PATHOGENESIS

Contact lens wear predisposes the cornea to infection through a number of mechanisms, including introduction of a contaminated foreign body to the corneal surface; interruption of the normal tear flow, which is essential to corneal immunity; induction of corneal epithelial microtrauma; alteration of ocular surface immunity; and induction of corneal hypoxia. Various hygiene-related factors increase the risk of both infectious and noninfectious corneal inflammatory events. See BCSC Section 3, Clinical Optics, for further discussion of noninfectious contact lens–related disease.

MANAGEMENT

Eliciting a history of contact lens wear is critical in the evaluation of corneal inflammation, and a history of lens wear should raise the suspicion of corneal infection. Bacteria are both the most common pathogen and the most immediate threat to vision. Therefore, unless otherwise indicated, initial management should provide coverage for the most common bacterial pathogen in contact lens–related keratitis, P aeruginosa, as is done in empiric therapy for bacterial keratitis unrelated to contact lens wear. Acanthamoeba and fungal pathogens should be suspected if the clinical presentation or clinical course is atypical.

Cortina MS, Tu EY. Antibiotic use in corneal and external eye infections. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2011, module 6.

PATHOGENESIS

Although bacterial keratitis restricted to the epithelial layer only has been reported, corneal pathogens generally must first adhere to the cornea and then invade and proliferate in the corneal stroma. Certain risk factors will often select for specific pathogens, based on their particular mechanism of adherence. For example, P aeruginosa becomes more pathogenic in lens-related biofilms, in turn enabling enhanced binding to molecular receptors exposed on injured epithelial cells. Once adherent, bacteria will proliferate and invade the corneal stroma, often with the aid of bacteria-specific proteases. Reactive host inflammation begins with the expression of various cytokines and chemokines, recruitment of inflammatory cells from the tears and limbal vessels, and subsequent secretion of matrix metalloproteinases leading to characteristic corneal necrosis. Reduction of bacterial loads and, potentially, direct control of the inflammatory response may reduce keratolysis. See BCSC Section 1, Update on General Medicine, for further discussion.

CLINICAL PRESENTATION

Rapid onset of pain is accompanied by conjunctival injection, photophobia, and decreased vision in patients with bacterial corneal ulcers. The rate of progression of these symptoms depends on the virulence of the infecting organism. Bacterial corneal ulcers are typically a single infiltrate and show a sharp epithelial demarcation with underlying dense, suppurative stromal inflammation that has indistinct edges and is surrounded by edema. P aeruginosa typically causes stromal necrosis with a shaggy surface and adherent mucopurulent exudate (Fig 10-15). An endothelial inflammatory plaque, marked anterior chamber reaction, and hypopyon frequently occur.

Patients with infections caused by slow-growing, fastidious organisms such as mycobacteria or anaerobes may have a nonsuppurative infiltrate and intact epithelium. Infectious crystalline keratopathy, for example, presents as densely packed, white, branching aggregates of organisms in the virtual absence of a host inflammatory response, shielded by the bacterial biofilm coating. Risk factors include corticosteroid use, contact lens wear, and previous corneal surgery. Infectious crystalline keratopathy has been reported with a number of bacterial and fungal species, most commonly α-hemolytic Streptococcus species (Fig 10-16).

LABORATORY EVALUATION

The prevalence of a particular causative organism depends on the geographic location and risk factors for the infection. Causative organisms in bacterial keratitis are listed in Table 10-5.

Studies indicate that for bacterial keratitis, clinical appearance of the infection is an unreliable guide in determining the causative pathogen. The successful use of topical fluoroquinolones in the 1990s led to a reduction in the number of cultures performed for cases of presumed infectious keratitis. The American Academy of Ophthalmology practice guidelines continue to recommend that initial cultures be obtained for infiltrates extending to the middle of the cornea, into deep stroma, or across a large area (>2 mm), as well as for patients whose history or clinical features suggest fungal, amebic, mycobacterial, or drug-resistant organisms as the causative agents. In addition to corneal culture, it may be helpful to culture contact lenses, contact lens cases and solutions, and any other potential sources of contamination, such as inflamed eyelids. Some correlation has been shown between cultures of such sources and corneal scrapings.

Table 10-5 Causes of Bacterial Keratitis

The yield for corneal cultures and smears is significantly higher before the initiation of antibiotic treatment, but cases unresponsive to such therapy should still be cultured, with some suggesting discontinuation of antibiotics for 12–24 hours to encourage yield. However, a positive smear result at any point does not obviate the need for broad-spectrum coverage, although it may cause coverage to be weighted toward a different class of microorganism and/or provide guidance for later treatment in the absence of a positive culture. (See Chapter 9 in this volume and BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, for discussion of specimen collection, culturing, staining, and interpretation.)

MANAGEMENT

In any keratitis, the primary goal of therapy is preservation of sight and corneal clarity. Bacterial pathogens can produce irreversible corneal scarring over a period of hours because of their rapid growth, keratolytic enzymes, and stimulation of destructive host immune responses. Therefore, therapy must be initiated before definitive diagnosis is obtained in order to rapidly reduce the bacterial load and minimize later visual disability.

Initial therapy consists of empiric, broad-spectrum topical antibiotics. In routine corneal ulcers, monotherapy with topical fluoroquinolones provides outcomes equivalent to those of combination therapy, because of the excellent penetration achieved with commercially available concentrations of fluoroquinolones. These antibiotics should initially be given every 30–60 minutes and then tapered in frequency according to the clinical response. In severe cases, administration of antibiotics every 5 minutes for 30 minutes as a loading dose can more rapidly achieve therapeutic concentrations in the corneal stroma. Second-generation fluoroquinolones (ciprofloxacin, ofloxacin) continue to have excellent Pseudomonas coverage but lack useful gram-positive activity. Third- and fourth-generation fluoroquinolones (eg, moxifloxacin, gatifloxacin, levofloxacin, and besifloxacin) have improved gram-positive and atypical mycobacterial coverage but limited activity against MRSA.

Alternatively, topical combination therapy with an agent active against gram-positive bacteria and another agent active against gram-negative bacteria can be used as initial therapy (Table 10-6). Although “fortified” antibiotics (compounded at increased concentrations compared with their commercial formulations in order to achieve therapeutic levels in the corneal stroma) are more difficult to obtain and may have a greater toxic effect on the ocular surface, the clinician should consider using them, especially in combination with vancomycin for gram-positive coverage when MRSA is suspected, with large or vision-threatening ulcers, or with prior antibiotic failure. Effectively treated, most infectious keratitis is culture negative after 48–72 hours. Once the offending microbe is identified or the clinical response shows improvement, appropriate monotherapy may be considered (see Table 10-6) to maintain coverage and reduce toxicity. However, laboratory sensitivities are based on antibiotic tissue levels achievable by systemic administration, and the levels achieved by topical administration are much higher. Often, a bacterial keratitis will respond in vivo even when in vitro data suggest resistance. Any changes in medical therapy should therefore be based primarily on clinical response. Several clinical parameters are useful for monitoring clinical response to antibiotic therapy:

Table 10-6 Initial Therapy for Bacterial Keratitis

• blunting of the perimeter of the stromal infiltrate

• decreased density of the stromal infiltrate

• reduction of stromal edema and endothelial inflammatory plaque

• reduction in anterior chamber inflammation

• reepithelialization

• cessation of corneal thinning

Systemic antibiotics—especially the fluoroquinolones, which have excellent ocular penetration—and intensive topical antibiotics are indicated in cases with suspected scleral and/or intraocular extension of infection.

The role of corticosteroid therapy for bacterial keratitis remains controversial. Tissue destruction results from a combination of the direct effects of the bacteria and an exuberant host inflammatory response consisting of polymorphonuclear leukocytes and proteolytic enzymes, which predominate even after corneal sterilization. Corticosteroids are effective at modifying this response, but they also inhibit the host response to infection. The literature strongly suggests that corticosteroid therapy administered prior to appropriate antibiotic therapy worsens prognosis. The literature is inconclusive, though, about steroid therapy used concomitantly with antibiotic therapy or after it is initiated, as demonstrated in a randomized clinical trial in which topical corticosteroids were given 48 hours after initiation of topical antibiotics for bacterial keratitis. At 3 months, no effect on final visual outcome or complication rate was seen, but a trend toward improved outcomes was noted in those patients with the worst initial vision who received corticosteroids and for the corticosteroid group at 1-year follow-up. Notably in this study, Nocardia keratitis, which is uncommon in the United States, fared worse with corticosteroid treatment.

The indiscriminate or universal use of corticosteroids is, therefore, unsupported but does not appear to increase the general risk of poor outcomes or complications in treated bacterial keratitis. In fact, certain patients may benefit from the addition of corticosteroids to antibiotic therapy. Future study of the appropriate timing and dosage may further refine the indications for corticosteroid use. As there is still significant risk associated with corticosteroid use in patients with bacterial or other forms of infectious keratitis not appropriately treated, following are recommended criteria for instituting corticosteroid therapy for bacterial keratitis:

• Corticosteroids should not be used in the absence of appropriate antibiotic therapy.

• The patient must be able to return for frequent follow-up examinations and demonstrate adherence to appropriate antibiotic therapy.

• No other associated virulent or difficult-to-eradicate organism is found or suspected.

Corticosteroid drops may be started in moderate dosages (prednisolone acetate or phosphate 1% every 6 hours), and the patient should be monitored at 24 and 48 hours after initiation of therapy. If the patient shows no adverse effects, the frequency of administration may be adjusted based on clinical response. Collagen crosslinking is increasingly used as an adjunctive therapy for bacterial keratitis, with anecdotal success; as this technology becomes more available in the United States, its precise role and application are evolving.

Penetrating keratoplasty (PK) for treatment of bacterial keratitis is indicated if the disease progresses despite therapy, descemetocele formation or perforation occurs, or the keratitis is unresponsive to antimicrobial therapy. The involved area should be identified preoperatively and an attempt made to circumscribe all areas of infection. Peripheral iridectomies are indicated, because seclusion of the pupil may develop from inflammatory pupillary membranes. Interrupted sutures are recommended. The patient should be treated with appropriate antibiotics, cycloplegics, and intense topical corticosteroids postoperatively. See Chapter 15 in this volume for a more detailed discussion of PK and BCSC Section 2, Fundamentals and Principles of Ophthalmology, for an in-depth discussion of ocular pharmacology.

American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern Guidelines. Bacterial Keratitis. San Francisco: American Academy of Ophthalmology; 2013. Available at www.aao.org/ppp.

Price MO, Tenkman LR, Schrier A, Fairchild KM, Trokel SL, Price FW Jr. Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg. 2012;28(10):706–713.

Schein OD, Glynn RJ, Poggio EC, Seddon JM, Kenyon KR. The relative risk of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. A case-control study. Microbial Keratitis Study Group. N Engl J Med. 1989;321(12):773–778.

Srinivasan M, Mascarenhas J, Rajaraman R; Steroids for Corneal Ulcers Trial Group. Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012;130(2):143–150.

Srinivasan M, Mascarenhas J, Rajaraman R; Steroids for Corneal Ulcers Trial Group. The steroids for corneal ulcers trial (SCUT): secondary 12-month clinical outcomes of a randomized controlled trial. Am J Ophthalmol. 2014;157(2):327–333.

PATHOGENESIS

Fungal keratitis is less common than bacterial keratitis, generally representing less than 5%–10% of corneal infections in reported clinical series in the United States. Filamentous fungal keratitis occurs more frequently in warmer, more humid parts of the United States than in other regions of the country. Trauma to the cornea with plant or vegetable material is the leading risk factor for fungal keratitis. Contact lens wear has emerged as another risk factor for the development of fungal keratitis. Topical corticosteroids are a major risk factor as well, as they appear to activate and increase the virulence of fungal organisms in part by reducing the cornea’s resistance to infection. Candida species cause ocular infections in immunocompromised hosts and in corneas with chronic erosions/ulceration from other causes. Systemic corticosteroid and immunosuppressant use in these patients may suppress the host immune response, thereby predisposing to fungal keratitis. Other common risk factors include corneal surgery (eg, PK, radial keratotomy) and chronic keratitis (eg, herpes simplex virus, herpes zoster, or vernal/allergic conjunctivitis).

In early 2006, an outbreak of contact lens–associated Fusarium keratitis was observed, first in Singapore and the Pacific Rim and then in the United States. The epidemic occurred in association with the use of Renu with MoistureLoc solution (Bausch + Lomb, Rochester, NY). Bausch + Lomb withdrew the solution from the world market on May 15, 2006, with a subsequent steep decline in Fusarium cases across the United States.

Chang DC, Grant GB, O’Donnell K, et al; Fusarium Keratitis Investigation Team. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA. 2006; 296(8):953–963.

CLINICAL PRESENTATION

Patients with fungal keratitis tend to have fewer inflammatory signs and symptoms during the initial period than those with bacterial keratitis and may have little or no conjunctival injection upon initial presentation. On the other hand, pain in fungal keratitis can be out of proportion to the relatively uninflamed cornea. Filamentous fungal keratitis frequently manifests as a gray-white, dry-appearing infiltrate that has irregular feathery or filamentous margins (Fig 10-18). Superficial lesions may appear gray-white; elevate the surface of the cornea; and have a dry, rough, or gritty texture detectable at the time of diagnostic corneal scraping. Occasionally, multifocal or satellite infiltrates may be present, although these are less common than previously reported. In addition, a deep stromal infiltrate may occur in the presence of an intact epithelium. An endothelial plaque and/or hypopyon may also occur if the fungal infiltrate(s) is sufficiently deep or large or has penetrated into the anterior chamber.

As the keratitis progresses, intense suppuration may develop, and the lesions may resemble those of bacterial keratitis. At this point, rapidly progressive hypopyon and anterior chamber inflammatory membranes may develop. Extension of fungal infection into the anterior chamber is often a cause of rapidly progressive anterior chamber inflammation. Occasionally, fungus may invade the iris or posterior chamber, and angle-closure glaucoma may develop from inflammatory pupillary block.

Yeast keratitis is most frequently caused by Candida species. This form of fungal keratitis frequently presents with superficial white, raised colonies in a structurally altered eye. Although most cases tend to remain superficial, deep invasion may occur with suppuration resembling keratitis induced by gram-positive bacteria.

LABORATORY EVALUATION

The fungal cell wall stains with Gomori methenamine silver but, except for Candida, does not take up Gram stain. Blood agar, Sabouraud dextrose agar, and brain–heart infusion agar are the preferred media for fungal culture. Because of progressive enhancements to in vitro antifungal sensitivity testing, these tests are better correlated with clinical outcomes for fungal keratitis and should be pursued. Confocal microscopy is very useful in detecting branching filaments in the cornea, as well as the individual septa found in the majority of corneal mold pathogens.

MANAGEMENT

Natamycin 5% suspension is recommended for the treatment of most cases of filamentous fungal keratitis, particularly those caused by Fusarium species, which are the most common causative agents for exogenous fungal keratitis occurring in the humid areas of the southern United States. Most clinical and experimental evidence suggests that topical amphotericin B (0.15%–0.30%) is the most efficacious agent available to treat yeast keratitis; most corneal yeast infections respond readily to the drug. Amphotericin B is also recommended for filamentous keratitis caused by Aspergillus species. Topical voriconazole 1% is increasingly utilized and has been effective in treating some cases of fungal keratitis unresponsive to other therapy; however, significant resistance has been reported, and a recent prospective, randomized clinical trial concluded that this agent is inferior to natamycin for empiric therapy, especially for F solani.

Systemic administration may be considered for treatment of more severe keratitis or keratitis with intracameral extension. The use of older azoles, including ketoconazole (200–600 mg/day), fluconazole (200–400 mg/day), and itraconazole (200 mg/day), for this purpose has been described. Oral voriconazole (200–400 mg/day) and posaconazole (800 mg/day) are rapidly replacing other oral antifungals because of their excellent intraocular penetration and broader spectrum of coverage. Alternatively, intrastromal administration of aqueous-soluble amphotericin B (5–10 μg/0.1 cc) or voriconazole (50–100 μg/0.1 cc) as primary or secondary treatment of deep fungal keratitis, and intracameral injection of either agent for intraocular extension are becoming more widely validated. Unresponsive cases of culture-proven or histologically proven fungal keratitis require definitive speciation of the pathogen as well as antifungal sensitivity testing. As classic morphologic identification is often inaccurate, a look-alike species or P insidiosum (discussed earlier) can be suspected in these cases. Collagen crosslinking has been investigated as an adjunctive therapy for fungal keratitis; it appears to have no role in deeper stromal disease and achieves mixed results in superficial fungal infections.

When the smear result is negative and fungal infection is suspected, repeated scrapings or biopsy may be necessary to identify fungal material. Furthermore, mechanical debridement may be beneficial for cases of superficial fungal keratitis. Fungal infiltration of the deep corneal stroma may not respond to topical antifungal therapy, because the penetration of these agents is reduced in the presence of an intact epithelium. Penetration of natamycin or amphotericin B has been shown to be significantly enhanced by debridement of the corneal epithelium, and animal experiments indicate that frequent topical application (every 5 min) for 1 hour can readily achieve therapeutic levels. Cases with progressive disease despite maximal topical and/or oral antifungal therapy may require therapeutic PK to prevent scleral or intraocular extension of the fungal infection. Both of these latter conditions carry a very poor prognosis for salvaging the eye.

Bunya VY, Hammersmith KM, Rapuano CJ, Ayres BD, Cohen EJ. Topical and oral voriconazole in the treatment of fungal keratitis. Am J Ophthalmol. 2007;143(1):151–153.

Loh AR, Hong K, Lee S, Mannis M, Acharya NR. Practice patterns in the management of fungal corneal ulcers. Cornea. 2009;28(8):856–859.

Prajna NV, Krishnan T, Mascarenhas J; Mycotic Ulcer Treatment Trial Group. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422–429.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.