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Corneal Infections From A (Acanthamoeba) to Z (Zoster) Joseph P. Shovlin, OD, FAAO This presentation begins with a review of the epidemiology and pathogenesis of ulcerative keratitis due to many causes. Several recent landmark studies will be analyzed in order to cite the risk factors associated with the increased incidence of corneal infection. Preventive measures in minimizing these occurrences will be stressed. The organisms most likely to be encountered will be reviewed along with the key measures used to make the important differential diagnosis between a sterile versus an infectious keratitis. TOPICS: Risk Factors and Pathogenesis of Ulcerative Keratitis The Differentials of Infiltrative Keratitis: Sterile v. Infectious Diagnosis and Treatment of Bacterial Keratitis Non-Bacterial (Fungal and Protozoan) Infections The Herpes Group: Simplex and Zoster Case Examples: Highlighting Differentials and Management Risk Factors for Bacterial Keratitis EXOGENOUS: contact lenses, especially extended wear, contaminated cases and solutions, patching a contact lens abrasion; trauma including foreign body, chemical and thermal injury; previous ocular surgery including loose sutures; medicamentosa, contaminated medications and make-up. OCULAR ADNEXAL DYSFUNCTION: misdirection of lashes; abnormal lid anatomy & function; tear deficiencies, conjunctivitis; neuropathy involving cranial nerve(s) III, V and VII; blepharitis, canaliculitis/dacryocystitis. CORNEAL ABNORMALITIES: hypesthesia, bullous keratopathy, erosive disorders, viral keratitis. SYSTEMIC DISEASE: diabetes mellitus; debilitating illness, especially malnutrition or respirator dependence; collagen vascular disorders, substance abuse, mental illness; exfoliative skin disease; immunocompromised patient; atopic dermatitis, vitamin A or B deficiency. IMMUNOSUPPRESSIVE THERAPY: systemic corticosteroids; topical immunosuppressive agents; systemic chemotherapy for malignancy, organ transplant or collagen vascular disease. Pathogenesis Epithelial Compromise- hypoxic, mechanical, osmotic Contact Lens Contamination- lens care products, case, cosmetics, skin flora, adherence to lens Cascade of Events- adherence of microorganism to surface of cornea, invasion of the cornea, spread and multiplication, induction of the host inflammatory response, encounter of microorganisms with host immune factors, tissue damage, tissue repair and recovery Epidemiology Incidence in Contact Lens Wear Daily Wear: approximately 1/2,500/year Overnight wear of extended wear lenses: estimates range from one case among 150-300 wearers/year Population at risk- probably 12,000-15,000 cases /year in U.S Clinical Features Symptomotology- pain, photophobia, decreased acuity, foreign body Signs-significant lid edema and reactive ptosis, conjunctival and ciliary injection, discharge, papillary response, stromal infiltration, surrounding edema, epithelial defect, anterior chamber reaction, cellular debris of the tear meniscus, and hypopyon Laboratory Confirmation/Scrapings Smears- Gram, Giemsa, acridine orange, acid fast, methenamine silver, calcofluor white Cultures- blood agar, chocolate agar (heated blood), thioglycolate broth, Sabouraud’s, Lowenstein-Jensen, non-nutrient agar, and others like Thayer-Martin medium for suspected Neisseria infection. Reasons to culture before treatment- reveal sensitivities of organisms to eliminate ineffective drugs to reduce toxicity, discriminate between static and cidal properties of antibiotics and guide modification in therapy, ineffectively treated organisms are often difficult to isolate, medico-legal component of the patient’s record. Corneal biopsy is indicated if there has been a poor response to treatment or if cultures have been negative on more than one occasion, and the clinical picture continues to suggest infection. Also, used where a deep suppurration is not accessible by scraping. The specimen should be sufficiently large to allow bisection; one section for culture and the other for histopathology. Specimen should be delivered to the technician without delay. Treatment Protocols for Bacterial Keratitis Assessment of Severity and Initial Plans Objectives To distinguish severe suppurative keratitis from non-severe Implications of virulent versus lesser virulent organisms Definition of latitudes of initial therapy Guidelines [Adapted from J. McCulley] Feature Suppurative/Severe Non-suppurative/Mild-Mod. Onset/progression acute/ rapid sub-acute, chronic/slowly progressive Virulence highly likely uncertain, doubtful Laboratory Studies immediate, urgent may delay Laboratory Materials standard special Initial Antibiotics based on smears/broad based on smears + biopsy/ antimicrobial agents latitude for deferral Broad spectrum of initial coverage: single agent (fluoroquinolones) vs. multiple agents Rapid, intensive topical therapy Daily evaluation Tailor antibiotic choice by culture results and clinical response Design and Drug Penetration Topical- every 15 min.- 1 hr. for initial 24-48 hrs. or altered loading dose Subconjunctival injections- once or twice daily for 1-2 days Intravenous antibiotics- only for impending perforation or scleral suppuration Modification of Therapy Objectives- eliminate replicating bacteria, avoid adverse reaction to the medication, control the destructive components of the inflammatory process Guidelines- avoid abrupt changes in therapy until the response can adequately be assessed and until the sensitivity tests are completed at the lab Expected response despite proper/ effective therapy: Organism Response S. aureus, S. pneumoniae may be relatively unchanged, then improve rapidly after 24-48 hrs.; organisms generally eliminated in 7-10 days Pseudomonas aeruginosa generally appears worse at 24 hrs.; organism may persist for 14 days or longer Bacteria of low virulence (ie. S. epidermidis) Mycobacterium, Filamentous fungi generally improve rapidly in 24-48 hrs.; organisms eliminated in 5-7 days slow response; may persist for weeks Resistant Bacteria Methicillin resistant Staphylococcus aureus and epidermidis Vancomycin resistant Enterococcus fecalis (group D Streptococcus) Aminoglycoside and Fluoroquinolone resistant Pseudomonas aeruginosa Beta lactamase producing Neisseria Atypical Mycobacteria Current antibiotic recommendation for suspected resistance: Vancomycin 20-30 mg/ml (Vancocin) and Ceftazidine 50 mg/ml (Fortaz/Pentacef) Gram positive organisms: Vancomycin 20-30 mg/ml (Vancocin) or Cefazolin 50 mg/ml (Ancef), .28% Lysostaphin, IV Linezolid (Zyvox) Gram negative organisms: Amikacin 10-20 mg/ml (Amikin) Adjuvant Therapy Cycloplegia- for comfort and to prevent synechiae Collagenase inhibitors (ie. EDTA, TCN, Galardin)- to minimize stromal destruction Heat (40 degrees C) Steroids- hazardous early in treatment, safety and efficacy not well established in most forms of microbial keratitis; helpful in reducing harmful destruction due to host response NSAIDs/ Analgesics- reduces inflammation and pain, may enhance antimicrobial(s) efficacy (NSAIDs) *anecdotal reports suggest very effective for pain in mycobacteria infections Tissue adhesives- for impending and actual perforations if small/ bacteriostatic Glaucoma medication- if needed, beta-blockers is drug of choice Debridement/ Biopsy- may improve antibiotic penetration Cryotherapy- possible role in sclerokeratitis Bandage lens/ Collagen shield- may promote re-epithelialization and allow for slow concentrated release of antibiotic Continuous antibiotic infusion devices- possible benefit in extensive sclerokeratitis Therapeutic keratoplasty- for large perforations, central/deep medically recalcitrant keratitis Termination of Therapy Elimination or substitute antibiotics only if directed by lab results Elimination of the less effective agent if combined microbial therapy initiated for monobacterial keratitis after lab results Measures of improvement: Blunting of the perimeter of stromal suppuration Reduction in the density of suppuration Reduction in cellular infiltrate and edema in surrounding stroma Reduction in the anterior chamber reaction Progressive re-epithelialization Reducing antimicrobials and adjuvants: Avoid abrupt cessation; prolonged therapy needed for Pseudomonas, Mycobacterium, Nocardia, anaerobes Reduce by “halving method”, substitute regular/commercial strength for fortified antibiotics when possible Penetrating Keratoplasty Progressive suppuration despite appropriate therapy Persistent infection Corneal perforation not managed by other method Non- Bacterial Infections (Protozoan and Fungal) Fungal Keratitis Fungi are primitive non-motile plant-like organisms. Yeast are uni-cellular and molds are multi-cellular filamentous structures. In the past 10 years there has been a definite increase in the prevalence of fungal keratitis in certain geographic areas, although nationwide there are probably only 300 cases per year. There are 40 different genera that cause keratomycoses; most are saprophytic. Classification of Fungi (Adapted from J. McCulley) Filamentous fungi; Molds Septate- most common cause of fungal keratitis, variable geographic distribution, mostly in the southern and southwestern United States,- Non-pigmented: Fusarium (most virulent due to complex enzymes + toxins), Aspergillus, Pigmented:Curvularia, Paecilomyces, Phialophora Non-septate- Mucoraceae (rare corneal pathogen) Risk Factors: corneal injury (frequently a tree branch or vegetative matter in an agricultural setting), soft contact lens wear (extended wear/therapeutic), chronic topical medication, systemic steroids, diabetes mellitus, radial keratotomy. Clinical Features of Keratomycoses Typical Atypical, severe Epithelium intact or ulcerated ulcerated Type of stromal non-suppurative, inflammation feathery infiltrate(s) Site of inflammation* focal or multi-focal, suppurative diffuse satellite infiltrates *typically accompanied by a mild iritis, endothelial plaque and hypopyon in severe infections; hypopyon is of no diagnostic value Yeasts- worldwide distribution: Candida- C. albicans, C. parapsilosis, C. tropicalis Risk Factors- protracted ulceration of the epithelium, topical steroid therapy, penetrating keratoplasty, bandage soft lenses Typical, common Atypical, rare Epithelium ulcerated intact Type of stromal suppurative non-suppurative focal or diffuse multifocal inflammation Site of inflammation Note: ring infiltrates or abscess is possible with an intact epithelium Keratomycoses Diagnosis- clinical suspicion, corneal scraping, superficial keratectomy (paracentesis) Diagnostic stains- Gram, Giemsa, GMS, PAS, KOH, acridine orange, Schwartzman’s, calcofluor white Culture media- Sabouraud dextrose agar (with gentamicin, without cyclohexamide), blood agar, brain-heart infusion agar with gentamicin @ 25 + 37 C Confocal microscopy- identifies hyphae, poor for Candida, a guide to therapeutic response Antifungal Drugs and Mechanism of ActionSterol Binding- Polyene drugs like Amphotericin B, Nystatin and Natamycin Inhibition of Sterol Synthesis- the Imidazoles including Miconazole, Ketoconazole, Clotrimazole, Fluconazole Interference with RNA Synthesis- Flucytosine (fluorinated pyrimidine) and Itraconazole (antimetabolites) Inhibition of Mitosis- Griseofulvin Initial Therapy- drugs are generally not introduced until definitive diagnosis is made. Topical*-Hyphae-Natamycin 5% (Natacyn) suspension (every hr. for 24-48 hrs.) Yeast or Pseudo-hyphae- Amphotericin B .1.5% (Fungizone) (every 15-20 minutes for 24-48 hrs.), Miconazole 1% (Micatin, Monistat) (every hr., but very toxic) as an alternate therapy. Clotrimazole (cream or powder) and Flucytosine (Ancobon tablets) converted to a 1% solution have been effective against Candida infection. Oral- Ketoconazole (Nizoral) (200-400 mg/day) or Fluconazole (Diflucan) (100-200 mg/day) [generally used for hyphae and endophthalmitis; Candida generally responds to topicals alone]; Itraconazole (Sporanox) is more effective against filamentous fungi especially Aspergilli .Reserve systemic treatment for deep keratitis, impending perforation, scleritis, endophthalmitis and post penetrating keratoplasty. Sub-conjunctival injection-Fluconazole (Diflucan) .5ml = 1mg daily pending initial response and identification of the organism. Other agents- atropine 1% or isoptohyoscine .25% 3x/day; glaucoma medication as needed; role of collagen shield as a delivery device not well defined. Avoid steroids in fungal keratitis since mold/yeast replicate more freely and microbial agents are generally only fungistatic. *topicals are often continued for 6 wks. or longer; watch for toxicity PREVENTION-minimize extended wear, therapeutic lens application whenever possible, avoid indiscriminate use of topical steroids. Acanthamoeba Keratitis Acanthamoeba keratitis remained a curiosity in the past; however recently this pathogen affecting primarily the cornea and sclera is recognized with increased frequency. Early detection will alter the course of therapy and ultimately affect outcome; therefore early diagnosis is critical. The risks factors that have been identified by epidemiologic studies, specifically as they relate to contact lens wear will be examined. THE ORGANISM- "a free living" protozoan (motile) with worldwide distribution; isolated from fresh water, well water, sea and brackish water, sewage, hot tubs, air, soil, wheat and barley; there may be high incidence areas following disasters (ie. Sacramento floods and hurricane, "Hugo") Acanthamoeba: >7 species show ocular parasitology [A. castellani, A. quina, A. culbertsoni, A. lugdunesis, A. polyphaga, A. hatchetti, A. rysodes, A griffini] Note: Sequence types are recommended as much less ambiguous units of classification than currently used species names. Forms: cyst (sessile)*and trophozoite (motile) *makes the organism resistant to freezing, desiccation, standard chlorination and a variety of antimicrobial agents Ocular Infections Clinical features- initial signs are non-specific; they include: patchy epithelial involvement (irregularity or pleomorphic focal or stellate epitheliopathy), suppurative/granulomatous or non-suppurative stromal keratitis, “bull’s eye” lesions, pseudo-guttata and iritis. More advanced signs include: a radial kerato-neuritis, ring infiltrate, nodular episcleritis, scleritis and hypopyon or hyphema; there may be a pseudo-membrane or adenopathy present. A remarkable lack of vascularization; often the only feature to help differentiating this infection from herpes simplex. Recently, early signs identified include a bull’s-eye lesion and the appearance of randomly distributed white spots on the cornea. Persistent epithelial defects immediately following penetrating keratoplasty may signal early amoebic infection. Symptomatology-usually unilateral pain disparate to ocular findings, often history to trauma +/or contact lens wear, symptoms generally wax and wane over time with chronicity. Laboratory Confirmation Corneal scrapings*- examined with Giemsa or tri-chrome stains, also culture with heated killed E. coli on non-nutrient agar or activated charcoal/yeast extract; other valuable tests include immunofluorescent techniques which include: calcofluor white and indirect immunofluorescent antibody testing. Standard culture negativity for bacteria, fungi, and virus expected. Cysts can sometimes be seen on soft lenses with high magnification. Confocal microscopy is an aid to early differential diagnosis, and the infection produces a "lightning flash" appearance at the radial nerve infiltrates. Polymerase chain reaction may be more sensitive than cultures as a diagnostic test. PCR analysis of the tears and epithelium may prove a useful tool in confirming an early diagnosis. Diagnosis is easier in the earlier stages with superficial disease. *biopsy with intact epithelium or graft histology Medical Therapy Reported improvement*- use one from the biocide/cationic antiseptic group plus or more of the following: Antibiotic/Aminoglycoside: paromomycin (Humatin), neomycin Antifungal: clotrimazole, ketoconazole (Nizoral), itraconazole (Sporanox), miconazole (Monistat, Micatin), fluconazole (Diflucon) Antiparasitic/Aromatic Diamidine: propamidine isethionate (Brolene), hydroxystilbamidine (Pentamidine),hexamidine diisethionate (Desomedine) Biocide/Cationic Antiseptic: polyhexamethylene biquanide (PHMB, Baquacil, Cosmocil), chlorhexidine digluconate, povidone-iodine (Betadine) *use one agent from at least two of the four categories above, plus oral ketoconazole or fluconazole, apply topicals every 30-60 minutes; for recalcitrants with significant ocular toxicity use drops in a three day cycle (hexamidine, paromomycin, and either PHMB or chlorhexidine) Supportive and adjunct therapy-debridement, conjunctival flaps, bandage lenses, debulking procedures, cryotherapy and steroids with caution**; grafts show a high recrudescence (NSAIDs seem to have little benefit in pain reduction when radial keratoneuritis is present) **inhibits metamorphogenesis and suppresses macrophages; also increases pathogenicity by accelerating trophozoite proliferation Success has been reported by Seals (1995) using 0.02% chlorhexidine digluconate & .1% propamidine isethionate has been reported. Recent reports have shown success with intensive mono-therapy using PHMB (0.02%) or chlorhexidine (0.02%) Initial dosing: given hourly around the clock for the first few days then tapered for usually 3-6 months. Concentrations can be increased with resistance to initial medical therapy (concern for increased toxicity) Related Risks and Prevention Accouterment- use of distilled water, tap/well water*, or saliva; bacterial contamination of case and care system a common factor *recent concern especially with rigid lens wear Disinfection- resistance to most chemical disinfection Corneal trauma- hypoxia, mechanical trauma with lens wear Note: should avoid swimming and using hot tubs with contact lens wear Additional Protozoan Additional amoeba- A similar infection may be caused by another amoeba besides Acanthamoeba, such as Naegleria, Hartmanella or Vahlkampfiid. Microsporidia- an obligate intracellular protozoan recently found on corneal scrapings of HIV infected patients from nasopharyngeal or urinary colonization. Generally it presents as a superficial punctate, multifocal keratitis (may be confined to the superficial cornea for months) in immuno-incompetent patients (genus-Encephalitozoon); a stromal keratitis is possible following trauma especially in immunocompetent individuals (genus-Nosema). A slight improvement has been noted with trimethoprim/sulfisoxazole. Recently itraconazole, propamidine isethionate, albendazole (benzimidazole), and especially topical fumagillin bicyclohexylammonium salt (Fumadil B), a bacteriostatic antibiotic secreted by Aspergillus, have shown some promise. Diagnosis is made by Gram’s stain, cytology with chromotrope-based stain, or by using electron or confocal microscope. The Herpes Group: Simplex and Zoster Defining the Herpes Family: Epidemiology 8 distinct DNA viruses HSV and HZV are the most common; Epstein Barr is also found to cause corneal insult. HSV-1 is the most common ocular pathogen; HSV-2 is more responsible for genital infections. 25% of the population is seropositive by age 4 and nearly 100% by age 60. Neonates often infected with HSV-2. Herpes Simplex Features Most are asymptomatic on primary infection; skin eruptions are not common after primary infection. Recurrent HSV is commonly found along the oral or nasal mucosa. Initial ocular presentation occurs on lid and conjunctiva 50% of the time. (anterior cornea 60% and stroma 6%). Unilateral follicular conjunctivitis is always suspicious for HSV infection. Steroids will trigger infectious keratitis. Conjunctival dendrites may be present without corneal findings. In children, primary infection manifests with fever and cutaneous outbreak around the lids. Outbreak is prolonged and less responsive to therapy. Bilateral involvement or prolonged HSV suggests comorbid disease (i.e. atopy, immunodeficiency or immunosuppression). Viral Detection Cell Cultures ELVIS (enzyme-linked virus inducible system)** PCR (polymerase chain reaction/DNA detection) HSV can be recovered by swabbing an untreated dendrite with a soft tipped applicator inoculating it into viral transport media or a viral culturette. ** high degree of sensitivity and specificity within 24 hrs. Herpes Simplex Clinical Presentation Four clinical presentations: epithelial, stromal, endotheliitis, and neurotrophic keratopathy Epithelial (Infectious): corneal vesicles, dendritic ulcer, geographic ulcer, marginal ulcer Stromal (Immune): infiltration, vascularization and scarring Endotheliitis: an infectious and inflammatory reaction (HSV or CMV); use anti-viral orals and topical steroids Neurotrophic: results from altered corneal innervation and decreased tear production Treatment and Management of Herpes Simplex Topical and orals can be used for any infectious process. Steroids are the mainstay for stromal/immune disease Avoid prolonged use of topical agents beyond 14-21 days. Limbal deficiency and conjunctival scarring are possible due to toxicity. Debridement is only indicated if there are new epithelial lesions with a history of stromal disease in the past. Oral prophylaxis is indicated with 2 or more episodes of infectious keratitis. Must monitor renal function. Herpes Zoster HZV is the etiologic agent of both varicella (chickenpox) and reactivation (shingles) Unlike HSV, HZV typically happens once in life (30% of adults). HZV established latency in the sensory root ganglia (maintained by a T-cell immune response that wanes with advancing age) Exposure to cases of chickenpox may serve as a “booster vacciine”. Herpes Zoster Kerato-uveitis Involves the ophthalmic division of the fifth cranial nerve. Without oral antivirals, 50% of HZV patients will experience ocular involvement. Long list of ocular complications including: persistent keratitis, uveitis, acute retinal necrosis, cranial nerve palsies and optic neuropathy. Complications are similar to HSV keratitis and include: punctate or pseudo dendritic keratitis (mucous plaque), stromal infiltrates, endotheliitis and neurotrophic keratopathy. Uveitis in severe cases is not uncommon. Recurrent Zoster Recurrent episodes (different locations) are somewhat atypical and practitioners must consider a sinister etiology. Patients should be worked up for occult malignancy or other reduced cell mediated immunity concerns (body scans, T4 and T8 subsets may be needed). HIV/CMV titers are suggested. 4.5X greater risk of stroke the 1st yr. Post-Herpetic Neuralgia Most frequent and debilitating complication of HZV regardless of the dermatomal distribution. A neuropathic pain syndrome that persists or develops after shingles’ rash has resolved. Main PHN risks: advancing age, severity of acute zoster pain and rash, a painful prodrome and ocular involvement. Prevention Through Vaccination Controversies….. Should healthcare providers be vaccinated? When is vaccination appropriate after having the shingles? When should one stop antivirals before/after vaccination? Should patients with active kerato-uveitis or corneal dendriform be vaccinated? Anti-Viral Agents: Orals and Topicals Oral Agents Acyclovir Valacyclovir* Famciclovir* Penciclovir* Topical Agents Trifluridine (Viroptic/non-selective) Ganciclovir (Zirgan/selectivel) *Better bioavailability and longer intracellular half-life than Acyclovir Interferon has been used as an adjunct Anti-Viral Resistance Rare event overall, but definitely more common in immunocompromised individuals. Any resistance does raise the concern for immuno-compromised states (i.e CA). TK mutants (encodes for key enzyme) are responsible. Some concern for prolonged prophylaxis and emerging resistance as in bacterial disease. Acyclovir resistance are often resistant to valacyclovir and crossresistance to famciclovir; 45% of resistant strains are resistant to ganciclovir. ACV efficacy may have reduced therapeutic effect in lactose intolerant patients. In vitro resistance assays and molecular characterization of isolates should be performed in refractory cases.