POSTULATED RISK FACTORS FOR AMD

Ageing
The Framingham Eye study (1976) showed the prevalence
65-74 years- 11%
75-85 years- 28%
Gender
Blue 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.

POSTULATED RISK FACTORS FOR AMD

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

POSTULATED RISK FACTORS FOR AMD

Nutrition
Several 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
Oestrogen
The use of exogenous
supplements in post menopausal
women lowered risk of AMD in a
study performed by the Eye
Case Control Study Group.

GENETICS
Family history of macular degeneration:

Autosomal dominant with variable penetration

In 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 AMD
The 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: SYMPTOMS
Initial 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: SYMPTOMS

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

MACULA: ANATOMY
MACULA
Foveola
Fovea

Umbo

Para-foveal zone
Peri-foveal zone

RETINAL PIGMENT EPITHELIUM

The retinal pigment epithelium (RPE)
is a single layer of hexagonally
shaped cells & attached to the
photoreceptor layer.
Functions 1.Maintain the photoreceptors
2.Absorption of stray light
3.Formation of the outer blood retinal
barrier
4.Phagocytosis 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.

TYPES

DRY AMD

Accounts for about 90% of all cases

Also 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 AMD

Drusen

DRY AMD
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 lost

DRY 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.

 Types:
Small: <63
Intermediate: 63-124
Large: >125
Hard:

generally small (<63 ), bright yellow, solid appearing drusen

with well defined margins
may be asymptomatic

Soft:

larger (>63 ), pale yellow, ill defined, fluffy margins

High risk for neovascular AMD

 Soft Drusen:
Membranous:

63-175
Pale, shallow appearing drusens

Granular:

About 250
Solid appearing drusens

Serous:

>500
Have pooled serous fluid
blister like appearance
May result in serous PED

HISTOPATHOLOGY
Drusen 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

PROGNOSIS
Patients 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.

WET AMD
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

Potential for rapid and severe visual

damage

WET AMD

WET AMD
Diagnostic criteria*
persons >50 years, characterized by the presence of
any of the following:
choroidal neovascularization
serous retinal pigment epithelial detachment
hemorrhagic retinal pigment epithelial detachment
fibrotic scar in the macula

*Takahashi K et al.Nihon Ganka Gakkai Zasshi. 2008

Dec;112(12):1076-84.

WET AMD

WET AMD

WET AMD

CNV lesion is well demarcated & its location may be

determined by closest point to the FAZ.
Lesion location is classified angiograpically as follows:1. Subfoveal: under the centre of FAZ
2. Juxtafoveal: 1-199 m from the centre of FAZ
3. Extrafoveal: >200 m & <2500 m from the centre of FAZ

Types:

Type I: CNV beneath RPE

Type II: CNV above RPE

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:

Drusenoid
Serous
Fibro vascular
Hemorrhagic

RPE DETACHMENT (PED)

RPE TEAR
Spontaneously 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

PROGNOSIS
Leakage 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.

AMD: STAGING
AREDS Categories:
No AMD (AREDS category 1)

No or a few small (<63 micrometres in diameter) drusen.

Early AMD (AREDS category 2)

Many small drusen or a few intermediate-sized (63-124 micrometres

in diameter) drusen, or macular pigmentary changes.

Intermediate AMD (AREDS category 3)

Extensive intermediate drusen or at least one large ( 125

micrometres) drusen, or geographic atrophy not involving the foveal
centre.

Advanced AMD (AREDS category 4)

Geographic atrophy involving the foveal centre (atrophic, or dry, AMD)

Choroidal neovascularisation (wet AMD)
evidence for neovascular maculopathy (subretinal haemorrhage,
serous retinal or retinal pigment epithelium detachments, lipid
exudates, or fibrovascular scar).

AMD: DIAGNOSTIC TOOLS

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

AMD: MANAGEMENT

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 mg
Copper (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 mg
Vitamin E - 400 IU
Beta-Carotene - 15 mg
Zinc - 80 mg
Copper - 2 mg
Lutein - 10 mg
Zeaxanthin - 2 mg
DHA - 350 mg
EPA - 650 mg

AMD: MANAGEMENT
Current treatment
1. Antiangiogenic drugs
2. Photodynamic therapy
3. Laser photocoagulation

ANTI ANGIOGENICS
Anti-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 VEGF
Has FDA approval for i.v. use in
metastatic colorectal, metastatic
breast and non-small cell carcinoma
of lung
Is being used off-label for choroidal
neovascularization based on results
of short-term studies
Dose- 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 trial

Compare safety and efficacy of ranibizumab and
bevacizumab

Currently under way

 Pegaptanib sodium (Macugen)

28 base ribonucleotide aptamer
Binds to Heparin-binding domain of
VEGF-A
Inactivates VEGF-A 165,189 and 206
isoforms
Given 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-A
Also blocks placental growth
factors-1 and 2
Two Phase III clinical trials
(VIEW-1 and VIEW-2) comparing
aflibercept to ranibizumab are
currently ongoing.

COMPLICATIONS
Common-

Raised intra-ocular pressure

Occasional

Cataract Formation
Intra-ocular hemorrhage

Rare

Endophthalmitis
Retinal Detachment

SURGICAL OPTIONS

Submacular excision of CNV

Macular translocation
Retinal rotation
Homologous Iris/Retinal pigment epithelium
transplantation
Autologous RPE transplantation

EMERGING TREATMENTS FOR AMD

Retaane (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

Factor
a 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, visionrobbing blood vessels under the retina.
safety and efficacy established in a Phase II study
Phase III clinical trial is planned

EMERGING TREATMENTS FOR AMD

ATG3 (mecamylamine)
(Contd.)
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 AMD
currently 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.

REHABILATATION
Low 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.

CLASSIFICATION
Endophthalmitis can be classified
according to the
Infectivity Infective / non infective ( sterile)
Mode of entry exogenous / endogenous
Type of etiological agent

Classification
Infectious

Exogenous

Post trauma
(PEI-IOFB)

Sterile (Infectivity)

Endogenous ( Mode of entry)

Post-operative

Fulminant

Acute

Blebitis

Chronic

Cont.
Etiological agent
Endophthalmitis

Bacterial

Fungal

viral

Parasitic

57

Gram positive bacteria

75%-85%

Gram negative bacteria

10%-15%

Fungi
3%

Staphylococcus
epidemidis (43%)

Pseudomonas (8%)

Aspergillus

Streptococcus spp
(20%)

Proteus (5%)

Fusarium

Staphylococcus aureus Haemophilus

(15%)
influenzae (1%)
Propionibacterium
acnes

Klebsiella( 0-1%)

Bacillus cereus (1%)

Coliform spp (0-1%)

Cephalosporium spp.

Exogenous Endophthalmitis
Vitreous 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 exterior
Maily bacterial

1)Post-op Endophthalmitis
Incidence: 0.05%
MC among all types: 49-76%
Surgery

Bascom Palmer Eye

Institute (1984-1994)

Katten et al
(1984-1989)

ECCE with and without

PCIOL

0.08%

0.072%

Secondary PCIOL

0.37%

0.3%

PPV

0.05%

0.05%

PK

0.18%

0.11%

Glaucoma filtration
surgery

0.12%

0.06%

Source of infection
Airborne

respiratory origin, air condition in O.T

Solution and medications
irrigating solutions, drops and ointment
skin antiseptic, viscoelastic and silicon oil
Tissue
periocular skin ,lid margin and lashes
conjuctival sac, Lacrimal sac
nasal mucosa, corneal graft
Objects and materials
surgical instruments, gloves, masks, IOL
Clinical Importance- all causes are preventable

Risk Factors
Preoperative 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 days)
(4-7days)
(>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 traumatic

Incidence-2-7%(unsterile conditions & contaminated objects)

Contributes to 17-40% of all cases
Penetrating ocular trauma is main culprit
Causative organisms

fulminant:
B. cereus
Streptococcus

acute:
chronic:
S.epidermidis(MC) fungi:
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 endophthalmitis

4-18% of all cases

After glaucoma filtration surgery
May occur at any time (months- years )after surgery
Most of the time through intact bleb via conjuctival flora
Poor prognosis as org. are more virulent
Causative organism
streptococci(MC)-faecalis,viridans,pneumoniae
H.influenzae
staph. are rare
Clinical signs
infected white bleb
Vitritis
Hypopyon

 Risk factors: use of antimitotic

agents,inferior blebs,conjunctivitis,contact
lens,periocular infections
Should be differentiated from BLEBITIS
Blebitis
- low virulence organism
- mild intraocular inflammation
- no Vitritis

Endogenous(Metastatic)
Endophthalmitis
2-15% of all cases
Hematogenous spread of organism from distant source
Retina and choroid primarily involved due to high
vascularity.
Fungi> bacteria
Candida(MC)>Aspergillus
Predisposing 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 Approach
Symptoms: Decreased or blurred vision
( sudden / severe acute)
( slowly / mildchronic)

Pain
Photophobia
Redness of eyes
Swollen eyelids
Discharge
White lesion in black part of the eye
Floaters
Fever

Signs
Initial visual acuity ( prognostic significance)
Ocular motility ( sign of orbital inflammation)
Eyelid
swollen , blepharospasm
Conjunctiva
hyperemia, chemosis, bleb examination if
present
Cornea
edematous, opacification , DM folds
keratic precipitate, infiltrates, occult penetration
Anterior chamber
cells, flare , fibrinous exudates and Hypopyon
Iris muddy,boggy,resistant to dilatation,post.synechiae

Pupil-absent or sluggish reaction to light

Lens - Membrane , exudates around IOL
Vitreous - 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 periphlebitis
IOP- usually low,may be high in early cases
Signs of penetrating injury and Intraocular foreign
body
Wound dehiscence

Cont.
OCULAR MEDIA CLARITY (I/O)
Grade 1- Media clarity, 6/12 view of the
retina.
Grade 2- Media clarity <6/12, can
visualize second order retinal vessels.
Grade 3- Can see only 1st order vessels.
Grade 4- Faint outline of Disc visible; red
reflex present.
Grade 5- Red reflex absent.

Fungal Endophthalmitis
Caused 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

Diagnosis
A) 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 studies
1) 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 IOFB
3) 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 tip
Chest X-ray
Other necessary investigation according to suspicion
like HIV

Treatment
GOALS
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

SURGICAL

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

Medical treatment
Intravitreal injection
- preferred route in all types of endophthalmitis.
- direct administration in vitreous
- by passes Blood Ocular Barrier.

Intravitreal injection
Vancomycin
Amikacin
Or
Ceftazidime

( 1.0 mg in 0.1 ml )
( 400ug in 0.1 ml)

Vancomycin
Amikacin

(25mg in 0.5ml)
(25mg in 0.5ml)

(2.25mg/0.1ml)

Subconjunctival injections

 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

Drugs

Doses

Vancomycin

1 gm iv.12 hrly
(10-30 mg/kg)

Ceftazidime

2 gm iv. Bd

Amikacin

250 mg iv. Tid

(15mg/kg)

Gentamycin

80 mg iv tid
(3-5mg/kg)

Ciprofloxacin

750 mg po.bd

Ofloxacin

200 mg 12 hrly

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

limit ocular damage

Routes - Intravitreal(dexa400mgm in 0.1ml),systemic, subconjuctival(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

Vitrectomy
Advantages ( 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 POE
Role of initial vitrectomy in management.
Patients : N = 420 patients having clinical evidence of POE
within 6 weeks of cataract surgery
Intervention
Random 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 measures

Evaluation of visual acuity and clarity of ocular media
at 3, 9, 12 months
No difference in outcome between PPV followed by I/V
group compared to vitreous tap and I/V if vision better
than light perception
No difference in final visual acuity or media clarity
whether or not EVS systemic antibiotic( Amikacin ,
Ceftazidime) were employed
Vision 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

Complications

Retinal necrosis
Retinal detachment
Retinal necrosis
Vitreous tap
Vitrectomy

Increased intraocular pressure

Retinal vascular occlusion
Optic neuropathy
Panophthalmitis
Hypotony

Ciliary body shut down

Leaking wound
Retinal detachment
Cyclodialysis cleft
Medication

Prevention
1 ) 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 vancomycin
3) 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

syndrome
acute, sterile postoperative anterior segment
inflammation following any anterior segment
surgery which is sterile/noninfectious
caused by a substance that enters the anterior
segment either during or immediately after surgery,
resulting in toxic damage to intraocular tissues
Symptoms: blurred vision(MC),pain usually
minimal/absent,redness
Signs: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 stroma
May have associated trabecular meshwork
damage which can lead to secondary glaucoma
How to differentiate from infectious
endophthalmitis:
signs appearing within the first 1248h
Symptoms:no pain
Signs:diffuse corneal edema
Good response to steroids

Reasons and Indications for

Antimicrobial Susceptibility Testing
(AST)
Goal

Offer guidance to physician in selecting effective

antibacterial therapy for a pathogen in a specific
body site

Performed 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 Strep

Dr.Sadaf Konain Ansari

Selecting Antimicrobial
Agents for Testing and
Reporting

Clinical & Laboratory Standards

Institute (CLSI)

Develop standards, methods, QC parameters,

and interpretive criteria for sensitivity
testing
If 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 agents
Follow CLSI recommendations
Each laboratory should have a battery of
antibiotics ordinarily used for testing
Drug formulary decided by medical staff,
pharmacists, and medical technologists

Dr.Sadaf Konain Ansari

Selection of Test Batteries

Generally, labs choose 10-15 antibiotics
to test susceptibility for GP organisms
and another 10-15 for GN organisms
Too many choices can confuse physicians
and be too expensive
Primary objective
Use the least toxic, most cost-effective, and most clinically
appropriate agents
Refrain from more costly, broader-spectrum agents
Dr.Sadaf Konain Ansari

Drug
Ampicillin

Example of Drug
Enterococcus
Formulary Staphylococcus spp.
X

Cefazolin

Clindamycin
Erythromycin
Linezolid

X
X

Oxacillin
Penicillin G

X
X

Rifampin

X
X

Streptomycin-2000

Tetracycline

Trimeth/ Sulfa
Vancomycin

X
X

X
Dr.Sadaf Konain Ansari

Drug

Example of Drug
Formulary
Enterobacteriaceae
Ps. aeruginosa

Ampicillin

Piperacillin/ Tazo.

Cefepime

Imipenem

Gentamycin

Tobramycin

Ciprofoxacin

Levofloxacin

Nitrofurantoin

Trimethoprim/Sulfa

X
Dr.Sadaf Konain Ansari

Definitions
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.

Dr.Sadaf Konain Ansari

Definitions (contd)
Susceptible S
Interpretive category that indicates an organism is
inhibited by the recommended dose, at the
infection site, of an antimicrobial agent
Intermediate I
Interpretive category that represents an organism
that may require a higher dose of antibiotic for a
longer period of time to be inhibited
Resistant R
Interpretive 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 AST

Agar dilution method

Broth macrodilution / Tube dilution
Broth microdilution
Disk diffusion method
Gradient diffusion method (E-Test)

Dr.Sadaf Konain Ansari

Standardization of Antimicrobial
Susceptibility Testing
Inoculum Preparation

Use 4-5 colonies

NOT just 1 colony
Inoculum Standardization

using 0.5
McFarland
standard

Dr.Sadaf Konain Ansari

Methods of Performing AST

Agar Dilution
Dilutions of antimicrobial agent added to agar
Growth on agar indicates MIC
Broth macrodilution/Tube Dilution Tests
Two-fold serial dilution series, each with 1-2
mL of antimicrobial
Too expensive and time consuming
Microdilution Tests
plastic trays with dilutions of antimicrobials
Dr.Sadaf Konain Ansari

Disk Diffusion/ Kirby- Bauer

Procedure
Use a well-isolated, 18-24 hour old
organism
Transfer organism to a broth
Either tryptic soy/sterile saline
Ensure a turbidity of 0.5 McFarland
Inoculate MH agar by swabbing in
three different directions Lawn of
growth
Place filter paper disks impregnated
with anitmicrobial agents on the agar
Invert and incubate for 16-18 hours
at35 oC in non-CO2

Dr.Sadaf Konain Ansari

Disk Diffusion/ KirbyBauer (contd)

During incubation, drug

diffuses into agar
Depending on the organism and
drug, areas of no growth form
a zone of inhibition
Zones are measured to
determine whether the
organism is susceptible,
intermediate, or resistant to
the drug

Dr.Sadaf Konain Ansari

E- test/ Gradient
Diffusion Method
MIC on a stick
Plastic strips
impregnated with
antimicrobial on one side
MIC scale on the other
side
Read MIC where zone
of inhibition intersects E
strip scale

Dr.Sadaf Konain Ansari

Automated
Antimicrobial Susceptibility Test Methods
Detect growth in micro volumes of broth with
various dilutions of antimicrobials
Detection via photometric, turbi-dimetric, or
fluoro-metric methods
Types
BD Phoenix
Microscan Walkaway
TREK Sensititre
Vitek 1 and 2
Dr.Sadaf Konain Ansari

Automated
Antimicrobial Susceptibility Test Methods

Advantages

Increased reproducibility
Decreased labor costs
Rapid results
Software
Detects multi-drug resistances
ESBLs
Correlates bacterial ID with sensitivity

Disadvantages
Cost
Dr.Sadaf Konain Ansari

Quality Control in
Susceptibility Testing
Reflects types of patient isolates & range of
susceptibility
Frequency of quality control depends on method,
CLSI, or manufacturer
Reference strains of QC material
American Type Culture Collection(ATCC)
E. coli ATCC* 25922
S. aureus ATCC* 25923

Dr.Sadaf Konain Ansari

The Superbugs (important to

remember)
Organisms resistant to previously effective drugs
MRSA
methicillin-resistant Staphylococcus aureus
mecA gene codes for a PBP that does not bind
beta-lactam antibiotics
Resistant to oxacillin
Vancomycin
VRE Enterococcus species
VISA/VRSA- Staphylococcus aureus

Dr.Sadaf Konain Ansari

The Superbugs: The BetaLactamases

Gram negative rods that have genes on
chromosomes that code for enzymes against certain
antimicrobials
ESBLs-extended spectrum beta lactamase
Resistant to extended spectrum cephalosporins, penicillins, aztreonam
Examples: E. coli, Klebsiella

Carbapenemases (CRE)

Klebsiella pneumoniae- KPC- Class A

Class B (NDM, VIM, IMP)- metallo beta lactamases
Resistant to penicillins, cephalosporins, carbapenems, and aztreonam

Cephalosporinases
AmpC enzyme
inducible
SPACE organisms

Dr.Sadaf Konain Ansari

Controlling the Superbugs

Labs Role
Recognize and report isolates recovered from clinical
specimens
Methods for identification include automated systems and
screening agars

Dr.Sadaf Konain Ansari

Controlling the Superbugs

Role of Health Care Workers/Facilities
Hand hygiene with the use of alcohol-based hand
rubs or soap and water after patient care
Contact precautions for patients identified as
colonized or infected with a superbug
Healthcare 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
Dr.Sadaf Konain Ansari

Continue

Dr.Sadaf Konain Ansari

References
http://www.biomerieux-diagnostics.com/servlet/srt/bio/clin
ical-diagnostics/dynPage?doc=CNL_CLN_PRD_G_PRD_CLN_22
http://www.cdc.gov/std/gonorrhea/lab/diskdiff.htm
http://www.who.int/drugresistance/Antimicrobial_Detection/en
/index.html
Kiser, 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

Exercise Questions

Dr.Sadaf Konain Ansari

What are ESKAPE

ESKAPEPathogens of Highest Concern The most serious, lifethreatening infections are caused by a group of drugresistant bacteria that the Infectious Diseases Society of
America (IDSA) has labeled the "ESKAPE" pathogens, because
they effectively escape the effects of antibacterial drugs

Dr.Sadaf Konain Ansari

Common Questions:
What stand for MIS, and MBC?
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.
Dr.Sadaf Konain Ansari

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

THANK YOU
Email:

Sdf_ansari@yahoo.com