Top Ten Oral Agentsand a Few other ThoughtsJ. JAMES THIMONS, O.D.,FAAO

MEDICAL DIRECTOR / OPHTHALMIC CONSULTANTS OF CONNECTICUT

JIMTHIMONS@GMAIL.COM

Disclosure

I am a consultant for or am on the Medical Advisory Board of: Allergan AlconAMO Advanced Vision Research InspireTLC Laser CenterCarl Zeiss MeditecSynemed

ANTI-VIRALS

ACYCLOVIR FAMVIR VALTREX

ANTI-VIRALS

CLINICAL APPLICATIONS ACUTE VS CHRONIC INFECTION

PRIMARY LESIONS

EPITHELIAL HERPES SIMPLEX

STROMAL HERPES SIMPLEX

HERPES ZOSTAR

HERPETIC IRIDOCYCLITIS

ANTI-VIRALS

SIDE EFFECTS RENAL FAILURE/ IMPAIRMENT

HYPERSENSITIVITY REACTIONS

FACIAL EDEMA

VISUAL HALLUCINATIONS

VARICELLA ZOSTAR-KERATITIS

PRIMARY INFECTION CHICKEN POX

VACCINATION RECOMMENDED BY AMERICAN ACAD of PEDIATRICS

RECURRENT INFECTION OPHTHALMIC INVOLVEMENT 10-255

OPHTHLAMIC ZOSTAR > OVER AGE 60

UNDER 40 50% IIMMUNOCOMPRIMISED

The Cyclines

Tetracycline, Doxycycline and Minocycline Isolated from Streptomyces

Effective against Gram +/ Gram -/Aerobic/ Anerobic/ Spirochetes/Rickettsia/Chlamydia

Similar action / different duration

Tetracyclines

Tetracycline (Sumycin) Doxycycline (Vibramycin) Coated doxycycline (Doryx)

Tetracycline (Sumycin)

Formulations 250mg, 500mg tablets/capsules: syrup 125mg/tsp

Dosages 250mg, 500mg q.i.d

Doxycycline (Vibramycin)

Formulations 50mg, 100mg capsules: 100mg tablet: suspension

25/tbs: syrup 50mg/tsp

Dosages 50mg, 100mg q.i.d

Oracia 40 mg sustained release/ regular

Periostat 20 mg

Most common use in dentistry

The Cyclines

Clinical Applications Brucellosis Rickettsia ( Rocky Mountain Spotted fever) Lyme Disease Chlamydia/ Trachoma Primary Meibomianitis Gonococcal Prophylaxis “Corneal melting” Syndrome Non Healing Corneal lesions Rosacea

The Cyclines

RCE PLD Lyme’s Microbial Keratitis Corneal “melt” syndrome

“How could I ever get mad at you”

GS a 33 y/o Caucasian female presented with a complaint of discomfort, watering and light sensitivity following blunt trauma.

PEX: VA: 20/20 OD – 20/30- OS SLE: 2 mm area of epithelial damage with staining

at 12:00 Occasional A/C cell 2+ injection

“How could I be mad at you”

Treatment: BCL 4th Generation FQ Acular PF

Symptoms resolved after 1 week of Tx Patient dismissed with instructions and Systane q4

hours Muro 128 Unguent hs

“ How could I be mad at you”

Patient returned to office 10 weeks later with c/o AM pain and return of symptoms.

D/C gtts after 4 weeks PEX:

VA: 20/30 SLE: As shown 2+ injection

Recurrent Erosions

Medical ManagementNocturnal lubricationNocturnal hypertonic salineBandage contact lensTreat underlying conditions

Recurrent Erosions

Contributing FactorsDry eyesBlepharitisExternal disease / tear

film abnormalities

Lipid Secretion: Meibomian Glands

Meibomian gland dysfunctionTransillumination ofmeibomian glands

Recurrent Erosions

Treatment Doxycycline 50 mg po bid

OM3’s

Azasite qd hs

BCL 30 day wear

Restasis

Omega 3 Fatty Acids

Re-esterized OM3 Ethyl Ester

Interim Analysis

Tear Osmolarity (mOsm/L)

Omega-3

Placebo

325.82

320.30

Wk 0 Wk 6 Wk 12

316.79

318.85

312.42

320.70

Interim Analysis• Corneal staining (measured on 0-

5 scale)

Chart1

Wk 0Wk 0

Wk6Wk6

Wk12Wk12

Omega-3

Placebo

1.5

1.67

0.97

1.23

0.44

1.25

Sheet1

Wk 0Wk6Wk12

Omega-31.50.970.44

Placebo1.671.231.25

Sheet1

Omega-3

Placebo

Sheet2

Sheet3

Interim Analysis

Ocular Symptom Disease Questionnaire

Omega-3

Placebo

34.95

22.05

Wk 0 Wk 6 Wk 12

22.92

15.44

15.54

15.93

Interim Analysis

Omega Index levels (%)

Omega-3

Placebo

4.48

4.79

Wk 0 Wk 12

8.49

4.49

Re-Esterified OM3’s

: http://prnomegahealth.com/glaucomasociety/

http://prnomegahealth.com/glaucomasociety/

A Challenger for the Title

Kashkouli, MB BJO 8/2014 110 patients with MGD randomly assigned

to: Doxy 200mg/ day x 1 month Azithromycin 500mg x1 then250mg x4

Significant improvement in both groups Bulbar hyperemia and ocular surface staining

better in Azith group Azith group showed significantly betteroverall

clinical response Doxy group showed increased GI symptoms

Take Your Time: It’s Worth it!

Fraunfelder, FW et al: Cornea 2010 12 subjects/ failed on initial therapy of lubrication/

NaCl Treated with bandage lens x 3 months 75 % had complete resolution at one year from

initial Tx 2 had symptoms but no signs 1 patient had symptoms and signs

The Way to a Man’s Eyelid is Thru His Stomach! BMJ Aug 2013 44 randomized trial meta-analysis 22 trials/ 5000 patients

Sequential therapy ( 2x daily PPI with Amoxicillan) was significantly better than triple therapy ( PPI, Clarithromycin, Metronidizole)

87% vs 72% outcome 14 trials 2750 patients

84% vs 75% Resitent to Tx sub Levofloxacin

Oral Antibiotics

PCN’s Cephalosporin’s Macrolides

Wow! What Happened While I was Asleep?

JR a 23 year old Caucasian female awoke with a pain, swelling and a pulsing ache over her left eye.

Pt. denies h/o trauma, prior occurrence or vision loss.

PEX: VA 20/20 OD , 20/20 OS EOM: Full without pain VF: CFTFC/ OU

Wow: What Happened While I Was Asleep?

Ta: 18/19 SLE: 2+3 Tender lid edema. Cornea clear,

AC=D&Q. Negative discharge. DFE: 0.2 OU Dx: ? Tx:

ular Bacterial Disease

Posterior Blepharitis Hordeola Canaliculitis Conjunctivitis Keratitis Dacryocystitis Dacroadenitis Preseptal/orbital cellulitis Endophthalmitis

Bacterial Flora of the Normal Eye/Adults

Staphylococcus epidermidis 75-90%*Diphteroids (C. xerosis) 20-33%Staphylococcus Aureus 20-25%*Streptococcus (S. viridan) 2-6%Hemophilus influenza 3% or moreStreptococcus pneumoniae 1-3%*Gram negative rods 1% or more*Pseudomonas aeruginosa 0-5%*

* Dominant organisms in microbial keratitis

Body depots of bacterial organisms

Skin: Lids/hands: Staph/Gr. (+) Nose/nasopharynx: Staph and GR (+) Kids: Hemophilus Oropharynx: Staph and StrepGr (+) Mouth: Strep/Bacteroides Stomach: Helicobacter pylori and rosaceae Small Intestine: Gr (+) cocci and bacilli Large intestine: Greatest conc of bacteria in

body (10 organisms/gm) anerobes-enterobacteria, enterococcus feacalis, E. coli

Genito-urinary tract: Chlamydia, E. coli, Neisseria gonorrhea (Ophthalmia neonatorum)

12

Bacterial conjunctivitis

In adults, 75% of cases caused by Gram positive pathogens Staphylococcus epidermidis, S. aureus,

Streptococcus pneumoniae

Very common in children under 6 years Causal agents of pediatric cases:

42% Haemophilus influenzae

35% S. pneumoniae

Everett et al, 1995Block et al, 2000

Common Ocular PathogensGram (+)

Staph epidermidis

Coagulase negative

Opportunistic pathogen

Frequent cause of CL keratitis

Normal flora

Chronic bleparitis

Staph aureus

Coagulase positive

Methacillin resistant strain

Exotoxins

Inflammatory disease

Abscess formation

Severe keratitis

Strep pneumonaeEnzymes/virulenceSeen in cold climatesPerforate in 7 daysassociated with erysipilus cellulitis

Strep Species

Important Penicillins

Ampicillin: Broad spectrum oral-QID dosing Amoxicillin: Pro-drug of Ampicillin, improved

absorption with lower GI side-effects Cloxacillin/Dicloxacillin: Intrinsic beta-

lactamase resistance Augmentin: Amox + Clavulanate Methicillin: IV prep for penicillinase producers Amp + Sulbactam: Unasyn: IV

Ticarcillin + Clavulonic acid: IV better penicillinase protection than methacillin

Gram (-) species

Pseudomonas Hemophilus Klebsiella Serratia Moraxella Neiserria

AugmentinIndications/Dosage forms

Indications: Preseptal cellulitis Dacryocystitis Pediatric Hemophilus Amoxicillin + Clavulanate@@@@ Dosage forms: 500 or 875mg tablets BID 125 or 250mg/5cc pediatric suspension

AugmentinAmoxacillin/Clavaulanate

Broad spectrum penicillin (Staph, Strep, Hemophilus

Effective against penicillinase producers-clavulanate blocks penicillinase@@@

High therapeutic index Bacteriocidal Low GI side-efffects Safe in pregnancy Watch out for allergy Cheap***

Plan B: The cephalosporins

Mechanism: Same as penicillin Bacteriostatic Low toxicity 3% allergic to pen are allergic to Ceph. Better penicillinase resistance than

penicillins

Know your generations

First Generation: Good GR (+) activity against penicillinase producers/poor Gr (-) activity especially Hemophilus (children)

Cefadroxil: Duricef-PO Cephazolin: IV- Ancef- Keratitis Cephalexin: PO-Keflex Cephadrine: PO- Velosef

tivity,

us Cefaclor: PO-Ceclor Cefuroxime: PO-Ceftin

Third Generation: Reduced GR (+) activity (Staph sp) with marked Gr (-) activity

Cefixime: PO- (Suprax) Cefpodoxime: PO - Vantin Cefprozil: PO - Cefzil

Pre-Septal Considerations

JAMA 2013 Dec. Dual cohorts of 95,000 each, older

adults (mean 76) who were users of Calcium Channel Blocker’s

Clarithromycin (inhibitsCYP3A4 which can cause increased CCB levels) vs: Azithromycin ( non inhibitor)

Measured for 30 days post treatment Risk for hospitalization 0.44% vs 0.22% due

to acute kidney injury All cause mortality 1.02% vs.0.59%

Macrolides

Erythromycin (E-Mycin) Azithromycin (Zithromax, Z-PAK)

Erythromycin (E-Mycin)

Formulations 250mg, 500mg tablets

Dosages 250mg, 500mg q.i.d., b.i.d

Azithromycin (Zithromax)

Formulations 250mg, 500mg 600mg tablets: suspension

100mg/5ml, 200mg/ml Z-PAK six 250 mg tablets, TRI-PAK three 500mg tablets

Dosages1 gm one dose administration for Chlamydia: 500mg

q.d. followed by 250mg q.d for four days

Fluoroquinolones

Levofloxacin (Levaquin) Ciprofloxacin (Cipro) Gatifloxacin (Tequin) Moxifloxicin (Avelox)

Corticosteroids

Prenisone (Deltason) Methylprednisolone (Medrol)

Levofloxacin (Levaquin)

Formulations 250mg, 500mg and 750mg tablets 25mg/ml oral

suspension

Dosages 250mg to 750mg q.d.

Ciprofloxacin (Cipro)

Formulations 100mg, 250mg, 500mg, 750mg and 1000mg tablets

Dosages 500 mg to 750mg b.i.d.

Gatifloxacin (Tequin)

Formulations 200mg and 400mg tablets

Dosages 400mg q.d.

Moxifloxicin (Avelox)

Formulations 200mg and 400mg tablets

Dosages 400mg q.d.

Steroids

99 % topical use in eye care Medrol Dose Pack most common Pred Forte Generic since January 2009 Lotemax/ Alrex & Durezol

Corticosteroids

Corticosteroids

Prenisone (Deltason) Methylprednisolone (Medrol)

Prednisone (Deltason)

Formulation 2.5mg, 5mg, 10mg, 20mg and 50mg tablets;

5mg/5ml solution/syrup

Dosage Varies based on condition

Methylprednisolone (Medrol)

Formulation 2mg, 4mg, 8mg, 16mg, 24mg and 32mg tablets

Medrol Dose Pak 21 4mg tablets

Dosage Varies based on condition

Clinical Case Examples

Scleritis Dermatitis Severe anterior uveitis Posterior uveitis Inflammatory preseptal cellulitis Progressive thyroid eye disease DLK

Interesting Facts

In steroid responders, onset of IOP elevation occurs after about two weeks of use

Time of onset often longer for systemic steroids Complex pathophysiologic factors result in increased

resistance to aqueous outflow

Steroids

99 % topical use in eye care Medrol Dose Pack most common Pred Forte Generic since January 2009 Lotemax/ Alrex & Durezol

STEROIDS

ORAL vs IV ADMINISTRATION INITIAL DOSE - 1mg/kg/day STANDARD TAPER

INITIAL THERAPY 2-3 DAYS, THEN TAPER AS INDICATED FOR CLINICAL RESPONSE

ALTERNATE DAY THERAPY- LONG TERM Tx- DOUBLE DOSE QOD THROUGH TAPER

STEROIDS

INHIBIT PROSTAGLANDIN AND LEUKOTRIENE ACTIVITY BY BLOCKING ACTION OF ENZYME PHOSPHOLIPASE A2.

Steroids

Oral vs. IV administration Initial dose determination (1mg/kg/day) Standard taper vs. alternate day therapy

Standard taper - start initial dose, monitor in 2-3 days, then taper as appropriate for clinical response

Alternate day therapy - for longer term therapy (more than 2-3 weeks), give double dose every other day, continue pattern throughout tapering process

Prednisone - Initial dose typically in 60-100 mg range as per above

Clinical Case Examples

Scleritis Severe anterior uveitis Posterior uveitis Inflammatory preseptal cellulitis Progressive thyroid eye disease DLK

Femtosecond Lasers and Keratomes

Photodisruption

Thousands of laser pulses are connected together in a spiral pattern to create a cleavage plane

DLK – Interface/edge Inflammation Cause(s) Too much energy (usually greater than 3.5uj) Edge angle too flat (usually less than 45° to 50°) Not enough topical steroid

Management Reduce horizontal and/or side cut energy Steepen edge angle (> 50° to 60°) Pre–peri–post op steroids to reduce cellular

infiltrates Post op meds generally same as mechanical

keratectomy

“Mirage” Edema

6 KHz

CASE #5

A 37-year-old white male was referred s/p lasik x 3 weeks with h/o decreased acuity OU (OD>OS).

Onset was gradual but patient has been symptomatic since Tx with pain/ou.

Surgical history revealed bilateral abrasions at the time of the procedure involving the inferior half of the cap and bed.

Patient has had two lifts and scrapes in two weeks

CASE #5

Physical exam revealed BVA 20/200 OD 20/100 OS.

External shows minimal injection & OU. SLE revealed 2+-3 epithelial irregularties/OU with

3+4 cystic changes, pseudodendrites and frank defects.

Ta- 18/20 @ 10

Case #5

Additionally the patient demonstrated 3+ interface haze OU contiguous with and extending beyond the area of epithelial change.

AC occasional cell. Remainder of exam WNL. Current medications: Pred Forte q3hour

IOP after DSEK

Price,FW AJO 2008 50 eyes/38 patients Mean CCT 701 microns Pnemotonometry: 20.3 mmHg +/-4.5 mmHg Pascal: 19.8 mmHg +/- 4.4 mmHg Goldmann: 15.9 mmHg +/- 4.9 mmHg If IOP is elevated with Goldmann it is probably real

Steroids vs.Immunomodulation Ashcroft DM; BMJ Mar 2005 Meta-analysis 25 trials Tacrolimus (Protopic) / Pimecrolimus

(Elidel) vs. Potent and Mild steroids Tacrolimus = Potent steroid > Mild Pimecrolimus< Potent Steroid FDA “Black Box” Recommended use:

Facial area( steroid atrophy) Pulse therapy Intolerant of steroids

NSAID’S

IBUPROFEN KETOROLAC INDOMETHACIN NAPROXEN TRAMADOL CELEBREX

NSAID’S

CLINICAL APPLICATIONS ANALGESIA

ANTI-INFLAMMATORY

MUSCULOSKELATAL/ MYOSITIS

ACUTE GOUT

DYSMENNORRHEA

CME

NSAID’S

CORNEAL OPACITIES( WHORL) TINNITUS FLUID RETENTION EPISTAXIS BREAST CHANGES ANEMIA/BLEEDING CONSTIPATION

NSAID’S

CLINICAL APPLICATIONS ANALGESIA

ANTI-INFLAMMATORY

MUSCULOSKELATAL/ MYOSITIS

ACUTE GOUT

DYSMENNORRHEA

CME

NSAIDS , H Pylori and Gastric Ulcers

Lancet 2002 Jan 5; 359: 14-22 1625 NSAID users

Peptic ulcer disease 42 % H Pylori patients

26% of non-infected patients

Peptic ulcer disease 36 % of NSAID users

8% of non users

Risk of bleeding ulcer (6.1x> in H Pylori on NSAIDS0

Narcotic Agents

Effective for severe acute pain Patient response variability due to individual

sensitivity of opioid receptors No addiction likely with short term use Dosage varies with drug used and patient Adverse effects is usually the limiting factor in

usage

Narcotic Agents

Hydrocodone (Schedule III) (Lortab, Vicodin) 2.5-7.0mg tid-qid with acetaminophen

Narcotic Agents

6 times more potent than codeine Less gastrointestinal problems Less sedation ?? euphoria

Important notification for patients

Drowsiness Dizziness Blurred vision Nausea/vomiting/constipation Take with food to avoid GI distress Avoid Etoh or other CNS agents Breathing distress

Contraindications

Bronchial asthma COPD Emphysema Pregnancy Hypersensitivity Prior addiction Renal/Liver dysfunction H/O Etoh use, Concurrent use of

CNS agents(Tricyclic antidepressants, Phenothiazines)

Narcotic agents

Directly affect opioid receptor Agonist, partial agonist, or mixed Bind to opioid receptors in brainstem, corticol

areas and spinal cord Mimic endorphins, producing a morphine like

effect whether natural or synthetic

Narcotic Agents

Effective for severe acute pain Patient response variability due to individual

sensitivity of opioid receptors No addiction likely with short term use Dosage varies with drug used and patient Adverse effects is usually the limiting factor in

usage

Narcotic Agents

Hydrocodone (Schedule III) (Lortab, Vicodin) 2.5-7.0mg tid-qid with acetaminophen

Narcotic Agents

6 times more potent than codeine Less gastrointestinal problems Less sedation ?? euphoria

Important notification for patients

Drowsiness Dizziness Blurred vision Nausea/vomiting/constipation Take with food to avoid GI distress Avoid Etoh or other CNS agents Breathing distress

Contraindications

Bronchial asthma COPD Emphysema Pregnancy Hypersensitivity Prior addiction Renal/Liver dysfunction H/O Etoh use, Concurrent use of

CNS agents(Tricyclic antidepressants, Phenothiazines)

Top Ten Oral Agents�and a Few other ThoughtsSlide Number 2Slide Number 3DisclosureANTI-VIRALSANTI-VIRALSANTI-VIRALSSlide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18VARICELLA ZOSTAR- KERATITISSlide Number 20Slide Number 21Slide Number 22The CyclinesTetracyclinesTetracycline (Sumycin)Doxycycline (Vibramycin)The CyclinesThe Cyclines“How could I ever get mad at you”Slide Number 30Slide Number 31“How could I be mad at you”“ How could I be mad at you”Slide Number 34Recurrent ErosionsRecurrent ErosionsSlide Number 37Slide Number 38Lipid Secretion: Meibomian GlandsRecurrent ErosionsOmega 3 Fatty AcidsInterim AnalysisInterim AnalysisInterim AnalysisInterim AnalysisRe-Esterified OM3’sA Challenger for the TitleTake Your Time: It’s Worth it!The Way to a Man’s Eyelid is Thru His Stomach!Oral AntibioticsWow! What Happened While I was Asleep?Wow: What Happened While I Was Asleep?Slide Number 53Ocular Bacterial DiseaseBacterial Flora of the Normal Eye/AdultsBody depots of bacterial organismsBacterial conjunctivitisCommon Ocular Pathogens�Gram (+)Important PenicillinsGram (-) speciesAugmentin�Indications/Dosage formsAugmentin�Amoxacillin/ClavaulanatePlan B: The cephalosporinsKnow your generationsSecond Generation: �Greater Gram (-) activity,�especially HemophilusPre-Septal ConsiderationsMacrolidesErythromycin (E-Mycin)Azithromycin (Zithromax)�FluoroquinolonesCorticosteroidsLevofloxacin (Levaquin)Ciprofloxacin (Cipro)Gatifloxacin (Tequin)Moxifloxicin (Avelox)SteroidsCorticosteroidsCorticosteroidsPrednisone (Deltason)Methylprednisolone (Medrol)Clinical Case ExamplesInteresting FactsSteroidsSTEROIDSSTEROIDSSteroidsClinical Case ExamplesFemtosecond Lasers and Keratomes Slide Number 89DLK – Interface/edge InflammationSlide Number 91CASE #5CASE #5Case #5IOP after DSEKSteroids vs.ImmunomodulationNSAID’SNSAID’SNSAID’SNSAID’SNSAIDS , H Pylori and Gastric UlcersNarcotic AgentsNarcotic AgentsNarcotic AgentsImportant notification for patientsContraindicationsNarcotic agentsNarcotic AgentsNarcotic AgentsNarcotic AgentsImportant notification for patientsContraindications