1139713852_bacterialkeratitis

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Updates on the Management of Bacterial Keratitis:

Updates on the Management of Bacterial Keratitis by Dr David P L Chan MRCSEd(Ophth) MMed(Ophth)

Current Strategy:

Current Strategy

Infective Keratitis:

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 cornea’s natural resistance to infection

Risk Factors-Exogenous factors :

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)

Risk Factors-Ocular Surface Disease:

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

Risk factors-Corneal Epithelial Abnormalities :

Risk factors-Corneal Epithelial Abnormalities Neurotrophic Keratopathy Disorders predisposing to recurrent corneal erosion Viral Keratitis Corneal epithelial oedema, especially bullous keratopathy

Risk factors-Systemic conditions:

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

Common etiological agents of bacterial keratitis in the U.S. (AAO Preferred Practice Pattern Aug 2005-Bacterial Keratitis) :

Class/Organism Common Isolates* Cases (%) Gram-Positive Isolates 44–90 Gram-positive Cocci Staphylococcus aureus 4–30 Coagulase negative Staphylococci 5–40 Streptococcus pneumoniae 1–25 Streptococcus viridans group 1–15 Gram-positive Bacilli Corynebacterium species 1-5 Propionibacterium species 1-12 Mycobacterium species 1-2 Gram-Negative Isolates 10–50 Gram-negative Bacilli Pseudomonas aeruginosa 5-45 Serratia marcescens 1-12 Proteus mirabilis 1-5 Enteric gram-negative bacilli, other 1-10 Gram-negative Coccobacillary organisms Haemophilus influenzae, other 1-6 Haemophilus species 1-5 Moraxella species and related species Gram-negative Cocci Neisseria species 1 Common etiological agents of bacterial keratitis in the U.S. (AAO Preferred Practice Pattern Aug 2005-Bacterial Keratitis)

Natural History of Bacterial Keratitis:

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

Prevention and Early Detection:

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)

Initial Assessment:

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

Initial Assessment:

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

Initial Assessment:

Initial Assessment Slit Lamp Biomicroscopy Eyelid margins Conjunctiva Sclera Cornea Anterior Chamber Anterior Vitreous

Diagnostic Tests:

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

Diagnostic Tests:

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.

Diagnostic Tests:

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

CULTURE MEDIA FOR BACTERIAL KERATITIS (AAO Preferred Practice Pattern-Bacterial Keratitis) :

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 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).

Diagnostic Tests:

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

Treatment:

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)

Single–drug therapy:

Single–drug 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: <2mm diameter, <2+AC cells & >2mm from visual axis

Combination Fortified-Antibiotic/ Systemic Therapy:

Combination Fortified-Antibiotic/ Systemic Therapy Severe infections Previously unresponsive to single-drug therapy Systemic Infection extending to sclera Impending or frank perforation Gonococcal keratitis

ANTIBIOTIC THERAPY OF BACTERIAL KERATITIS (AAO BCSC 2005-2006):

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 with 9–14 mg/ml 20 mg in 0.5 ml Tobramycin/Gentamicin 3 or 5 mg/ml or Fluoroquinolones Gram-positive cocci Cefazolin 50 mg/ml 100 mg in 0.5 ml Vancomycin* 15–50 mg/ml 25 mg in 0.5 ml Bacitracin* 10,000 IU Moxifloxacin or Gatifloxacin 3 or 5 mg/ml Gram-negative rods Tobramycin/Gentamicin 9–14 mg/ml 20 mg in 0.5 ml Ceftazidime 50 mg/ml 100 mg in 0.5 ml Fluoroquinolones 3 or 5 mg/ml Gram-negative cocci† Ceftriaxone 50 mg/ml 100 mg in 0.5 ml Ceftazidime 50 mg/ml 100 mg in 0.5 ml Fluoroquinolones 3 or 5 mg/ml Non-tuberculous mycobacteria Amikacin 20–40 mg/ml 20 mg in 0.5 ml Clarithromycin‡ 3 or 5 mg/ml Fluoroquinolones Nocardia Amikacin 20–40 mg/ml 20 mg in 0.5 ml Trimethoprim/sulfamethoxazole: 16 mg/ml trimethoprim 80 mg/ml sulfamethoxazole

Treatment:

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

Modification of Therapy :

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)

Features suggestive of positive response to treatment :

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)

Role of Corticosteroid :

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

Corticosteroid Therapy:

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

Corticosteroid Therapy:

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

Complicated case :

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

Emerging Trends:

Emerging Trends

Bacterial Keratitis: Current Treatment Choice:

Bacterial Keratitis: Current Treatment Choice Topical fluoroquinolones are preferred for most non-severe cases 1 Monotherapy with fluoroquinolones has shown clinical equivalence to combination therapy with fortified tobramycin/cefazolin 2 No differences in overall clinical efficacy or time to 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 agent 1 1. American Academy of Ophthalmology. Preferred Practice Pattern: Bacterial Keratitis. Aug 200 5 2. Hyndiuk RA, et al. Ophthalmology. 1996;103:1854-1863.

Bacterial Ocular Pathogens: Ulcerative Keratitis :

Bacterial Ocular Pathogens: Ulcerative Keratitis Levey SB, et al. Cornea. 1997;16:383-386. 47.4% 21.1% 13.2% 5.3% 5.3% 7.9% Staphylococcus epidermidis Pseudomonas aeruginosa Staphylococcus aureus Serratia Streptococcus pneumoniae Other Distribution of Organisms in Monomicrobial Cases (%)

Contact Lens (CL) related Bacterial Keratitis:

Contact Lens (CL) related Bacterial Keratitis 30% (1999-2002) of ALL cases of bacterial keratitis related to CL use 12% (1996-1999) Significant increase (p<0.05) 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 Will’s Eye Hospital

Emerging Challenges to Current Strategy:

Emerging Challenges to Current Strategy

Trends in Fluoroquinolone Resistance Among Bacterial Keratitis Isolates :

Trends in Fluoroquinolone Resistance Among Bacterial Keratitis Isolates Goldstein MH, et al. Ophthalmology. 1999;106:1313-1318. % of Isolates With Ciprofloxacin Resistance Streptococcus sp Staphylococcus aureus Other Staphylococcus sp 5.8 9.4 11.4 26.5 35.0 15.3 17.3 21.2 19.5 38.9 51.0 61.1 31.6 53.8 50.0 0 10 20 30 40 50 60 70 1993 1994 1995 1996 1997

Widespread Resistance to Third-Generation Fluoroquinolones:

Widespread Resistance to Third-Generation Fluoroquinolones In Vitro Susceptibility of Staphylococcus aureus to Third-Generation Fluoroquinolones: Campbell Laboratory Survey Year 1993 1994 1995 1996 1997 1998 1999 2000 2001 Percentage Susceptible (%) 0 10 20 30 40 50 60 70 80 90 100 Keratitis Endophthalmitis Conjunctivitis/Blepharitis Kowalski et al. Ophthalmol Clin North Am. 2003.

Ciprofloxacin Resistant Pseudomonas Keratitis Prashant G et al Ophthalmology July 1999 :

Ciprofloxacin Resistant Pseudomonas Keratitis Prashant G et al Ophthalmology July 1999 Culture-proven cases of pseudomonas reviewed between 1991 to 1998 (N=141) 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

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

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

Microbiological Profile of Post-LASIK Keratitis :

Microbiological Profile of Post-LASIK Keratitis Chang et al. Surv Ophthalmol. 2004. Gram-positive bacteria S aureus (17) S pneumoniae (3) S viridans (2) S epidermidis (2) Nocardia (1) Rhodococcus (1) 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) P aeruginosa (2) Acanthamoeba (1) Polymicrobial (4)

Emergence of 4th Generation Fluoroquinolones:

Emergence of 4 th Generation Fluoroquinolones

Overview: Second- and Third- Generation Fluoroquinolones :

Overview: Second- and Third- Generation Fluoroquinolones Agent (Concentration) Indication(s) Treatment Duration* Additional Preservative † 2nd Generation Ciprofloxacin (0.3%) Conjunctivitis Corneal ulcers 0.006% BAK Ofloxacin (0.3%) Conjunctivitis Corneal ulcers 7 days 9 days 0.005% BAK 7 days 14 days 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. † BAK=benzalkonium chloride.

Overview: Fourth-Generation Fluoroquinolones :

Overview: Fourth-Generation Fluoroquinolones Agent (Concentration) Indication Treatment Duration Additional Preservative* Gatifloxacin (0.3%) Bacterial conjunctivitis Days 1-2 Days 3-7 0.005% BAK Moxifloxacin (0.5%) Bacterial conjunctivitis None * BAK=benzalkonium chloride. 7 days Dosing Q 2 H QID TID

Evolution of the Quinolones:

Evolution of the Quinolones Nalidixic Acid Norfloxacin Lomefloxacin Ciprofloxacin Ofloxacin Sparfloxacin Grepafloxacin Levofloxacin Gatifloxacin Moxifloxacin Limited spectrum of activity Extended spectrum Enhanced activity against Gram-negatives Extended spectrum Enhanced activity against Gram-positives, streptococci, anaerobes, atypical mycobacteria Improved pharmacokinetic properties H 3 C N C 2 H 5 N O COOH HN N F N O COOH N H 3 C-N F CH 3 N O COOH O N H OCH 3 F N O COOH HN N H H American Pharmaceutical Association; 2000.

Clinically Available Ophthalmic Solutions of Fourth-Generation Fluoroquinolones:

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.

Mechanism of Action:

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 (4 th Gen Fluoroquinolones targets both)

Mechanism of Action:

Mechanism of Action DNA-Gyrase Gram+ve Gram-ve Mycobacterium tuberculosis Topo-isomerase IV Gram+ve

Fluoroquinolones: Mechanism of Action:

Fluoroquinolones: Mechanism of Action Levy SB. Sci American. March 1998:46-53.

Mechanism of Resistance:

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)

Resistance to Fluoroquinolones:

Resistance to Fluoroquinolones Levy SB. Sci American. March 1998:46-53.

Resistance to Fluoroquinolones:

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

Resistance to Fluoroquinolones:

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 4 th Gen fluoroquinolones have a theoretical decreased pathogen resistance because of the dual mechanism of action targeting multiple enzymes …….Hence requiring 2 mutations

Fluoroquinolones: Resistance :

Fluoroquinolones: Resistance In vitro test results suggest that moxifloxacin and gatifloxacin are less likely than earlier-generation agents to be affected by genetic mutations 1,2 or selection for resistance 2,3 Additionally, Moxifloxacin has a unique Bicyclic “bulky” side-chain at C-7 “Specifically Engineered” to inhibit cell’s efflux pump mechanism Increases drug’s length of stay in bacterial cell Maximizes potency Further inhibits resistance 3 1. Tankovic J, et al. J Antimicrob Chemother . 1999;43(suppl B):12-23. 2. Schedletzky H, et al. J Antimicrob Chemother . 1999;43(suppl B):31-37. 3. Balfour JAB, Lamb HM. Drugs . 2000;59:115-139.

Potency - Gram Positive:

Potency - Gram Positive

In Vivo Studies of Fluoroquinolones Against Multidrug-Resistant Staphylococcal Keratitis:

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

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 Gatifloxacin Is Superior to the Older Fluoroquinolones for the Prevention of MDR S aureus Keratitis Post-LASIK Tungsiripat et al. Am J Ophthalmol . 2003.

Dajcs JJ et al- (Antimicrob Agents Chemother 2004):

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 * c olony f orming u nits

PowerPoint Presentation:

Ofloxacin-sensitive MSSA and MRSA

Dajcs et al:

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

PowerPoint Presentation:

Ofloxacin-resistant MSSA and MRSA

Potency-Gram Negative:

Potency-Gram Negative

Quantitative comparison of of fluoroquinolones therapies of experimental Gram-negative bacterial keratitis (rabbit )animal models:

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)

Potency- Atypical Mycobacterium:

Potency- Atypical Mycobacterium

Microbiology Post-LASIK Keratitis :

Microbiology Post-LASIK Keratitis Dhaliwal D. Unpublished data and literature review. 2002. Atypical Mycobacteria M chelonae/abscessus M fortuitum M mucogenicum S aureus S epidermidis 4% S pneumoniae S viridans 3% Nocardia 3% P aeruginosa (1%) Fungi Curvularia Fusarium Aspergillus 6% Not Identified 5% Mixed infection 3% Culture negative 5% 51% 14% 4% Herpes simplex (1%)

Post-LASIK Keratitis :

Post- LASIK Keratitis 1. Holmes GP, et al. Clin Infect Dis . 2002;34:1039-1046. 2. Pushker N, et al. J Refract Surg . 2002;18:280-286. 3. Holland E. J Refract Surg . Oct 2002:48-53. 4. Giaconi J, et al. J Cataract Refract Surg . 2002;28:887-890. 5. Suresh PS, Rootman DS. J Cataract Refract Surg . 2002;28:720-721. 6. Garg P, et al. Ophthalmology. 2001;108:121-125. Opportunistic organisms Predominantly atypical mycobacteria and Gram-positives 1,2 Associated with clustered cases 1 Altered host defense with deep inoculation of organisms 2,3 5 cases of bilateral infection reported in medical literature 4-6 Treatment may require flap amputation and prolonged treatment with antibiotics Mycobacterium chelonae Post-LASIK Keratitis Photo courtesy of Cornea Color Atlas & Synopsis of Clinical Ophthalmology 2003 (Wills Eye Hospital Series) by CJ Rapuano and WJ Heng.

Environmental Sources of Atypical Mycobacteria:

Environmental Sources of Atypical Mycobacteria Environmental reservoirs 1 37% of samples 50% tap water 48% pools 33% ice machines 16% eye wash stations Infections 2 >50 % post-LASIK infections 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. Acid Fast Stain Photo courtesy of Eduardo Alfonso, MD.

Moxifloxacin vs Gatifloxacin Against Atypical Mycobacteria:

Moxifloxacin vs Gatifloxacin Against Atypical Mycobacteria MIC 90 ( g/mL)* *MIC=minimum inhibitory concentration. Schlech B, Alfonso E, et al. Accepted for presentation at the Ocular Microbiology and Immunology Group meeting – November 15, 2003.

Moxifloxacin and Gatifloxacin Atypical Mycobacteria MIC90s1 in Relation to VIGAMOX™ Solution and ZYMAR™ Cornea Concentrations2 :

24.8 m g/g Moxifloxacin and Gatifloxacin Atypical Mycobacteria MIC90s 1 in Relation to VIGAMOX™ Solution and ZYMAR™ Cornea Concentrations 2 2. Robertson SM, et al. Poster presented at Annual Meeting of the Association for Research in Vision and Ophthalmology; April, 2004. 4.9 m g/g Moxifloxacin Gatifloxacin 1. Schlech B, Alfonso E, et al. Accepted for presentation at the Ocular Microbiology and Immunology Group meeting – November 15, 2003.

Comparison of Potency between Fluoroquinolones (Rookaya Mathar et al AJO April 2002):

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 : 4 th generation more potent that 3 rd Gram –ve : 3 rd and 4 th generation equally potent Gram +ve Moxifloxacin >Gatifloxacin Gram –ve both 4 th generations are equally potent

Tissue Penetration:

Tissue Penetration

Cornea Penetration (Cmax) of Moxifloxacin and Gatifloxacin in a Rabbit Model (T.I.D. Dosing x 3 Days + 1 gtt Day 4):

Cornea Penetration (C max ) of Moxifloxacin and Gatifloxacin in a Rabbit Model (T.I.D. Dosing x 3 Days + 1 gtt Day 4) Robertson SM, et al. Poster presented at Annual Meeting of the Association for Research in Vision and Ophthalmology; April, 2004. Concentration ( µg/g )

Moxifloxacin solution achieves a higher concentration in the conjunctiva than other fluoroquinolones :

Moxifloxacin solution achieves a higher concentration in the conjunctiva than other fluoroquinolones Conjunctival Concentration µg/g *Trademarks are the property of their respective owners. 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 .

Moxifloxacin 0.5% reaches concentrations 3.8 times higher than Gatifloxacin 0.3% in Aqueous Humor (cataract Sx):

Moxifloxacin 0.5% reaches concentrations 3.8 times higher than Gatifloxacin 0.3% in Aqueous Humor (cataract Sx) Kim DH, Stark WJ, O’Brien 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 Aqueous Concentration n = 25 n = 25 *p<0.01 * Moxifloxacin 0.5% ophthalmic solution met the MIC for FQ-resistant Staphylococcus aureus, while gatifloxacin 0.3% ophthalmic solution did not † 3.8 x higher

Tissue Penetration- Moxifloxacin vs Gatifloxacin:

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

Safety:

Safety

Safety (Animal Studies) :

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)

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

Clinical Safety pediatric/non-pediatric patients ( AM Woodside, 2005 Nov Surv Ophthal) 1,978 patients pooled from 5 different centers No serious treatment–related 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

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

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 (n=30) 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

Ideal Treatment for Bacterial Keratitis :

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

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

4th Gen vs 2nd- and 3rd-Generation Ocular Fluoroquinolones: Summary 4 th Generation is more effective against Gram-positive organisms while maintaining coverage against Gram-negative organisms 1 Fluoroquinolone-resistant organisms 1 Atypical mycobacteria 2 4 th Generation is Highly soluble with excellent penetration into ocular tissue BAK-free/self-preserved (moxifloxacin) Formulated at near-neutral pH (6.8) (moxifloxacin) Less likely to select for resistance 3,4 1. Mather R, et al. Am J Ophthalmol. 2002;133:463-466. 2. Gillespie SH, Billington O. J Antimicrob Chemother. 1999;44:393-395. 3. Schedletzky H, et al . J Antimicrob Chemother. 1999;43(suppl B):31-37. 4. Balfour JAB, Lamb HM. Drugs. 2000;59:115-139.

4th Generation Fluoroquinolones:

4 th 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

The case for combination fortified antibiotic therapy:

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

Conclusion:

Conclusion The advocacy of 4 th generation fuoroquinolones as a 1 st 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 4 th 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 4 th 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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