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 should be made to circumscribe all areas of infection. Peripheral iridectomies are indicated, because patients may develop seclusion of the pupil 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 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; 2008. Available at: www.aao.org/ppp.
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.
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. Epub 2011 Oct 10.
Atypical Mycobacteria
Atypical mycobacteria are important pathogens in post-LASIK infections (Fig 5-17). The most common pathogens are Mycobacterium fortuitum and Mycobacterium chelonei, which may be found in soil and water. These organisms should be suspected in delayed-onset postrefractive infections, classically with recalcitrant, nonsuppurative infiltrates. The diagnosis may be confirmed with acidfast stain or culture on Lowenstein-Jensen media. Treatments include oral and topical clarithromycin, moxifloxacin, and gatifloxacin. Amikacin, previously the only treatment option, has been largely replaced by these newer treatment options.
Chang MA, Jain S, Azar DT. Infections following laser in situ keratomileusis: an integration of the published literature. Surv Ophthalmol. 2004;49(3):269–280.
Hyon JY, Joo MJ, Hose S, Sinha D, Dick JD, O’Brien TP. Comparative efficacy of topical gatifloxacin with ciprofloxacin, amikacin, and clarithromycin in the treatment of experimental Mycobacterium chelonae keratitis. Arch Ophthalmol. 2004;122(8):1166–1169.
Figure 5-17 Atypical mycobacterial LASIK infection. (Courtesy of Elmer Y. Tu, MD.)
Fungal Keratitis
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 is emerging 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 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 may suppress the host’s 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 [HSV], 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 and 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 5- 18). Superficial lesions may appear graywhite; 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 the anterior chamber.
Figure 5-18 Fungal keratitis caused by Fusarium solani with characteristic dry, white stromal infiltrate with feathery edges.
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 seen in cases with 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, Sabouraud’s, and brain–heart infusion media are preferred media for fungal culture. Confocal microscopy is very useful in detecting branching filaments in the cornea as well as individual septa found in the majority of corneal mold pathogens.
MANAGEMENT Natamycin 5% suspension is recommended for 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, although significant resistance has been reported and a recent clinical trial concluded that this agent is inferior to natamycin for empiric therapy.
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 mcg/0.1 cc) or voriconazole (50–100 mcg/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.
In the presence of a negative smear when 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.
Acanthamoeba Keratitis
PATHOGENESIS Acanthamoebae are free-living ubiquitous protozoa found in freshwater and soil. They are resistant to killing by freezing; desiccation; and the levels of chlorine routinely used in municipal water supplies, swimming pools, and hot tubs. They may exist as motile trophozoites or dormant cysts. Initial corneal epithelial adherence is thought to be mediated by a mannose-binding protein, with subsequent stromal invasion promoted by the expression of a mannose-induced protein (MIP133) and various collagenases. In Western countries, the majority (≈90%) of reported cases of amebic keratitis have been associated with contact lens use, with the remainder associated with various other risk factors. Historically, episodic outbreaks of disease have been associated with water contamination, as for example, homemade saline contact lens solutions that were inappropriately made, contaminated tap water due to river flooding in the United States, or contaminated rooftop cisterns in the United Kingdom.
Over the past 10 years, an increased number of Acanthamoeba cases have been observed in the United States, particularly on the East Coast and in the Midwest. Two initial case-control studies found an association between Acanthamoeba keratitis and the use of Complete MoisturePlus multipurpose cleaning solution (Advanced Medical Optics, Santa Ana, CA) for soft contact lens care, resulting in the voluntary recall of the product from the market in May 2007. Unfortunately, the outbreak persisted, requiring a second multistate case-control study led by the Centers for Disease Control in 2011. To date, the study has been unable to identify a single, definitive source.
Joslin CE, Tu EY, McMahon TT, Passaro DJ, Stayner LT, Sugar J. Epidemiological characteristics of a Chicago-area Acanthamoeba keratitis outbreak. Am J Ophthalmol. 2006;142(2):212–217.
Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acanthamoeba keratitis. Am J Ophthalmol. 2007;144(2):169–180.
CLINICAL PRESENTATION Patients with amebic keratitis are classically described as having severe ocular pain; photophobia; and a protracted, progressive course. Frequently, they have shown no therapeutic response to a variety of topical antimicrobial agents. However, Acanthamoeba infection is localized to the corneal epithelium in early cases and may manifest as a mildly symptomatic, diffuse punctate epitheliopathy or dendritic epithelial lesion. Cases with epithelial dendrites are often misdiagnosed as herpetic keratitis and treated with antiviral agents and/or corticosteroids. Stromal infection typically occurs in the central cornea, and early cases have a gray-white superficial, nonsuppurative infiltrate. As the disease progresses, a centered, partial or complete ring infiltrate in the central cornea is frequently observed (Fig 5-19). When noted, inflamed corneal nerves, called radial perineuritis or radial keratoneuritis, are nearly pathognomonic of amebic keratitis; limbitis; focal, nodular, or diffuse scleritis; or even dacryoadenitis may be seen as well. Disease is bilateral in 7%–11% of patients. Although intraocular extension may occur, consecutive encephalitis has not been reported.
Figure 5-19 Ring infiltrate in Acanthamoeba keratitis. (Courtesy of Elmer Y. Tu, MD.)
LABORATORY EVALUATION Diagnosis of Acanthamoeba keratitis is made by visualizing amebae in stained smears or by culturing organisms obtained from corneal scrapings. However, culture yield is laboratory-dependent, with larger studies reporting only 35%–50% positivity for Acanthamoeba; a significant number of cases are treated based on clinical presentation and/or confocal microscopy findings. Lamellar corneal biopsy may be required to establish the diagnosis in some cases. Contact lenses and related paraphernalia can be examined, but significant contamination without disease has been demonstrated.
Amebae are seen in smears stained with Giemsa or with periodic acid–Schiff (PAS), calcofluor white, or acridine orange stains. Nonnutrient agar with E coli or Enterobacter aerogenes overlay is the preferred medium for culturing amebae, although the organisms also grow well on buffered charcoal–yeast extract agar. Characteristic trails form as the motile trophozoites travel across the surface of the culture plate. In vivo confocal microscopy can also be used to show organisms, particularly the cyst forms (Fig 5-20).
Figure 5-20 In vivo confocal microscopy image of Acanthamoeba cysts. (Courtesy of Elmer Y. Tu, MD.)
MANAGEMENT Early diagnosis of Acanthamoeba keratitis is the most important prognostic indicator of a successful treatment outcome. Diagnostic delay is common, however, because of the nonspecific presentation of the disease and the need for special microbiological diagnostic methods. Clinical
features that suggest a diagnosis of Acanthamoeba keratitis rather than herpes simplex virus (HSV) keratitis include
noncontiguous or multifocal pattern of granular epitheliopathy and subepithelial opacities (unlike the contiguous, dendritic pattern in HSV keratitis)
disproportionately severe pain (unlike disproportionately mild pain secondary to trigeminal nerve involvement in HSV)
presence of epidemiologic risk factors such as contact lens use or exposure to possibly contaminated freshwater
failure to respond to initial antiviral therapy
Cases identified early, defined as epithelial or anterior stromal, have an excellent visual prognosis and generally respond well to epithelial debridement, followed by an extended (3–4 months) course of antiamebic therapy. The presence of deep stromal inflammation, a ring infiltrate, or extracorneal manifestations significantly worsens the prognosis because of the development of stromal scarring and often means longer treatment (up to a year or more), other adjunctive therapy, or therapeutic keratoplasty is required.
A number of antimicrobial agents have been recommended for medical treatment of Acanthamoeba keratitis based on their in vitro amebicidal effects as well as their clinical effectiveness. Agents used for topical administration include
diamidines: propamidine, hexamidine
biguanides: polyhexamethylene biguanide (polyhexanide), chlorhexidine aminoglycosides: neomycin, paromomycin
imidazoles/triazoles: voriconazole, miconazole, clotrimazole, ketoconazole, itraconazole
Of these, only the biguanides have been shown to have consistent in vitro and clinical efficacy against both cysts and trophozoites, with the others primarily effective against trophozoites. Therefore, the mainstay of pharmacologic treatment is a biguanide, with a diamidine sometimes used early in the course of therapy, although successful resolution can be achieved with a biguanide alone. A comparison of biguanides did not detect a difference between chlorhexidine 0.02% and polyhexamethylene biguanide (PHMB) 0.02%. Single-agent systemic voriconazole treatment has been shown to be efficacious in some recalcitrant cases.
Although it encourages acanthamoebal excystment in vitro, corticosteroid use has not been shown to improve or worsen clinical outcomes. Much of the morbidity of Acanthamoeba keratitis is from the exuberant host response, which causes noninfectious corneal and extracorneal complications, including scleritis, glaucoma, and cataracts. Some authors have suggested that the judicious use of topical and systemic immunosuppressants in selected cases is valuable after the patient has been treated for a period of at least 2 weeks.
Traditionally, keratoplasty has been reserved for vision rehabilitation after completion of treatment or for cases that are progressing despite maximal medical therapy and leading to possible perforation. However, recent reports find that with effective anti-Acanthamoeba agents used as adjunctive therapy, keratoplasty may now have a lower rate of recurrent infection and the primary risk factor for graft failure is late inflammatory sequelae, including glaucoma. Further, lamellar and penetrating keratoplasties in active disease can have successful visual outcomes. Medical treatment is preferred, however, in the vast majority of cases. Because late recurrences can occur when medical therapy is stopped before completion, it is advisable to perform any optical keratoplasties only after a