334 ● External Disease and Cornea

Infections of the Cornea and Sclera

Bacterial Keratitis
Bacterial infection of the eye is a common sight-threatening condition that may present with
explosive onset and rapidly progressive stromal inflammation. Untreated, it often leads to
progressive tissue destruction with corneal perforation or extension of infection to adjacent
tissue. Bacterial keratitis is frequently associated with risk factors that disturb the corneal
epithelial integrity.
In the United States, the most frequent risk factor for bacterial keratitis is contact lens
(CL) wear, which has been identified in 19%–42% of patients with culture-proven microbial
keratitis and accounts for up to one-third of emergency department visits for corneal infec-
tion. The risk of corneal infection is almost tenfold higher in those who wear contact lenses
than in those who do not. The risk is higher still in patients who wear their contact lenses
overnight, and it is positively correlated with the number of consecutive days that lenses are
worn without removal. Results of a large epidemiologic study in Australia indicated an an-
nual incidence of cosmetic contact lens–related microbial keratitis per 10,000 individuals of
1.2 for daily rigid gas-permeable CL wear, 1.9 for daily soft CL wear, and 19.5 for overnight
soft CL wear. The use of disposable lenses for extended-wear and high–oxygen permeable
silicone CL material did not appear to prevent microbial keratitis. Daily disposable soft CL
use is felt by many clinicians to be the safest regimen. Poor CL hygiene is also a significant
risk factor for microbial keratitis. Orthokeratology has been associated with an elevated in-
cidence of corneal infection, similar to that of overnight contact lens wear.
The following are additional risk factors of bacterial keratitis:
• trauma
• contaminated ocular medications
• impaired local and systemic defense mechanisms
• disruption of the corneal surface
American Academy of Ophthalmology Refractive Management/Intervention Panel, Hoskins
Center for Quality Eye Care. Preferred Practice Pattern Guidelines. Refractive Errors and
Refractive Surgery. American Academy of Ophthalmology; 2017. www.aao.org/ppp
Stapleton F, Keay L, Edwards, K, et al. The incidence of contact lens–related microbial
keratitis in Australia. Ophthalmology. 2008;115(10):1655–1662.

CLINICAL PRESENTATION In patients with bacterial corneal ulcers, there is rapid onset of pain
accompanied by conjunctival injection, photophobia, and decreased vision. The rate of
progression of these symptoms depends on the virulence of the infecting organism.

CLINICAL PEARL
Bacterial corneal ulcers typically present as a single infiltrate in the paracentral or
midperipheral cornea with an epithelial defect and underlying superficial infiltrate
(Fig 12-9). Some cases involve a more intense inflammatory response characterized
by dense, suppurative stromal inflammation with indistinct edges and surrounding
edema and stromal cells, even several millimeters away from the infiltrate (Fig 12-10).
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 335

Figure 12-9 Bacterial keratitis with an epithe- Figure  12-10Bacterial keratitis with dense
lial defect and underlying superficial infiltrate. suppurative stromal inflammation and sur-
(Courtesy of Shahzad I. Mian, MD.) rounding edema. (Courtesy of Shahzad I. Mian, MD.)

Figure  12-11Suppurative ulcerative keratitis Figure  12-12 Bacterial keratitis with stro-
caused by Pseudomonas aeruginosa. mal infiltrate and hypopyon. (Courtesy of Rob-
ert S. Feder, MD.)

Pseudomonas aeruginosa typically causes stromal necrosis and adherent mucopurulent exu-
date (Fig 12-11). An endothelial inflammatory plaque, marked anterior chamber reaction,
and hypopyon are also common in bacterial keratitis (Fig  12-12). The hypopyon can be
subtle early on; it may be found nasally or temporally, if the patient has been lying down.
Patients with infections caused by slow-growing, fastidious organisms, such as my-
cobacteria or anaerobes, may have a nonsuppurative infiltrate and an intact epithelium.
Infectious crystalline keratopathy, for example, presents as densely packed, white or crys-
talline, branching, snowflake-like aggregates with almost no host inflammatory response
because the microorganisms are shielded by a biofilm. Risk factors of this condition in-
clude corticosteroid use, contact lens wear, and previous corneal surgery with or without
retained sutures. Infectious crystalline keratopathy has been attributed to various bacte-
rial and fungal agents, most commonly α-hemolytic Streptococcus species (Fig 12-13).
PATHOGENESIS Corneal pathogens adhere first to the corneal surface and then invade and
proliferate in the corneal stroma. Certain risk factors tend to be selective for specific patho-
gens, based on the pathogen’s mechanism of adherence. For example, P aeruginosa is more
pathogenic in contact lens–related biofilms, in which binding to receptors on injured epithelial
336 ● External Disease and Cornea

Figure  12-13 Infectious crystalline keratopa-

thy in a corneal graft caused by α-hemolytic
Streptococcus species.

cells is facilitated. After adhering, infiltration of the corneal stroma occurs, often mediated
by bacteria proteases. The host responds with inflammation, comprising cytokine and che-
mokine expression, recruitment of inflammatory cells from the tears and limbal vessels, and
secretion of matrix metalloproteinases, which result in characteristic corneal necrosis. Reduc-
tion of bacterial load and direct control of the inflammatory response are interventions aimed
at decreasing keratolysis. See BCSC Section 1, Update on General Medicine.
LABORATORY EVALUATION For bacterial keratitis, the clinical appearance of the infection is
not a reliable indicator of the causative pathogen. Instead, certain risk factors and geo-
graphic location may be helpful in ascertaining the disease agent. Causative organisms are
listed in Table 12-8.

GUIDELINES FOR OBTAINING CULTURES AND SMEARS

According to guidelines from the American Academy of Ophthalmology (AAO),
specimens should be obtained for smears or cultures in the following cases:

• the corneal infiltrate is central, large, or associated with significant

stromal involvement or melting
• the infection is chronic or unresponsive to broad-spectrum antibiotic
therapy
• there is a history of corneal surgeries
• atypical clinical features are present, suggestive of fungal, amebic, or
mycobacterial keratitis.
• there are multiple sites of corneal infiltration
• perforation has increased the likelihood of endophthalmitis*

American Academy of Ophthalmology Cornea/External Disease Committee, Hoskins

Center for Quality Eye Care. Preferred Practice Pattern Guidelines. Bacterial Keratitis.
American Academy of Ophthalmology; 2018. www.aao.org/ppp

*Note: Anterior chamber tap for culture or intracameral antibiotic injection routinely performed in cases
of endophthalmitis is generally not done in the presence of infectious corneal ulceration.
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 337

Table 12-8 Causes of Bacterial Keratitis

Common Organisms Uncommon Organisms
Enterobacteriaceae (Proteus spp, Enterobacter spp, Corynebacterium spp
Serratia spp) Moraxella spp
Pseudomonas aeruginosa (most common organism Mycobacterium spp
in soft contact lens wearers) Neisseria spp
Staphylococcus aureus Nocardia spp
Staphylococcus epidermidis Non–spore-forming anaerobes, eg:
Streptococcus pneumoniae and other Actinomyces spp
Streptococcus spp Propionibacteria spp

In addition to culturing corneal specimens, it may be helpful to culture samples obtained

from contact lenses, contact lens cases and solutions, and any other potential sources of con-
tamination, such as inflamed eyelids. The microbial yield in specimens collected for corneal
cultures and smears is significantly higher before the initiation of antibiotic treatment, but
specimens should still be cultured in cases of treatment failure. Some have suggested that
antibiotics should be discontinued for 12 to 24 hours to increase the yield of the pathogen.
Positive results of a smear do not obviate broad-spectrum treatment coverage but may guide
coverage toward a different class of microorganism in the absence of positive culture find-
ings. (See BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, for discussion of
specimen collection, culturing, staining, and interpretation.) Culture results should always be
interpreted in the context of the clinical condition of the patient. Negative results do not nec-
essarily mean there is no infection. Acanthamoeba and fungal pathogens should be suspected
if the history or appearance is suggestive, or if the clinical course has been atypical.
MANAGEMENT The primary goal of therapy is preservation of sight and of corneal integrity.
Bacterial pathogens can cause irreversible corneal scarring over a period of hours because
of their rapid proliferation, keratolytic enzyme activity, and stimulation of destructive host
immune responses. To reduce bacterial load and minimize risk of visual loss, initiation of
therapy is advised before a definitive diagnosis is obtained.
Initial therapy consists of empiric, broad-spectrum topical antibiotics. In routine cor-
neal ulcers, topical fluoroquinolone monotherapy has excellent penetration at commer-
cially available concentrations and provides outcomes equivalent to those of combination
therapy. The recommended regimen for fluoroquinolones is every 30 to 60 minutes ini-
tially and then tapering in frequency according to the clinical response. In severe cases,
administration of antibiotics every 5 minutes for 30 minutes as a loading dose may be
considered. 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 be-
sifloxacin) have improved gram-positive and atypical mycobacterial coverage, compared
with predecessors, but have limited activity against methicillin-resistant Staphylococcus
aureus (MRSA). Alternatively, topical combination therapy with an agent active against
gram-positive bacteria and another agent active against gram-negative bacteria can be
given initially (Table 12-9).
Table 12-9 Initial Therapy for Bacterial Keratitis
Organism Antibiotic Topical Dose Subconjunctival Dose
Gram-positive cocci Cefazolin 50 mg/mL 100 mg in 0.5 mL
Vancomycin 25–50 mg/mL a 25–50 mg/mL 25 mg in 0.5 mL
Moxifloxacin, gatifloxacin, levofloxacin, besifloxacin 5–6 mg/mL Not available
Gram-negative rods Tobramycin 9–14 mg/mL 20 mg in 0.5 mL
Ceftazidime 50 mg/mL 100 mg in 0.5 mL
Ciprofloxacin, ofloxacin, moxifloxacin, gatifloxacin, levofloxacin, besifloxacin 3–6 mg/mL Not available
No organism or multiple types Fortified cefazolin 50 mg/mL 100 mg in 0.5 mL
of organisms with
Fortified tobramycin 9–14 mg/mL 20 mg in 0.5 mL
or
Fluoroquinolones 3–6 mg/mL Not available
Gram-negative cocci Ceftriaxone 50 mg/mL 100 mg in 0.5 mL
Ceftazidime 50 mg/mL 100 mg in 0.5 mL
Ciprofloxacin, ofloxacin, moxifloxacin, gatifloxacin, levofloxacin, besifloxacin 3–6 mg/mL Not available
Mycobacteria Clarithromycin 10 mg/mL 0.03%
Moxifloxacin, gatifloxacin, besifloxacin 5–6 mg/mL Not available
Amikacin 20–40 mg/mL 20 mg in 0.5 mL

a
For resistant Staphylococcus spp.
Notes for Table 12-9: Preparation of topical antibiotics
Cefazolin 50 mg/mL
1. Add 9.2 mL of artificial tears to a vial of cefazolin in 1 g (powder for injection).
2. Dissolve. Take 5 mL of this solution and add it to 5 mL of artificial tears.
3. Refrigerate and shake well before instillation.
Vancomycin 50 mg/mL (Dilution can be extrapolated to a 15–25 mg/mL concentration by a compounding pharmacy.)
1. Add 10 mL of 0.9% sodium chloride for injection USP (no preservatives) or artificial tears to a 500-mg vial of vancomycin to produce a solution of 50 mg/mL.
2. Refrigerate and shake well before instillation.
Ceftazidime 50 mg/mL
1. Add 9.2 mL of artificial tears to a vial of ceftazidime 1 g (powder for injection).
2. Dissolve. Take 5 mL of this solution and add it to 5 mL of artificial tears.
3. Refrigerate and shake well before instillation.
Tobramycin 14 mg/mL
1. Withdraw 2 mL of tobramycin injectable from vial (40 mg/mL).
2. Add 2 mL to a tobramycin ophthalmic solution (5 mL) to give a 14 mg/mL solution.
3. Refrigerate and shake well before instillation.
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 339

In general, administration of a topical cycloglegic agent is recommended to reduce

discomfort and prevent pupillary block related to inflammation. IOP should be moni-
tored during therapy and may be reduced with topical medication if needed.
Fortified antibiotics (compounded at higher concentrations than the commercially
available counterparts) may be administered for severe ulcers when increased drug con-
centration in the corneal stroma is desired. Fortified antibiotics generally are difficult
to obtain and have greater toxicity. Fortified vancomycin may be considered for gram-
positive coverage of large or vision-threatening ulcers, when MRSA is suspected, or after
failure of the initial therapy. With effective treatment, most infectious keratitis cases will
have negative culture results by 48 to 72 hours. Once the offending microbe is identi-
fied or there is clinical improvement, appropriate monotherapy may be considered (see
Table 12-9) to reduce toxicity while maintaining coverage. Continued administration of
fortified antibiotics beyond 7 days is not advisable because of increased toxicity. At times,
bacterial keratitis will improve with antibiotic therapy even when in vitro data suggest
resistance of the causative agent to that antibiotic. Therefore, the clinical response should
guide the choice of medical therapy.
Several parameters are useful for monitoring improvement in the clinical response to
antibiotic therapy:
• reepithelialization
• blunting of the perimeter of the stromal infiltrate
• decreased density of the stromal infiltrate (caution: stromal loss will also result in
corneal clearing)
• cessation of corneal thinning
• reduction in stromal edema and endothelial inflammatory plaque
• reduction in anterior chamber inflammation
Systemic antibiotics—especially fluoroquinolones, which have excellent ocular
penetration—and intensive topical antibiotics are indicated in cases with suspected scleral
and/or intraocular extension of infection but generally are not used in routine cases of
bacterial keratitis.
The role of corticosteroid therapy for bacterial keratitis remains controversial. Tissue
destruction results from a combination of the direct effects of the bacteria and the host
inflammatory response, including the release of proteolytic enzymes, which persist after
corneal sterilization. Corticosteroids are effective at controlling inflammation but inhibit
the host response to infection. The literature strongly suggests that corticosteroid therapy
administered prior to appropriate antibiotic therapy worsens prognosis. In a randomized
clinical trial in which topical corticosteroids were given 48 hours after initiation of topical
antibiotics for bacterial keratitis, no effect on final visual outcome or complication rate
was seen at 3 months. There were trends toward improved outcomes in patients with the
poorest vision at baseline who received corticosteroids and for the entire corticosteroid
group at 1 year. In this study, cases of keratitis caused by Nocardia, which is uncommon in
the United States, had worse outcomes with corticosteroid treatment.
Although corticosteroid use is unsupported, it generally does not increase the risk of
poor outcomes or complications in treated bacterial keratitis, and certain patients benefit
from the addition of corticosteroids to antibiotic therapy.
340 ● External Disease and Cornea

The following are recommendations for conditions of bacterial keratitis in which cor-
ticosteroid therapy should not be given:
• in the absence of appropriate antibiotic therapy
• if the patient is unable to return for frequent follow-up or adhere to antibiotic
therapy
• if any other virulent or difficult-to-eradicate organism is found or suspected
Corticosteroid 1% drops may be started every 6 hours beginning 48 hours after ini-
tiation of antibiotic therapy. If the patient experiences no adverse effects, the frequency
of administration may be adjusted based on clinical response. If a patient on long-term
topical steroid therapy presents with bacterial keratitis, the corticosteroids should be de-
creased, with an expectation of increased inflammation. If fungal or Acanthamoeba in-
fection is suspected, corticosteroids should be stopped. Additional measures, including
lubrication, bandage contact lenses, and patching, may be needed to promote reepitheli-
alization and reduce keratolysis. Collagen crosslinking may be considered as adjunctive
therapy for bacterial keratitis; however, there is not sufficient evidence to support its use
in primary management of bacterial keratitis.
Surgical treatment of bacterial keratitis is indicated if the disease progresses despite
therapy or is otherwise unresponsive to therapy—or if descemetocele formation or perfora-
tion occurs. Lamellar keratoplasty (LK) may be preferable to penetrating keratoplasty (PK)
because LK is associated with lower risk of intraocular seeding of infection, formation of
peripheral anterior synechiae, glaucoma, and cataract formation associated with entering
the anterior chamber. Descemetocele and perforations smaller than 2 mm may be managed
with tissue adhesive as a therapeutic modality (see Chapter 5). Amniotic membrane grafting
is not recommended when the infection has not resolved completely, has not been clearly
identified, or if a corneal perforation is present. Peripheral iridectomy should be performed
during PK because extensive synechiae may develop from inflammatory membranes. In-
terrupted sutures are recommended, and the patient should be given appropriate topical
antibiotics and cycloplegia. There is disagreement regarding topical corticosteroid use post-
keratoplasty, particularly if the bacterial infection has not been controlled. See Chapter 16 in
this volume for a more detailed discussion of LK and 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, Hoskins Center for
Quality Eye Care. Preferred Practice Pattern Guidelines. Bacterial Keratitis. American
Academy of Ophthalmology; 2018. 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.
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 341

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.

Atypical mycobacteria
Although Staphylococcus is the most common causative agent in early onset keratitis follow-
ing refractive surgery, atypical mycobacteria frequently are associated with laser in situ ker-
atomileusis (LASIK)-related infections that occur 1 week or later postsurgically (Figs 12-14,
12-15). The most common atypical mycobacteria are Mycobacterium fortuitum and M che-
lonae, which are found in soil and water. These organisms should be suspected in delayed-
onset post-LASIK infection, particularly with recalcitrant, nonsuppurative infiltrates. After
LASIK, the surgical flap should be lifted to obtain specimens for culture. Positive results
should be confirmed with acid-fast staining or culture on Löwenstein-Jensen medium.
Medical treatment options include oral and topical clarithromycin, amikacin, linezolid, and
fluoroquinolones with antimycobacterial activity, including moxifloxacin, besifloxacin, and
gatifloxacin.
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.

Fungal Keratitis
In the United States, fungal keratitis is less common than bacterial keratitis, accounting for
less than 10% of corneal infections; filamentous fungal keratitis occurs more frequently in
warm, humid regions.

Figure 12-14 Atypical mycobacterial infection Figure  12-15 Atypical mycobacterial

following laser in situ keratomileusis (LASIK). infection. (Courtesy of Christopher J. Rapuano,
(Courtesy of Elmer Y. Tu, MD.) MD.)
342 ● External Disease and Cornea

Risk factors for fungal keratitis include the following:

• trauma to the cornea with plant or vegetable material (the leading risk factor)
• contact lens wear
• corticosteroid use (corticosteroids activate and increase the virulence of fungal or-
ganisms and dampen host resistance to infection.)
• chronic corneal erosions/ulceration from other causes
• chronic keratitis (eg, due to HSV, herpes zoster, or vernal/atopic keratoconjunctivitis)
• systemic immunosuppression (which predisposes individuals to fungal keratitis
[eg, Candida])
• corneal surgery (eg, penetrating keratoplasty, endothelial keratoplasty)
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 early signs and
symptoms of an inflammatory response than do patients with bacterial keratitis and may
have little or no conjunctival injection at presentation. However, the severity of pain in fun-
gal keratitis can be disproportionately greater than the amount of corneal inflammation.
In the initial stage, filamentous fungal keratitis manifests as a gray-white, nonsup-
purative infiltrate with irregular feathery or filamentous margins (Fig 12-16). Superficial
lesions may elevate the surface of the cornea and have a dry, rough, or gritty texture de-
tectable at time of diagnostic corneal scraping. Multifocal or satellite infiltrates may be
present. In addition, a deep stromal infiltrate may develop in the presence of an intact
epithelium. An endothelial plaque or hypopyon may also occur, particularly if the fungal
infiltrate is deep or large, or if it has penetrated into the anterior chamber.
As fungal keratitis progresses, intense suppuration may develop, and the infiltrates
may resemble those of bacterial keratitis. Rapidly progressive hypopyon and inflammatory
membranes of the anterior chamber also may occur, potentially signaling extension of the
fungal infection into the anterior chamber. Occasionally, fungus may invade the iris or pos-
terior chamber, precipitating angle-closure glaucoma secondary to inflammatory pupillary
block.
Candida species are the most common organisms causing yeast keratitis, which
presents as superficial white, raised colonies. Infection is usually superficial, but deep

Figure 12-16 Fungal keratitis caused by Fusar-

ium solani with characteristic dry-appearing,
white stromal infiltrate with feathery edges.
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 343

invasion may occur, with suppuration resembling that of keratitis induced by gram-positive
bacteria.
LABORATORY EVALUATION Results of smears stained with acridine orange, calcofluor white,
or potassium hydroxide (KOH) can assist the clinician in making a rapid diagnosis. Blood
agar, Sabouraud dextrose agar, and brain–heart infusion agar are the preferred media for
fungal culture, and in vitro antifungal sensitivity testing can be helpful in optimizing med-
ical treatment. Confocal microscopy is an effective tool for detecting branching filaments
and individual septa, which are common findings of mold pathogens in the cornea. PCR
may be applied for highly sensitive detection of fungal infections.
MANAGEMENT Natamycin 5% suspension is recommended for treatment of filamentous
fungal keratitis, particularly those caused by Fusarium species. Topical amphotericin B
0.15% is highly efficacious in cases of yeast keratitis such as Candida species. Ampho-
tericin B is also recommended for filamentous keratitis caused by Aspergillus species. Use
of topical voriconazole 1% has increased, and efficacy has been demonstrated in cases
of fungal keratitis unresponsive to other therapy; however, drug resistance has been re-
ported, and a recent prospective, randomized clinical trial concluded that voriconazole is
inferior to natamycin for empiric therapy, especially for Fusarium solani.
Systemic treatment may be considered for severe keratitis or keratitis with scleral or
intracameral extension. Ketoconazole (200–600 mg/day), fluconazole (200–400 mg/day),
or itraconazole (200 mg/day) may be used, but oral voriconazole (200–400 mg/day) and
posaconazole (800  mg/day) have excellent intraocular penetration and broad coverage
and have been rapidly supplanting these older drugs. Alternatively, intrastromal injection
of aqueous-soluble amphotericin B (5–10 µg/0.1 mL) or voriconazole (50–100 µg/0.1 mL)
as primary or secondary treatment of deep fungal keratitis, and intracameral injection
of either agent for intraocular extension, are becoming more widely validated. Culture-
proven or histologically proven fungal keratitis that does not respond to therapy warrants
speciation of the pathogen and antifungal sensitivity testing. Corneal crosslinking has
been investigated as an adjunct therapy for fungal keratitis, but it appears to have no effect
in deep stromal disease and mixed results in superficial fungal infections.
When smear results are negative and fungal infection is suspected, repeat scrapings or
corneal biopsy may be necessary. Mechanical debridement may be beneficial in cases of super-
ficial fungal keratitis. In cases of fungal infiltration of the deep corneal stroma, topical antifun-
gal therapy may be ineffective because penetration of these agents is reduced in the presence of
an intact epithelium. Penetration of natamycin or amphotericin B can be enhanced by debride-
ment of the corneal epithelium. Patients with progressive disease despite maximum topical
and/or oral antifungal therapy may require therapeutic LK or PK to prevent scleral or intra-
ocular extension of the fungal infection; however, the prognosis for salvaging the eye is poor.
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.
Ferrer C, Alio JL. Evaluation of molecular diagnosis in fungal keratitis. Ten years of
experience. J Ophthalmic Inflamm Infect. 2011; 1(1):15–22.
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.
344 ● External Disease and Cornea

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.

Acanthamoeba keratitis
Since 2003, a growing number of Acanthamoeba cases have occurred in the United States,
particularly on the East Coast and in the Midwest. Results of 2 case-control studies showed
an association between Acanthamoeba keratitis and use of Complete Moisture Plus mul-
tipurpose solution (formerly Advanced Medical Optics) for cleaning soft contact lenses,
resulting in the voluntary recall of the product in May 2007. Unfortunately, the outbreak
persisted, prompting a second multistate case-control study in 2011, led by the Centers for
Disease Control and Prevention.
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 usually experience the following:
• severe ocular pain that is greater than expected from clinical findings
• photophobia
• a protracted, progressive course
The disease is bilateral in 7%–11% of patients and often is unresponsive to topical anti-
microbial agents. In the early stage, infection with Acanthamoeba is localized to the corneal
epithelium or just posterior and may present as diffuse epitheliopathy with coarse punctate
features, subepithelial opacities, or dendritic epithelial lesions. Epithelial pseudodendrites
often are misdiagnosed as herpetic keratitis and treated with antiviral agents and/or corticoste-
roids. Stromal infection typically manifests in the central cornea; early cases have a gray-white,
superficial, nonsuppurative infiltrate. As the disease progresses, a partial or complete central
ring infiltrate is often encountered (Fig 12-17). When seen, inflamed corneal nerves, known
as radial perineuritis or radial keratoneuritis, are nearly pathognomonic of amebic keratitis.

Figure 12-17 Ring infiltrate in Acanthamoeba

keratitis. (Courtesy of Shahzad I. Mian, MD.)
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 345

Limbitis, scleritis (focal, nodular, or diffuse), or dacryoadenitis may be seen as well. Although
intraocular extension may occur, consecutive encephalitis has not been reported.
Clinical features that favor a diagnosis of Acanthamoeba keratitis over HSV keratitis
include the following:
• presence of epidemiologic risk factors, such as contact lens use or exposure to a hot
tub or potentially contaminated freshwater
• disproportionately severe ocular pain (unlike the disproportionately mild pain sec-
ondary to trigeminal nerve involvement in HSV)
• a noncontiguous or multifocal pattern of granular epitheliopathy and subepithelial
opacities (unlike the contiguous, dendritic pattern in HSV keratitis)
• failure of antiviral therapy to eradicate the infection

PATHOGENESIS Acanthamoeba is a genus of free-living ubiquitous protozoa found in freshwater

and soil. Freezing, desiccation, and typical chlorine levels in municipal water supplies, swim-
ming pools, and hot tubs are not sufficient to kill Acanthamoeba. Ocular exposure to well water
and swimming in fresh water or ponds while wearing contact lenses increases risk of infection.
Acanthamoeba may exist as motile trophozoites or dormant cysts. In Western countries, ap-
proximately 90% of reported cases of amebic keratitis have been associated with contact lens
use, with the remainder linked to various other risk factors. Historically, episodic outbreaks of
disease have been associated with water contamination, such as homemade saline contact
lens solutions, groundwater affected by river flooding, or contaminated rooftop cisterns.
LABORATORY EVALUATION Diagnosis of Acanthamoeba keratitis is made by visualizing amebae
in stained smears (eg, Giemsa, periodic acid–Schiff, calcofluor white, acridine orange) or by
culturing organisms obtained from corneal scrapings on nonnutrient agar with overlay of
E coli or Enterobacter aerogenes. Buffered charcoal–yeast agar also may be used as a substrate.
In culture, characteristic trails form as the motile trophozoites travel across the surface of
the plate. In vivo confocal microscopy can be performed to visualize Acanthamoeba cysts
(Fig 12-18). Culture yield varies among laboratories, with findings of large studies indicat-
ing only 35% to 50% positivity for Acanthamoeba despite suggestive clinical presentation or

Figure  12-18In vivo confocal microscopy

image of Acanthamoeba cysts (arrows). (Cour-
tesy of Elmer Y. Tu, MD.)
346 ● External Disease and Cornea

confocal microscopy. Examination of contact lenses and related paraphernalia may be advis-
able. Lamellar corneal biopsy may be required to establish the diagnosis.
MANAGEMENT Early diagnosis of Acanthamoeba keratitis is the most important indicator of
a good prognosis. However, diagnostic delay is common because of the nonspecific pre-
sentation of the disease and the specialized microbiological methods needed for diagnosis.
Cases identified early, which are defined as epithelial or anterior stromal, have an excel-
lent visual prognosis and generally respond well to epithelial debridement, followed by a
3- to 4-month course of antiamebic therapy. Findings of deep stromal inflammation, a ring
infiltrate, or extracorneal manifestations worsen the prognosis and often necessitate longer
treatment (a year or more), other adjunctive therapy, or therapeutic keratoplasty.
Several antimicrobial agents have been recommended for medical treatment of Acan-
thamoeba keratitis based on their in vitro amebicidal effects as well as their clinical effec-
tiveness. Topical agents include the following:
• diamidines: propamidine, hexamidine
• biguanides: polyhexamethylene biguanide (polyhexanide), chlorhexidine
• aminoglycosides: neomycin, paromomycin
• imidazoles/triazoles: voriconazole, miconazole, clotrimazole, ketoconazole, itraconazole
Only the biguanides have consistent in vitro and clinical efficacy against cysts and
trophozoites; the other agents are effective primarily against trophozoites. Therefore, bi-
guanides are the mainstay of pharmacologic treatment. Diamidines may be given early
in the course of therapy, but resolution of the infection can be achieved with a biguanide
alone. In a comparison of biguanides, chlorhexidine 0.02% and polyhexamethylene bi-
guanide (PHMB) 0.02% performed similarly. Single-agent systemic treatment with voricon-
azole may be efficacious in recalcitrant cases.

CLINICAL PEARL
Corticosteroid exposure induces acanthamoebal excystment in vitro and may
worsen clinical outcomes when used prior to effective anti-acanthamoebal therapy.

Much of the morbidity of Acanthamoeba keratitis, including scleritis, glaucoma, and

cataract, can be attributed to the exuberant host response. The judicious use of topical and
systemic immunosuppressants may be beneficial after the patient has received at least 2 weeks
of anti-acanthamoebal therapy.
Traditionally, keratoplasty has been reserved for vision rehabilitation after completion of
treatment or for cases that progress despite maximal medical therapy and are at risk of perfora-
tion. Recent results have indicated that LK and PK may reduce the rate of recurrent infection
and improve visual outcomes when combined with adjunctive anti-acanthamoebal agents.
However, medical treatment is preferred in the vast majority of cases. It is advisable to per-
form optical keratoplasty only after a full course of amebicidal therapy because recurrence
is possible when medical therapy is ended prematurely. Corneal crosslinking is not currently
recommended for the treatment of Acanthamoeba keratitis because of efficacy concerns.
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 347

Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update 2009.

Am J Ophthalmol. 2009;148(4):487–499.e2.
Robaei D, Carnt N, Minassian DC, Dart JK. The impact of topical corticosteroid use before
diagnosis on the outcome of Acanthamoeba keratitis. Ophthalmology. 2014;121(7):1383–1388.
Robaei D, Carnt N, Minassian DC, Dart JK. Therapeutic and optical keratoplasty in the
management of Acanthamoeba keratitis: risk factors, outcomes, and summary of the litera-
ture. Ophthalmology. 2015;122(1):17–24.
Tu EY. Acanthamoeba and other parasitic corneal infections. In: Mannis MJ, Holland EJ, eds.
Cornea. Vol 1. 4th ed. Elsevier; 2017:976–985.
Tu EY, Joslin CE, Sugar J, Shoff ME, Booton GC. Prognostic factors affecting visual outcome
in Acanthamoeba keratitis. Ophthalmology. 2008;115(11):1998–2003.

Corneal Stromal Inflammation Associated With Systemic Infection

Nonsuppurative stromal keratitis can be caused by the following:
• reactive arthritis
• congenital or acquired syphilis
• Lyme disease
• tuberculosis
• leprosy
• onchocerciasis
See BCSC Section 9, Uveitis and Ocular Inflammation for further discussion.

Microsporidiosis
CLINICAL PRESENTATION Based on the patient’s immune status, 1 of 2 presentations of micro-
sporidial infection may occur. Immunocompetent individuals may experience corneal stro-
mal keratitis, whereas those who are immunocompromised (particularly those with AIDS)
may have conjunctivitis and epithelial keratopathy (Fig  12-19). Immunocompromised

Figure  12-19 Microsporidial epitheliopathy.

(Courtesy of Woodford S. Van Meter, MD.)
348 ● External Disease and Cornea

patients may also have disseminated microsporidiosis involving the sinuses, respiratory tract,
or gastrointestinal tract.
Common symptoms include ocular irritation, photophobia, decreased vision, and
bilateral conjunctival injection with little or no associated inflammation. Depending on
the genus of the microsporidium, the condition may manifest as stromal keratitis or kera-
toconjunctivitis. In the keratoconjunctivitis variant, corneal findings include superficial
nonstaining opacities described as “mucoid” in appearance, dense areas of fine punctate
fluorescein staining, and a clear corneal stroma, with minimal or no iritis.
LABORATORY EVALUATION Microsporidosis-positive conjunctival biopsy specimens stained
with Brown and Hopps solution and visualized with light microscopy exhibit small
gram-positive spores in epithelial cells (Fig 12-20). Transmission electron microscopy
(Fig 12-21), immunofluorescence antibody techniques, or elaborate tissue culture tech-
niques may also be used for evaluation.
PATHOGENESIS Microsporidia are intracellular protozoa known to cause ocular infection.
Initially recognized as an opportunistic pathogen in individuals with immunosuppres-
sion, this organism is increasingly being identified as the cause of infection in immuno-
competent persons, especially in Southeast Asia. Deep stromal infection may present as
chronic, progressive keratitis in immunocompetent patients.
MANAGEMENT Restoration of immune function can lead to resolution of microsporidial
keratitis. Although there is no definitive treatment, topical fumagillin has been used suc-
cessfully for microsporidial keratoconjunctivitis, with little toxic effect. Topical treatment
with voriconazole 1% and oral itraconazole 200 mg 2 times per day may also be effective.
In severe infection, granulomatous inflammation may lead to necrotic thinning and per-
foration necessitating PK. Medical therapy generally must be prolonged, and recurrence is
common after treatment discontinuation. Topical fluoroquinolones (ciprofloxacin 0.3%,

Figure 12-20 Intracellular spores of microsporidia viewed under light microscopy. (Courtesy of

Woodford S. Van Meter, MD.)
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 349

Figure  12-21 Visualization of microsporidia by electron microscopy. (Courtesy of Woodford  S.  Van
Meter, MD.)

moxifloxacin 0.5%, gatifloxacin 0.5%, levofloxacin 0.5%, and norfloxacin 0.3%) as mono-
therapy or in combination with topical fumagillin or systemic albendazole have been ef-
fective for the treatment of microsporidial keratitis, with resolution in 99% of cases even
on topical fluoroquinolone monotherapy.
Joseph J, Sridhar MS, Murthy S, Sharma S. Clinical and microbiological profile of microsporidial
keratoconjunctivitis in southern India. Ophthalmology. 2006;113(4):531–537.
Loh RS, Chan CM, Ti SE, Lim L, Chan KS, Tan DT. Emerging prevalence of microsporidial
keratitis in Singapore: epidemiology, clinical features, and management. Ophthalmology.
2009;116(12):2348–2353.

Loiasis
Infection with Loa loa (loiasis) and other filarial nematodes can result in conjunctivitis and
dermatologic manifestations. The microfilarial stage of the parasite is transmitted from
human to human by the bite of an infected female deerfly indigenous to West and Central
Africa. A migrating worm burrows subcutaneously at about 1 cm/min but is most con-
spicuous when it is seen or felt wriggling under the periocular skin or bulbar conjunctiva
(Fig 12-22). Extraction of the filarial worm cures the conjunctivitis; antiparasitic treat-
ment then is administered for disseminated infestation. Diethylcarbamazine may be given
2 mg/kg 3 times a day for 3 weeks and repeated as necessary. Ivermectin 150 mg/kg may also
be effective, but significant adverse effects have been reported in patients with prominent in-
travascular loiasis. Concurrent administration of corticosteroids and/or antihistamines may
be necessary to minimize allergic reactions.

Microbial Scleritis
Bacterial and fungal infections of the sclera are rare. Most cases result from the extension of
microbial keratitis involving the peripheral cornea. Trauma and exposure to contaminated
350 ● External Disease and Cornea

Figure 12-22 Subconjunctival loiasis. (Courtesy of Woodford S. Van Meter, MD.)

Figure  12-23 Bacterial scleritis occurring 2 weeks after pterygium surgery. (Courtesy of Kirk  R.
Wilhelmus, MD.)

foreign bodies (including scleral buckles) are possible risk factors. Bacterial scleritis may
manifest in sclera damaged by previous pterygium surgery, especially when beta irradiation
or mitomycin has been used (Fig 12-23). Bacteria and fungi can also invade tissue of the
eye wall surrounding a scleral surgical wound, often leading to endophthalmitis. Scleral in-
flammation may accompany syphilis, tuberculosis, or leprosy, as well as infection with Acan-
thamoeba species, Nocardia species, or atypical mycobacteria. Tuberculous scleritis should
be considered in chronic steroid-dependent scleritis or in surgically induced necrotizing
scleritis. Diffuse or nodular scleritis is an occasional complication of ocular infection with
varicella-zoster virus.
 CHAPTER 12: Bacterial, Fungal, and Parasitic Infections ● 351

LABORATORY EVALUATION Suppurative scleritis can be assessed in the same manner as mi-
crobial keratitis. Antimicrobial therapy can be initiated after results of smears and cultures
are obtained. If the overlying epithelium is intact, obtaining a scleral or episcleral biopsy
specimen is recommended for culture, histologic examination, and molecular diagnostic
testing. The workup of nonsuppurative scleritis is guided by the history and by findings
from the examination.
MANAGEMENT Topical antimicrobial therapy is the same as for microbial keratitis. Because
of the difficulty in controlling microbial scleritis, subconjunctival injections and intrave-
nous antibiotics may also be used. Results of long-term oral therapy have been favorable.