5.1. Bacterial Keratitis
Infectious keratitis constitutes a sight-threatening ocular emergency and requires prompt recognition and immediate referral to an ophthalmologist. Bacterial keratitis results from a breakdown in the corneal epithelial barrier and subsequent bacterial invasion of the corneal stroma. Bacterial invasion and white cell infiltration of the cornea leads to tissue destruction and may even lead to perforation if therapy is not instituted in a timely manner. Because of the destructive nature of this disease process
and the cornea's fragile composition, all bacterial infections of the cornea result in some degree of corneal scarring and opacification, regardless of how soon therapy is instituted. Therefore, the amount of corneal scarring and the extent to which vision is affected is largely determined by the time interval between disease onset and disease control. Staphylococcal and streptococcal species are the predominant corneal pathogens.
The risk factors that appear to be the most important in the elderly include dry eye disease, involutional lid abnormalities, diabetes mellitus, and surgical trauma. All of these conditions predispose the elderly patient to corneal epithelial breakdown and corneal bacterial invasion.
Patients generally complain of a unilateral decrease in vision, eye redness, pain, light sensitivity (photophobia), tearing, and mucoid discharge. Clinically the eye will manifest marked conjunctival injection, a moderate amount of purulent discharge, corneal clouding, and a well-demarcated corneal white cell infiltrate, which appears as a dense white opacity on direct illumination with a penlight (see Fig. 5). There may also be a visible layering of pus in the anterior chamber (hypopyon), which is usually a sterile inflammatory response. Fluorescein staining will demonstrate the size and location of the corneal epithelial defect.
As it was pointed out earlier, prompt antibiotic therapy is crucial for limiting the extent of corneal tissue damage; however, an attempt should be made to obtain diagnostic cultures prior to initiating antibiotic therapy. Treatment should not be withheld, however, if culturing materials are not readily available. Recent studies have found no significant increase in adverse outcomes when diagnostic scraping and culture are not performed at the outset of therapy (5,6).
Although Gram-positive organisms cause the majority of community-acquired non-contact lens-related bacterial keratitis, broad-spectrum topical antibiotics are the mainstay of therapy. Most ophthalmologists prescribed specially formulated high concentration antibiotic eyedrops (i.e., cefazolin, 50 mg/mL and tobramycin 14 mg/mL) with an instillation frequency of every 30-60 min around the clock for the first 24-72 h. The primary care physician's role in these cases will often be to institute temporizing measures, while the patient is enroute to the ophthalmologist for definitive therapy. Commercially available fluoroquinolone eyedrops ( Ciloxan™ or Ocuflox™) provide the best form of temporizing therapy because of their broad spectrum of antimicrobial activity. Additionally, these agents have been shown to effectively treat bacterial kerati-tis at their commercially available concentrations (7). Both agents require very frequent instillation (i.e., every 15-30 min for the first 2 h) at the onset of therapy to provide adequate tissue loading of the antibiotic. Beyond the tissue-loading period, the instillation frequency can be reduced to every hour.
Effective prevention for this condition entails ensuring that at-risk individuals are receiving appropriate ophthalmic management of their predisposing conditions. In the elderly, dry eye disease and involutional lid malpositions are the most common predisposing risk factors for the development of infectious keratitis. Both predisposing conditions constitute age-related degenerative changes affecting the eye and thus, have a high prevalence among the elderly. The prevalence of dry eye disease, for example, steadily increases with age, with prevalence rates increasing from 2% in individuals 45 yr of age up to 16% in individuals 80 yr of age (8). Similarly, the generalized lid laxity and diminution of muscle tone associated with aging result in structural eyelid malpositions that almost exclusively affect the elderly. It is also important to note that several common systemic conditions and a number of over-the-counter and prescription medications predispose elderly patients to developing dry eye disease. Rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, and other autoimmune/collagen-vascular disorders all produce a decrease in tear production as a result of autoimmune-mediated destruction of conjunctival-based lacrimal gland tissue. The systemic medications that adversely affect tear production include ^-adrenergic inhibitors and diuretics used to treat hypertension, tricyclic antidepressants, anti-parkinsonian agents, and over-the-counter cold or hay fever preparations.
5.2. Viral Keratitis
Herpes simplex and varicella-zoster are the two most common corneal viral pathogens. HSV is the most common cause of infectious keratitis in the United States, causing an estimated 500,000 cases of infectious keratitis each year (9). Herpes zoster ophthalmicus is the term given to the herpes zoster occurring in the first division of the trigeminal nerve, which innervates the ocular surface. Involvement of the ophthalmic
division of the trigeminal nerve accounts for 9-16% of cases of varicella-zoster occurring annually in the United States and is associated with severe, chronic ocular complications (11). Unlike bacterial keratitis, viral keratitis does not require a breach in the corneal epithelial layer to become established.
The epithelial keratitis produced by HSV is characterized by thin branching dendritic ulcerations, which are best seen with fluorescein staining (see Fig. 6). The lesions are usually centrally or paracentrally located and each linear branch of the dendritic ulcer terminates in bulblike conglomerations commonly referred to as "terminal bulbs." This infection is predominantly unilateral, with bilateral involvement only rarely seen. Patients will typically report symptoms of sharp eye pain, light sensitivity, tearing, and blurring of vision. It is interesting to note that although most patients complain of eye pain, objective testing of corneal sensitivity in the area of the dendritic lesion will demonstrate decreased or absent corneal sensitivity.
Varicella-zoster virus (VZV) epithelial keratitis clinically appears very similar to HSV epithelial keratitis but has several important distinguishing features. First, VZV keratitis is usually accompanied by a vesicular eruption involving the periorbital skin in a dermatomal pattern (see Fig. 7). The epithelial keratitis and the rash typically appear together. However, ocular involvement can be delayed, and it is important to note that ocular involvement does not occur in every case of VZV facial dermatitis. Ocular involvement occurs in approximately 50-72% of patients with periocular zoster (11). A vesicular eruption extending to the tip of the nose indicates involvement of the nasociliary nerve, which is a branch of the ophthalmic division of the trigeminal nerve. This clinical finding, known as "Hutchinson's sign," has an 85% predictability of the
eye being involved (12). Other differentiating features of VZV epithelial keratitis include the absence of terminal bulbs, smaller and less branching dendrites, more profound corneal anesthesia, and the lack of recurrences. HSV has been found to recur in approximately 33% of patients within 2 yr of the initial episode (13).
The diagnosis of HSV and VZV keratitis is generally made clinically. Because of their unique features, both conditions can be diagnosed in the majority of cases based on the clinical appearance of the lesions, the history of present illness, and the patient's symptomatology. When necessary, confirmation of the diagnosis can be made by cul-turing a swab or scrape of the corneal epithelium. Alternatively, fluorescent immunoassay of corneal epithelial cells reacting with HSV monoclonal antigen, polyclonal recombinant polymerase chain reaction amplification, and Southern blot analysis of HSV or VZV genomic sequences may be used for diagnosis confirmation.
The management of HSV epithelial keratitis consists of the topical administration of antiviral eyedrops. Several agents have been shown to be efficacious in treating this condition; however, at present, only one agent, trifluridine (Viroptic™ 1%) has been shown to have a greater than 90% cure rate. The recommended dosing regimen is one drop every 2 h, but no more than nine times a day for the first 3-5 d. The frequency of administration should be decreased to five times a day once the epithelium heals or the fifth day is reached. Topical therapy should be continued for at least 2 wk, but no more than 3 wk, because of the risk of drug toxicity. The drop frequency should continue to be tapered over the remainder of the treatment period.
Currently, there are no topical antiviral agents that have been shown to be effective in treating VZV-related epithelial keratitis. Treatment for this condition is aimed at preventing ocular complications and consists of oral acyclovir, 800 mg five times a day for 10 d, if within 72 h of the appearance of the skin lesions. The epithelial disease is benign and usually resolves spontaneously.
5.3. Fungal Keratitis
Fungal keratitis is one of the most devastating ocular infections encountered in ophthalmic clinical practice. The destructive nature of these infections is largely due to the lack of effective topical antifungal agents and the organisms' ability to resist host defenses. This fact, coupled with the innate virulence of fungal organisms, makes early detection an absolute requisite for achieving therapeutic success. Fungi, like bacteria, require a breach in the corneal epithelium in order to penetrate the cornea and produce tissue destruction. Fungal infections have been primarily associated with corneal trauma due to vegetable or organic material (e.g., tree branch, nylon lawn trimmer).
The leading corneal pathogens include Fusarium, Aspergillus, and Candida. These organisms cause the overwhelming majority of corneal fungal infections and appear to have climate specificity. Fusarium is the predominant corneal pathogen in the warmer southern United States, whereas Candida is the predominant corneal pathogen in the cooler northern United States. Aspergillus is found both in the northern and southern United States. Candida corneal infections are notable for occurring mainly in the setting of a compromised ocular surface (i.e., prolonged topical corticosteroid use, hypesthetic cornea from HZV, severe dry eye disease, and the like).
Fungal keratitis classically presents as an indolent infection with the infectious process evolving over a matter of days to weeks. In most infections, symptoms and signs typically develop within 1 or 2 d of inoculation, but because of the less fulminant evolution, patients are not motivated to seek medical attention until days or weeks later. The characteristic clinical appearance of a fungal keratitis consists of a gray-white stromal infiltrate with feathery or fluffy borders usually accompanied by several satellite lesions adjacent to the primary focus of infection. The corneal surface often appears to have a dry coarse texture and the epithelium at the margins of the ulcer tends to be heaped up. Keratomycosis is also frequently associated with sterile hypopyon formation.
The diagnostic evaluation involves culturing for both bacteria and fungi using blood and chocolate agar plates for bacterial isolation and Sabouraud agar for fungal isolation. Smears for Gram and Giemsa stains and potassium hydroxide preparation are obtained as well. Patients should be referred immediately to an ophthalmologist to have definitive culturing performed. If initial cultures are negative, patients often require corneal biopsy and special fungal staining of the biopsied tissue.
The treatment of fungal keratitis requires a prolonged course of medical therapy. The antifungal agents currently available are primarily fungistatic and have poor penetration into the cornea. Therefore, protracted courses of therapy are necessary in order to achieve adequate antifungal tissue levels for a sufficient period of time to eradicate the organism. It is generally recommended that therapy for fungal keratitis be continued for at least 12 wk. Empiric therapy is usually started with natamycin (5%) eyedrops, which is the only ocular antifungal preparation commercially available in the United States. Natamycin belongs to the polyene class of antifungal agents and has been shown to be most effective against filamentous fungi, such as Aspergillus and Fusarium. This agent is administered every 30-60 min around the clock for the first 24-72 h. Unfortunately, natamycin has poor corneal penetration and therefore, has limited efficacy in those cases in which the organism lies deep within the corneal stroma. Amphotericin B is the drug of choice for treating fungal keratitis produced by yeasts, such as Candida. Topical preparations of amphotericin B can be made by a hospital pharmacy. The recommended concentration is 0.15%. Oral flucytosine (150 mg/kg) is often used in combination with amphotericin in treating Candida corneal infections, because of the demonstrated synergistic effects. Other antifungals commonly used to treat fungal keratitis include clotrimazole 1% vaginal cream, miconazole 1% fabricated from the intravenous preparation, oral fluconazole (400-800 mg/d), and oral ketoconazole (200-400 mg/d). Fungal infections unresponsive to medical therapy require corneal transplantation for disease eradication.
Because corneal trauma is the predominant risk factor for the development of fungal keratitis, patients should be strongly encouraged to wear protective eyewear when they are performing yard work. Moreover, patients with severe dry eye disease or hypesthetic corneas require frequent follow-up with an ophthalmologist to monitor the status of their ocular surface.
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