronic post operative etc -endogenous endophthalmitis

ComplicationsRetinal necrosis Retinal detachment Retinal necrosis Vitreous tap VitrectomyIncreased intraocular pressure Retinal vascular occlusion Optic neuropathy Panophthalmitis Hypotony Ciliary body shut down Leaking wound Retinal detachment Cyclodialysis cleft Medication

Prevention1 ) PRE-OPERATIVE a) preexisting conditions e.g.blepharitis, conjunctivitis , dacryocyctitis,, infected contra- lateral socket

b) povidone iodine ( BETADINE) drops

c) meticulous draping

d) topical antibiotic 2) INTRA-OPERATIVE irrigation of A/C with vancomycin3) POST OPERTAIVE anterior sub-tenon antibiotic / sub conj. antibiotic

Bleb related 1) early diagnosis and treatment of conjunctivitis. 2) wearing of contact lens should be discouraged. 3) treatment of associated periocular infections.Traumatic 1) safety goggles. 2) timely and appropriate management of ocular trauma.Endogenous 1) adequate and timely management of systemic illness. 2) intravenous drug abuse reduction. 3) control of all predisposing factors.

Toxic anterior segment syndromeacute, sterile postoperative anterior segment inflammation following any anterior segment surgery which is sterile/noninfectiouscaused by a substance that enters the anterior segment either during or immediately after surgery, resulting in toxic damage to intraocular tissuesSymptoms: blurred vision(MC),pain usually minimal/absent,rednessSigns:limbus-to-limbusdiffuse corneal edema, marked A/S inflammation-hypopyon,fibrin

May damage to iris which can cause a permanently dilated/irregular pupil with thinning of iris stromaMay have associated trabecular meshwork damage which can lead to secondary glaucomaHow to differentiate from infectious endophthalmitis:signs appearing within the first 1248hSymptoms:no painSigns:diffuse corneal edemaGood response to steroids

Reasons and Indications for Antimicrobial Susceptibility Testing (AST)GoalOffer guidance to physician in selecting effective antibacterial therapy for a pathogen in a specific body sitePerformed on bacteria isolated from clinical specimens if the bacterias susceptibility to particular antimicrobial agents is uncertain

Susceptibilities NOT performed on bacteria that are predictably susceptible to antimicrobials

Ex. Group A StrepDr.Sadaf Konain Ansari

Selecting Antimicrobial Agents for Testing and ReportingClinical & Laboratory Standards Institute (CLSI)Develop standards, methods, QC parameters, and interpretive criteria for sensitivity testingIf necessary, can alter the breakpoints of the SIR ( susceptible, intermediate, resistant) based on emerging resistance

Dr.Sadaf Konain Ansari

Selecting Antimicrobial Agents for Testing and Reporting (contd)There are approximately 50 antibacterial agentsFollow CLSI recommendationsEach laboratory should have a battery of antibiotics ordinarily used for testingDrug formulary decided by medical staff, pharmacists, and medical technologists Dr.Sadaf Konain Ansari

Selection of Test BatteriesGenerally, labs choose 10-15 antibiotics to test susceptibility for GP organisms and another 10-15 for GN organismsToo many choices can confuse physicians and be too expensivePrimary objectiveUse the least toxic, most cost-effective, and most clinically appropriate agentsRefrain from more costly, broader-spectrum agents


Example of Drug FormularyDr.Sadaf Konain Ansari

DrugEnterococcusStaphylococcus spp.AmpicillinXCefazolinXClindamycinErythromycinXLinezolidXXOxacillinXPenicillin GXXRifampinXStreptomycin-2000XTetracyclineXXTrimeth/ SulfaXVancomycinXX

Example of Drug FormularyDr.Sadaf Konain Ansari

DrugEnterobacteriaceaePs. aeruginosaAmpicillinXPiperacillin/ Tazo.XXCefepimeXXImipenemXXGentamycinXXTobramycinXXCiprofoxacinXXLevofloxacinXXNitrofurantoinXTrimethoprim/SulfaX

DefinitionsMinimum inhibitory concentration(MIC)Lowest concentration of an antimicrobial agent that visibly inhibits the growth of the organism.

Minimum bactericidal concentration (MBC)Lowest concentration of the antimicrobial agent that results in the death of the organism.Dr.Sadaf Konain Ansari

Definitions (contd)Susceptible SInterpretive category that indicates an organism is inhibited by the recommended dose, at the infection site, of an antimicrobial agentIntermediate IInterpretive category that represents an organism that may require a higher dose of antibiotic for a longer period of time to be inhibitedResistant RInterpretive category that indicates an organism is not inhibited by the recommended dose, at the infection site, of an antimicrobial agent.Dr.Sadaf Konain Ansari

Methods of Performing ASTAgar dilution methodBroth macrodilution / Tube dilutionBroth microdilutionDisk diffusion methodGradient diffusion method (E-Test)Dr.Sadaf Konain Ansari

Standardization of Antimicrobial Susceptibility TestingInoculum PreparationUse 4-5 colonies NOT just 1 colonyInoculum Standardizationusing 0.5 McFarland standardDr.Sadaf Konain Ansari

Methods of Performing ASTAgar DilutionDilutions of antimicrobial agent added to agarGrowth on agar indicates MICBroth macrodilution/Tube Dilution TestsTwo-fold serial dilution series, each with 1-2 mL of antimicrobial Too expensive and time consumingMicrodilution Testsplastic trays with dilutions of antimicrobialsDr.Sadaf Konain Ansari

Disk Diffusion/ Kirby- BauerProcedureUse a well-isolated, 18-24 hour old organismTransfer organism to a brothEither tryptic soy/sterile salineEnsure a turbidity of 0.5 McFarlandInoculate MH agar by swabbing in three different directions Lawn of growth Place filter paper disks impregnated with anitmicrobial agents on the agarInvert and incubate for 16-18 hours at35 oC in non-CO2 Dr.Sadaf Konain Ansari

Disk Diffusion/ Kirby-Bauer (contd)During incubation, drug diffuses into agarDepending on the organism and drug, areas of no growth form a zone of inhibitionZones are measured to determine whether the organism is susceptible, intermediate, or resistant to the drugDr.Sadaf Konain Ansari

E- test/ Gradient Diffusion MethodMIC on a stickPlastic strips impregnated with antimicrobial on one sideMIC scale on the other sideRead MIC where zone of inhibition intersects E strip scaleDr.Sadaf Konain Ansari

Automated Antimicrobial Susceptibility Test Methods

Detect growth in micro volumes of broth with various dilutions of antimicrobialsDetection via photometric, turbi-dimetric, or fluoro-metric methodsTypesBD PhoenixMicroscan WalkawayTREK SensititreVitek 1 and 2


Automated Antimicrobial Susceptibility Test Methods

AdvantagesIncreased reproducibilityDecreased labor costsRapid resultsSoftwareDetects multi-drug resistancesESBLsCorrelates bacterial ID with sensitivityDisadvantagesCostDr.Sadaf Konain Ansari

Quality Control in Susceptibility TestingReflects types of patient isolates & range of susceptibilityFrequency of quality control depends on method, CLSI, or manufacturerReference strains of QC materialAmerican Type Culture Collection(ATCC) E. coli ATCC* 25922S. aureus ATCC* 25923


The Superbugs (important to remember)Organisms resistant to previously effective drugsMRSA methicillin-resistant Staphylococcus aureusmecA gene codes for a PBP that does not bind beta-lactam antibioticsResistant to oxacillinVancomycinVRE Enterococcus speciesVISA/VRSA- Staphylococcus aureus


The Superbugs: The Beta-Lactamases

Gram negative rods that have genes on chromosomes that code for enzymes against certain antimicrobialsESBLs-extended spectrum beta lactamaseResistant to extended spectrum cephalosporins, penicillins, aztreonamExamples: E. coli, KlebsiellaCarbapenemases (CRE)Klebsiella pneumoniae- KPC- Class AClass B (NDM, VIM, IMP)- metallo beta lactamasesResistant to penicillins, cephalosporins, carbapenems, and aztreonamCephalosporinasesAmpC enzymeinducibleSPACE organismsDr.Sadaf Konain Ansari

Controlling the SuperbugsLabs RoleRecognize and report isolates recovered from clinical specimensMethods for identification include automated systems and screening agars


Controlling the SuperbugsRole of Health Care Workers/FacilitiesHand hygiene with the use of alcohol-based hand rubs or soap and water after patient careContact precautions for patients identified as colonized or infected with a superbugHealthcare personnel education about the methods of transmission, contact precautions, and proper use of hand hygiene Minimization of invasive devices (catheters, etc.)Proper administration of antimicrobial agents where therapy is selected for susceptible organisms for the proper duration


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Referenceshttp://www.biomerieux-diagnostics.com/servlet/srt/bio/clinical-diagnostics/dynPage?doc=CNL_CLN_PRD_G_PRD_CLN_22http://www.cdc.gov/std/gonorrhea/lab/diskdiff.htmhttp://www.who.int/drugresistance/Antimicrobial_Detection/en/index.htmlKiser, K. M., Payne, W. C., & Taff, T. A. (2011). Clinical Laboratory Microbiology: A Practical Approach . Upper Saddle River, NJ: Pearson Education.Mahon, C. R., Lehman, D. C., & Manuselis, G. (2011). Textbook of Diagnostic Microbiology (4th ed.). Maryland Heights, MO: Saunders.Murray, P. R. (2013,May). Carbapenem-resistant Enterobacteriaceae: what has happened, and what is being done. MLO, 45(5), 26-30.Dr.Sadaf Konain Ansari

Dr.Sadaf Konain AnsariExercise Questions

ESKAPEPathogens of Highest Concern The most serious, life- threatening infections are caused by a group of drug- resistant bacteria that the Infectious Diseases Society of America (IDSA) has labeled the "ESKAPE" pathogens, because they effectively escape the effects of antibacterial drugsWhat are ESKAPEDr.Sadaf Konain Ansari

Minimum inhibitory concentration(MIC)Lowest concentration of an antimicrobial agent that visibly inhibits the growth of the organism.

Minimum bactericidal concentration (MBC)Lowest concentration of the antimicrobial agent that results in the death of the organism.What stand for MIS, and MBC?Dr.Sadaf Konain AnsariCommon Questions:

Susceptible SInterpretive category that indicates an organism is inhibited by the recommended dose, at the infection site, of an antimicrobial agentIntermediate IInterpretive category that represents an organism that may require a higher dose of antibiotic for a longer period of time to be inhibitedResistant RInterpretive category that indicates an organism is not inhibited by the recommended dose, at the infection site, of an antimicrobial agent.What stands for S, I and R?Dr.Sadaf Konain AnsariCommon Questions:

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