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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. Infective Keratitis. 30,000 cases annually in the US (Bacterial, Fungal and Acanthanoeba) (Pepose JS et al AJO 1992)

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Updates on the Management of Bacterial Keratitis

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  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 cornea’s 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)

  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 • Educationon 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 (AAOPreferred Practice Pattern-Bacterial Keratitis) 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. 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

  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)

  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. 1996;103:1854-1863.

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

  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 (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

  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. 1999;106:1313-1318.

  36. 100 90 80 70 60 Percentage Susceptible (%) 50 40 30 Keratitis 20 Endophthalmitis 10 Conjunctivitis/Blepharitis 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 Year 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 (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

  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 FungiCandida (5)Fusarium (3) Aspergillus(2) Curvularia(2) Scedosporium (1) Unidentified fungus (1) MycobacteriaM chelonae (32)M abscessus (6)M szulgai (5)M fortuitum (2)M mucogenicum (2) Gram-positive bacteriaS 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. † BAK=benzalkonium chloride.

  42. Overview: Fourth-Generation Fluoroquinolones TreatmentDuration Agent(Concentration) 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 7 days None TID * BAK=benzalkonium chloride.

  43. Evolution of the Quinolones O O O COOH F COOH F COOH H3C N N N N N N N H3C-N O CH3 C2H5 HN H 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® 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

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

  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 1998:46-53.

  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

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