Updates on the Management of Bacterial Keratitis

1
Updates on the Management of Bacterial Keratitis

• by
• Dr David P L Chan
• MRCSEd(Ophth) MMed(Ophth)

2
Current Strategy
3
Infective Keratitis

• 30,000 cases annually in the US(Bacterial, Fungal
  and Acanthanoeba)
• (Pepose JS et al AJO 1992)
• Bacterial Keratitis rarely occurs in normal eyes
  because of human corneas natural resistance to
  infection

4
Risk Factors-Exogenous factors

• Contact lens use
• Trauma
• Previous ocular/eyelid surgery
• Loose sutures
• Previous Corneal Surgery (incl. Lasik PRK)
• Medication related and medicamentosa
  (contaminated ocular medications, topical NSAIDS,
  anesthetics, antimicrobials, preservatives,
  glaucoma medications)
• Immunosuppresion
• Factitious disease (incl. anesthetic abuse)

5
Risk Factors-Ocular Surface Disease

• Misdirection of eyelashes
• Abnormalities of eyelid anatomy and function
  (incl. exposure)
• Tear film deficiencies
• Adjacent infections conjunctivitis incl
  gonococcal, blepheritis, canaliculitis,
  dacrocysytitis

6
Risk factors-Corneal Epithelial Abnormalities

• Neurotrophic Keratopathy
• Disorders predisposing to recurrent corneal
  erosion
• Viral Keratitis
• Corneal epithelial oedema, especially bullous
  keratopathy

7
Risk factors-Systemic conditions

• Diabetes mellitus
• Debilitating illness ( malnourishment and
  respirator dependence)
• Collagen vascular disease
• Substance abuse
• Deramtological/ mucous membrane disorders (e.g.
  Stevens-Johnson syndrome, ocular cicatricial
  pemphigoid)
• Immunosuppressed status
• Atopic dermatitis/
• Gonococcal infection and conjunctivitis
• Vitamin A deficiency

8
Common etiological agents of bacterial keratitis
in the U.S.(AAO Preferred Practice Pattern Aug
2005-Bacterial Keratitis)
Class/Organism Common Isolates Common Isolates Cases ()
Gram-Positive Isolates Gram-Positive Isolates 4490 4490
Gram-positive Cocci Staphylococcus aureus Staphylococcus aureus 430
Gram-positive Cocci Coagulase negative Staphylococci Coagulase negative Staphylococci 540
Gram-positive Cocci Streptococcus pneumoniae Streptococcus pneumoniae 125
Gram-positive Cocci Streptococcus viridans group Streptococcus viridans group 115
Gram-positive Bacilli Corynebacterium species Corynebacterium species 1-5
Gram-positive Bacilli Propionibacterium species Propionibacterium species 1-12
Gram-positive Bacilli Mycobacterium species Mycobacterium species 1-2
Gram-Negative Isolates Gram-Negative Isolates 1050 1050
Gram-negative Bacilli Pseudomonas aeruginosa Pseudomonas aeruginosa 5-45
Gram-negative Bacilli Serratia marcescens Serratia marcescens 1-12
Gram-negative Bacilli Proteus mirabilis Proteus mirabilis 1-5
Gram-negative Bacilli Enteric gram-negative bacilli, other Enteric gram-negative bacilli, other 1-10
Gram-negative Coccobacillary organisms Haemophilus influenzae, other Haemophilus influenzae, other 1-6
Gram-negative Coccobacillary organisms Haemophilus species   1-5
Gram-negative Coccobacillary organisms Moraxella species and related species   1-5
Gram-negative Cocci Neisseria species Neisseria species 1
9
Natural History of Bacterial Keratitis

• Corneal scarring
• (significant visual loss if invl. central visual
  axis)
• Corneal perforation
• Endophthalmitis
• Rapid progression(24 hrs)-pseudomonas, gonococcal
• Indolent course atypical mycobacteria, viridans
  type streptococcus

10
Prevention and Early Detection

• Screening of patient with high risk factors
• Education on use of extended wear contact lens
• Protective eye wear for work and sports
• Treatment of ocular surface disease
• Use of prophylactic antibiotics is controversial
  both in its effectiveness and risk of promoting
  bacterial resistance
• (except in the following -removal of loose
  suture corneal FB)

11
Initial Assessment

• History
• Ocular symptoms
• Review of prior ocular surgery
• Review of other medical problems
• Current ocular medications
• Drug allergies

12
Initial Assessment

• Examination
• General appearance of the patient including skin
  conditions
• Facial examination
• Eyelids and eyelid closure
• Conjunctiva
• Nasolacrimal apparatus
• Corneal sensation

13
Initial Assessment

• Slit Lamp Biomicroscopy
• Eyelid margins
• Conjunctiva
• Sclera
• Cornea
• Anterior Chamber
• Anterior Vitreous

14
Diagnostic Tests

• Majority of community acquired infections are
  successfully treated empirically without smears
• (Macleod SD et el, Ophthalmology 1996)

15
Diagnostic Tests

• Role of smears cultures
• Useful in guiding modification of therapy in
  patients with poor clinical response to initial
  broad spectrum therapy
• Allows elimination of unnecessary drugs hence
  reducing toxicity
• In cultures taken from patients not responding
  to empirical treatment, treatment may be stopped
  for 12 to 24 hours prior to re-culturing.

16
Diagnostic Tests

• Smears cultures are indicated in infections
• Prior to initiating treatment in sight
  threatening and severe keratitis
• Deep and large stromal infiltrates involving the
  visual axis
• Re-cultures are Necessary
• Chronic
• Unresponsive to broad spectrum antibiotic
• Features suggestive of fungal, amoebic or
  mycobacterial keratitis

17
CULTURE MEDIA FOR BACTERIAL KERATITIS (AAO
Preferred Practice Pattern-Bacterial Keratitis)
Standard Media Common Isolates
Blood agar Aerobic and facultatively anaerobic bacteria, including P. aeruginosa, S. aureus, S. epidermidis, S. pneumoniae
Chocolate agar Aerobic and facultatively anaerobic bacteria, including H. influenzae, N. gonorrhea, and Bartonella species
Thioglycollate broth Aerobic and facultatively anaerobic bacteria
Supplemental Media Supplemental Media
Anaerobic blood agar (CDC, Schaedler, Brucella) P. acnes, Peptostreptococcus
Löwenstein-Jensen medium Mycobacteria species, Nocardia species
Middlebrook agar Mycobacteria species
Thayer-Martin agar Pathogenic Neisseria species
NOTE Fungi and acanthamoeba can be recovered on
blood agar. However, more specific media are
available (fungi Sabouraud dextrose agar,
brain-heart infusion agar acanthamoeba buffered
charcoal yeast extract, blood agar with E. coli
overlay).
18
Diagnostic Tests

• Corneal Biopsy
• Lack of response
• More that 1 negative culture result
• Deep stromal infiltrate with normal overlying
  tissue
• With a corneal graft on standby

19
Treatment

• Initial
• Topical antibiotic eye drops are able to achieve
  high tissue levels and is the preferred choice of
  treatment in most cases.
• Topical antibiotic ointment at bedtime may be
  useful in less severe cases as an adjunctive
  treatment
• Sub-conjunctival antibiotics maybe helpful in
  cases of imminent scleral spread or perforation
  or when adherence to treatment regime is in
  question
• Systemic therapy maybe useful in cases where
  there is scleral or intraocular involvement or
  systemic infection (gonorrhea)

20
Singledrug therapy

• Using fluoroquinolones shown to be as effective
  as combination fortified antibiotics
• (The Ofloxacin Study Group-Ophthalmology 1997)
• Concerns wrt increasing resistance
• Reports of increase perforation in severe
  keratitis (retrospective, non randomised)
• (PLT Mallari et al AJO 2001)
• Rule of 2 lt2mm diameter, lt2AC cells gt2mm from
  visual axis

21
Combination Fortified-Antibiotic/ Systemic Therapy

• Severe infections
• Previously unresponsive to single-drug therapy
• Systemic
• Infection extending to sclera
• Impending or frank perforation
• Gonococcal keratitis

22
ANTIBIOTIC THERAPY OF BACTERIAL KERATITIS (AAO
BCSC 2005-2006)
Organism Antibiotic Topical Concentration Subconjunctival Dose
No organism identified or multiple types of organisms Cefazolin 50 mg/ml 100 mg in 0.5 ml
No organism identified or multiple types of organisms with 914 mg/ml 20 mg in 0.5 ml
No organism identified or multiple types of organisms Tobramycin/Gentamicin 3 or 5 mg/ml  
No organism identified or multiple types of organisms or    
No organism identified or multiple types of organisms Fluoroquinolones    
Gram-positive cocci Cefazolin 50 mg/ml 100 mg in 0.5 ml
Gram-positive cocci Vancomycin 1550 mg/ml 25 mg in 0.5 ml
Gram-positive cocci Bacitracin 10,000 IU  
Gram-positive cocci Moxifloxacin or Gatifloxacin 3 or 5 mg/ml  
Gram-negative rods Tobramycin/Gentamicin 914 mg/ml 20 mg in 0.5 ml
Gram-negative rods Ceftazidime 50 mg/ml 100 mg in 0.5 ml
Gram-negative rods Fluoroquinolones 3 or 5 mg/ml  
Gram-negative cocci Ceftriaxone 50 mg/ml 100 mg in 0.5 ml
Gram-negative cocci Ceftazidime 50 mg/ml 100 mg in 0.5 ml
Gram-negative cocci Fluoroquinolones 3 or 5 mg/ml  
Non-tuberculous mycobacteria Amikacin 2040 mg/ml 20 mg in 0.5 ml
Non-tuberculous mycobacteria Clarithromycin 3 or 5 mg/ml 20 mg in 0.5 ml
Non-tuberculous mycobacteria Fluoroquinolones   20 mg in 0.5 ml
Nocardia Amikacin 2040 mg/ml 20 mg in 0.5 ml
Nocardia Trimethoprim/sulfamethoxazole 16 mg/ml 20 mg in 0.5 ml
Nocardia trimethoprim 80 mg/ml 20 mg in 0.5 ml
Nocardia sulfamethoxazole   20 mg in 0.5 ml
23
Treatment

• Severe keratitis may require a loading dose
• (Every 5-15 mins for the 1st hour, followed by
  every 15mins-1hour around the clock)
• Cycloplegics to relief pain from cilary spasm and
  reduce synechial formation

24
Modification of Therapy

• Efficacy of treatment is judged primarily on the
  clinical response towards the current treatment
• Culture results may have an impact on
  modification of therapy especially when the
  response to treatment is poor
• If, however, condition is improving therapy need
  not necessarily be adjusted solely on the basis
  of laboratory results
• Dual antibiotic treatment may not be necessary
  once the causative organism is confirmed after
  all cultures are reported
• Modification should be done if the eye show lack
  of improvement or stabilisation after 48-72hrs
  after treatment (NB Pseudomonas)

25
Features suggestive of positive response to
treatment

• Reduction in pain
• Reduced amount of discharge
• Lessened eyelid edema or conjunctival injection
• Decreased density of the stromal infiltrate in
  the absence of progressive stromal loss
• Reduced stromal edema and endothelial
  inflammatory plaque
• Consolidation and sharper demarcation of the
  perimeter of the stromal infiltrate
• Reduced anterior chamber cell, fibrin, or
  hypopyon
• Initial re-epithelialisation
• Cessation of progressive corneal thinning
• (AAO. BCSC Cornea 2005-2006)

26
Role of Corticosteroid

• Many believe judicious use of steroids can
  reduce morbidity (Leibowitz HM et al, Arch
  Ophthalmology 2002)
• () Suppression of inflammation subsequent
  scarring
• (-) Recurrence of infection
• (-) Inhibition of collagen synthesis
• (-) Local immunosuppression
• (-) Increased IOP

27
Corticosteroid Therapy

• Patients who were treated with corticosteroids
  prior to the onset of infection should have the
  corticosteroids regime tapered off or stopped
  altogether until the infection is controlled

28
Corticosteroid Therapy

• In order to have successful steroid therapy
• use minimal amount of corticosteroid required to
  achieve control of inflammation
• optimal timing (Abx response, c/s results, not
  fungal inf.)
• careful dose regulation
• use of adequate and appropriate concomitant
  antibiotic
• close follow-up
• IOP monitoring

29
Complicated case

• Perforations, progressive unresponsive disease,
  endophthalmitis
• Tissue Adhesives
• Therapeutic or Tectonic Penetrating Keratoplasty

30
Emerging Trends
31
Bacterial Keratitis Current Treatment Choice

• Topical fluoroquinolones are preferred for most
  non-severe cases1
• Monotherapy with fluoroquinolones has shown
  clinical equivalence to combination therapy with
  fortified tobramycin/cefazolin2
• No differences in overall clinical efficacy or
  timeto cure
• Fewer treatment failures with ciprofloxacin
• Fewer patients reported ocular discomfort with
  ciprofloxacin
• Combination therapy (e.g., cefazolin
  fluoroquinolone) is required for severe infection
  or eyes unresponsive to treatment with a single
  agent1

1. American Academy of Ophthalmology. Preferred
Practice Pattern Bacterial Keratitis. Aug 2005
2. Hyndiuk RA, et al. Ophthalmology.
19961031854-1863.
32
Bacterial Ocular PathogensUlcerative Keratitis
47.4
Distribution of Organisms in Monomicrobial Cases
()
21.1
13.2
7.9
5.3
5.3
Staphylococcus epidermidis
Pseudomonasaeruginosa
Staphylococcus aureus
Serratia
Streptococcus pneumoniae
Other
Levey SB, et al. Cornea. 199716383-386.
33
Contact Lens (CL) related Bacterial Keratitis

• 30 (1999-2002) of ALL cases of bacterial
  keratitis related to CL use
• 12 (1996-1999)
• Significant increase (plt0.05)
• 43 of CL related infections related to daily
  wear frequent replacement soft CL
• 33 of positive culture results grew P.
  aureuginosa

Mah-Sadorra JH et al Cornea 2005 -Retrospective
Case Series from Wills Eye Hospital
34
Emerging Challenges to Current Strategy
35
Trends in Fluoroquinolone ResistanceAmong
Bacterial Keratitis Isolates
70
61.1
60
53.8
51.0
50.0
50
Streptococcus sp
38.9
40
31.6
of Isolates With Ciprofloxacin Resistance
OtherStaphylococcus sp
35.0
26.5
30
21.2
Staphylococcusaureus
17.3
20
15.3
19.5
11.4
9.4
5.8
10
0
1993
1994
1995
1996
1997
Goldstein MH, et al. Ophthalmology.
19991061313-1318.
36
Widespread Resistance toThird-Generation
Fluoroquinolones
In Vitro Susceptibility of Staphylococcus aureus
to Third-Generation Fluoroquinolones Campbell
Laboratory Survey
Kowalski et al. Ophthalmol Clin North Am. 2003.
37
Ciprofloxacin Resistant Pseudomonas
KeratitisPrashant G et al Ophthalmology July
1999

• Culture-proven cases of pseudomonas reviewed
  between 1991 to 1998 (N141)
• 1991 6.2 Ciprofloxacin Resistant
• 1998 23 Ciprofloxacin Resistant
• 76.7 of cases with isolated ciprofloxacin
  resistance did not show improvement with initial
  empirical treatment with ciprofloxacin

38
In vitro susceptibility of bacterial keratitis
pathogen to ciprofloxacin(Kunimoto et al LV
Prasad Institute-Ophthalmology 1999)

• 1558 corneal isolates tested for susceptibility
  to ciprofloxacin
• 32.5 Gram ve cocci not susceptible
• 13.3 Gram ve not susceptible

39
Microbiological Profile ofPost-LASIK Keratitis
Fungi Candida (5) Fusarium (3)
Aspergillus (2) Curvularia (2) Scedosporium
(1) Unidentified fungus (1)
Mycobacteria M chelonae (32) M abscessus
(6) M szulgai (5) M fortuitum (2) M
mucogenicum (2)
Gram-positive bacteria S aureus (17) S
pneumoniae (3) S viridans (2) S epidermidis
(2) Nocardia (1) Rhodococcus (1)
P aeruginosa (2)
Acanthamoeba (1)
Polymicrobial (4)
Chang et al. Surv Ophthalmol. 2004.
40
Emergence of 4th Generation Fluoroquinolones
41
Overview Second- and Third-Generation
Fluoroquinolones
AdditionalPreservative
Agent(Concentration)
Treatment Duration
Indication(s)
2nd Generation Ciprofloxacin (0.3)
Conjunctivitis Corneal ulcers
0.006 BAK
7 days 14 days
Ofloxacin (0.3)
Conjunctivitis Corneal ulcers
7 days 9 days
0.005 BAK
3rd Generation Levofloxacin (0.5)
Bacterial conjunctivitis
7 days
0.005 BAK
Dosing regimen for bacterial conjunctivitis
1-2 drops every 2-4 hours on days 1 and 2 QID on
days 3-7. BAKbenzalkonium chloride.
42
Overview Fourth-Generation Fluoroquinolones
Agent(Concentration)
TreatmentDuration
AdditionalPreservative
Indication
Dosing
Gatifloxacin (0.3)
Bacterial conjunctivitis
Days 1-2 Days 3-7
0.005 BAK
Q 2 H QID
Moxifloxacin (0.5)
Bacterial conjunctivitis
None
7 days
TID
BAKbenzalkonium chloride.
43
Evolution of the Quinolones
Norfloxacin Lomefloxacin Ciprofloxacin Ofloxacin
Sparfloxacin Grepafloxacin Levofloxacin
Gatifloxacin Moxifloxacin
NalidixicAcid
O
F
COOH
H
HN
N
N
OCH3
H

• Extended spectrum
• Enhanced activity against
• Gram-positives, streptococci,
• anaerobes, atypical mycobacteria
• Improved pharmacokinetic
• properties

• Extended spectrum
• Enhanced activity against
• Gram-negatives

• Limited spectrum
• of activity

American Pharmaceutical Association 2000.
44
Clinically Available Ophthalmic Solutions of
Fourth-Generation Fluoroquinolones
ZYMAR (gatifloxacin ophthalmic solution) 0.3 Vigamox (moxifloxacin ophthalmic solution) 0.5
Approved 2003 2003
Indication Bacterial conjunctivitis Bacterial conjunctivitis
Most Frequently Reported Adverse Events Conjunctival irritation, increased lacrimation, keratitis, and papillary conjunctivitis Conjunctivitis, decreased visual acuity, dry eye, keratitis, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, subconjunctival hemorrhage, and tearing
Formulation 0.005 benzalkonium chloride (BAK) No preservative
ZYMAR PI.Vigamox PI.
45
Mechanism of Action

• Targets DNA Gyrase (Topo-isomerase II) and
  Topo-isomerase IV
• Inhibits DNA replication ? death of bacterium
• Breaks in the double stranded DNA ? death of a
  replicating cell
• Fluoroquinolones target one or both enzymes (4th
  Gen Fluoroquinolones targets both)

46
Mechanism of Action
DNA-Gyrase Gramve Gram-ve Mycobacterium tuberculosis
Topo-isomerase IV Gramve
47
Fluoroquinolones Mechanism of Action
Levy SB. Sci American. March 199846-53.
48
Mechanism of Resistance

• Mutation of target enzymes
• Formation of gyrase protecting proteins
• Reduction in cell permeability
• Increase in drug efflux
• Production enzymes that degrade fluoroquinolones
  (only in fungi)

49
Resistance to Fluoroquinolones
Levy SB. Sci American. March 199846-53.
50
Resistance to Fluoroquinolones

• Develops in a step wise fashion
• Lowered susceptibility is associated with porins
  that regulate intracellular drug concentration
• Occur spontaneously or selectively by suboptimal
  fluoroquinolone Rx
• Much of resistance has been caused by systemic,
  agricultural and vetinary use

51
Resistance to Fluoroquinolones

• Topical use less likely to cause resistance due
  to the very high concentrations achieved
• Moxifloxacin is able to achieve concenetration
  levels 10,000 times above MIC
• 4th Gen fluoroquinolones have a theoretical
  decreased pathogen resistance because of the dual
  mechanism of action targeting multiple enzymes
• .Hence requiring 2 mutations

52
Fluoroquinolones Resistance

• In vitro test results suggest that moxifloxacin
  and gatifloxacin are less likely than
  earlier-generation agents to be affected by
  genetic mutations1,2 or selection for
  resistance2,3
• Additionally, Moxifloxacin has a unique Bicyclic
  bulky side-chain at C-7
• Specifically Engineered to inhibit cells
  efflux pump mechanism
• Increases drugs length of stay in bacterial
  cell
• Maximizes potency
• Further inhibits resistance3

1. Tankovic J, et al. J Antimicrob Chemother.
199943(suppl B)12-23. 2. Schedletzky H, et al.
J Antimicrob Chemother. 199943(suppl B)31-37.
3. Balfour JAB, Lamb HM. Drugs. 200059115-139.
53
Potency - Gram Positive
54
In Vivo Studies of Fluoroquinolones Against
Multidrug-Resistant Staphylococcal Keratitis

• Several in vivo studies demonstrate the efficacy
  of gatifloxacin against multidrug-resistant (MDR)
  Staph aureus in animal models of LASIK
• Suggestive of greater potency against Gram
  positive organism cf earlier generations of
  fluoroquinolones

55
Gatifloxacin Is Superior to the Older
Fluoroquinolones for the Prevention of MDR S
aureus Keratitis Post-LASIK
BSS (Control) Flap stromal bed fully
infected, flap dislodged
Ciprofloxacin Stromal infiltrates indicate
keratitis
Levofloxacin Corneal edema, stromal infiltrates
Gatifloxacin Clear cornea
Tungsiripat et al. Am J Ophthalmol. 2003.
56
Dajcs JJ et al- (Antimicrob Agents Chemother
2004)

• Early (active replication) and late treatment in
  rabbit models
• Ofloxacin-sensitive MRSA and MSSA keratitis
• Treated with moxifloxacin, levofloxacin or
  ciprofloxacin
• Early treatment All agents reduced by at least
  5-log CFU /cornea as compared to untreated
• Late treatment moxifloxacin was most effective
  in reducing S. aureus
• colony forming units

57
Ofloxacin-sensitive MSSA and MRSA
58
Dajcs et al

• Ofloxacin-resistant MRSA and MSSA
• Early treatment moxifloxacin and levofloxacin
  was better able to reduce S. aureus colonies (4.5
  3.5-log) than ciprofloxacin(0.5 log)
• Late treatment only moxifloxacin was able to
  significantly reduce S. aureus CFU/cornea as cf
  to untreated

59
Ofloxacin-resistant MSSA and MRSA
60
Potency-Gram Negative
61
Quantitative comparison of of fluoroquinolones
therapies of experimental Gram-negative bacterial
keratitis (rabbit )animal models

• Treatment of ciprofloxacin-sensitive P.
  aueriginosa keratitis with moxifloxacin and
  earlier generation fluoroquinolones
• Resulted in 5 or greater log reduction of
  CFU)/cornea cf to untreated eyes.
• Demonstrates the similar potency moxifloxacin has
  with earlier fluoroquinolones

(Thibodeux et al Curr Eye Res2004)
62
(No Transcript)
63
Potency- Atypical Mycobacterium
64
Microbiology Post-LASIK Keratitis
S aureus
14
Fungi Curvularia Fusarium Aspergillus
6
Atypical Mycobacteria M chelonae/abscessus
M fortuitum M mucogenicum
4
S epidermidis
51
4
S pneumoniae
3
S viridans
3
Nocardia
3
Mixed infection
5
Herpes simplex (1)
5
P aeruginosa (1)
Culture negative
Not Identified
Dhaliwal D. Unpublished data and literature
review. 2002.
65
Post-LASIK Keratitis

• Opportunistic organisms
• Predominantly atypical mycobacteria and
  Gram-positives1,2
• Associated with clustered cases1
• Altered host defense with deep inoculation of
  organisms2,3
• 5 cases of bilateral infection reported in
  medical literature4-6
• Treatment may require flap amputation and
  prolonged treatment with antibiotics

Mycobacterium chelonae Post-LASIK KeratitisPhoto
courtesy of Cornea Color Atlas Synopsis of
Clinical Ophthalmology 2003 (Wills Eye Hospital
Series) by CJ Rapuano and WJ Heng.
1. Holmes GP, et al. Clin Infect Dis.
2002341039-1046. 2. Pushker N, et al. J Refract
Surg. 200218280-286. 3. Holland E. J Refract
Surg. Oct 200248-53. 4. Giaconi J, et al. J
Cataract Refract Surg. 200228887-890. 5. Suresh
PS, Rootman DS. J Cataract Refract Surg.
200228720-721.6. Garg P, et al. Ophthalmology.
2001108121-125.
66
Environmental Sources of Atypical Mycobacteria

• Environmental reservoirs1
• 37 of samples
• 50 tap water
• 48 pools
• 33 ice machines
• 16 eye wash stations
• Infections2
• gt50 post-LASIK infections

Acid Fast Stain
1. Miller D, et al. Poster presented at Annual
Meeting of the Association for Research in Vision
and Ophthalmology May 5, 2003 Ft. Lauderdale,
Fla. 2. Dhaliwal D. Unpublished data and
literature review. 2002.
Photo courtesy of Eduardo Alfonso, MD.
67
Moxifloxacin vs Gatifloxacin AgainstAtypical
Mycobacteria
MIC90 (?g/mL)
MICminimum inhibitory concentration.
Schlech B, Alfonso E, et al. Accepted for
presentation at the Ocular Microbiology and
Immunology Group meeting November 15, 2003.
68
Moxifloxacin and Gatifloxacin Atypical
Mycobacteria MIC90s1 in Relation to VIGAMOX
Solution and ZYMAR Cornea Concentrations2
Moxifloxacin
Gatifloxacin
1. Schlech B, Alfonso E, et al. Accepted for
presentation at the Ocular Microbiology and
Immunology Group meeting November 15, 2003.
2. Robertson SM, et al. Poster presented at
Annual Meeting of the Association for Research in
Vision and Ophthalmology April, 2004.
69
Comparison of Potency between Fluoroquinolones
(Rookaya Mathar et al AJO April 2002)

• In vitro susceptibilities and potencies of
  fluoroquinolones using bacteria isolated from
  clinical cases of endophthalmitis
• Gram ve 4th generation more potent that 3rd
• Gram ve 3rd and 4th generation equally potent
• Gram ve Moxifloxacin gtGatifloxacin
• Gram ve both 4th generations are equally potent

70
Tissue Penetration
71
Cornea Penetration (Cmax) ofMoxifloxacin and
Gatifloxacin in a Rabbit Model (T.I.D. Dosing x 3
Days 1 gtt Day 4)
Concentration(µg/g)
Robertson SM, et al. Poster presented at Annual
Meeting of the Association for Research in Vision
and Ophthalmology April, 2004.
72
Moxifloxacin solution achieves a higher
concentration in the conjunctiva than other
fluoroquinolones
Conjunctival Concentration µg/g
The conjunctival concentration achieved with
VIGAMOX solution 20 minutes after a single drop
in healthy volunteers is bactericidal against
both Gram positive and Gram negative organisms.
Wagner RS, Cockrum P, Abelson M, Shapiro A,
Torkildson G, et al. Evaluation of moxifloxacin
and ciprofloxacin concentrations in human
conjunctival tissue following administration of
moxifloxacin HCl 0.5 (Vigamox) and ciprofloxacin
0.3 (Ciloxan) ophthalmic solution. Accepted for
publication Archives of Ophthalmology.
Trademarks are the property of their respective
owners.
73
Moxifloxacin 0.5 reaches concentrations 3.8
times higher than Gatifloxacin 0.3 in Aqueous
Humor (cataract Sx)

3.8 x higher
plt0.01
Aqueous Concentration
n 25
n 25

Moxifloxacin 0.5 ophthalmic solution met the MIC
for FQ-resistant Staphylococcus aureus, while
gatifloxacin 0.3 ophthalmic solution did not
Kim DH, Stark WJ, OBrien TP. Comparative ocular
penetration of perioperative topically
administered fourth generation fluoroquinolones
with cataract surgery. Current Medical Research
and Opinion, 2005, 21(1). ZYMAR is a registered
trademark of it respective owner
74
Tissue Penetration-Moxifloxacin vs Gatifloxacin

• Moxifloxacin has achieves a higher level of
  tissue penetration
• Higher concentration 0.5 vs. 0.3
• Presence of both lipophilic and hydrophilic
  properties
• pH 6.8 closer to physiological 7.0-more soluble

75
Safety
76
Safety (Animal Studies)

• Extremely high concentration of moxifloxacin
  instilled onto rabbit and monkey eyes-no
  significant ocular effects
• No systemic effects
• No significant difference between gatifloxacin
  and moxifloxacin on healing rates in wounded
  cornea
• both are safe to use under these conditions
• In vitro studies suggestive moxifloxacin has a
  low potential for dose- and time-dependant
  cytotoxicity
• (Mcgee et al, Surv Ophthalmol Nov 2005)

77
Clinical Safety pediatric/non-pediatric patients
( AM Woodside, 2005 Nov Surv Ophthal)

• 1,978 patients pooled from 5 different centers
• No serious treatmentrelated adverse events
  reported
• Ocular side effects generally mild in intensity
• Transient ocular discomfort and conjunctival
  hyperemia
• Resolved after several minutes
• Since Dec 31 2004 date of product launch- only 12
  adverse reports of ocular irritation reported
• 3.6 million units of moxifloxacin sold
• Safety profile similar between pediatric and non
  pediatric patients

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A Comparison of the Fourth-Generation
Fluoroquinolones Gatifloxacin 0.3 and
Moxifloxacin 0.5 in Terms of Ocular Tolerability

• Gatifloxacin 0.3 was significantly better
  tolerated than moxifloxacin 0.5 as measured by
  degree of (n30)
• conjunctival hyperemia (p 0.0005)
• vascularity (p 0.0005),
• ocular irritation (p 0.001)
• pain (p 0.001).
• Administration of moxifloxacin 0.5 resulted in a
  significant decrease in pupil size compared with
  baseline (p 0.004). Prostaglandin?
• findings suggest the presence of intolerability,
  which is either dependent on the concentration of
  fluoroquinolone or associated with the intrinsic
  properties of the moxifloxacin molecule
• (Eric Donnenfeld et al Curr Med Res Opin
  20(11)1753-1758, 2004)
• supported in part by an unrestricted educational
  grant from Allergan, Inc

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Ideal Treatment for Bacterial Keratitis

• Ideal antimicrobial would demonstrate
• Enhanced Gram-positive coverage (including
  Streptococcus)
• Continued strong Gram-negative activity
• Improved coverage of atypical organisms
• Good tolerance
• Low toxicity
• Bactericidal efficacy
• Good corneal penetration
• Coverage of resistant bacteria
• Decreased propensity to develop resistance

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4th Gen vs 2nd- and 3rd-Generation Ocular
Fluoroquinolones Summary

• 4th Generation is more effective against
• Gram-positive organisms while maintaining
  coverage against Gram-negative organisms1
• Fluoroquinolone-resistant organisms1
• Atypical mycobacteria2
• 4th Generation is
• Highly soluble with excellent penetration
  intoocular tissue
• BAK-free/self-preserved (moxifloxacin)
• Formulated at near-neutral pH (6.8)
  (moxifloxacin)
• Less likely to select for resistance3,4

1. Mather R, et al. Am J Ophthalmol.
2002133463-466. 2. Gillespie SH, Billington O.
J Antimicrob Chemother. 199944393-395. 3.
Schedletzky H, et al. J Antimicrob Chemother.
199943(suppl B)31-37. 4. Balfour JAB, Lamb HM.
Drugs. 200059115-139.
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4th Generation Fluoroquinolones

• Theoretically reduced opportunity for resistance
  with double mutation
• Improved tissue penetration
• Improved cellular retention
• Improved potency
• Reduces toxicity
• Coverage comparable to combination antibiotic
  therapy
• Too good to be true?
• Most evidence is based on animal studies
• Need for human RCT specifically to address
  treatment efficacy in bacterial keratitis and in
  comparison to established fortified combination
  antibiotic therapy

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The case for combination fortified antibiotic
therapy

• ()Well established practice for severe bacterial
  keratitis
• ()Lower cost of drug
• ()Broad spectrum of coverage
• But
• (-)Increase toxicity
• (-)Damage to ocular surface

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Conclusion

• The advocacy of 4th generation fuoroquinolones as
  a 1st line treatment for bacterial keratitis must
  be tempered with past experience of resistance in
  the previous generations of fluoroquinolones.
• In the absence of RCT to show superior or equal
  efficacy by 4th generation fluoroquinolones in
  the treatment of severe keratitis, it would be
  prudent to continue with established practice in
  the use of combined fortified antibiotic regime
  (cephalosporin and aminoglycoside)
• The use of 4th generation fluoroquinolones should
  be held in reserve both in its ocular as well as
  systemic use in order to minimise the risk of
  development of significant resistance in the
  bacterial population.

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Thank You