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Anterior Segment

Grand RoundsEYE-SIGHT 20/20

September 14, 2014

Jimmy D. Bartlett, O.D., D.Sc., FAAO

Professor Emeritus, The University of Alabama at Birmingham

President, PHARMAKON Group

Birmingham, Alabama

ANTERIOR SEGMENT GRAND

ROUNDSCourse Title:

DISCLOSURE STATEMENT

Please silence all mobile devices.

Alcon

Allergan

Bausch & Lomb

Jobson Medical Publishing

Lecturer: Jimmy D. Bartlett, O.D., D.Sc., FAAO

Professor Emeritus, School of Optometry

The University of Alabama at

Birmingham

Commercial Break (Simbrinza) Disclosure Statement� Alcon

� Allergan

� Bausch & Lomb Pharmaceuticals

� Jobson Publishing Group

� United States Pharmacopeia

� Wolter Kluwers Health

Please silence all mobile devices.

Swollen Painful Eyelid

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MRSA UPDATE

Methicillin-Resistant Staphylococcus

Aureus

Penicillins

� Gram-positive

� Penicillins G and V

� Penicillinase-resistant penicillins

� Methicillin, nafcillin, cloxicillin, dicloxacillin

� Extended spectra

� Ampicillin, amoxicillin

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The acronym MRSA signifies

that the isolates are resistant to all

beta-lactam antibiotics, not just

methicillin

Evolving Prevalence of MRSA

� S. aureus resistance was first discovered in

1944

� MRSA prevalence is now 3%-53%

� In the US, approx 14% of S. aureus isolates

(bacterial conjunctivitis) are methicillin-

resistant

� Excluding endophthalmitis, nationally the

prevalence of ocular MRSA is about 40%

Range of MRSA Eye Infections

� Blepharoconjunctivitis (78%)

� Keratitis (15%)

� Cellulitis (2.5%)

� Dacryocystitis (2.5%)

� Endophthalmitis (2%)

Freidlin J., et al. Am J Ophthalmol 2007; 144: 313-315.

Best Therapeutic Options

Ocular TRUST

� A longitudinal nationwide antimicrobial

susceptibility surveillance program specific

to ocular isolates

�S. aureus

�Coagulase-negative staphylococci

�S. pneumoniae

�H. influenzae

Asbell, PA, et al. Am J Ophthalmol 2008; 145: 951-958.

Susceptibility Testing

� In vitro susceptibility testing to nine antimicrobials

� Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin

� Azithromycin

� Trimethoprim

� Tobramycin

� Polymyxin B

� Penicillin

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8

50

959389

62

17

100 99

Ocular TRUST 2: S. aureus

Susceptibility

MSSA (N=71) MRSA (N=84)

20

40

60

80

100

% S

us

ce

pti

ble

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Asbell PA, ASCRS 2008

Antibiotic Resistance Monitoring

in Ocular MicRorganisms

(ARMOR)

• Ocular Surveillance Program across the US

• Profiles in vitro activity of ophthalmic agents against ocular isolates:

‒ Staphylococcus aureus

‒ Coagulase-negative staphylococci

‒ Streptococcus pneumoniae

‒ Haemophilus influenzae

• Tested concurrently for susceptibility to besifloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, azithromycin, tobramycin, trimethoprim, vancomycin

Antibiotic MIC Range MIC50

MIC90

Vancomycin ≤0.25 – 2 0.5 1

Besifloxacin ≤0.008 – 4 0.03 1

Moxifloxacin ≤0.008 – 64 0.06 8

Gatifloxacin ≤0.03 – 256 0.12 8

Ciprofloxacin ≤0.015 – 512 0.5 256

Tobramycin ≤0.06 – >256 0.5 256

Azithromycin ≤0.25 – >512 128 >512

Haas W et al. Presented at: ARVO 2011; May 1-5, 2011; Ft Lauderdale, FL; Poster D1129.

� 50.0% of ocular S aureus isolates were MRSA

� 39.9% of ocular S aureus isolates were FQ resistant

Besifloxacin MIC90 for All

Staphylococcus aureus Isolates

*N=228.Percent resistance based on oxacillin and ciprofloxacin breakpoints.

Besifloxacin (Besivance)

Suspension

� NOT used systemically

� FDA-approved for bacterial

conjunctivitis

� FDA-approved dosage: TID for 7 days

� Pediatric approval: ages 1 and older

� Preserved with 0.01% BAK

� Durasite vehicle for long retention time

on ocular surface

First and Only Ophthalmic

Chlorofluoroquinolone

� Fluorine at C6

� Chlorine at C8

Durasite Vehicle

� Mucoadhesive polymer matrix

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Besifloxacin Tear Concentrations

Relative to MIC90 for Ciprofloxacin-

Resistant MRSA and MRSE

� At 12 hours

postinstillation,

concentration of

besifloxacin

remains higher than

the MIC90 for

MRSA-CR and

MRSE-CR

Proksch JW , et al. J Ocul Pharmacol Ther. 2009;25:335-343.

Haas W, et al. Antimicrob Agents Chemother. 2009;53(8):3552-3560.

.

1

10

100

1000

0 4 8 12

Con

cen

trati

on

, µ

g/m

L

Time, h

MIC90 for MRSA-CR and MRSE-CR

Treatment Options for Initial

Empirical Therapy of MRSA

� Topical

�Vancomycin

�Besifloxacin

�Trimethoprim/polymyxin B

Antibiotic Combinations

Trimethoprim/Sulfamethoxazole

Trimethoprim/Sulfamethoxazole

Name Formulation

Trimethoprim/sulfamethoxazole

(generic)

80 mg trim/400 mg sulf

160/800 mg (double

strength)

40/200 mg/5ml

Bactrim, Bactrim DS

Cotrim, Cotrim DS

Septra, Septra DS

Same as above

Case Report

� 35 year-old WF

� Internal hordeolum, right upper lid

� Severe allergy to penicillin

� “Mycin drugs” upset stomach

� “Can’t swallow pills”

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Bactrim is a Sulfonamide!

Treatment Options for Initial

Empirical Therapy of MRSA

� Oral

�Trimethoprim/sulfamethoxazole

�Clindamycin

�Doxycycline

�Tedizolid (Sivextro)

Rivera AM, et al. Mayo Clin Proc 2011; 86: 1230-1243.

Treatment Options for Initial

Empirical Therapy of MRSA

� Intravenous (monotherapy)

�Vancomycin

�Daptomycin

�Linezolid

�Telavancin

�Ceftaroline

�Tigecycline

Rivera AM, et al. Mayo Clin Proc 2011; 86: 1230-1243.

β-Blocker Allergy?

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Preservative-Free TimololBAK-Free Glaucoma

Medications

� Timoptic in Ocudose

� Timoptic XE

� Alphagan-P

� Travatan Z

� Zioptan

� Cosopt-PF

Contact Allergy� Type IV reaction

� Suspect contact allergy if

�No history of allergy

�Lower lid and inferior conjunctiva most

affected

Management of Contact Dermatitis

� Steroid dermatologic ointments or creams

� Triamcinolone 0.1% crmor ung

� Loteprednol 0.5% ung

� Hydrocortisone 1.0% crm, ung, gel

Case Example

Before One Week Later

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Hole-y Cornea!

Case Report

Dellen

� Small area of corneal thinning located at the limbus

� Caused by localized drying of the cornea

� Causes of tearfilm disruption leading to dellen

�Local elevations (pterygium, pinguecula, chemosis, bleb, etc.)

�Systemic medications with anticholinergic side effects

Drugs Causing Dry Eye (and

Possibly Dellen)

� Anticholinergics

� Antihistamines

� Phenothiazines

� Anti-anxiety agents

� Tricyclic antidepressants

� Vitamin A analogs

Anticholinergics

• 1-2 mg oral atropine reduces aqueous tear

secretion from 15 µl/min to 3 µl/min

• 1-2 mg oral scopolamine reduces tear

secretion from 5 µl/min to 0.8 µl/min

Other Anticholinergic Agents

� Sominex (diphenhydramine)

� Lomotil (diphenoxylate and atropine)

� Detrol LA (tolterodine)

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Why Do Antihistamines

(and many other meds!)

Cause Dry Eye?

Parasympathetic (Cholinergic)

Innervation of Lacrimal Gland

Antihistamines

• H1 blockers reduce both aqueous and mucinproduction

• As little as 4 mg daily of chlorpheniramine maleate can produce positive Schirmer test

• Four days of once-daily loratadine (Claritin) can induce dry eye and corneal staining

• Can aggravate underlying condition of dry eye

Oxybutynin (Oxytrol) Transdermal

(Rx to OTC January 25, 2013)

Pulmonary Drugs with

Anticholinergic Activity

• Atrovent (ipratropium)

• Spiriva (tiotropium)

Miscellaneous Agents

• Phenothiazines

• Antianxiety agents

• Most antidepressants

have anticholinergic

activity

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Antidepressants Causing Dry Eye

• Celexa

• Cymbalta

• Effexor XR

• Lexapro

• Nardil

• Paxil

• Prozac

• Sinequan

• Wellbutrin

• Zoloft

Accutane Has Been

Discontinued– New Isotretinoin

Trade Names:

� Amnesteem

� Claravis

� Sotret

� Myorisan

� Absorica

Descriptive Words in Package

Insert Suggesting “Dry Eye”

� Anticholinergic

� Cholinergic antagonist

� Antimuscarinic

� Muscarinic antagonist

� Parasympatholytic

PI for Oxytrol Transdermal

� http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

� Or just Google “Drugs at FDA”

So Where Do I Find Package

Inserts?

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What If I Don’t Have Time For

All That?!!

Use Epocrates on Smartphone

or Tablet

Epocrates Rx Diagnosis of Dellen

� Foreign body sensation or ocular discomfort

� Focal conjunctival injection

� Small, oval, saucer-like excavation usually less than 2.0 mm located on corneal side of limbus, more frequently on temporal side

� Clearly defined borders, but base appears hazy and dry

� Epithelium is typically intact and fluorescein pools in the excavation

� Early, stroma is intact but thin due to loss of fluid

� True scarring with or without vascularization can occur if allowed to persist

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Management

� Treatment is directed toward rehydrating the cornea and, if possible, removing the cause

� Non-preserved artificial tears Q2H and lubricating ointment HS usually allow resolution within 48 hours

� Severe dellen may require prophylactic topical antibiotics

� Inflammatory conditions should be treated appropriately

Commercial Break (Prolensa)

What’s That White Spot

on the Cornea?

What is the best management of

this patient? D/C contact lenses +

A. Artificial tears

B. Topical steroid alone

C. Topical antibiotic alone

D. Topical steroid-antibiotic combo

E. Patch the eye with topical antibiotic ung

and cycloplegic

Infiltrative Keratitis/CLARE/CIE

� Initially thought to be primarily due to hypoxia

�An inflammatory response to toxins produced by less virulent strains of gram negative bacteria

�Recurrent episodes common

�CLARE is NOT a marker for microbial keratitis

Sweeney, et al. Eye Contact Lens 2007

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Differential Diagnosis of Corneal

Ulcers vs. Sterile InfiltratesUlcer (MK)

� Rare

� Usually painful

� Tend to be central

� 1 to 1 staining defect to

lesion ratio

� Cells in anterior chamber

� Generalized conjunctival

injection

� Usually solitary lesion

� Possible tear lake debris

� Eyelid swollen

Infiltrate

� Common

� Mild pain

� Tend to be peripheral

� Staining defect size relatively

small

� No cells in anterior chamber

� Sector skewed injection

pattern

� Can be multiple lesions

� Clear tear lake

� Eyelid not swollen

Infiltrate

� Common

� Mild pain

� Tend to be peripheral

� Staining defect size relatively

small

� No cells in anterior chamber

� Sector skewed injection

pattern

� Can be multiple lesions

� Clear tear lake

� Eyelid not swollen

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Management of CLARE/CIE

� Topical steroid alone

� If cornea is clear/no epithelial compromise

� Combination antibiotic/steroid

�Pulse-dose q2h for 1-2 days, then q.i.d. for 4-5 days

� Address CL hygiene and wearing time: Daily wear only!

�Otherwise, CLARE is likely to recur

Preferred Antibiotic-Steroid

Combos

Treatment of acute ocular surface and

eyelid inflammation in an atopic,

pregnant female

PUFFY (REALLY, REALLY

PUFFY) EYELIDS

32 Year-Old AA Female

� “This morning I was having a permanent in my

hair”

� “Some of the solution dripped into my eyes”

� “My eyes immediately swelled and are

extremely itchy. They are so swollen, I can

hardly see.”

� 4 months pregnant

� Has asthma and eczema, and so does her father

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Oral Antihistamines for ACUTE

Allergic Angioedema

Oral H1 Antihistamines

� Often prescribed based on sedative properties

� Formulations include syrups, tablets, capsules and sustained-release

� Indicated for moderate to severe eyelid edema and chemosis

Classification by CNS Sedation� Nonsedating

�Fexofenadine (Allegra)

�Loratadine (Claritin)

�Desloratadine (Clarinex)

�Cetirizine (Zyrtec)

� Mildly sedating

�Chlorpheniramine (Chlor-Trimeton)

�Brompheniramine (Dimetane)

� Strongly sedating

�Diphenhydramine (Benadryl)

Nonsedating Antihistamines

� Loratadine (Claritin)

� Claritin D

� Desloratadine (Clarinex)

� Clarinex D

� Cetirizine (Zyrtec)

� Zyrtec D

� Fexafenadine (Allegra)

� Allegra D

Loratadine (Claritin)

Dosage Formulations:

� 10 mg tablet; QD

� Syrup

� Claritin D-24 h

� Claritin D-12 h

� 10 mg Reditabs

� Alavert

(Dissolves in Mouth)

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Mildly Sedating Antihistamines

� Brompheniramine (Dimetane)

�Adult dosage 4 mg q 6-8 h

� Chlorpheniramine (Chlor-Trimeton)

�Adult dosage 4 mg q 6-8 h

Side Effects

� Sedation

�Avoid alcohol and opioids!

� Palpitations

� Drying of throat/bronchi AND EYES

� Mydriasis

� GI/GU disturbances

�Take with meals or adjust dose

Contraindications

� Alcohol, opioid analgesics

� Avoid antihistamines with strong anticholinergic effects in peptic ulcer disease, prostatic hypertrophy (BPH), bladder obstruction, angle-closureglaucoma

� Lactation/3rd trimester pregnancy

What is the Best (Safest) Allergy

Treatment During Pregnancy?

Generic Name Trade Name Pregnancy

Category

Dosing

Frequency

Alcaftadine Lastacaft B QD

Nedocromil Alocril B BID-QID

Lodoxamide Alomide B QID

Cromolyn sodium Opticrom, Crolom B QID

Chlorpheniramine Chlor-Trimeton B QID

Loratadine Claritin B QD

Cetirizine Zyrtec B QD

Diphenhydramine Benadryl B QID

Avoid Oral Antihistamines for

Long-Term Therapy

Potential Issues

� Elevated blood pressure when used with

decongestants

� Dry eye

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Bee Sting… or ?

Is the Corneal Picture

Simplex or Zoster?

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Differential Between HSK and

HZKHerpes Simplex Herpes Zoster

Pain Mild to moderate Severe

Dendrite appearance Larger, more branching,

discrete, delicate pattern,

more central

Smaller, less branching,

coarse, blunted pattern,

usually peripheral

Epithelium Ulcerated Blunted dendrite with

slightly raised edges

Fluorescein staining Prominent Dull and irregular

End bulbs Present Absent

Recurrence Common Rare

Herpes Zoster Ophthalmicus

Etiology

� Recurrent varicella-zoster virus

� Occurs most often in immunocompromised patients

� Physical and emotional trauma, immunosuppressive medications, irradiation, cancer, TB, and HIV can reactivate the virus

� Diagnosis of HZO in patients younger than 45 years warrants testing for HIV

Diagnosis

� Headache, malaise, fever, chills

� Followed in one or two days by neuralgic pain

� Followed in 2 or 3 days by hot, hyperesthesia and edema of dermatomes

� Unilateral vesicular eruption

� Vesicles become yellow and turbid and form eschars by day 7-10

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Treatment of Skin Lesions

� Avoid drying lotions

� Oral antihistamines may

prevent itching

� Warm solution of aluminum

acetate (Burow’s)

�Apply 15-30 min, QD to

TID

� Oculoplastic consultation

Ophthalmic Management

� No therapy may

be required

� Topical steroids

for corneal

edema and

anterior uveitis

� Oral analgesics

Acyclovir

� Should be started within 72 hours of skin

lesions

� 800 mg 5 times daily for 7-10 days

Acyclovir Formulations

� 200 mg capsule

� 400 mg tablet

� 800 mg tablet

� 200 mg/5 ml suspension

(banana flavor)

Benefits of Acyclovir Therapy

� Dendriform

keratopathy

� Stromal keratitis

� Anterior uveitis

� Acute and chronic

pain

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Valacyclovir (Valtrex)

� Prodrug of acyclovir

� Available as 500 mg

tablet

� Dosage is 1000 mg

tid x 7 days

Famciclovir (Famvir)

� Prodrug of penciclovir

� Available as 125, 250, 500 mg tablet

� Dosage is 500 mg tid x 7 days

Side Effects of Antivirals

� GI

�Nausea

�Diarrhea

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Contraindications

� Hypersensitivity

� Intolerance

� For immunocompromised patients, avoid

valacyclovir

�Risk of thrombocytopenia, which can be

fatal

�Famciclovir is okay

Don’t Forget These!

� Slit lamp exam

�Uveitis?

� IOP

� Dilated fundus exam

�Retinitis?

Herpes Zoster Neuralgia

� Varies from minor tingling and numbness to

excruciating pain

� Postherpetic neuralgia

Capsaicin for Postherpetic

Neuralgic PainNot For Use In The Eye!