2015 MEEI Vitrectomy Course Program

We gratefully acknowledge our sponsors for this course:

Alcon LaboratoriesDutch Ophthalmic USA

Santen Pharmaceutical Co., Ltd.

VR Magic

Leica Surgical

Mira, Inc.

OCULUS Surgical, Inc.

Synergetics, Inc.

Zeiss

Schedule & A

ssignments

Course Schedule

Friday, July 31Mass. Eye And Ear - 243 Charles Street

12:00 pm Registration & Lunch - 3rd Floor (Meltzer Hallway)

12:30 pm Welcoming Remarks John Loewenstein, Dean Eliott, Demetrios Vavvas

12:45 pm Ergonomics Robert Bhisitkul

1:00 pm Scleral Buckling Pearls Lucy Young

1:15 pm Vitrectomy for Primary RD Demetrios Vavvas

1:30 pm Pneumatic Retinopexy Pearls David Zacks

1:45 pm ERM Carl Regillo

2:00 pm PFO / Silicone Oil / Gases Timothy Olsen

2:15 pm Giant Tears Stanley Chang

2:30 pm Break - 3rd Floor (Meltzer Hallway)

2:45 pm PANEL 1 - PPV, SB, PRDeeba Husain (Moderator)

Raj Apte, Yannek Leiderman, Harry Flynn, Lejla Vajzovic, Odette Houghton

3:45 pm Principles and Instrumentation for PPV Steve Charles

4:00 pm Visualization Illumination Raymond Iezzi

4:15 pm Vitrectomy for Trauma Dean Eliott

4:30 pm PVR Ivana Kim

4:45 pm Break - 3rd Floor (Meltzer Hallway)

5:00 pm Diabetic Retinopathy Gil Grand

5:15 pm Endophthalmitis Harry Flynn

5:30 pm Vitrectomy for Macular Hole Vasiliki Poulaki

5:45 pm Questions

6:00 pm Reception - 7th Floor (Lank Dining Room)

Course Schedule

Saturday, August 1Mass. Eye And Ear - 243 Charles Street

7:15 am Breakfast - 6th Floor (Front Elevator) and S Floor (Back Elevators)

8:00 am AM SESSION - See Fellow Assignment Sheet for individual locations & times

11:15 am Break - 3rd Floor (Meltzer Hallway), S Floor (Back Elevator), and 6th Floor (Front Elevator)

11:30 am Panel 2 - PVR, Retinectomies, Instruments Amani Fawzi (Moderator)

Flavio Rezende, Leo Kim, Shizuo Mukai, Steven Ness, Jorge Arroyo

12:00 pm Panel 3 - Macular Hole, ILM, Staining, InstrumentsFrank Koch (Moderator)

Ronald Gentile, Netan Choudhry, Jason Comander, Caroline Baumal, David Wu

12:30 pm Lunch - 7th Floor (Lank Dining Room)

2:00 pm PM SESSION - See Fellow Assignment Sheet for individual locations & times

5:00 pm “Top 10 things to Keep Your Attending AND YOU Happy” Ronald Gentile

5:45 pm Questions

Taj Hotel Boston - 15 Arlington Street

6:00 pm Reception & Dinner - Rooftop

Fellow Assignments6th Annual Vitrectomy Course - Saturday, August 1

AM SESSION

Fellows FL 8:00 9:00 10:00

1-3 S OR 1 - Scleral Buckle OR 8 - EVA OR 9 - Constellation

4-6 S OR 8 - EVA OR 9 - Constellation OR 1 - Scleral Buckle

7-9 S OR 9 - Constellation OR 1 - Scleral Buckle OR 8 - EVA




19-21 6th OR 63 - Scleral Buckle OR 64 - VersaVIT OR 65 - Constellation

22-24 6th OR 64 - VersaVIT OR 65 - Constellation OR 63 - Scleral Buckle

25-27 6th OR 65 - Constellation OR 63 - Scleral Buckle OR 64 - VersaVIT

Fellows FL 8:00 - 9:30 9:30-11:00

28-41 3rd Sloane - Dry Simulators Meltzer - Small Group B

42-54 3rd Meltzer - Small Group A Sloane - Dry Simulators

PM SESSION

Fellows FL 14:00 - 15:30 15:30-17:00

1-14 3rd Sloane - Dry Simulators Meltzer - Small Group B

15-27 3rd Meltzer - Small Group A Sloane - Dry Simulators

Fellows FL 14:00 15:00 16:00







46-48 6th OR 63 - Scleral Buckle OR 64 - VersaVIT OR 65 - Constellation

49-51 6th OR 64 - VersaVIT OR 65 - Constellation OR 63 - Scleral Buckle

52-54 6th OR 65 - Constellation OR 63 - Scleral Buckle OR 64 - VersaVIT

MA

PS & D

IREC

TION

S

3rd Floor - Lectures & Dry Lab

Please Note: Whenever possible, please use the front elevators.


S Floor - Wet Labs


6th Floor - Wet Labs

Saturday Dinner - The Taj Hotel, Roofdeck

PRESEN

TATION

S

Robert Bhisitkul, M

D, PhD

Rob

ert B

hisi

tkul

, MD

, PhD

Robert Bhisitkul, M

D, PhD

Lucy Young, MD

, PhD

Lucy

You

ng, M

D, P

hD

Lucy Young, MD

, PhD

Lucy

You

ng, M

D, P

hD

Lucy Young, MD

, PhD

Lucy

You

ng, M

D, P

hD

Lucy Young, MD

, PhD

Dem

etrios Vavvas, MD

, PhD

Dem

etri

os V

avva

s, M

D, P

hD

Dem

etrios Vavvas, MD

, PhD

Dem

etri

os V

avva

s, M

D, P

hD

Dem

etrios Vavvas, MD

, PhD

Dem

etri

os V

avva

s, M

D, P

hD

David Zacks, M

D, PhD

Dav

id Z

acks

, MD

, PhD

Carl R

egillo, MD

, FAC

S

Car

l Reg

illo,

MD

, FA

CS

Carl R

egillo, MD

, FAC

S

Timothy O

lsen, MD

Tim

othy

Ols

en, M

D

Timothy O

lsen, MD

Tim

othy

Ols

en, M

D

Timothy O

lsen, MD

Tim

othy

Ols

en, M

D

Timothy O

lsen, MD

Tim

othy

Ols

en, M

D

Timothy O

lsen, MD

Tim

othy

Ols

en, M

D

Timothy O

lsen, MD

Stanley Chang, M

D

Stan

ley

Cha

ng, M

D

Stanley Chang, M

D

Steve Charles, M

D

Stev

e C

harl

es, M

D

Steve Charles, M

D

Stev

e C

harl

es, M

D

Steve Charles, M

D

Stev

e C

harl

es, M

D

Steve Charles, M

D

Stev

e C

harl

es, M

D

Raym

ond Iezzi, MD

, MS

Ray

mon

d Ie

zzi,

MD

, MS

Raym

ond Iezzi, MD

, MS

Ray

mon

d Ie

zzi,

MD

, MS

Dean Elliot, M

D, FA

CS

Dea

n El

liot,

MD

, FA

CS

Dean Elliot, M

D, FA

CS

Dea

n El

liot,

MD

, FA

CS

Dean Elliot, M

D, FA

CS

Dea

n El

liot,

MD

, FA

CS

Dean Elliot, M

D, FA

CS

Dea

n El

liot,

MD

, FA

CS

Ivana Kim

, MD

7/10/14

1

Vitrectomy for PVR

Ivana Kim, MD Associate Professor

Massachusetts Eye and Ear Infirmary Harvard Medical School

The challenge of PVR

¥  Time consuming ¥  Higher failure rate ¥  Economics

Why some surgeons enjoy these cases

¥  Challenge your skills ¥  Service to patients ¥  Help a colleague

What is PVR ¥  An excessive healing/scarring process

–  Think “keloid” (S. Charles) –  Typically seen 1-3 months after initial repair –  Multiple cytokines implicated

¥  PDGF, TGF-β, MCP-1, bFGF, HGF, CTGF, EGF, VEGF, etc.

–  RPE cells and glial (Müller) cells are key players

¥  Risk factors –  Increased vascular permeability –  Large/giant/multiple tears –  Vitreous hemorrhage –  Uveitis –  Choroidal detachments

¥  Common cause for surgical failure

Classification Updated 1991

¥  Grade A –  Vitreous haze, pigment clumps in vitreous or inferior

retina

Classification ¥  Grade B

–  Wrinkling of inner retinal surface, retinal stiffness, vessel tortuosity, rolled edge of retinal break

Ivan

a K

im, M

D

Ivana Kim

, MD

Ivan

a K

im, M

D

Ivana Kim

, MD

M. G

ilbert Grand, M

D

M. G

ilber

t Gra

nd, M

D

M. G

ilbert Grand, M

D

M. G

ilber

t Gra

nd, M

D

M. G

ilbert Grand, M

D

M. G

ilber

t Gra

nd, M

D

M. G

ilbert Grand, M

D

M. G

ilber

t Gra

nd, M

D

M. G

ilbert Grand, M

D

M. G

ilber

t Gra

nd, M

D

M. G

ilbert Grand, M

D

M. G

ilber

t Gra

nd, M

D

Harry Flynn, M

D

Har

ry F

lynn

, MD

Harry Flynn, M

D

Har

ry F

lynn

, MD

Harry Flynn, M

D

Har

ry F

lynn

, MD

Harry Flynn, M

D

Vasiliki Poulaki, MD

, PhD

Vasi

liki P

oula

ki, M

D, P

hD


, PhD

Vasi

liki P

oula

ki, M

D, P

hD


, PhD

Ronald G

entile, MD

Ron

ald

Gen

tile,

MD

Ronald G

entile, MD

Ron

ald

Gen

tile,

MD

Ronald G

entile, MD

Ron

ald

Gen

tile,

MD

Ronald G

entile, MD

Ron

ald

Gen

tile,

MD

Ronald G

entile, MD

Ron

ald

Gen

tile,

MD

Ronald G

entile, MD

Ron

ald

Gen

tile,

MD

AD

DITIO

NA

L MATER

IALS

SCLERAL BUCKLING PEARLS M. Gilbert Grand, MD - The Retina Institute, St. Louis, MO

SCLERAL BUCKLING PEARLS - M. Gilbert Grand, MD (Continued)

RECOGNITION, TREATMENT

AND PREVENTION OF

ENDOPHTHALMITIS

UPDATED: 2015

Harry W. Flynn, Jr., MD

Nidhi Relhan MD

Bascom Palmer Eye Institute

University of Miami School of Medicine

900 NW 17th Street, Miami, FL. 33136

Phone: (305) 326-6118

Fax: (305) 326-6417

Email: [email protected]

[email protected]

2

RECOGNITION, TREATMENT, AND

PREVENTION OF ENDOPHTHALMITIS:

UPDATE 2015

Use of Guidelines:

The guidelines included in this document are based on the authors experience and opinions as

well as on a review of published endophthalmitis studies. High level, evidence-based

recommendations from randomized clinical trials are not available for many clinical issues.

However, clinical case-series and case reports are usually available for even rare causes of

infection. This document provides guidance for an overall approach to managing

endophthalmitis but does not always apply to the care of an individual patient. Depending on

a spectrum of clinical features, sensitive and resistant organisms, and systemic risk factors, it is

anticipated that it will be necessary to approach some patients’ needs in different ways. The ultimate judgement regarding treatment of the individual patient must be made by the

physician in light of all of the clinical circumstances as well as on the resources available to the

physician. The guidelines in this document should not be deemed to be inclusive of all proper

methods of care exclusive of other methods which may achieve similar outcomes. The

current document is not a medical-legal resource but is rather intended an overview of

endophthalmitis.

A. Classification (most frequent organisms in various clinical settings):

1. Postoperative:

a. Acute-onset postoperative endophthalmitis: Coagulase (-) staphylococci,

Staphylococcus aureus, Streptococcus, Gram-negative bacteria

b. Delayed-onset (chronic) pseudophakic endophthalmitis (> 6 weeks postop):

P. acnes, Coagulase (-) staphylococci, Fungi

c. Conjunctival filtering bleb-associated endophthalmitis: Streptococcus species,

Hemophilus influenza, Staphylococcus

2. Post-traumatic: Bacillus species (30-40%), Staphylococcus

3. Endogenous: Candida species, S. aureus, Gram-negative bacteria,

4. Keratitis-associated: Pseudomonas, Staphylococcus

5. Intravitreal injection-associated: Staphylococcus/Streptococcus

3

B.

C.

D. B Acute-onset postoperative endophthalmitis at BPEI :

*NA – Not available

Acute-onset endophthalmitis after cataract surgery (2002-2014) at BPEI by year:

Year #/Total Incidence rate

2002 00/2809 0.00

2003 03/2883 0.10

2004 01/2957 0.03

2005 01/3344 0.03

2006 01/3544 0.03

2007 01/3929 0.03

2008 00/4218 0.00

2009 01/4884 0.02

2010 00/4865 0.00

2011 01/5211 0.02

2012 03/4861 0.06

2013 04/4729 0.08

2014 02/4340 0.05

Total 17/52574 0.03*

*Without the use of intracameral antibiotics

1984-1994 1995-2001 2002-2009 2010-2014

Procedure #/Total Incidence #/Total Incidence #/Total Incidence #/Total Incidence

CE + IOL 34/41,654 0.08% 08/21,972 0.04% 08/28,568 0.03% 10/23472 0.04%

PPV 03/6,557 0.05% 02/7,429 0.03% 02/18,492 0.01% 1/13049 0.01%

Cornea 05/2,805 0.18% 02/2,362 0.08% 03/2,788 0.11% 6/4423 0.13%

Secondary IOL 05/1,367 0.37% 01/485 0.21% 01/1,783 0.06% NA* NA*

Glaucoma 04/3,233 0.12% 04/1,970 0.20% 00/5,041 0.00% 3/3050 0.10%

Totals 51/55,616 0.09% 17/34,218 0.05% 14/56,672 0.03% 20/44004 0.04%

4

2. Post-traumatic endophthalmitis (incidence)

a. After open globe injury (larger studies) • Barr (1982) (3.2%) 04/122

• Brinton (1984) (7.4%) 19/257

• Thompson (1995) (5.0%) 13/258

b. With retained intraocular foreign body (IOFB)

• Williams (1988) (13%) 14/105

• National Eye Trauma System (1993) (6.9%) 34/492

I. Metallic IOFB (7.2%)

II. Non-metallic IOFB (7.3%)

III. Organic IOFB (6.3%)

3. Endogenous endophthalmitis- associated risk factors:

a. Elderly or debilitated patients

b. IV drug abuse

c. Indwelling catheters

d. History of abdominal surgery

4. Keratitis associated- increased in advanced corneal ulcers and keratoprosthesis

5. Intravitreal injection- rare (< 1/5000)

C. Diagnostic Features

1. Postoperative endophthalmitis

a. Acute-onset endophthalmitis- signs and symptoms:

• Marked intraocular inflammation (100%)

• Hypopyon (86%)

• Reduced vision (100%)

• Pain (75%) b. Delayed-onset endophthalmitis- signs:

• P. acnes- white intracapsular plaque, granulomatous uveitis, fibrin strands in

anterior chamber, vitritis

• Coagulase negative Staphylococcus – Vitritis, Hypopyon

• Fungi – Vitreous infiltrates, “string of pearls” lesions

c. Bleb-associated endophthalmitis- purulent bleb, hypopyon, marked intraocular

inflammation.

2. Trauma - hypopyon, periphlebitis, vitreous infiltrates around IOFB

3. Endogenous- chorioretinal infiltrate, vitritis, history of systemic disease

4. Keratitis- marked intraocular inflammation/hypopyon

5. Intravitreal injections- fibrin/marked intraocular inflammation

5

D. Possible risk factors for endophthalmitis

a. Immunocompromise (Diabetes mellitus, systemic disease) b. Operative preparation (Xylocaine jelly before Povidone-iodine prep)

c. Intraoperative complications (vitreous loss)

d. Perioperative factors (surface bacteria)

e. Wound construction (wound leak; inferior wound placement)

f. Chronic blepharitis

E. Treatment Options (usually outpatient)

1. Needle tap (usually performed in minor OR)

a. Peribulbar anesthesia

b. Povidone-iodine prep

c. 23 gauge needle (one inch)- may use butterfly needle

d. Inject IOABs in separate syringes

2. Pars plana vitrectomy (PPV)- Transconjunctival PPV 23 or 25 gauge

a. Peribulbar anesthesia

b. Povidone-iodine prep

c. 2 instrument approach (when view limited) vs. standard 3 port PPV

d. Inject IOABs in separate syringes

F. Clinical Management of Suspected Acute-Onset Bacterial Endophthalmitis

1. Initial approach (usually outpatient treatment)

a. Obtain intraocular specimen by needle tap or by vitrectomy (use peribulbular

anesthesia)

b. Administer intravitreal antibiotics (0.1 ml of each)

c. Administer intravitreal steroids (0.1 ml – optional)

d. Consider periocular antibiotics and steroids

e. Postoperative topical antibiotics, steroids, and cycloplegics (started on the first

morning after initial treatment)

f. Postoperative systemic antibiotics (generally not used; can be considered for the

more severe cases: rapid onset, LP vision, large hypopyon, no red reflex)

2. Follow-up approach

a. If clinically worsening status at 48-72 hours, consider repeating intraocular cultures

and/or re-injection of intraocular antibiotics (and intraocular steroids).

b. Consider vitrectomy if not performed initially. Change topical antibiotics if

indicated by results of cultures and/or clinical course

6

G. Recommended Initial Antibiotic and Drug Therapy

1. Acute-onset Postoperative Bacterial Endophthalmitis:

a. Intravitreal:

• Vancomycin 1 mg/0.1 ml

• Ceftazidime 2.25 mg/0.1 ml or Amikacin 0.4 mg/0.1 ml

• Dexamethasone 0. 4 mg/0.1 ml (optional)

b. Periocular (subconjunctival): Optional

• Vancomycin 25 mg

• Ceftazidime 100 mg

• Dexamethasone 12 to 24 mg

c. Topical (started on first postoperative day): Optional

• Vancomycin 25 mg/ml q 1 hour (during day)

• Ceftazidime 50 mg/ml q 1 hour (during day)

• Topical steroids and cycloplegics (q.i.d)

d. Systemic: usually - none

(when used, it is generally reserved for eyes with more severe inflammation,

LP vision, rapid-onset, glaucoma drainage device, panophthalmitis)

• Vancomycin 1 gram IV q 12 hours and Ceftazidime 1 gram IV q 12 hours

Or

• Oral fluoroquinolone for susceptible organisms (Levofloxacin 500-

750mg once daily)

2. Delayed-Onset (Chronic) Postoperative Endophthalmitis

a. Intravitreal: (bacterial cases)

• Vancomycin 1.0 mg/0. 1 ml


• Dexamethasone 0.4 mg/0. 1 ml (optional) – Not used in the initial

treatment until the organism is identified.

b. Intravitreal: (fungal cases)

• Voriconazole 0.1mg/0.2ml or

• Amphotericin 0.005 mg/0.1 ml

c. Periocular (subconjunctival): Optional




d. Topical (started on first postoperative day): Optional


• Ceftazidime 50 mg/ml q I hour (during day)


e. Systemic: usually none

(but consider in more severe cases) (bacterial vs. fungal etiology)

7

3. Conjunctival Filtering Bleb-Associated or Glaucoma Drainage Implant Endophthalmitis:

a. Intravitreal:



• Dexamethasone 0.4 mg/0.1 ml (optional)

b. Periocular (subconjunctival): Preferred in bleb cases




c. Topical (started on first postoperative day):




d. Systemic: usually none but consider oral fluoroquinolone in eyes with marked

inflammation, LP vision, rapid onset.

4. Post-Traumatic Endophthalmitis

a. Intravitreal:


• Ceftazidime 2.25 mg/0.1 ml or Amikacin 0.4 mg/0.1 ml)

• Dexamethasone 0.4 mg/0.1 ml (depending on clinical history, this option

may be used)

b. Periocular (subconjunctival): Preferred








d. Systemic (generally reserved for more severe cases):

• Vancomycin 1 gram IV q 12 hours and Ceftazidime 1 gram IV q 12 hours

Or

• Oral fluoroquinolone for susceptible organisms (Levofloxacin 500-

750mg once daily)

8

5. Endogenous Fungal Endophthalmitis

a. Intravitreal:

• Voriconazole 0.1mg/0.2ml or Amphotericin-B 0.005 mg/0.1 ml

• Usually do not use Dexamethasone 0.4 mg/0.1 ml


• Vancomycin 25 mg and

• Dexamethasone 12 mg to 24 mg (must have anti-fungal coverage)



• Topical amphotericin-B has poor intraocular penetration and is not used

d. Systemic antibiotics (selected in consultation with internist):

• Voriconazole 200 mg p.o. b.i.d. for 2-4 weeks or

• Fluconazole 200mg p.o. b.i.d. for 2-4 weeks or

• Itraconazole 200 mg p.o. b.i.d. for 2-4 weeks or

• Ketoconazole 200 mg p.o. b.i.d. for 2-4 weeks or

• Amphotericin B 0.25 to 1.0 mg/kg of body weight/IV over 6 hours as

tolerated (only if disseminated disease present)

6. Endogenous Bacterial Endophthalmitis

a. Intravitreal:

• Vancomycin 1.0 mg/0.1 ml


• Dexamethasone 0.4 mg/0.1 ml (optional)


• Vancomycin 25mg

• Ceftazidime 100mg





• Topical steroids and/or cycloplegics (q.i.d)

d. Systemic antibiotics (selected in consultation with internist):

• Vancomycin 1 gram IV q 12 hours or Ceftazidime 1 gram IV q 12 hours

Or

• Oral fluoroquinolones for susceptible organisms (Levofloxacin

500-750mg once daily)

9

H. Preparation of Intravitreal Antibiotics/Antifungals

NOTE: Intraocular antibiotics are prepared in a volume of 10 ml or greater volume and labeled in

a sealed sterile vial. The physician will withdraw the appropriate dose in a tuberculin syringe for

injection into the eye.

Vancomycin (VANCOCIN) 1 mg/0.1 ml

1. Begin with 500 mg vial of Vancomycin (this is a powder)

2. Add 10 ml of 0.9% Sodium Chloride for Injection, USP (no preservatives) (or BSS) to 500

mg vial in #l

3. Inject 2 ml of solution #2 into a sterile empty vial

4. Add 8 ml of 0.9% Sodium Chloride for Injection, USP (no preservative)(or BSS) to

produce a solution containing 1 mg/0.1 ml Vancomycin

5. Seal the vial containing solution #4.

Ceftazidime (FORTAZ) 2.25 mg/0.1 ml

1. Begin with 500 mg vial of Ceftazidime (this is a powder)

2. Add 10 ml of 0.9% Sodium Chloride for Injection, USP (no preservatives) (or BSS) to 500

mg vial in #1

3. Inject 1 ml of the solution #2 into an empty sterile vial.

4. Add 1.2 ml of Sodium Chloride for Injection, USP (no preservatives) into the vial #2 to

produce a solution containing 2.25 mg/0.1 ml ceftazidime.

5. Seal the vial containing solution #4.

Amikacin (AMIKIN) 0.4 mg/0.1 ml

1. Begin with 500 mg/2 ml vial of amikacin

2. Inject 0.16 ml of solution #1 (40 mg) into sterile empty vial

3. Add 9.84 ml of 0.9% Sodium Chloride Injection, USP (no preservatives to produce a

solution of 0.4mg/0.1 ml amikacin

4. Seal the vial containing #3

Amphotericin B (FUNGIZONE) 0.005 mg/0.1 ml

1. Begin with a vial containing 50 mg of amphotericin B

2. Add 10 ml of Sterile Water for Injection USP (no preservatives) to vial in # 1

3. Inject 0.1 ml of solution #2 into a sterile empty vial

4. Add 9.9 ml of Sterile Water for Injection, USP (no preservatives) to vial in #3 to produce

a solution containing 0.0005 mg/0.1 ml amphotericin B

5. Seal the vial containing solution #4

Voriconazole (Vfend I.V. powder) 0.050 mg/0.1. ml

1. Reconstitute a 200mg vial of voriconazole (Vfend I.V. ®) powder with 19 mL of

preservative-free sterile water for injection.

2. Withdraw 1 mL of voriconazole solution from step 1 and q.s. to make 20 mL with

preservative-free sterile water for injection.

3. Transfer the solution from step 2 in 10 mL aliquots to each of 2 sterile empty vials. Seal

the vial.

10

I. Preparation of Subconjunctival Antibiotics

(Dilutions should be made with non-bacteriostatic sterile water)

J. Preparation of Fortified Topical Antibiotics:

1. Vancomycin (VANCOCIN) 25 mg/ml

a. Add 20 ml of 0.9% Sodium Chloride Injection, USP (no preservatives) or Tears

Naturale artificial tears to a 500 mg vial of Vancomycin to produce a Solution of

25 mg/ml Vancomycin

b. Refrigerate and shake well before instillation

2. Ceftazidime (FORTAZ) 50 mg/ml

a. Add 9.2 ml of Tears Naturale to a vial of Ceftazidime 1gm (powder for injection)

b. Dissolve. Take 5 ml of this solution and add it to 5 ml of Tears Naturale

c. Refrigerate and shake well before instillation

3. Amikacin (AMIKIN) 8 mg/ml

a. Add 0.48 ml of Amikacin (500 mg/2 ml) to make a volume with sterile preservative

free water of 15 ml

b. Refrigerate and shake well before instillation.

Amt. in Package Vol.Added Vol. for Inj. Dose Antibiotic

Amikacin

Ampicillin

Clindamycin

Cephalothin

Cefazolin

Ceftazidime

Chloramphenicol

Gentamicin

Methicillin

Tobramycin

Vancomycin

100mg/2 ml

1gm

600mg/4ml

1gm

500mg

500mg

1gm

80mg/2ml

1gm

80mg/2ml

500 mg

0

5ml

0

5ml

2.5ml

2.5ml

5ml

0

5ml

0

5ml

0.5ml

0.5ml

0.33ml

0.5ml

0.5ml

0.5ml

0.5ml

0.5ml

0.5ml

0.5ml

0.25ml

25mg

100mg

50mg

100mg

100mg

100mg

100mg

20mg

100mg

20mg

25mg

11

K. Endophthalmitis Vitrectomy Study (EVS)

1. Purpose:

a. To determine the role of immediate 3 port pars plana vitrectomy versus immediate

tap/biopsy

b. To determine the role of IV antibiotics versus no IV antibiotics

2. EVS Entry Criteria:

a. Clinical diagnosis within 6 weeks of CE or secondary IOL

b. Hypopyon or clouding of AC or vitreous media sufficient to obscure clear

visualization of second-order retinal arterioles

c. The cornea and AC were clear enough to visualize some part of iris.

d. The cornea was clear enough to allow the possibility of PPV.

e. Visual acuity: worse than 20/50 but at least light perception.

3. EVS Results:

a. No difference in final VA or media clarity whether or not systemic antibiotics were

employed.

b. No difference in outcomes between immediate 3 port PPV vs. tap/biopsy for

patients with hand motion or better vision.

c. For patients with initial visual acuity of LP only, much better visual results occurred in

the immediate 3 port PPV group (versus tap/biopsy group)

• 3 times more likely to achieve 20/40 (33% vs. 11%)

• 2 times more likely to achieve 20/100 (56%vs.30%) • Less likely to incur <5/200 (20% vs. 47%)

12

4. EVS Microbiologic Isolates

“Confirmed growth” - 69.3% (291/420)

Coagulase negative micrococci - 70.0%

Staphylococcus aureus - 9.9%

Streptococcus species - 9.0%

Enterococcus species - 2.2%

Gram negative organisms - 5.9%

Miscellaneous gram positive - 3.1%

5. EVS Microbiologic Isolates/Antibiotic Sensitivities

a. Gram positive organisms - 94.2% (274/291)

(all sensitive to vancomycin)

b. Gram negative organisms - 6.5% (19/291) (17/19 were sensitive to both amikacin and ceftazidime and 2/19 were resistant to

both)

6. Rates of (+) culture from a single source

a. aqueous alone 4%

b. undiluted vitreous 21%

c. vitrectomy cassette 8.9%

7. EVS Visual Acuity (20/40) Outcomes versus Microbiology Results

Visual Acuity (N = 123) No or

Equivocal

(N = 187) Coag (-)

micrococci growth

(N = 56) Other

gram (+)

(N = 16) Gram (-)

(N = 12) Mixed growth

≥ 20/40

≥ 20/100

≥ 5/200

55%

80%

92%

62%

84%

96%

29%

43%

63%

44%

56%

69%

25%

42%

92%

13

8. EVS Media Clarity Outcomes (20/40 or better view to retina) at final follow-up (9-

or 12- months) by Microbiologic Results vs Initial Treatment

Microbiology Results Vitrectomy TAP/Biopsy

N (n) % N (n) %

Total 200 179 90 191 159 83

No. growth/equiv. 56 51 91 65 58 89

Coag. (-) micrococci 94 94 100 90 81 90

Other gram-positive 35 22 63 23 10 44

Gram-negative 8 5 63 8 6 75

Polymicrobial 7 7 100 5 4 80

N = total number of patients n = number achieving ≥ 20/40 view to retina

9. EVS Outcomes: Causes of VA < 20/40 at Final Follow-up

n % N = 185

Pigmentary degeneration of the macula

Macular edema

No apparent cause

Macular distortion or preretinal membrane

Presumed optic nerve damage

Corneal opacity or irregularity

Phthisis bulbi or atrophia bulbi

Posterior capsular opacity

Retinal detachment

Macular ischemia

Vitreous opacification

Other miscellaneous

33

32

26

15

13

11

13

07

08

06

03

18

18

17

14

08

07

06

07

04

04

03

02

10

N = total number of patients n = number achieving 20/40 view to retina

14

10. Additional Procedures (ADPROC) (10.5% or 44/420 EVS Patients)

Early ADPROC= within 7 days

Late ADPROC= 8 days to 1 year

a. Early ADPROC in each treatment category:

• 8% in 3 port PPV group versus 13% in tap/biopsy group

• 12% in IV antibiotics group versus 9% no IV antibiotics group.

• 86% for worsening ocular inflammation

• 14% for complications of the initial procedure

b. Early ADPROC by organisms isolated

• Gram (+) coag. negative or no growth 5%

• Gram (-) or other gram (+) 30%

c. Early ADPROC Recultures performed: 82% (36/44)

• Positive growth • Reculture positive by treatment category

(i) Initial 3 port PPV group

39%

13%

(14/36)

(ii) Initial tap/biopsy group 71%

• Recultures positive by organism isolated

(i) Gram (+) coag. neg. (e.g. Staph. epi.) 17%

(ii) Gram (+) other (e.g. Streptococci) 40%

(iii) Gram (-) organisms (e.g. Serratia) 60%

d. Visual acuity outcomes ≥ 20/40

ADPROC= Additional Procedures after Initial Rx

ADPROC 15%

NO ADPROC 57%

11. Factors associated with higher rates of both gram (-) and other gram (+) organisms:

a. Symptom-onset within 2 days of surgery

b. Light perception only visual acuity

c. Afferent pupillary defect

d. Wound abnormalities

e. Corneal infiltrate

f. Hypopyon > 1.5 mm

g. Loss of red reflex

h. Eyelid swelling

15

12. Other EVS Findings

a. Diabetes associated with higher yield of coagulase negative staphylococci

b. If retinal vessel was visible on initial exam (N = 42), isolates were gram (+),

coagulase-negative micrococci or no/equivocal growth

c. 40% (85/211) had prep with povidone-iodine at cataract surgery (when

information was recorded)

d. Ten patients had received antibiotics in the infusion fluid.

13. RD rates: Overall incidence was 8.3%

a. LP initial vision (15%) vs > LP vision…………………... (05%)

b. Initial PPV group (7%) vs. Tap/Biopsy group…………… (09%)

c. Attempted RD repair in 23 of 35……………………... (66%)

d. VA ≥ 20/40 - No RD (55%) vs. with RD……………… (26%)

14. Diabetes (58/420 had DM)

a. VA ≥ 20/40 outcomes in overall EVS patients:

( • Non-diabetic……….(55%)

• Diabetic……………(39%)

b. VA ≥ 20/40 outcomes in Diabetic patients with better than LP vision at baseline

• Initial PPV………....(57%)

• Initial TAP/Biopsy...(40%)

L. Endophthalmitis Prevention:

1. Selective prophylactic systemic therapy for open globe injuries

a. Vancomycin 1 gram IV q 12 hours and Ceftazidime 1 gram IV q 12 hours

Or

b. Levofloxacin 500-750 mg (orally once daily)

2. Identify high risk patients before elective surgery

a. Chronic Blepharitis

b. Lacrimal drainage abnormalities

c. Prosthesis in fellow eye

d. Active infection elsewhere

3. Preparation of operative field

a. Pre-prep in holding room (5% povidone-iodine solution)

b. Second 10% povidone-iodine prep immediately before surgery

c. Drape to cover lashes and lid margins

4. Use of Prophylactic Antibiotics (controversial)

a. Preoperative topical antibiotics – No definitive studies

b. Subconjunctival antibiotics at the end of surgery

c. Intracameral antibiotics (ESCRS Cefuroxime Study-2007)

• Emergence of resistant organisms

• Enormous cost for all cataract procedures

• Risk of toxicity or contamination

5. Discard old topical medications (esp. glaucoma drops used prior to surgery)

16

General References:

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8;9:95-108. Review. PubMed PMID: 25609911; PubMed Central PMCID: PMC4293922.

Doft BH. Managing infectious endophthalmitis: Results of the Endophthalmitis Vitrectomy Study.

American Academy of Ophthalmology (Focal Points: Clinical Modules). San Francisco.Vol 15; No.3, 1997.

Packer M, Chang DF, Dewey SH, Little BC, Mamalis N, Oetting TA, Talley-Rostov A, Yoo SH for the ASCRS

Cataract Clinical Committee. Prevention, diagnosis, and management of acute postoperative

bacterial endophthalmitis. J Cataract Refract Surg 2011; 37:1699–1714. PMID: 21782382

Wykoff CC, Parrott MB, Flynn HW Jr, Shi W, Miller D, Alfonso EC. Nosocomial acute-onset

postoperative endophthalmitis at a university teaching hospital (2002-2009). Am J Ophthalmol. 2010

Sep;150(3):392-398.e2. PubMed PMID: 20619391.

Alfonso EC, Flynn HW Jr. Controversies in endophthalmitis prevention. The risk for emerging

resistance to vancomycin. Arch Ophthalmol. 1995 Nov;113(11):1369-70. Review. PubMed PMID: 7487593.

Endophthalmitis and Cataract Surgery:

Scott IU, Flynn HW Jr., Endophthalmitis: Prevention and Management. In: Han Eds: Cataract Surgery

and Retinal Diseases: Optimizing Visual Outcome. BMC, Philadelphia. ISBN: 978-0-615-84030-7, 2013.

Pathengay A, Schwartz SG, Flynn Jr HW. and Miller D. Endophthalmitis Following Cataract Surgery:

Clinical Features, Treatment and Prophylaxis. DOI: 10.5772/22751. Book Chapter – 20. Available online at

- http://www.intechopen.com/books/cataract-surgery/endophthalmitis-following-cataract-surgery-clinical-features-

treatment-and-prophylaxis

Shirodkar AR, Pathengay A, Flynn HW Jr, Albini TA, Berrocal AM, Davis JL, Lalwani GA, Murray TG, Smiddy WE,

Miller D. Delayed- versus acute-onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012

Mar;153(3):391-398.e2. PubMed PMID: 22030353; PubMed Central PMCID: PMC3381653.

Hung JH, Huang YH, Chang TC, Tseng SH, Shih MH, Wu JJ, Huang FC. A cluster of endophthalmitis caused

by Mycobacterium abscessus after cataract surgery. J Microbiol Immunol Infect. 2014 Mar 20. pii: S1684-

1182(14)00028-0. PMID: 24657068

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Prolonged Curvularia Endophthalmitis Due to Organism Sequestration. JAMA Ophthalmol.

2014;132(9):1123-1126. PMID: 24903581

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caused by Achromobacter xylosoxidans after cataract surgery. Retina. 2014 Mar;34(3):583-6. PubMed

PMID: 24150240.

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82. Review. PubMed PMID: 22727298.

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Following Cataract Surgery: A Review. Asia Pacific Academy of Ophthalmology 12/2011;1(1):35-42. PMID:

26107016

http://www.intechopen.com/books/cataract-surgery/endophthalmitis-following-cataract-surgery-clinical-features-treatment-and-prophylaxis

http://www.intechopen.com/books/cataract-surgery/endophthalmitis-following-cataract-surgery-clinical-features-treatment-and-prophylaxis

17

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surgery (2000-2004): incidence, clinical settings, and visual acuity outcomes after treatment. Am J

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Miller D. Delayed- versus acute-onset endophthalmitis after cataract surgery. Am J Ophthalmol. 2012

Mar;153(3):391-398.e2. PubMed PMID: 22030353; PubMed Central PMCID: PMC3381653.

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associated with corneal suture infections. J Ophthalmic Inflamm Infect. 2013 Jun 11;3(1):51. PubMed PMID:

23758694; PubMed Central PMCID: PMC3717107.

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Pseudophakic Endophthalmitis Caused by Propionibacterium Acnes. Ophthalmic Surg Lasers Imaging.

2010 Mar 9:1-3. PMID: 20337310

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surgery. Arch Ophthalmol 2000;118: 572-575. PMID: 10766146

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surgery among the U.S. Medicare population increased between 1994 and 2001. Ophthalmology. 2005

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surgery. Incidence, clinical features, causative organisms, and visual outcomes. J Cataract Refract Surg

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outcomes of cataract extraction. Retinal detachment and endophthalmitis after outpatient cataract

surgery. Ophthalmology 101: 100-106, 1994. PMID: 8302540.

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Moloney TP, Park J. Microbiological isolates and antibiotic sensitivities in culture-proven

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antibiotic sensitivity in endophthalmitis: a 25-year review. Ophthalmology. 2014 Aug;121(8):1634-42.

Review. PubMed PMID: 24702755.

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Combined Ceftazidime and Amikacin Resistance Among Gram-Negative Isolates in Acute-Onset

Posoperative Endophthalmitis: Prevalence, Antimicrobial Susceptibilities, and Visual Acuity

Outcome. J Ophthalmic Inflamm Infect 2013 Oct 25;3(1):62. PMID: 24161048

Miller D, Chang JS, Flynn HW, Alfonso EC. Comparative in vitro susceptibility of besifloxacin and seven

comparators against ciprofloxacin- and methicillin-susceptible/nonsusceptible staphylococci. J Ocul

Pharmacol Ther. 2013 Apr;29(3):339-44. PMID: 23289847

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versus blood culture bottles in culturing vitrectomy cassette vitreous in infectious endophthalmitis.

Am J Ophthalmol. 2013 Aug;156(2):349-354.e2. PubMed PMID: 23668678.

Schimel AM, Miller D, Flynn HW Jr. Endophthalmitis isolates and antibiotic susceptibilities: a 10-year

review of culture-proven cases. Am J Ophthalmol. 2013 Jul;156(1):50-52.e1. PubMed PMID: 23540710.

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presentation and outcome by culture result. Clin Ophthalmol. 2011;5:739-44. PubMed PMID: 21691583;

PubMed Central PMCID: PMC3116799.

Schimel AM, Miller D, Flynn HW Jr. Evolving fluoroquinolone resistance among coagulase-negative

Staphylococcus isolates causing endophthalmitis. Arch Ophthalmol. 2012 Dec;130(12):1617-8. PubMed

PMID: 23229711.

Benz MS, Scott IU, Flynn HW Jr, Unonius N, Miller D. Endophthalmitis isolates and antibiotic sensitivities: a

6-year review of culture-proven cases. Am J Ophthalmol. 2004 Jan;137(1):38-42. PubMed PMID: 14700642.

20

Donahue SP, Kowalski RP, Jewart BH, Friberg TR. Vitreous cultures in suspected endophthalmitis. Biopsy

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Arch Ophthalmol. 1989 Sep;107(9):1334-7. PubMed PMID: 2675804.

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Delayed-onset Bleb associated Endophthalmitis :

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associated endophthalmitis in the United States. Clin Ophthalmol. 2015 Feb 12;9:317-22. PubMed PMID:


Brillat-Zaratzian E, Bron A, Aptel F, Romanet JP, Cornut PL, Vandenesch F, Boisset S, Maurin M, Chiquet C.

FRIENDS Group: clinical and microbiological characteristics of post-filtering surgery endophthalmitis.

Graefes Arch Clin Exp Ophthalmol. 2014 Jan;252(1):101-7. PMID: 24248809

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management of delayed-onset bleb-associated endophthalmitis. Int J Inflam. 2012;2012:503912. PubMed

PMID: 22288020; PubMed Central PMCID: PMC3263617.

Jacobs DJ, Leng T, Flynn HW Jr, Shi W, Miller D, Gedde SJ. Delayed-onset bleb-associated endophthalmitis:

presentation and outcome by culture result. Clin Ophthalmol. 2011;5:739-44. PubMed PMID: 21691583;

PubMed Central PMCID: PMC3116799.

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2008): causative organisms and visual acuity outcomes. Retina. 2011 Feb;31(2):344-52. PubMed PMID:

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features and visual acuity outcomes. Ophthalmology. 2002 May;109(5):985-91. Review. PubMed PMID:

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filtering blebs. Ophthal. Surg 1994:25: 88-91. PMID: 8183519.

21

Brown RH,Yang LH, Walker SD Lynch MG, Martinez LA, Wilson LA. Treatment of bleb infection after

glaucoma surgery. Arch Ophthalmol 1994: 112: 57-61. PMID: 8285894.

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trabeculectomy with adjunctive 5-fluorouracil. Ophthalmology 1991: 98: 1053-1060. PMID: 1891213.

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blebs. Ophthalmology 1985: 92: 964-972. PMID: 3895104.

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Endophthalmitis Associated with Glaucoma Drainage Implant:

Gedde SJ, Scott IU, HomayounT, Kevin K, Luu M, Budenz DL, Greenfield DS, Flynn HW Jr. Late endophthalmitis

associated with glaucoma drainage implants. Arch Ophthalmology 2001:108: 1-5. PMID: 11425695

Stewart MW, Bolling JP, Bendel RE. Nocardia brasiliensis endophthalmitis in a patient with an exposed

Ahmed glaucoma drainage implant. Ocul Immunol Inflamm. 2013;21(1):69-70. PMID: 23323584

Ahmed Y, Pathengay A, Flynn HW Jr, Isom R. Delayed-Onset Endophthalmitis Associated with Ex-PRESS

Mini Glaucoma Shunt®. Ophthalmic Surgery Lasers & Imaging 2012; 43: e62-e63. PMID: 22785601

Prophylaxis and Preparation for Surgery:

Apt L, Isenberg SJ, Yoshimori R, Spierer A. Outpatient topical use of povidone-iodine in preparing the eye

for surgery. Ophthalmology. 1989 Mar;96(3):289-92. PubMed PMID: 2652027.

Ahmed Y, Scott IU, Pathengay A, Bawdekar A, Flynn HW Jr. Povidone-iodine for endophthalmitis

prophylaxis. Am J Ophthalmol. 2014 Mar;157(3):503-4. PubMed PMID: 24528933.

Schimel AM, Alfonso E, Flynn HW Jr. Need for Antibiotic Prophylaxis for Pseudophakic

Endophthalmitis - Letter to the editor - Reply. JAMA Ophthalmol. 2015 May 28. PubMed PMID: 26022494.

Rudnisky CJ, Wan D, Weis E. Antibiotic choice for the prophylaxis of post-cataract extraction

endophthalmitis. Ophthalmology. 2014 Apr;121(4):835-41. PubMed PMID: 24326107.

Wykoff CC, Flynn HW Jr, Rosenfeld PJ. Prophylaxis for endophthalmitis following intravitreal injection:

antisepsis and antibiotics. Am J Ophthalmol. 2011 Nov;152(5):717-9.e2. PubMed PMID: 22017840.

Wykoff CC, Flynn HW Jr. Endophthalmitis after intravitreal injection: prevention and management.

Retina. 2011 Apr;31(4):633-5. PubMed PMID: 21836399.

Wykoff CC, Flynn HW Jr., Han DP. Allergy to Povidone-Iodine and Cephalosporins: The Clinical

Dilemma in Ophthalmic Use. Am J Ophthalmol 2011; 151: 4-6. PMID: 21163372.

Kaiser RS, Prenner J, Scott IU, Brucker AJ, Flynn HW Jr, Williams GA, Ho AC, Regillo CD, Capone A, Avery R,

Eliott D, Dugel P, Pollack J. The Microsurgical Safety Task Force: evolving guidelines for minimizing the

risk of endophthalmitis associated with microincisional vitrectomy surgery. Retina. 2010 Apr;30(4):692-

22

9. PubMed PMID: 20386097.

Scott IU, Flynn HW Jr. The role of topical antibiotic prophylaxis for intravitreal injections. Arch

Ophthalmol. 2007 Jul;125(7):974-6. PubMed PMID: 17620584.

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Jan;27(1):10-2. PubMed PMID: 17218909.

Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW Jr. In vitro fluoroquinolone resistance in staphylococcal

endophthalmitis isolates. Arch Ophthalmol. 2006 Apr;124(4):479-83. PubMed PMID: 16606872.

Aiello LP, Brucker AJ, Chang S, Cunningham ET Jr, D'Amico DJ, Flynn HW Jr, Grillone LR, Hutcherson S, Liebmann

JM, O'Brien TP, Scott IU, Spaide RF, Ta C, Trese MT. Evolving guidelines for intravitreous injections. Retina.

2004 Oct;24(5 Suppl):S3-19. Review. PubMed PMID: 15483476.

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Antibiotics in the Irrigating Fluid/Intracameral Injection:

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1669, 2003. PMID: 12917192

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intracameral antibiotics necessary? JAMA Ophthalmol. 2014 Nov;132(11):1269-70. PubMed PMID: 25125316.

Rahman N, Murphy CC. Impact of intracameral cefuroxime on the incidence of postoperative endophthalmitis

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Moshfeghi AA, Batlle IR, Sobrin L, Eliott D. Postoperative Hemorrhagic Occlusive Retinal Vasculitis:

Expanding the Clinical Spectrum and Possible Association with Vancomycin. Ophthalmology. 2015

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resistance to vancomycin. Arch Ophthalmol 1995;113: 1369-1370. PMID: 7487593

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385-390. PMID: 1861260

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Cataract Clinical Committee. Prevention, diagnosis, and management of acute postoperative

24

bacterial endophthalmitis. Cataract Refract Surg 2011; 37:1699–1714. PMID: 21782382

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prophylaxis: Potential role of moxifloxacin. J Cataract Refract Surg 2007; 33: (10)1790-1800. PMID: 17889778

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intracameral antibiotics at a single academic institution. J Cataract Refract Surg 2015; 41: 58-66. PMID:

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Refract Surg. 2014 Nov;40(11):1940-1. PMID: 25442899

ESCRS:

Rahman N, Murphy CC. Impact of intracameral cefuroxime on the incidence of postoperative

endophthalmitis following cataract surgery in Ireland. Ir J Med Sci. 2015 Jun;184(2):395-8. PubMed PMID:

24846749.

Barry P. Adoption of intracameral antibiotic prophylaxis of endophthalmitis following cataract

surgery: update on the ESCRS Endophthalmitis Study. J Cataract Refract Surg. 2014 Jan;40(1):138-42.

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Sousa JC. Postcataract surgery endophthalmitis after introduction of the ESCRS protocol: a 5-year

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Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns in 9 European

countries. J Cataract Refract Surg. 2013 Sep;39(9):1421-31. PMID: 23988244

García-Sáenz MC,Arias-Puente A, Rodríguez-Caravaca G, Bañuelos JB. Effectiveness of intracameral

cefuroxime in preventing endophthalmitis after cataract surgery Ten-year comparative study. J

Cataract Refract Surg. 2010; 36(2):203-7. PMID: 20152598

Chang DF, Braga-Mele R, Mamalis N, Masket S, Miller KM, Nichamin LD, Packard RB, Packer M; ASCRS Cataract

Clinical Committee. Prophylaxis of postoperative endophthalmitis after cataract surgery: results of

the 2007 ASCRS member survey. J Cataract Refract Surg. 2008; 34(4): 531-2; author reply 532-3. PMID:

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Endophthalmitis ESCRS Study Group. Prophylaxis of postoperative endophthalmitis following cataract

surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract

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ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: Case for a

European multicenter study. J Cataract Refract Surg. 2006; 32(3): 396-406. PMID: 16631046

Barry P, Seal DV, Gettinby G, Lees F, Peterson M, Revie CW, ESCRS Endophthalmitis Study Group. ESCRS study

of prophylaxis of postoperative endophthalmitis after cataract surgery: Preliminary report of

principal results from a European multicenter study. J Cataract Refract Surg. 2006; 32(3): 407-10. Erratum

in: J Cataract Refract Surg. 2006; 32(5): 709. PMID: 16631047.

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Bohigian,GM, Letter: ESCRS study of endophthalmitis prophylaxis Journal of Cataracts & Refractive

Surgery, 2006; 32(9)1406-1407. PubMed PMID: 16931233.

Peter Barry. Reply: ESCRS study of endophthalmitis prophylaxis Journal of Cataract & Refractive

Surgery, Volume 32, Issue 9, September 2006;32 (9)1407.

Endophthalmitis – Organisms and Outcomes

Kuriyan AE, Sridhar J, Flynn HW Jr, Smiddy WE, Albini TA, Berrocal AM, Forster RK, Belin PJ, Miller D.

Endophthalmitis caused by Enterococcus faecalis: clinical features, antibiotic sensitivities, and

outcomes. Am J Ophthalmol. 2014 Nov;158(5):1018-23. PubMed PMID:25089354; PubMed Central PMCID:

PMC4250282.

Sridhar J, Flynn HW Jr, Kuriyan AE, Dubovy S, Miller D. Endophthalmitis caused by Klebsiella species. Retina.

2014 Sep;34(9):1875-81. PubMed PMID: 24801652; PubMed Central PMCID: PMC4145028.

Kuriyan AE, Weiss KD, Flynn HW Jr, Smiddy WE, Berrocal AM, Albini TA, Miller D. Endophthalmitis caused by

streptococcal species: clinical settings, microbiology, management, and outcomes. Am J Ophthalmol.

2014 Apr;157(4):774-780.e1. PubMed PMID: 24418264; PubMed Central PMCID: PMC3972252.

Sridhar J, Kuriyan AE, Flynn HW Jr, Smiddy WE, Venincasa VD, Miller D. Endophthalmitis caused by Serratia

marcescens: Clinical Features, Antibiotic Susceptibilities, and Treatment Outcomes. Retina. 2015

Jun;35(6):1095-100. PubMed PMID: 25741815.

Sridhar J, Kuriyan AE, Flynn HW Jr, Miller D. Endophthalmitis caused by Pseudomonas aeruginosa: Clinical

Features, Antibiotic Susceptibilities, and Treatment Outcomes. Retina. 2015 Jun;35(6):1101-6. PubMed

PMID: 25658178.

Sanghi S, Pathengay A, Jindal A, Raval V, Nayak S, Sharma S, Bawdekar A, Flynn HW Jr. Acute-onset

postoperative endophthalmitis caused by multidrug-resistant Klebsiella pneumoniae. Clin Ophthalmol.

2014 Sep 16;8:1783-5. PubMed PMID: 25258505; PubMed Central PMCID: PMC4172197.

Gentile RC, Shukla S, Shah M, Ritterband DC, Engelbert M, Davis A, Hu DN. Microbiological Spectrum and

Antibiotic Sensitivity in Endophthalmitis: A 25-Year Review. Ophthalmology. 2014 Aug;121(8):1634-42.

PMID: 24702755

Chhablani J, Sudhalkar A, Jindal A, Das T, Motukupally SR, Sharma S, Pathengay A, Flynn HW Jr.

Stenotrophomonas maltophilia endogenous endophthalmitis: clinical presentation, antibiotic

susceptibility, and outcomes. Clin Ophthalmol. 2014 Aug 18;8:1523-6. PubMed PMID: 25170244; PubMed

Central PMCID: PMC4144939.


Prolonged Curvularia endophthalmitis due to organism sequestration. JAMA Ophthalmol. 2014

Sep;132(9):1123-6. PubMed PMID: 24903581.



Matthews JL, Dubovy SR, Goldberg RA, Flynn HW Jr. Histopathology of streptococcus mitis/oralis

26

endophthalmitis after intravitreal injection with bevacizumab: a report of 7 patients. Ophthalmology.

2014 Mar;121(3):702-8. PubMed PMID: 24439760.

Kuriyan AE, Weiss KD, Flynn HW Jr, Smiddy WE, Berrocal AM, Albini TA, Miller D. Endophthalmitis caused by

streptococcal species: clinical settings, microbiology, management, and outcomes. Am J Ophthalmol.

2014 Apr;157(4):774-780.e1. PubMed PMID: 24418264; PubMed Central PMCID: PMC3972252.

Villegas VM, Emanuelli A, Flynn HW Jr, Berrocal AM, Miller D, Kao AA, Dubovy SR, Alfonso E. Endophthalmitis

caused by Achromobacter xylosoxidans after cataract surgery. Retina. 2014 Mar;34(3):583-6. PubMed

PMID: 24150240.

Jacobs DJ, Grube TJ, Flynn HW Jr, Greven CM, Pathengay A, Miller D, Sanke RF, Thorman J. Intravitreal

moxifloxacin in the management of Ochrobactrum intermedium endophthalmitis due to metallic

intraocular foreign body. Clin Ophthalmol. 2013;7:1727-30. PubMed PMID: 24039392; PubMed Central PMCID:

PMC3770343.

Chang JS, Flynn HW Jr, Miller D, Smiddy WE. Stenotrophomonas maltophilia endophthalmitis following

cataract surgery: clinical and microbiological results. Clin Ophthalmol. 2013;7:771-7. PubMed PMID:


Khera M, Pathengay A, Jindal A, Jalali S, Mathai A, Reddy Pappuru R, Relhan N, Das S, Sharma S, Flynn HW Jr.

Vancomycin-Resistant Gram-Positive Bacterial Endophthalmitis: Epidemiology, Treatment Options,

and Outcomes. J Ophthalmic Inflamm Infect. 2013 Apr 22;3(1):46. PMID: 23607574.

Bispo PJ, Alfonso EC, Flynn HW Jr. and Miller D. Emerging 8-Methoxyfluoroquinolone Resistance Among

Methicillin-Susceptible Staphylococcus Epidermidis Isolates Recovered from Patients with

Endophthalmitis. J. Clin. Microbiol. 2013, 51(9): 2959-2963. PMID: 23824766

Jindal A, Moreker MR, Pathengay A, Khera M, Jalali S, Majji A, Mathai A, Sharma S, Das T, Flynn HW Jr.

Polymicrobial endophthalmitis: prevalence, causative organisms, and visual outcomes. J Ophthalmic

Inflamm Infect. 2013 Jan 7;3(1):6. PubMed PMID: 23514425; PubMed Central PMCID: PMC3589210.

Goldberg RA, Flynn HW Jr, Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after

intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology.

2013 Jul;120(7):1448-53. PubMed PMID: 23453511; PubMed Central PMCID: PMC3702685.

Haddock LJ, Flynn HW Jr, Dubovy SR, Khurana RN, Egbert PR. Histopathologic correlation of Aspergillus

endophthalmitis following uncomplicated cataract surgery. Clin Ophthalmol. 2012;6:1573-7. PubMed


Scartozzi R, Tom D, Liggett PE, Flynn HW Jr. Postoperative endophthalmitis caused by Candida

parapsilosis: clinical features and treatment outcomes. Ophthalmic Surg Lasers Imaging. 2011 Mar 10;42

Online:e37-9. PubMed PMID: 21410086.

Wykoff CC, Parrott MB, Flynn HW Jr, Shi W, Miller D, Alfonso EC. Nosocomial acute-onset postoperative

endophthalmitis at a university teaching hospital (2002-2009). Am J Ophthalmol. 2010 Sep;150(3):392-

398.e2. PubMed PMID: 20619391.

Javey G, Albini TA, Flynn HW Jr. Resolution of Pigmented Keratic Precipitates Following Treatment of

Pseudophakic Endophthalmitis Caused by Propionibacterium Acnes. Ophthalmic Surg Lasers Imaging.

2010 Mar 9:1-3. PubMed PMID: 20337310.

Javey G, Schwartz SG, Moshfeghi AA, Asrani S, Flynn HW Jr. Methicillin-resistant Staphylococcus

27

epidermidis isolation from the vitrectomy specimen four hours after initial treatment with

vancomycin and ceftazidime. Clin Ophthalmol. 2010 Mar 4;4:101-4. PubMed PMID: 20234775; PubMed Central

PMCID: PMC2835531.

Major JC Jr, Engelbert M, Flynn HW Jr, Miller D, Smiddy WE, Davis JL. Staphylococcus aureus

endophthalmitis: antibiotic susceptibilities, methicillin resistance, and clinical outcomes. Am J

Ophthalmol. 2010 Feb;149(2):278-283.e1. Nov 18. PubMed PMID: 19926069.

Leng T, Flynn HW Jr, Miller D, Murray TG, Smiddy WE. Endophthalmitis caused by proteus species:

antibiotic sensitivities and visual acuity outcomes. Retina. 2009 Jul-Aug;29(7):1019-24. PubMed PMID:

19584659.

Miller JJ, Scott IU, Flynn HW Jr, Smiddy WE, Murray TG, Berrocal A, Miller D. Endophthalmitis caused by

Bacillus species. Am J Ophthalmol. 2008 May;145(5):883-8. PubMed PMID: 18295182.

Miller DM, Vedula AS, Flynn HW Jr, Miller D, Scott IU, Smiddy WE, Murray TG, Venkatraman AS.

Endophthalmitis caused by staphylococcus epidermidis: in vitro antibiotic susceptibilities and clinical

outcomes. Ophthalmic Surg Lasers Imaging. 2007 Nov-Dec;38(6):446-51. PubMed PMID: 18050805.

Eifrig CW, Scott IU, Flynn HW Jr, Smiddy WE, Newton J. Endophthalmitis after pars plana vitrectomy:

Incidence, causative organisms, and visual acuity outcomes. Am J Ophthalmol. 2004 Nov;138(5):799-802.


Yoder DM, Scott IU, Flynn HW Jr, Miller D. Endophthalmitis caused by Haemophilus influenzae.

Ophthalmology. 2004 Nov;111(11):2023-6. PubMed PMID: 15522367.

Scott IU, Matharoo N, Flynn HW Jr, Miller D. Endophthalmitis caused by Klebsiella species. Am J

Ophthalmol. 2004 Oct;138(4):662-3. PubMed PMID: 15488803.

Miller JJ, Scott IU, Flynn HW Jr, Smiddy WE, Corey RP, Miller D. Endophthalmitis caused by Streptococcus

pneumoniae. Am J Ophthalmol. 2004 Aug;138(2):231-6. PubMed PMID: 15289132.

Benz MS, Scott IU, Flynn HW Jr, Unonius N, Miller D. Endophthalmitis isolates and antibiotic sensitivities: a

6-year review of culture-proven cases. Am J Ophthalmol. 2004 Jan;137(1):38-42. PubMed PMID: 14700642.

Eifrig CW, Scott IU, Flynn HW Jr, Miller D. Endophthalmitis caused by Pseudomonas aeruginosa.

Ophthalmology. 2003 Sep;110(9):1714-7. PubMed PMID: 13129867.

Scott IU, Loo RH, Flynn HW Jr, Miller D. Endophthalmitis caused by enterococcus faecalis: antibiotic

selection and treatment outcomes. Ophthalmology. 2003 Aug;110(8):1573-7. PubMed PMID: 12917175.

Scott IU, Lieb DF, Flynn HW Jr, Dessouki A, Murray TG, Miller D. Endophthalmitis caused by

Mycobacterium chelonae: selection of antibiotics and outcomes of treatment. Arch Ophthalmol. 2003

Apr;121(4):573-6. PubMed PMID: 12695258.

Berrocal AM, Scott IU, Miller D, Flynn HW Jr. Endophthalmitis caused by Moraxella osloensis. Graefes Arch

Clin Exp Ophthalmol. 2002 Apr;240(4):329-30. Epub 2002 Mar 5. PubMed PMID: 11981649.

Berrocal AM, Scott IU, Miller D, Flynn HW Jr. Endophthalmitis caused by Moraxella species. Am J

Ophthalmol. 2001 Nov;132(5):788-90. PubMed PMID: 11704047.

Chaudhry NA, Flynn HW Jr, Smiddy WE, Miller D. Xanthomonas maltophilia endophthalmitis after

cataract surgery. Arch Ophthalmol. 2000 Apr;118(4):572-5. PubMed PMID: 10766146.

28

Chaudhry NA, Flynn HW Jr, Murray TG, Tabandeh H, Mello MO Jr, Miller D. Emerging ciprofloxacin-resistant

Pseudomonas aeruginosa. Am J Ophthalmol. 1999 Oct;128(4):509-10. PubMed PMID: 10577596.

Clark WL, Kaiser PK, Flynn HW Jr, Belfort A, Miller D, Meisler DM. Treatment strategies and visual acuity

outcomes in chronic postoperative Propionibacterium acnes endophthalmitis. Ophthalmology. 1999

Sep;106(9):1665-70. PubMed PMID: 10485532.

Aaberg TM Jr, Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative endophthalmitis

survey. A 10-year review of incidence and outcomes. Ophthalmology. 1998 Jun;105(6):1004-10. PubMed

PMID: 9627649.

Cohen SM, Flynn HW Jr, Miller D. Endophthalmitis caused by Serratia marcescens. Ophthalmic Surg Lasers.

1997 Mar;28(3):195-200. PubMed PMID: 9076792.

Foster RE, Martinez JA, Murray TG, Rubsamen PE, Flynn HW Jr, Forster RK. Useful visual outcomes after

treatment of Bacillus cereus endophthalmitis. Ophthalmology. 1996 Mar;103(3):390-7. PubMed PMID:

8600414.

Rosenfeld SI, Jost BF, Litinsky SM, Gelender H, Glatzer RJ, Flynn HW Jr. Persistent Torulopsis magnoliae

endophthalmitis following cataract extraction. Ophthalmic Surg. 1994 Mar;25(3):154-6. PubMed PMID:

8196918.

Mao LK, Flynn HW Jr, Miller D, Pflugfelder SC. Endophthalmitis caused by Staphylococcus aureus. Am J

Ophthalmol. 1993 Nov 15;116(5):584-9. PubMed PMID: 8238218.

Winward KE, Pflugfelder SC, Flynn HW Jr, Roussel TJ, Davis JL. Postoperative Propionibacterium

endophthalmitis. Treatment strategies and long-term results. Ophthalmology. 1993 Apr;100(4):447-51. PubMed

PMID: 8479698.

Irvine WD, Flynn HW Jr, Miller DA, Pflugfelder SC. Endophthalmitis caused by gram-negative organisms.

Arch. Ophthalmol 1992: 110: 1450-1454. PMID: 1417545

Brod RD, Flynn HW Jr, Clarkson JG, Pflugfelder SC, Culbertson WW, Miller DA. Endogenous Candida

endophthalmitis. Ophthalmology 1990: 97: 666-674. PMID: 2188195

Mao LK, Flynn HW Jr, Miller D, Pflugfelder SC. Endophthalmitis caused by streptococcal species. Arch


Vahey JB, Flynn HW Jr. Results in the management of Bacillus endophthalmitis. Ophthalmic Surg. 1991

Nov;22(11):681-6. PubMed PMID: 1792034.

Kervick GN, Flynn HW Jr, Alfonso E, Miller D. Antibiotic therapy for Bacillus species infections. Am J

Ophthalmol. 1990 Dec 15;110(6):683-7. PubMed PMID: 2248335.

Zambrano W, Flynn HW Jr, Pflugfelder SC, Roussel TJ, Culbertson WW, Holland S, Miller D. Management

options for Propionibacterium acnes endophthalmitis. Ophthalmology. 1989 Jul;96(7):1100-5. PubMed

PMID: 2788852.

Davis JL, Koidou-Tsiligianni A, Pflugfelder SC, Miller D, Flynn HW Jr, Forster RK. Coagulase-negative

staphylococcal endophthalmitis. Increase in antimicrobial resistance. Ophthalmology. 1988

Oct;95(10):1404-10. PubMed PMID: 3265776.

29

Exogenous Fungal Endophthalmitis

Mithal K, Pathengay A, Bawdekar A, Jindal A, Vira D, Relhan N, Choudhury H, Gupta N, Gupta V, Koday NK, Flynn

HW Jr. Filamentous fungal endophthalmitis: results of combination therapy with intravitreal

amphotericin B and voriconazole. Clin Ophthalmol. 2015 Apr 13;9:649-55. PubMed PMID: 25926714; PubMed


Silva RA, Sridhar J, Miller D, Wykoff CC, Flynn HW Jr. Exogenous fungal endophthalmitis: an analysis of

isolates and susceptibilities to antifungal agents over a 20-year period (1990-2010). Am J Ophthalmol.

2015 Feb;159(2):257-64.e1. PubMed PMID: 25449001.

Weng CY, Parke DW 3rd, Walter SD, Isom RF, Chang JS, Flynn HW Jr. Candida glabrata endophthalmitis

transmitted from graft to host after descemet stripping automated endothelial keratoplasty. JAMA

Ophthalmol. 2014 Nov;132(11):1381-3. PubMed PMID: 25124791.


Prolonged Curvularia endophthalmitis due to organism sequestration. JAMA Ophthalmol. 2014

Sep;132(9):1123-6. PubMed PMID: 24903581.

Vilela RC, Vilela L, Vilela P, Vilela R, Motta R, Pôssa AP, de Almeida C, Mendoza L. Etiological agents of fungal

endophthalmitis: diagnosis and management. Int Ophthalmol. 2014 Jun;34(3):707-21. PMID: 24081913

Buchta V, Feuermannová A, Váša M, Bašková L, Kutová R, Kubátová A, Vejsová M. Outbreak of fungal

endophthalmitis due to Fusarium oxysporum following cataract surgery. Mycopathologia. 2014

Feb;177(1- 2):115-21. PMID: 24381050

Schwartz SG, Davis JL, Flynn HW Jr., Exogenous Endophthalmitis. In: Intraocular Inflammation, M Zierhut, S

Ohno, F Orefice, C Pavesio, NA Rao eds. New York: Springer, Avai 10-29-2013.

McMillan BD, Miller GJ, Nguyen J. Rare case of exogenous Candida dubliniensis endophthalmitis: a case

report and brief review of the literature. J Ophthalmic Inflamm Infect. 2014 May 2;4:11. PMID: 24860628.

Lingappan A, Wykoff CC, Albini TA, Miller D, Pathengay A, Davis JL, Flynn HW Jr. Endogenous fungal

endophthalmitis: causative organisms, management strategies, and visual acuity outcomes. Am J

Ophthalmol. 2012 Jan;153(1):162-6.e1. PubMed PMID: 21917234.

Scartozzi R, Tom D, Liggett PE, Flynn HW Jr. Postoperative endophthalmitis caused by Candida

parapsilosis: clinical features and treatment outcomes. Ophthalmic Surg Lasers Imaging. 2011 Mar 10;42

Online:e37-9. PubMed PMID: 21410086.

Wykoff CC, Flynn HW Jr, Miller D, Scott IU, Alfonso EC. Exogenous fungal endophthalmitis: microbiology

and clinical outcomes. Ophthalmology. 2008 Sep;115(9):1501-7, 1507.e1-2. PubMed PMID: 18486220.

Gregori NZ, Flynn HW Jr, Miller D, Scott IU, Davis JL, Murray TG, Williams B Jr. Clinical features,

management strategies, and visual acuity outcomes of Candida endophthalmitis following cataract

surgery. Ophthalmic Surg Lasers Imaging. 2007 Sep-Oct;38(5):378-85. PubMed PMID: 17955842.

Callanan D, Scott IU, Murray TG, Oxford KW, Bowman CB, Flynn HW Jr. Early onset endophthalmitis caused

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Growth Factor Injections. Curr Ophthalmol Rep. 2014 Mar 1;2(1):1-5. PubMed PMID: 24579059; PubMed


39

Matthews JL, Dubovy SR, Goldberg RA, Flynn HW Jr. Histopathology of streptococcus mitis/oralis

endophthalmitis after intravitreal injection with bevacizumab: a report of 7 patients. Ophthalmology.

2014 Mar;121(3):702-8. PubMed PMID: 24439760.

Tabandeh H, Boscia F, Sborgia A, Ciracì L, Dayani P, Mariotti C, Furino C, Flynn HW Jr. Endophthalmitis

associated with intravitreal injections: office-based setting and operating room setting. Retina. 2014

Jan;34(1):18-23. PubMed PMID: 24362413.

Chao DL, Gregori NZ, Khandji J, Goldhardt R. Safety of bilateral intravitreal injections delivered in a

teaching institution. Expert Opin Drug Deliv. 2014 Jul;11(7):991-3. PMID: 24815986.

Chen RW, Rachitskaya A, Scott IU, Flynn HW Jr. Is the use of topical antibiotics for intravitreal injections

the standard of care or are we better off without antibiotics? JAMA Ophthalmol. 2013 Jul;131(7):840-2.


Hahn P, Kim JE, Stinnett S, Chung MM, Dugel PU, Flynn HW Jr, Huang SS, Sadda SR, Mahmoud TH; American

Society of Retina Specialists Therapeutic Surveillance Committee. Aflibercept-related sterile

inflammation. Ophthalmology. 2013 May;120(5):1100-101.e1-5. PubMed PMID: 23642742.

Goldberg RA, Flynn HW Jr, Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after

intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology.

2013 Jul;120(7):1448-53. PubMed PMID: 23453511; PubMed Central PMCID: PMC3702685.

Shienbaum G, Flynn HW Jr., Editorial: Compounding Bevacizumab for Intravitreal Injection: Does USP

<797> Always Apply? Retina 2013 Vol 33, No 9; 1733-1734. PMID: 23851633.

Gonzalez S, Rosenfeld PJ, Stewart MW. Perspective, Avastin Doesn’t Blind People, People Blind People.

Am J Ophthalmol 2012; 153: 196-203. PMID: 22264942.

Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis

after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012 Feb;153(2):204-208.e1. PubMed PMID:


Schimel AM, Scott IU, Flynn HW Jr. Endophthalmitis after intravitreal injections: should the use of face

masks be the standard of care? Arch Ophthalmol. 2011 Dec;129(12):1607-9. PubMed PMID: 22159682.

Wykoff CC, Flynn HW Jr, Rosenfeld PJ. Prophylaxis for endophthalmitis following intravitreal injection:

antisepsis and antibiotics. Am J Ophthalmol. 2011 Nov;152(5):717-9.e2. PubMed PMID: 22017840.

Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, Schwartz SG, Davis JL, Murray TG, Smiddy WE, Berrocal AM, Dubovy

SR, Lee WH, Albini TA, Lalwani GA, Kovach JL, Puliafito CA. Endophthalmitis after intravitreal vascular

[corrected] endothelial growth factor antagonists: a six-year experience at a university referral

center. Retina. 2011 Apr;31(4):662-8. Erratum in: Retina. 2012 Jul;32(7):1441. PubMed PMID: 21836400.

Wykoff CC, Flynn HW Jr., Han DP. Allergy to Povidone-Iodine and Cephalosporins: The Clinical

Dilemma in Ophthalmic Use. Am J Ophthalmol 2011; 151: 4-6. PMID: 21163372.

Wykoff CC, Flynn HW Jr. Endophthalmitis after intravitreal injection: prevention and management.

Retina. 2011 Apr;31(4):633-5. PubMed PMID: 21836399.

Kim SJ,Toma HS. Antimicrobial resistance and ophthalmic antibiotics: 1-year results of a longitudinal

controlled study of patients undergoing intravitreal injections. Arch Ophthalmol. 2011 Sep; 129(9):1180-8.

PMID: 21911665.

40

McCannel CA. Meta-Analysis of Endophthalmitis after intravitreal injection of anti-vascular endothelial

growth factor agents, causative organisms and possible prevention strategies. Retina 2011: 31:654–661.

PMID: 21330939.

Kim SJ, Toma HS, Midha NK, Cherney EF, Recchia FM, Doherty TJ. Antibiotic resistance of conjunctiva and

nasopharynx evaluation study: A prospective study of patients undergoing intravitreal injections.

Ophthalmology. 2010 Dec; 117(12):2372-8. PMID: 20656351.

Klein KS, Walsh MK, Hassan TS, Halperin LS, Castellarin AA, Roth D, Driscoll S, Prenner JL. Endophthalmitis

after anti-VEGF injections. Ophthalmology. 2009 Jun;116(6):1225.e1. PubMed PMID: 19486799.

Scott IU, Flynn HW Jr., Endophthalmitis Prophylaxis for Intravitreal Injections. Retinal Physician 2008; 5(4):

26, 27, 48.

Roth DB, Flynn HW Jr., Distinguishing Between Infectious and Noninfectious Endophthalmitis after

Intravitreal Triamcinolone Injection. Am J Ophthalmol 2008; 146: 346-347. PMID: 18724979.

Fintak DR, Shah GK, Blinder KJ, Regillo CD, Pollack J, Heier JS, Hollands H, Sharma S. Incidence of

endophthalmitis related to intravitreal injection of Bevacizumab and Ranibizumab. Retina 2008; 28:

1395-9. PMID: 18827737.

Pilli S, Kotsolis A, Spaide RF, Slakter J, Freund KB, Sorenson J, Klancnik J, Cooney M. Endophthalmitis

associated with intravitreal anti-VEGF therapy injections in an office setting. Am J Ophthalmol 2008;

145: 879-82. PMID: 18329624.

Roth DB, Flynn HW Jr., Distinguishing Between Infectious and Noninfectious Endophthalmitis After

Intravitreal Triamcinolone Injection. Am J Ophthalmol 2008; 146: 346-347. PMID: 18724979.

Scott IU, Flynn HW Jr. Reducing the risk of endophthalmitis following intravitreal injections. Retina 2007,

27: 10-12. PMID: 17218909.

Jager RD, Aiello LP, Patel SC, Cunningham ET. Jr. Risk of intravitreous injection: a comprehensive review.

Retina 2004: 24: 676-698. PMID: 15492621

Ta CN, Minimizing the risk of endophthalmitis following intravitreous injection. Retina 2004: 24: 699-

705. PMID: 15492622

Vote BJ, Buttery R, Polkinghorne PJ. Endophthalmitis after intravitreal injection of frozen pre-prepared

TPA for pneumatic displacement of submacular hemorrhage. Retina 2004: 24: 808-809. PMID: 15492643.

Sutter FKP, Gillies MC. Pseudo-endophthalmitis after intravitreal injection of triamcinolone. Br J

Ophthalmol 2003: 87: 972-974. PMID: 12881337.

Benz M, Murray TG, Dubovy SR, Katz RS, Eifrig CW. Endophthalmitis caused by M. chelonae (abcessus)

after intravitreal triamcinolone. Arch Ophthalmol 2003: 121: 271-273. PMID: 12583797.

Roth DB, Chieh J, Spirn MJ, Green SN, Yarian DL, Chaudhry NA. Noninfectious endophthalmitis associated

with intravitreal triamcinolone injection. Arch Ophthalmol 2003: 121: 1279-1282. PMID: 12963610.

Nelson ML, Tennant MT, Sivalingam A, Regillo CD, Belmont JB, Martidis A. Infectious and presumed

noninfectious endophthalmitis after intravitreal triamcinolone acetonide injection. Retina. 2003

Oct;23(5):686-91. PubMed PMID: 14574256.

41

Moshfeghi DM, Kaiser PK, Scott IU, Sears JE, Benz M, Sinesterra JP, Kaiser RS, Bakri SJ, Maturi RK, Belmont J, Beer

PM, Murray TG, Quiroz-Mercado H, Mieler WF. Acute endophthalmitis following intravitreal

triamcinolone acetonide injection. Am J Ophthalmol. 2003 Nov;136(5):791-6. PubMed PMID: 14597028.

Parke DW. Intravitreal triamcinolone and endophthalmitis. Am J Ophthalmol. 2003 Nov;136(5):918-9.


Aiello LP, Brucker AJ, Chang S, Cunningham ET Jr, D'Amico DJ, Flynn HW Jr, Grillone LR, Hutcherson S, Liebmann

JM, O'Brien TP, Scott IU, Spaide RF, Ta C, Trese MT. Evolving guidelines for intravitreous injections. Retina.

2004 Oct;24(5 Suppl):S3-19. Review. PubMed PMID: 15483476.

Endophthalmitis Management Using Silicone Oil:

Ornek N, Apan T, Ogurel R, Ornek K. Comparison of the antimicrobial effect of heavy silicone oil and

conventional silicone oil against endophthalmitis-causing agents. Indian J Ophthalmol. 2014 Apr;62(4):388-

91. PMID: 24817741.

Kaynak S, Oner FH, Kocak N, Cingil G. Surgical management of postoperative endophthalmitis:

Comparison of 2 techniques. J. Cataract Refract Surg 2003;29: 966-969. PMID: 12781284.

Ozdamar A, Aras C, Ozturk R, Akin E, Karacorlu M, Ercikan C. In vitro antimicrobial activity of silicone oil

against endophthalmitis causing agents. Retina 1999;19: 122-126. PMID: 10213237.

Siqueira RC, Gil AD, Canamary F, Minari M, Jorge R. Pars plana vitrectomy and silicone oil tamponade for

acute endophthalmitis treatment. Arq Bras Oftalmol. 2009 Jan-Feb; 72(1):28-32. PMID: 19347118.

Yan H, LuY,Yu J, Han J, Zhang J, Chen S, XuY. Silicone oil in the surgical treatment of traumatic

endophthalmitis. Eur J Ophthalmol. 2008 Sep-Oct; 18(5):680-4. PMID: 18850542.

Pinarci EY, Yesilirmak N, Bayar SA, Sizmaz S, Akkoyun I, Yilmaz G. The results of pars plana vitrectomy and

silicone oil tamponade for endophthalmitis after intravitreal injections. Int Ophthalmol. 2013

Aug;33(4):361-5. PMID: 23277209.

Endophthalmitis After Pars Plana Vitrectomy:

Dave VP, Pathengay A, Schwartz SG, Flynn HW Jr. Endophthalmitis following pars plana vitrectomy: a

literature review of incidence, causative organisms, and treatment outcomes. Clin Ophthalmol. 2014

Oct 31;8:2183-8. Review. PubMed PMID: 25382968; PubMed Central PMCID: PMC4222626.

Henry CR, Schwartz SG, Flynn HW Jr. Endophthalmitis following pars plana vitrectomy for vitreous

floaters. Clinical Ophthalmology 8:1649-1653, 2014. PMID: 25210434 PMCID: PMC4155899.

Nahas Z, Shienbaum G, Smiddy WE, Flynn HW Jr. Hypopyon and pseudoendophthalmitis 1 month after

vitrectomy for retinal detachment with subretinal hemorrhage. Ophthalmic Surg Lasers Imaging Retina.

2013 May-Jun;44(3):281-3. PubMed PMID: 23676232.

Scott IU, Flynn HW Jr, Acar N, Dev S, Shaikh S, Mittra RA, Arevalo JF, Kychenthal A, Kunselman A. Incidence of

42

endophthalmitis after 20-gauge vs 23-gauge vs 25-gauge pars plana vitrectomy. Graefes Arch Clin Exp

Ophthalmol. 2011 Mar;249(3):377-80. PubMed PMID: 20853005.

Scott IU, Flynn HW Jr, Dev S, Shaikh S, Mittra RA, Arevalo JF, Kychenthal A, Acar N. Endophthalmitis after 25-

gauge and 20-gauge pars plana vitrectomy: incidence and outcomes. Retina. 2008 Jan;28(1):138-42.


Kunimoto DY, Kaiser RS. Incidence of endophthalmitis after 20 and 25 gauge vitrectomy. Ophthalmology

2007; 114: 2133-2137. PMID: 17916378.

Scott IU, Flynn HW Jr. Endophthalmitis after pars plana vitrectomy. Retinal Physician 2006: 3: 61-64.

Eifrig CW, Scott IU, Flynn HW Jr, Smiddy WE, Newton J. Endophthalmitis after pars plana vitrectomy:

Incidence, causative organisms, and visual acuity outcomes. Am J Ophthalmol. 2004 Nov;138(5):799-802.


Cohen SM, Flynn HW Jr, Murray TG, Smiddy WE. Endophthalmitis after pars plana vitrectomy. The

Postvitrectomy Endophthalmitis Study Group. Ophthalmology. 1995 May;102(5):705-12. Review. PubMed PMID:

7777268.

Kaiser RS, Prenner J, Scott IU, Brucker AJ, Flynn HW Jr., et al. The Microsurgical Safety Task Force: Evolving

guidelines for minimizing the risk of endophthalmitis associated with microincisional vitrectomy

surgery. Retina 2010 April; 30(4): 692-699. PMID: 20386097.

Foster RE, Rubsamen PE, Joondeph BC, Flynn HW Jr., Smiddy WE. Concurrent Endophthalmitis and Retinal

Detachment. Ophthalmology. 1994 Mar;101(3):490-8. PubMed PMID: 8127569.

Johnson RN, Flynn HW Jr, Parel JM, Portugal LM. Transient hypopyon with marked anterior chamber fibrin

following pars plana vitrectomy and silicone oil injection. Arch Ophthalmol. 1989 May;107(5):683-6.


Miscellaneous:

Townsend J, Pathengay A, Flynn HW Jr., Miller D. Management of Endophthalmitis While Preserving the

Uninvolved Crystalline Lens. Clinical Ophthalmology 2012: 6; 453-457. PMID: 22536036.

Nguyen JK, Fung AE, Flynn HW Jr, Scott IU. Hypopyon and pseudoendophthalmitis associated with

chronic vitreous hemorrhage. Ophthalmic Surg Lasers Imaging 2006;37: 317-319. PMID: 16898394.

Sulkes DJ, Flynn HW Jr, Scott IU, Feuer WJ, Christmas J. Evaluating outpatient versus inpatient costs in

endophthalmitis management. Retina 2002;22: 747-751. PMID: 12476101.

Jones DB. Emerging antibiotic resistance: real and relative. Arch Ophthalmol 1996;114: 91-92. PMID:

8540859.

Kim JE, Flynn HW Jr, Rubsamen PE, Murray TG, Davis JL, Smiddy WE. Endophthalmitis in patients with

retained lens fragments after phacoemulsification. Ophthalmology 1996;103: 575-578. PMID: 8618754.

Scott IU, Flynn HW Jr, Feuer W. Endophthalmitis after secondary IOL implantation: a case/control

study. Ophthalmology 1995;102: 1925-1931. PMID: 9098297.

43

Foster RE, Rubsamen PE, Joondeph BC, Flynn HW, Smiddy WS: Concurrent endophthalmitis and retinal

detachment. Ophthalmology 1994;101:490-498. PMID: 8127569.

Ormerod LD, Puklin JE, McHenry JG, McDermott ML. Scleral flap necrosis and infectious endophthalmitis

after cataract surgery with a scleral tunnel incision. Ophthalmology 1993;100: 159-163. PMID: 8437821.

Irvine WD, Flynn HW Jr, Murray TG, Rubsamen PE. Retained lens fragments after phacoemulsification

manifesting as marked intraocular inflammation with hypopyon. Am J Ophthalmol 1992;114: 610-614.

PMID: 1443024.

Huang S, Brod R, Flynn HW Jr. Endophthalmitis management while preserving the uninvolved crystalline

lens. Am J Ophthalmol 1991;112: 695-701. PMID: 1957906.

Stonecipher KG, Parmley VC, Jensen H, Rowsey JJ. Infectious endophthalmitis following sutureless cataract

surgery. Arch Ophthalmol 1991;109: 1562-1563. PMID: 1755738.

1

Clinical Trials in Diabetic Retinopathy

2015

Harry W. Flynn Jr., M.D.

Nidhi Relhan, M.D.

Bascom Palmer Eye Institute

900 N.W. 17th Street

Miami, FL 33136

Phone: (305) 326-6118

Fax: (305) 326-6417

E-mail: [email protected]

mailto:[email protected]

2

Clinical Trials in Diabetic Retinopathy I. Laser Trials 1. DRS 2. ETDRS 3. DRCR (Protocol A) 4. DRCR (Protocol B) 5. DRCR (Protocol F) 6. DRCR (Protocol K) 7. DRCR (Protocol V) II. Pharmacotherapy Trials

1. DRCR (Protocol I)

2. DRCR (Protocol N)

3. DRCR (Protocol T)

4. DRCR (Protocol S)

5. READ I

6. READ II

7. RISE/RIDE

8. RESTORE

9. BOLT

10. FAME

11. DAVINCI

12. VIVID/VISTA

13. LUCIDATE III. Vitreoretinal Surgery Trials

1. DRCR (Protocol D) 2. DRVS 3. ETDRS – Report 17

IV. Medical Management Trials 1. DCCT/EDIC 2. UKPDS 3. FIELD 4. ACCORD

3

1. Laser Trials

(1) Diabetic Retinopathy Study (DRS)

The Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy: Clinical Application of Diabetic Retinopathy Study (DRS) Findings: DRS Report No. 8. Ophthalmology 88: 583-600, 1981. The Diabetic Retinopathy Study Research Group: Four risk factors for severe visual loss in diabetic retinopathy: DRS Report No. 3. Arch Ophthalmol 97: 654-655, 1979.

The DRS was a randomized, prospective clinical trial evaluating photocoagulation (PDR) treatment to one eye of patients with clear media and advanced NPDR or PDR in both eyes. The primary outcome measurement in the DRS was severe visual loss (SVL) defined as a visual acuity of less than 5/200 on two consecutive follow-up examinations four months apart.

The DRS demonstrated a 50% or greater reduction in the rates of SVL in eyes treated with PRP compared to untreated control eyes during follow up of up to 5 years.

DRS “high-risk” PDR was defined as any one of the following:

o Mild (1/4 to 1/3 disc area) neovascularization of the disc (NVD) with vitreous hemorrhage.

o Moderate to severe NVD with or without vitreous hemorrhage. o Moderate (1/2 disc area) neovascularization elsewhere (NVE) with

vitreous hemorrhage

Another way of defining DRS “high-risk PDR is by any three of the four Retinopathy Risk Factors:

o The presence of vitreous or preretinal hemorrhage. o The presence of new vessels. o Location of new vessels on or near the optic disc. o Moderate to severe extent of new vessels.

The DRS recommended prompt PRP of eyes with high-risk PDR because this

group had the highest risk of SVL. The complications of argon laser PRP in the DRS were generally mild but included a drop in visual acuity of one or more lines in 11% and visual field loss in 5%.

Diabetic Retinopathy Clinical Research Network 2014

4

(2) The Early Treatment Diabetic Retinopathy Study (ETDRS)

The ETDRS was a randomized, prospective study evaluating photocoagulation and aspiring

treatment of diabetic patients with less than high-risk PDR in both eyes. The primary outcome measurement in the ETDRS was moderate visual loss (MVL) comparing baseline with follow up visual acuities. MLV was defines as a doubling of the visual angle (e.g., a drop from 20/20 to 20/40 or from 20/50 to 20/100), a drop of 15 or more letters on ETDRS visual acuity charts, or a drop of 3 or more lines of Snellen equivalent.

It defined clinically significant macular edema (CSME) as any one of the following:

o Retinal edema located at or within 500 μm of the center of the macula. o Hard exudates at or within 500μm of the center if associated with thickening

of adjacent retina. o A zone of thickening larger than one disc area if located within 1 disc diameter

of the center of the macula.

Classification of diabetic retinopathy o Non-proliferative Diabetic Retinopathy (NPDR)

Mild - At least one: Microaneurysms or Dot/blot hemorrhages Moderate – Marked hemorrhages/microaneurysms or Cotton

wool spots (CWS) or Venous beading (VB) not fulfilling the 4-2-1 rule.

Severe/Very Severe – as per 4-2-1 Rule: – Marked hemorrhages/microaneurysms in all 4 quadrants VB in 2 or more quadrants or IRMAʼs in 1 quadrant Severe - if 1 of the above 3 features present Very Severe - if 2 of the above 3 features present

o Proliferative Diabetic Retinopathy (PDR) – Including high-risk

The Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema. Arch Ophthalmol 103: 1796-1806, 1985. The Early Treatment Diabetic Retinopathy Study Research Group: Early Photocoagulation for diabetic retinopathy. ETDRS Report No. 9. Ophthalmology (Suppl) 98: 766-785, 1991. The Early Treatment Diabetic Retinopathy Study Research Group: Effects of Aspirin Treatment on Diabetic Retinopathy. ETDRS Report No. 20. Arch Ophthalmol 113: 52-55, 1995. Flynn HW JR., Chew EY, Simons BD, et al. Pars plana vitrectomy in the Early Treatment Diabetic Retinopathy Study. ETDRS Report No. 17. Ophthalmology 99: 1351-1357, 1992.

5

The ETDRS addresses three issues:

o 1) The efficacy of laser treatment for macular edema. It showed a 50% or greater

reduction in the rates of MVL in laser treated eyes with CSME (compared to untreated control eyes)

o 2) The timing for initiating PRP. The ETDRS stated that provided follow up can be maintained, scatter panretinal photocoagulation was not recommended for eyes with mild or moderate NPDR. When NPDR becomes more severe and approaches the high-risk stage, scatter PRP treatment can be considered and usually should not be delayed when the retinopathy reaches the high-risk stage.

o 3) The value of aspirin treatment. At a dosage of 650mg per day, aspirin did not alter the rates of progression of diabetic retinopathy, had no influence on visual acuity outcomes, and did not increase the risk of vitreous hemorrhage. Therefore at this dosage, there appears to be no ocular contraindication to the use of aspirin in persons with diabetes who require it for treatment of cardiovascular diseases or for other medical indications.

Vitrectomy in the ETDRS was a secondary issue. Vitrectomy was performed in 208 (5.6%) of the 3711 patients (243 eyes) enrolled in the ETDRS. The 5-year vitrectomy rates in the ETDRS were 5.4% in patients assigned to aspirin and 5.2% in patients assigned the placebo. For eyes with more severe retinopathy and macular edema, the 5-year rate for the combined endpoint of severe visual loss or occurrence of vitrectomy was higher (10.3%) in eyes assigned to deferral of photocoagulation unless HRC developed and was lower (5.6%) in full scatter treated eyes to 6.9% in mild scatter treated eyes) in the groups assigned to early PRP treatment.

6

(3) DRCR (Protocol A)

Comparison of the Modified Early Treatment Diabetic Retinopathy Study and Mild Macular Grid Laser

Photocoagulation Strategies for Diabetic Macular Edema

Writing Committee for the Diabetic Retinopathy Clinical Research Network

Objective: To compare 2 laser photocoagulation techniques for treatment of diabetic macular edema: the modified Early Treatment Diabetic Retinopathy Study (ETDRS) direct/grid photocoagulation technique and a potentially milder (but potentially more extensive) mild maculargrid(MMG)lasertechniqueinwhichmicroan- eurysms are not treated directly and small mild burns are placed throughout the macula, whether or not edema is present.

Methods: Two hundred sixty-three subjects (mean age, 59 years) with previously untreated diabetic macular edema were randomly assigned to receive laser photocoagulation by either the modified ETDRS (162 eyes) or MMG (161 eyes) technique. Visual acuity, fundus photographs, and optical coherence tomography measurements were obtained at baseline and at 3.5, 8, and 12 months. Treatment was repeated if diabetic macular edema persisted.

Main Outcome Measure: Change in optical coherence tomography measurements at 12-month follow-up.

Results: Among eyes with a baseline central subfield thickness of 250 µm or greater, central subfield thickening decreased by an average of 88 µm in the modified ETDRS group and by 49 µm in the MMG group at 12-month follow-up (adjusted mean difference, 33 µm; 95% confidence interval, 5-61 µm; P = .02). Weighted inner zone thickening by optical coherence tomography decreased by 42 µm in the modified ETDRS group and by 28 µm in the

MMG group (adjusted mean difference, 14 µm; 95% confidence interval, 1-27 µm; P=.04); maximum retinal thickening (maximum thickening of the central and 4 inner sub- fields) decreased by 66 and 39 µm, respectively (adjusted mean difference, 27 µm; 95% confidence interval, 6-47 µm; P=.01), and retinal volume decreased by 0.8 and 0.4 mm3, respectively (adjusted mean difference, 0.3 mm3; 95% confidence interval, 0.02-0.53 mm3; P = .03). At 12 months, the mean change in visual acuity was 0 letters in the modified ETDRS group and 2 letters worse in the MMG group (adjusted mean difference, 2 letters; 95% confidence interval, −0.5 to 5 letters; P = .10).

Conclusions: At 12 months after treatment, the MMG technique was less effective at reducing optical coherence tomography–measured retinal thickening than the more extensively evaluated current modified ETDRS laser photocoagulation approach. However, the visual acuity outcome with both approaches is not substantially different. Given these findings, a larger long-term trial of the MMG technique is not justified.

Application to Clinical Practice: Modified ETDRS focal photocoagulation should continue to be a standard approach for treating diabetic macular edema. Trial Registration: clinicaltrials.gov Identifier: NCT00071773.

Arch Ophthalmol . 2007;125:469-480

7

(4) DRCR (Protocol B)

8

(5) DRCR (Protocol F)

9

(6) DRCR (Protocol K)

10

(7) DRCR (Protocol V)

Comparative Effectiveness Study of Laser, Observation and

Ranibizumab for DME in eyes with Very Good VA.

(NCT01909791)

Official Title: Treatment for Central-Involved Diabetic Macular Edema in Eyes With Very

Good Visual Acuity.

Study Type: Interventional/Randomized/Safety - Efficacy Study / Parallel Assignment /

Single Blind (Outcomes Assessor) Masking

Primary Objective - To compare the % of eyes that have lost at least 5 letters of visual

acuity at 2 years compared with baseline mean visual acuity in eyes with central-involved

DME and good visual acuity defined as a Snellen equivalent of 20/25 or better (electronic-

ETDRS letter score of 79 or better) that receive

(1) Prompt focal/grid photocoagulation + deferred anti-VEGF,

(2) Observation + deferred anti-VEGF, or

(3) Prompt anti-VEGF

Secondary Objective - Other visual acuity outcomes

• Percentage of eyes needing anti-VEGF treatment

• Optical Coherence Tomography (OCT) Outcomes

• Proportion of eyes avoiding vitreous hemorrhage or panretinal photocoagulation

(PRP) or vitrectomy for PDR

• Safety Outcomes

• Associated treatment and follow-up exam costs

Current Status – Recruiting participants

Estimated Completion Date – March 2017

11

II. Pharmacotherapy Trials

(1) DRCR Protocol I

12

(1) DRCR Protocol I (3 year Results)

Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt versus Deferred Laser Treatment Three-Year Randomized Trial Results

Diabetic Retinopathy Clinical Research Network* Writing Committee: Michael J. Elman, MD,1 Haijing Qin, MS,2 Lloyd Paul Aiello, MD,3 Roy W. Beck, MD,2 Neil M. Bressler, MD,4 Frederick L. Ferris III, MD,5 Adam R. Glassman, MS,2 Raj K. Maturi, MD, PC,6 Michele Melia, ScM2

Objective: To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for >24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema (DME). Design: Multicenter, randomized clinical trial. Participants: Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods: Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (>24 weeks) focal/grid laser treatment. Main Outcome Measures: Best-corrected visual acuity and safety at the 156-week (3-year) visit. Results: The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4 –5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a >10-letter gain/loss was 42% and 56% (P = 0.02), whereas the respective percentage of eyes with a >10-letter gain/loss was 10% and 5% (P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively (P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 µm or more on time-domain optical coherence tomography were 36% in both groups (P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups. Conclusions: These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012;119:2312–2318

13

(1) DRCR Protocol I (5 year Results)

14

(2) DRCR (Protocol N)

15

(2) DRCR (Protocol N)

16

Results

17

Discussion

18

(4)DRCR (Protocol T)

19

(3)DRCR (Protocol S)

Submitted to JAMA (2015) for publication

Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Trial. Objective – Compare efficacy and safety of PRP versus intravitreous ranibizumab for PDR. Design – Multicenter, randomized, non-inferiority trial enrolling 305 patients (394 study eyes) with PDR. Interventions – PRP or intravitreous 0.5mg ranibizumab Main Outcome Measures – Primary Outcome: Mean change in visual acuity from baseline to 2 years (non-inferiority margin of 5 letters). Results – Manuscript submitted

20

(5) READ-1 Study

Am J Ophthalmol. 2006 Dec;142(6):961-9.

Abstract PURPOSE: The role of vascular endothelial growth factor (VEGF) in diabetic macular edema (DME) was tested with ranibizumab, a specific antagonist of VEGF. DESIGN: A nonrandomized clinical trial. METHODS: Ten patients with chronic DME received intraocular injections of 0.5 mg of ranibizumab at baseline and at one, two, four, and six months. The primary outcome was change in foveal thickness between baseline and seven months, and the secondary outcome measures were changes from baseline in visual acuity and macular volume. RESULTS: Mean values at baseline were 503 microm for foveal thickness, 9.22 mm3 for macular volume, and 28.1 letters (20/80) read on an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart. At seven months (one month after the fifth injection), the mean foveal thickness was 257 microm, which was a reduction of 246 microm (85% of the excess foveal thickness present at baseline; P = .005 by Wilcoxon signed-rank test for likelihood that this change is due to ranibizumab rather than chance). The macular volume was 7.47 mm3, which was a reduction of 1.75 mm3 (77% of the excess macular volume at baseline; P = .009). Mean visual acuity was 40.4 letters (20/40), which was an improvement of 12.3 letters (P = .005). The injections were well-tolerated with no ocular or systemic adverse events. CONCLUSION: Intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in 10 patients with DME, which demonstrated that VEGF is an important therapeutic target for DME. A randomized, controlled, double-masked trial is needed to test whether intraocular injections of ranibizumab provide long-term benefit to patients with DME.

Vascular Endothelial Growth Factor Is a

Critical Stimulus for Diabetic Macular Edema

QUAN DONG NGUYEN, MD, MSC, SINAN TATLIPINAR, MD, SYED MAHMOOD SHAH,MBBS, JULIA A. HALLER, MD, EDWARD QUINLAN, MD, JENNIFER SUNG, MD,

INGRID ZIMMER-GALLER, MD, DIANA V. DO, MD,AND PETER A. CAMPOCHIARO, MD

● PURPOSE: The role of vascular endothelial growth

factor (VEGF) in diabetic macular edema (DME) was

tested with ranibizumab, a specific antagonist of VEGF.● DESIGN: A nonrandomized clinical trial.● METHODS: Ten patients with chronic DME received

intraocular injections of 0.5 mg of ranibizumab at base-

line and at one, two, four, and six months. The primary

outcome waschange in foveal thicknessbetween baseline

and seven months, and the secondary outcome measures

were changes from baseline in visual acuity and macular

volume.● RESULTS: Mean values at baseline were 503 m for

foveal thickness, 9.22 mm3 for macular volume, and

28.1 letters(20/80) readon an Early Treatment Diabetic

Retinopathy Study (ETDRS) visual acuity chart. At

seven months (one month after the fifth injection), the

mean foveal thickness was 257 m, which was a reduc-

tion of 246 m (85% of the excess foveal thickness

present at baseline; P .005 by Wilcoxon signed-rank

test for likelihood that thischange isdue to ranibizumab

rather than chance). Themacular volumewas7.47 mm3,

which was a reduction of 1.75 mm3 (77% of the excess

macular volume at baseline; P .009). Mean visual

acuity was 40.4 letters (20/40), which was an improve-

ment of 12.3 letters (P .005). The injections were

well-tolerated with no ocular or systemic adverse events.● CONCLUSION: Intraocular injections of ranibizumab

significantly reduced foveal thickness and improved vi-

sual acuity in 10 patients with DME, which demon-

strated that VEGF isan important therapeutic target for

DME. A randomized, controlled, double-masked trial is

needed to test whether intraocular injections of ranibi-

zumab provide long-term benefit to patients with DME.

(Am J Ophthalmol 2006;142:961–969. © 2006 by

Elsevier Inc. All rights reserved.)

DIABETIC RETINOPATHY IS THE MOST PREVALENT

cause of vision lossin working aged individualsin

developed countries.1 Severe vision loss occurs

because of traction retinal detachments that complicate

retinal neovascularization, but the most common cause of

moderate vision loss is macular edema. Macular edema

occurs from the leakage of plasma into the central retina,

which causes it to thicken because of excess interstitial

fluid. The excess interstitial fluid is likely to disrupt ion

fluxesand the thickening of the macula results in stretch-

ingand distortion of neurons. Thereisreversiblereduction in

visual acuity, but over time theperturbed neuronsdie, which

results in permanent visual loss.

The leakage of plasma in patientswith diabetic macular

edema (DME) isvisualized by fluorescein angiography and

may be focal because of leakage from microaneurysms or

diffuse. Microaneurysms are thought to occur because of

hyperglycemia-induced pericyte death, which weakens the

wallsof retinal vesselsand resultsin thesmall aneurysmsin

which endothelial cellsare perturbed causing them to lose

their barrier qualities and leak.2 However, diffuse leakage

from retinal capillaries that do not show visible structural

changes(such asmicroaneurysms) isalso a common feature

of DME. This could be due to microscopic damage to

retinal vessels that are not visible in images that are

obtained during fluorescein angiography but could also be

due the presence of excessive amountsof pro-permeability

factors.

Recently, retinal hypoxia has been implicated in the

pathogenesis of DME.3 Hypoxia causes increased expres-

sion of vascular endothelial growth factor (VEGF), which

is a potent inducer of vascular permeability that has been

shown to cause leakage from retinal vessels.4,5 Thus, it is

reasonable to hypothesize that VEGF contributes to DME.

Supplemental Material available at AJO.com.Accepted for publication Jun 29, 2006.

From the The Wilmer Eye Institute, The Johns Hopkins UniversitySchool of Medicine, Baltimore, Maryland.

Supported by the Innovative Grant Award from the Juvenile DiabetesResearch Foundation; by a scholarship from the Scientific and Techno-logical Research Council of Turkey (S.T.); and by a K23 CareerDevelopment Award (EY 13552) from the National Eye Institute(Q.D.N.). The study drug was provided by Genentech, Inc.

Inquiries to Peter A. Campochiaro, MD, Maumenee 719, The WilmerEye Institute, The Johns Hopkins University School of Medicine, 600North Wolfe St, Baltimore, MD 21287–9277; e-mail: [email protected]

© 2006 BY ELSEVIER INC. ALL RIGHTS RESERVED.0002-9394/06/$32.00 961doi:10.1016/j.ajo.2006.06.068

21

(6) READ-2 Study

22

(6) READ-2 Study (Two-Year Outcomes)

23

(7) RISE and RIDE Study

24

(7) Results from RIDE and RISE

Vision-Related Function after Ranibizumab Treatment for Diabetic Macular Edema

Neil M. Bressler, MD,1 Rohit Varma, MD,2 Ivan J. Suñer, MD,3 Chantal M. Dolan, PhD,4 James Ward, PhD,4 Jason S. Ehrlich, MD, PhD,4 Shoshana Colman, PhD,4 Adam Turpcu, PhD,4 for the RIDE and RISE Research Groups*

Objective: To examine the effects of intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Fran- cisco, CA) treatment on patient-reported vision-related function, as assessed by 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores, in patients with visual impairment secondary to center- involved diabetic macular edema (DME). Design: Within 2 randomized, double-masked, phase 3 clinical trials (RIDE [A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema {ME} With Center Involvement Secondary to Diabetes Mellitus; NCT00473382] and RISE [A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema {ME} With Center Involvement Secondary to Diabetes Mellitus; NCT00473330]), the NEI VFQ-25 was administered at baseline and at the 6-, 12-, 18-, and 24-month follow-up visits. Participants: Three hundred eighty-two (100%) RIDE patients and 377 (100%) RISE patients. Intervention: Patients were randomized 1:1:1 to monthly injections of intravitreal ranibizumab 0.3 or 0.5 mg or sham. Study participants could receive macular laser for DME from month 3 onward if specific criteria were met. Main Outcome Measures: Exploratory post hoc analysis of mean change from baseline in NEI VFQ-25 scores at 12 and 24 months. Results: Across all treatment arms, 13% to 28% of enrolled eyes were the better-seeing eye. For all eyes in RIDE and RISE, the mean change in NEI VFQ-25 composite score improved more in ranibizumab-treated eyes at both the 12- and 24-month visits compared with sham treatment. For the better-seeing eyes at baseline, the mean change in composite score with 0.3 mg ranibizumab at the 24-month visit was 10.9 more (95% confidence interval [CI], 2.5e19.2) than sham for RIDE patients and 1.3 more (95% CI, -10.5 to 13.0) than sham for RISE patients. For the worse-seeing eyes at baseline, the mean change in composite score with 0.3 mg ranibizumab at the 24-month visit was 1.0 more (95% CI, -4.7 to 6.7) than sham for RIDE patients and 1.8 more (95% CI, -2.7 to 6.2) than sham for RISE patients. Similar results for most of these outcomes were seen with 0.5 mg ranibizumab. Conclusions: These phase 3 trials demonstrated that ranibizumab treatment for DME likely improves patient-reported vision-related function outcomes compared with sham, further supporting treatment of DME with ranibizumab. Ophthalmology 2014;-:1-12.

25

(8) RESTORE Study

26

(9) BOLT Study

27

(9) BOLT Study (24 Month Data)

28

(10) FAME Study

29

(10) FAME Study

30

(11) DAVINCI Study

31

(11) DAVINCI Study

32

(12) VISTA and VIVID - Study

33

(13) LUCIDATE - Study

Abstract PURPOSE: To compare the functional and structural effects of ranibizumab versus macular laser therapy in patients with center-involving diabetic macular edema. DESIGN: Prospective, randomized, single-masked clinical trial. METHODS: SETTING: Single center. STUDY POPULATION: Thirty-three eyes of 33 patients with center-involving diabetic macular edema, with best corrected visual acuity of 55 to 79 Early Treatment Diabetic Retinopathy Study letters at baseline, completing the 48-week study period. INTERVENTION: Subjects were randomized 2:1 to 3 loading doses of ranibizumab then retreatment every 4 weeks as required; or macular laser therapy at baseline, repeated as required every 12 weeks. Exploratory Outcome Measures: Structural imaging studies included greatest linear dimension and area of foveal avascular zone, perifoveal capillary dropout grade, and presence of morphologic features of diabetic macular edema on Spectralis optical coherence tomography (Heidelberg Engineering GmbH, Heidelberg, Germany). Functional measures: Visual acuity, retinal sensitivity in the central 4 and 12 degrees on microperimetry, color contrast sensitivity protan and tritan thresholds, pattern and full-field electroretinogram amplitudes and implicit times, and multifocal electroretinogram amplitude distribution. These were reported at 12, 24, and 48 weeks. RESULTS: Ranibizumab-treated subjects gained 6.0 vs 0.9 letters lost for laser, demonstrated improved tritan and protan color contrast thresholds, and improved retinal sensitivity. Electrophysiologic function also improved after ranibizumab therapy. No safety issues were evident. Better retinal thickness reduction and structural improvement in optical coherence tomography features of diabetic macular edema were seen with ranibizumab therapy than in the laser group. There was no evidence of progressive ischemia with ranibizumab therapy. CONCLUSIONS: Ranibizumab therapy in the treatment of diabetic macular edema seems to

improve retinal function and structure as demonstrated by this evaluation of different

assessment methods.

34

III. Vitreoretinal Surgery Trials

(1) DRCR Protocol D

35

(1) DRCR Protocol D

36

(2) DRVS

Abstract Six hundred sixteen eyes with recent severe diabetic vitreous hemorrhage reducing visual acuity to 5/200 or less for at least one month were randomly assigned to either early vitrectomy or deferral of vitrectomy for one year. After two years of follow-up, 25% of the early vitrectomy group had visual acuity of 10/20 or better compared with 15% in the deferral group (P = .01). In patients with Type I diabetes, who were on the average younger and had more-severe proliferative retinopathy, there was a clear-cut advantage for early vitrectomy, as reflected in the percentage of eyes recovering visual acuity of 10/20 or better (36% vs 12% in the deferral group, P = .0001). No such advantage was found in the Type II diabetes group (16% in the early group vs 18% in the deferral group), but evidence that this advantage differed by diabetes type was of borderline significance.

37

(3) ETDRS - Report 17

Abstract BACKGROUND:

The Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3711 patients with mild-to-

severe nonproliferative or early proliferative diabetic retinopathy in both eyes. Patients were

randomly assigned to aspirin 650 mg/day or placebo. One eye of each patient was assigned randomly

to early photocoagulation and the other to deferral of photocoagulation. Follow-up examinations

were scheduled at least every 4 months, and photocoagulation was initiated in eyes assigned to

deferral as soon as high-risk proliferative retinopathy was detected. Aspirin was not found to have

an effect on retinopathy progression or rates of vitreous hemorrhage. The risk of a combined end

point, severe visual loss or vitrectomy, was low in eyes assigned to deferral (6% at 5 years) and was

reduced by early photocoagulation (4% at 5 years). Vitrectomy was carried out in 208 patients

during the 9 years of the study. This report presents baseline and previtrectomy characteristics and

visual outcome in these patients.

METHODS:

Information collected at baseline and during follow-up as part of the ETDRS protocol was

supplemented by review of clinic charts for visual acuity and ocular status immediately before

vitrectomy.

RESULTS:

Vitrectomy was performed in 208 (5.6%) of the 3711 patients (243 eyes) enrolled in the ETDRS. The

5-year vitrectomy rates for eyes grouped by their initial photocoagulation assignment were as

follows: 2.1% in the early full scatter photocoagulation group, 2.5% in the early mild scatter group,

and 4.0% in the deferral group. The 5-year rates of vitrectomy (in one or both eyes) were 5.4% in

patients assigned to aspirin and 5.2% in patients assigned to a placebo. The indications for vitrectomy

were either vitreous hemorrhage (53.9%) or retinal detachment with or without vitreous

hemorrhage (46.1%). Before vitrectomy, visual acuity was 5/200 or worse in 66.7% of eyes and

better than 20/100 in 6.2%. One year after vitrectomy, the visual acuity was 20/100 or better in

47.6% of eyes, including 24.0% with visual acuity of 20/40 or better.

CONCLUSIONS:

With frequent follow-up examinations and timely scatter (panretinal) photocoagulation, the 5-year

cumulative rate of pars plana vitrectomy in ETDRS patients was 5.3%. Aspirin use did not influence

the rate of vitrectomy.

38

IV. Medical Management Trials

(1) DCCT study

39

(1) DCCT/EDIC Study

40

(2) UKPDS study

41

(3) FIELD study

42

(4) ACCORD

43

(4) ACCORD

44

Diabetic Retinopathy Clinical Research Network (DRCRnet)

1. Browning DJ, Glassman AR, Aiello LP, Bressler NM, Bressler SB, Danis RP, Davis MD, Ferris FL, Huang SS, Kaiser PK, Kollman C, Sadda S, Scott IU, Qin H; Diabetic Retinopathy Clinical Research Network. Optical coherence tomography measurements and analysis methods in optical coherence tomography studies of diabetic macular edema. Ophthalmology.2008 Aug;115(8):1366-71, 1371.e1 (Published). (Manuscript) | View Publication

2. Browning DJ, Altaweel MM, Bressler NM, Bressler SB, Scott IU; Diabetic Retinopathy Clinical Research Network. Diabetic macular edema: what is focal and what is diffuse?. Am J Ophthalmol.2008 Nov;146 (5):649-55.e1-6. (Published). (Manuscript) | View Publication

3. Glassman AR, Beck RW, Browning DJ, Danis RP, Kollman C; Diabetic Retinopathy Clinical Research Network Study Group. Comparison of optical coherence tomography in diabetic macular edema, with and without reading center manual grading from a clinical trials perspective. Invest Ophthalmol Vis Sci.2009 Feb;50 (2):560-6 (Published). (Manuscript) | View Publication

4. Sun JK, Aiello LP, Stockman M, Cavallerano JD, Kopple A, Eagan S, Qin H, Kollman C, Beck RW, Glassman AR; Diabetic Retinopathy Clinical Research Network. Effects of dilation on Electronic-ETDRS Visual Acuity in diabetic patients. Invest Ophthalmol Vis Sci.2009 Apr;50(4):1580-4. (Published). (Manuscript) | View Publication

5. Bhavsar AR, Googe JM Jr, Stockdale CR, Bressler NM, Brucker AJ, Elman MJ, Glassman AR; Diabetic Retinopathy Clinical Research Network. The Risk of Endophthalmitis Following Intravitreal Injection in the DRCR.net Laser-Ranibizumab-Triamcinolone Clinical Trials. Arch Ophthalmol. 2009 Dec;127(12):1581-3 (Published). (Manuscript) | View Publication

6. Ferris FL, Miller KM, Glassman AR, Beck RW; Diabetic Retinopathy Clinical Research Network. A proposed method of logarithmic transformation of ocular coherence tomography data for use in clinical research. Ophthalmology 2010 Aug;117:1512–1516 (Published). (Manuscript) | View Publication

7. Sun JK, Aiello LP, Cavallerano JD, Stockman M, Miller KM, Qin H, Beck RW, Glassman AR; Diabetic Retinopathy Clinical Research Network. Visual acuity testing using autorefraction or pinhole as compared with manual DRCR protocol refraction in individuals with diabetes. Ophthalmology.2011 Mar;118:537–542 (Published). (Manuscript) | View Publication

8. Gangaputra S, Almukhtar T, Glassman AR, Aiello LP, Bressler NM, Bressler SB, Danis RP, Davis MD, for the Diabetic Retinopathy Clinical Research Network. Comparison of Film and Digital Fundus Photographs in Eyes of Individuals with Diabetes Mellitus. IOVS 2011 Aug;52:6168-73 (Published). (Manuscript) | View Publication

9. Bhavsar AR, Stockdale CR, Ferris FL III, Brucker AJ, Bressler NM, Glassman AR, for the Diabetic Retinopathy Clinical Research. Update on Risk of Endophthalmitis After Intravitreal Drug Injections

45

and Potential Impact of Elimination of Topical Antibiotics. Arch Ophthalmol. 2012 Jun;130(6):809-810 (Published). (Manuscript) | View Publication

10.Bressler SB, Almukhtar T, Bhorade A, Bressler NM, Glassman AR, Huang S, Jampol LM, Kim JE, Melia M, for the Diabetic Retinopathy Clinical Research Network. Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema and the Risk of Sustained IOP Elevation or Ocular Hypotensive Treatment. JAMA Ophthalmology. 2014 (Submitted for Publication). (Manuscript)

11.Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, Berger BB, Bressler NM, for the Diabetic Retinopathy Clinical Research Network. Ranibizumab plus prompt or deferred laser for diabetic macular edema in eyes with vitrectomy prior to anti-vascular endothelial growth factor therapy. Retina. 2014 (Submitted for Publication). (Manuscript)

12.Jampol LM, Bressler NM, Glassman AR. Revolution to a new standard treatment of diabetic macular edema. JAMA. 2014 Jun 11;311(22):2269-70 (Published). (Manuscript)

Protocol A - Laser Photocoagulation for Diabetic Macular Edema

1. Diabetic Retinopathy Clinical Research Network, Browning DJ, Glassman AR, Aiello LP, Beck RW, Brown DM, Fong DS, Bressler NM, Danis RP, Kinyoun JL, Nguyen QD, Bhavsar AR, Gottlieb J, Pieramici DJ, Rauser ME, Apte RS, Lim JI, Miskala PH. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology.2007 Mar;114(3):525-36 (Published). (Manuscript) | View Publication

2. Writing Committee for the Diabetic Retinopathy Clinical Research Network, Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, Danis RP, Davis MD, Feman SS, Ferris F, Friedman SM, Garcia CA, Glassman AR, Han DP, Le D, Kollman C, Lauer AK, Recchia FM, Solomon SD. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol.2007 Apr;125(4):469-80 (Published). (Manuscript) | View Publication

3. Davis MD, Bressler SB, Aiello LP, Bressler NM, Browning DJ, Flaxel CJ, Fong DS, Foster WJ, Glassman AR, Hartnett ME, Kollman C, Li HK, Qin H, Scott IU; Diabetic Retinopathy Clinical Research Network Study Group. Comparison of time-domain OCT and fundus photographic assessments of retinal thickening in eyes with diabetic macular edema. Invest Ophthalmol Vis Sci.2008 May;49(5):1745-52 (Published). (Manuscript) | View Publication

4. Browning DJ, Apte RS, Bressler SB, Chalam KV, Danis RP, Davis MD, Kollman C, Qin H, Sadda S, Scott IU; Diabetic Retinopathy Clinical Research Network. Association of the extent of diabetic macular edema as assessed by optical coherence tomography with visual acuity and retinal outcome variables. Retina.2009 Mar;29(3):300-5 (Published). (Manuscript) | View Publication

5. Scott IU, Danis RP, Bressler SB, Bressler NM, Browning DJ, Qin H; Diabetic Retinopathy Clinical Research Network. Effect of focal/grid photocoagulation on visual acuity and retinal thickening in eyes with non- center-involved diabetic macular edema. Retina 2009 May;29(5):613-7 (Published). (Manuscript) | View Publication

6. Danis RP, Scott IU, Qin H, Altaweel MM, Bressler NM, Bressler SB, Browning DJ, Kollman C; Diabetic Retinopathy Clinical Research Network. Association of fluorescein angiographic features with visual acuity and with OCT and stereoscopic color fundus photographic features of DME in a randomized clinical trial. Retina.2010 Dec;30(10):1627-37 (Published). (Manuscript) | View Publication

46

Protocol B - Intravitreal Triamcinolone Acetonide versus Laser Study

1. Bhavsar AR, Ip MS, Glassman AR; DRCRnet and the SCORE Study Groups. The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials. Am J Ophthalmol.2007 Sep;144(3):454-6 (Published). (Manuscript) | View Publication

2. Ip MS, Bressler SB, Antoszyk AN, Flaxel CJ, Kim JE, Friedman SM, Qin H; Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone and focal/grid photocoagulation for diabetic macular edema: baseline features. Retina.2008 Jul-Aug;28(7):919-30 (Published). (Manuscript) | View Publication

3. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology.2008 Sep;115 (9):1447-9.e1-10 (Published). (Manuscript) | View Publication

4. Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol.2009 Mar;127(3):245-51 (Published). (Manuscript) | View Publication

5. Bressler NM, Edwards AR, Beck RW, Flaxel CJ, Glassman AR, Ip MS, Kollman C, Kuppermann BD, Stone TW; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch Ophthalmol. 2009 Dec;127(12):1566-71 (Published). (Manuscript) | View Publication

6. Aiello LP, Edwards AR, Beck RW, Bressler NM, Davis MD, Ferris FL, Glassman AR, Ip MS, Miller KM, for the Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2010 May;117(5):946-953 (Published). (Manuscript) | View Publication

7. Lauer AK, Bressler NM, Edwards AR, for the Diabetic Retinopathy Clinical Research Network. Frequency of Intraocular Pressure Increase within Days After Intravitreal Triamcinolone Injections in the Diabetic Retinopathy Clinical Research Network. Arch Ophthalmol. 2011 Aug;129(8):1097-1099. (Published). (Manuscript)

Protocol C - OCT Diurnal Variation Study

1. Diabetic Retinopathy Clinical Research Network, Danis RP, Glassman AR, Aiello LP, Antoszyk AN, Beck RW, Browning DJ, Ciardella AP, Kinyoun JL, Murtha TJ, Topping TM, Shami M, Sharuk GS, Wells JA 3rd. Diurnal variation in retinal thickening measurement by optical coherence tomography in center-involved diabetic macular edema. Arch Ophthalmol.2006 Dec;124(12):1701-7 (Published). (Manuscript) | View Publication

2. Diabetic Retinopathy Clinical Research Network, Krzystolik MG, Strauber SF, Aiello LP, Beck RW, Berger BB, Bressler NM, Browning DJ, Chambers RB, Danis RP, Davis MD, Glassman AR, Gonzalez VH, Greenberg PB, Gross JG, Kim JE, Kollman C. Reproducibility of macular thickness and volume using

47

Zeiss optical coherence tomography in patients with diabetic macular edema. Ophthalmology.2007 Aug;114(8):1520-5 (Published). (Manuscript) | View Publication

Protocol D - Vitrectomy Study

1. Diabetic Retinopathy Clinical Research Network Writing Committee on behalf of the DRCR.net, Haller JA, Qin H, Apte RS, Beck RW, Bressler NM, Browning DJ, Danis RP, Glassman AR, Googe JM, Kollman C, Lauer AK, Peters MA, Stockman ME. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010 Jun;117:1087-1093.e3 (Published). (Manuscript) | View Publication

2. Diabetic Retinopathy Clinical Research Network. Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema. Retina. 2010 Oct;30(9):1488-95 (Published). (Manuscript) | View Publication

Protocol E - Peribulbar Triamcinolone Acetonide Study

1. Diabetic Retinopathy Clinical Research Network, Chew E, Strauber S, Beck R, Aiello LP, Antoszyk A, Bressler N, Browning D, Danis R, Fan J, Flaxel C, Friedman S, Glassman A, Kollman C, Lazarus H.. Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology.2007 Jun;114(6):1190-6 (Published). (Manuscript) | View Publication

2. Chew EY, Glassman AR, Beck RW, Bressler NM, Fish GE, Ferris FL, Kinyoun JL; Diabetic Retinopathy Clinical Research Network. Ocular side effects associated with peribulbar injections of triamcinolone acetonide for diabetic macular edema. Retina. 2011 Feb;31(2):284-9 (Published). (Manuscript) | View Publication

Protocol F - PRP Study

1. Diabetic Retinopathy Clinical Research Network, Brucker AJ, Qin H, Antoszyk AN, Beck RW, Bressler NM, Browning DJ, Elman MJ, Glassman AR, Gross JG, Kollman C, Wells JA 3rd. Observational study of the development of diabetic macular edema following panretinal (scatter) photocoagulation given in 1 or 4 sittings. Arch Ophthalmol.2009 Feb;127(2):132-40 (Published). (Manuscript) | View Publication

Protocol G - Subclinical Diabetic Macular Edema Study

1. Bressler NM, Edwards AR, Antoszyk AN, Beck RW, Browning DJ, Ciardella AP, Danis RP, Elman MJ, Friedman SM, Glassman AR, Gross JG, Li HK, Murtha TJ, Stone TW, Sun JK; Diabetic Retinopathy Clinical Research Network. Retinal thickness on Stratus optical coherence tomography in people with diabetes and minimal or no diabetic retinopathy. Am J Ophthalmol.2008 May;145(5):894-901 (Published). (Manuscript) | View Publication

2. Diabetic Retinopathy Clinical Research Network. Observational Study of Subclinical Diabetic Macular Edema. Eye (Lond). 2012 Jun;26(6):900-1 (Published). (Manuscript) | View Publication

48

Protocol H - Bevacizumab (Avastin) Phase 2 Study

1. Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, Beck RW, Bressler NM, Chan CK, Elman MJ, Friedman SM, Greven CM, Maturi RK, Pieramici DJ, Shami M, Singerman LJ, Stockdale CR. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology.2007 Oct;114(10):1860-7 (Published). (Manuscript) | View Publication

2. Scott IU, Bressler NM, Bressler SB, Browning DJ, Chan CK, Danis RP, Davis MD, Kollman C, Qin H; Diabetic Retinopathy Clinical Research Network Study Group. Agreement between clinician and reading center gradings of diabetic retinopathy severity level at baseline in a phase 2 study of intravitreal bevacizumab for diabetic macular edema. Retina.2008 Jan;28(1):36-40 (Published). (Manuscript) | View Publication

Protocol I - Laser-Ranibizumab-Triamcinolone for DME

1. Diabetic Retinopathy Clinical Research Network. Expanded 2-year Follow-up of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. 2011 Apr;118(4):609-14. (Published). (Manuscript) | View Publication

2. The Diabetic Retinopathy Clinical Research Network. Rationale for the Diabetic Retinopathy Clinical Research Network Intravitreal Anti-VEGF Treatment and Follow-up Protocol for Center-involved Diabetic Macular Edema. Ophthalmology. 2011 Dec;118:e5-e14 (Published). (Manuscript) | View Publication

3. Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM; for the Diabetic Retinopathy Clinical Research Network. Evaluation of Masking Study Participants to Intravitreal Injections in a Randomized Clinical Trial. Arch Ophthalmol. 2012 Feb;130(2):190-194 (Published). (Manuscript) | View Publication

4. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 June;117(6):1064-1077.e35 (Published). (Manuscript) | View Publication

5. Bressler S, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, Wells JA, for the Diabetic Retinopathy Clinical Research Network. Factors Associated with Changes in Visual Acuity and OCT Thickness at 1 Year after Treatment for Diabetic Macular Edema with Ranibizumab. Arch Ophthalmol. 2012 Sep;130(9):1153-1161 (Published). (Manuscript) | View Publication

6. The Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, Ferris FL III, Glassman AR, Maturi RK, Melia M. Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt vs Deferred Laser Treatment: 3-year Randomized Trial Results. Ophthalmology 2012;119:2312–18 (Published). (Manuscript) | View Publication

7.Bressler SB, Qin H, Melia M, Bressler NM, Beck RW, Chan CK, Grover S, Miller DG, Stone T, for the Diabetic Retinopathy Clinical Research Network. Exploratory Analysis of Effect of Intravitreal

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Ranibizumab or Triamcinolone on Worsening of Diabetic Retinopathy in a Randomized Clinical Trial. JAMA Ophthalmol. 2013; 131(8):1033-1040 (Published). (Manuscript)

8.Bressler SB, Almukhtar T, Aiello LP, Bressler NM, Ferris FL III, Glassman AR, Greven CM, for the Diabetic Retinopathy Clinical Research Network. Green or Yellow Laser Treatment for Diabetic Macular Edema: Exploratory Assessment within the Diabetic Retinopathy Clinical Research Network. Retina. 2013 Nov- Dec;33(10):2080-8. (Published). (Manuscript)

9. Bressler SB, Almukhtar T, Bhorade A, Bressler NM, Glassman AR, Huang S, Jampol LM, Kim JE, Melia M, for the Diabetic Retinopathy Clinical Research Network. Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema and the Risk of Sustained IOP Elevation or Ocular Hypotensive Treatment. JAMA Ophthalmol. JAMA Ophthalmol. 2015 May 1;133(5):589-97. (Published). (Manuscript) 10. Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, Berger BB, Bressler NM, for the Diabetic Retinopathy Clinical Research Network. Ranibizumab plus prompt or deferred laser for diabetic macular edema in eyes with vitrectomy prior to anti-vascular endothelial growth factor therapy. Retina. 2014 (Accepted). (Manuscript) 11. Elman MJ, Ayala A, Bressler NM, Browning D, Flaxel CJ, Glassman AR, Jampol LM, Stone TW; Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for Diabetic Macular Edema with Prompt versus Deferred Laser Treatment: 5-Year Randomized Trial Results. Ophthalmology. 2015 Feb;122(2):375-81. (Published). (Manuscript)

Protocol J - Laser-Ranibizumab-Triamcinolone for DME Plus PRP

1. Diabetic Retinopathy Clinical Research Network. Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Macular Edema Following Focal/Grid Laser for Diabetic Macular Edema in Eyes Also Receiving Panretinal Photocoagulation. Retina. 2011 June;31 (6):1009-27 (Published). (Manuscript) | View Publication

Protocol K - Laser Response

1. Diabetic Retinopathy Clinical Research Network. The course of response to focal/grid photocoagulation for diabetic macular edema. Retina.2009 Nov-Dec;29(10):1436-43 (Published). (Manuscript) | View Publication

Protocol L - Autorefraction and VA Reproducibility Study

1. The Diabetic Retinopathy Clinical Research Network. Evaluation of Visual Acuity Measurements after Autorefraction versus Manual Refraction in Eyes with and without Diabetic Macular Edema. Arch Ophthalmol. 2012 Apr; 130:470-479 (Published). (Manuscript) | View Publication

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Protocol N - Intravitreal Ranibizumab for Vitreous Hemorrhage from

PDR Study

1. Diabetic Retinopathy Clinical Research Network. Randomized Clinical Trial Evaluating Intravitreal Ranibizumab or Saline for Vitreous Hemorrhage from Proliferative Diabetic Retinopathy. JAMA Ophthalmol. 2013 Mar 1;131(3):283-93. doi: 10.1001/jamaophthalmol.2013.2015. (Published). (Manuscript)

2. Bhavsar AR, Torres K, Bressler NM, Glassman AR, Jampol LM, Kinyoun JL, for the Diabetic Retinopathy Clinical Research Network. One Year Results Evaluation Following Short Term Use of Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy. JAMA Ophthalmol. July 2014;132(7):889- 890 (Published). (Manuscript)

Protocol O - TD/SD OCT Comparison and Reproducibility

1. Diabetic Retinopathy Clinical Research Network. Retinal Thickness in People with Diabetes and Minimal or No Diabetic Retinopathy: Heidelberg Spectralis Optical Coherence Tomography. IOVS December 2012 53:8154-8161 (Published). (Manuscript) | View Publication

2.Diabetic Retinopathy Clinical Research Network. Reproducibility of Optovue RTVue Optical Coherence Tomography Retinal Thickness Measurements and Conversion to Equivalent Zeiss Stratus Metrics in Diabetic Macular Edema. JAMA Ophthal. 2014 (Submitted for Publication). (Manuscript)

3.Diabetic Retinopathy Clinical Research Network Writing Committee. Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time- domain metrics in diabetic macular edema. JAMA Ophthalmol. Published online July 24, 2014. doi:10.1001/jamaophthalmol.2014.1698 (Published). (Manuscript)

Protocol P - Cataract Surgery with Center-Involved DME Study

1. Diabetic Retinopathy Clinical Research Network. Pilot Study of Individuals with Diabetic Macular Edema Undergoing Cataract Surgery. JAMA Ophthalmol. 2014 Feb 1;132(2):224-6. (Published). (Manuscript)

Protocol Q - Cataract Surgery without Center-Involved DME Study

1. Diabetic Retinopathy Clinical Research Network. Writing Committee: Baker CW, Almukhtar T, Bressler NM, Glassman AR, Grover S, Kim SJ, Murtha TJ, Rauser ME, Stockdale C.. Macular Edema After Cataract Surgery In Eyes Without Pre-operative Central-involved Diabetic Macular Edema. JAMA Ophthalmol. 2013 Jul;131 (7):870-9. (Published). (Manuscript)

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Protocol R - Phase II non-Central DME NSAID Study

1.Friedman SM, Almukhtar TH, Baker CW, Glassman AR, Elman MJ, Bressler NM, Maker MP, Jampol LM, Melia M, Diabetic Retinopathy Clinical Research Network. Topical Nepafenec in Eyes with Non-Central Diabetic Macular Edema. Retina. 2015 May;35(5):944-56. doi: 10.1097/IAE.0000000000000403 (Published). (Manuscript)

Protocol S - Prompt PRP vs Ranibizumab+Deferred PRP for PDR Study

1. Diabetic Retinopathy Clinical Research Network. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Trial. JAMA. Jun 2015 (Submitted for Publication). (Manuscript)

Protocol T - Aflibercept, Bevacizumab and Ranibizumab Comparison for DME Study

1. Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, Arnold-Bush B, Baker CW, Bressler NM, Browning DJ, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici DJ, Sun JK, Beck RW. Comparative Effectiveness Randomized Clinical Trial of Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema. N Engl J Med 2015; 372:1193-1203. DOI: 10.1056/NEJMoa1414264 (Published). (Manuscript) | View Publication

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2015 MEEI Vitrectomy Course Program

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