Noel Rosado MD
September 8, 2013
Microbial keratitis or infectious corneal ulcer is due to
the proliferation of microorganisms (including
bacteria, fungi, viruses, and parasites) and associated
inflammation and tissue destruction within the
It is a potentially sight-threatening condition and
frequently presents as an ocular emergency.
Bacterial keratitis is the most common cause of
suppurative corneal ulceration, which rarely occurs in
the normal eye because of the human cornea's natural
resistance to infection.
The accurate incidence of bacterial keratitis is not known.
It is estimated that 30 000 cases of microbial keratitis occur
in the USA annually.[
An estimated 10 to 30 individuals per 100 000 contact lens
wearers develop microbial keratitis annually in the USA
Bacterial keratitis is one of the leading causes of corneal
blindness in developing nations, usually caused by ocular
Occasionally, severe or refractory bacterial keratitis
requires surgery. Statistics from the Eye Bank Association
of America demonstrate that approximately 1% of all
corneal transplants are performed as a result of microbial
Bacterial keratitis usually occurs in patients with
predisposing factors, which can compromise normal ocular
Eyelid trauma or any abnormality of the lid closure can
compromise this defense mechanism.
Abnormalities of tear components, tear volume, or tear
drainage system are the principal causes of a compromised
Chronic colonization and infection of the eyelid margin or
lacrimal outflow system can predispose cornea to bacterial
infection when minor trauma occurs.
An intact corneal epithelium is an important defense
factor of the eye.
Compromised corneal epithelial integrity caused by
contact lens wear, corneal trauma, or corneal surgery is
an important predisposing factor to bacterial ulcers.
Also, inappropriate use of topical antibiotics could
eliminate the natural protection by the normal flora
and predispose the cornea to the development of
opportunistic infections, particularly when combined
with corneal disease or trauma.
Trauma, including chemical and
thermal injuries, foreign bodies,
and local irradiation can
predispose to bacterial keratitis.
Corneal infection can occur from
contamination of topical solutions
and the tips or caps of eye dropper
Chronic abuse of topical
anesthetics can disrupt the corneal
epithelium and render it at risk for
The most common risk factor for bacterial keratitis in
All types of contact lenses, including hard, gas-permeable,
soft, disposable, and cosmetic lenses, have been implicated
in microbial keratitis.
Contact lens users have a 1.5% chance of developing
infectious keratitis during a lifetime of contact lens wear.
Three groups of patients have an increased risk of contact
lens-related infectious keratitis:
Patients with a corneal transplant
Patients wearing a bandage
lens for chronic keratopathy.
Ocular surface diseases such as cicatricialpemphigoid,
Stevens-Johnson syndrome, atopic
keratoconjunctivitis, radiation and chemical injury,
and vitamin A deficiency can lead to
squamousmetaplasia of the ocular surface epithelium
and cause an unstable tear film, which can predispose
to bacterial infection.
Bacterial keratitis can complicate corneal epithelial
erosions associated with corneal epithelial basement
membrane dystrophy,lattice corneal dystrophy, and
vernal or atopic keratoconjunctivitis
Bacterial keratitis after corneal transplantation can
occur at any time postoperatively.
Postkeratoplasty use of extended wear soft contact
lenses has been a major risk factor.
Loose, broken, or exposed sutures can harbor ocular
flora and permit an entry site for microbes
Systemic conditions such as
malnutrition, diabetes, collagen vascular diseases, or
chronic alcoholism may also compromise the ocular
surface and increase the risk of microbial keratitis
caused by unusual organisms
In patients with AIDS (acquired immunodeficiency
syndrome), microbial keratitis does not appear to be
more prevalent than in the normal population.
However, the keratitis tends to be more severe and
more resistant to therapy in these patients.
Clinical signs and symptoms of microbial
keratitis are variable.
Severe bacterial keratitis usually has a
history of rapid onset of pain,
photophobia, decreased vision,
conjunctival injection, anterior chamber
reaction, and/or hypopyon.
The clinical findings usually cannot
readily distinguish the causing organism.
Nonetheless, clinical diagnosis is possible
when a pertinent history is available or
the organisms present with characteristic
However, many microorganisms such as
fungi or Acanthamoebacan cause
masquerading syndromes mimicking
Differential diagnosis of bacterial keratitis includes
infectious and noninfectious causes of corneal
Include fungi (both yeast and mold), parasites
(including protozoa such as Acanthamoeba),
nematodes (such as Onchocerca), and viral infection.
Viruses including herpes simplex virus (HSV),
varicella-zoster virus (VZV), and Epstein-Barr virus
(EBV) produce immunologically mediated corneal
infiltrates that may resemble a bacterial, fungal,
or Acanthamoeba keratitis.
Viruses can also cause a true suppurativekeratitis, as in
necrotizing stromal disease.
Collagen vascular disorders (e.g. rheumatoid arthritis,
systemic lupus erythematosus), vasculitic disorders
(e.g. polyarteritisnodosa, Wegener's granulomatosis),
and other inflammatory disorders such as sarcoidosis
may produce infiltrative keratitis.
Other causes include dermatologic disorders (e.g.
severe ocular rosacea) and allergic conditions (e.g.
vernal and atopic keratoconjunctivitis).
The purpose of the clinical evaluation is to:
Evaluate predisposing or aggravating factors in order to
construct a differential diagnosis,
To assess the severity of the disease and the associated
To initiate appropriate management in a timely manner.
Obtaining a detailed history is important and should
include ocular symptoms (e.g. degree of pain, redness,
discharge, blurred vision, photophobia, duration of
symptoms, circumstances surrounding the onset of
symptoms) and review of prior ocular history (including
previous infectious keratitis, ocular surgery, contact lens
wear,trauma, and dry eye)
Important to document baseline visual acuity
An external examination should be performed with
particular attention to the followings:
General appearance of the patient, including skin
Eyelids and lid closure
Corneal sensation (assess prior to instillation of topical
Eyelid margins (meibomian gland dysfunction,
ulceration, eyelash abnormalities including trichiasis,
irregularities, nasolacrimal obstructions or punctal
Tear film (dry eye or debris)
Conjunctiva (discharge, erythema, follicles, papillae,
cicatrization, keratinization, membrane,
pseudomembrane, ulceration, scars, foreign bodies)
Sclera (inflammation, ulceration, nodules or ischemia)
Cornea (epithelial defects, punctatekeratopathy,
edema, stromal infiltrates, thinning, or perforation).
The location, density, size, shape, depth,
character of infiltrate margin (suppurative,
necrotic, feathery, soft, crystalline), and
color of the corneal ulcer should be carefully
evaluated and documented.
The endothelium and associated anterior
chamber inflammation (cell, flare,
hypopyon, or fibrin) should not be
Fluorescein or rose Bengal staining may
provide additional information, such as the
presence of dendrites, pseudodendrites,
loose or exposed sutures, and epithelial
Attention should also be directed to the
contralateral eye for clues to etiology as well
as possible similar pathology.
Clinical features suggestive of bacterial keratitis
include suppurativestromal infiltrate (particularly
those greater than 1 mm in size) with edema, and
white cell infiltration in surrounding stroma.
An epithelial defect is typically present.
An anterior chamber reaction is often seen.
The corneal ulcer is
considered to be severe if
The lesion progresses
Has an infiltration
dimension larger than
Involves deeper than one-
third of the corneal
Presents with impending
or overt perforation
Has scleral involvement.
Pseuodmonasaeruginosa is the most common
Gram-negative pathogen isolated from severe
The increasing prevalence
of Pseudomonas keratitis in otherwise healthy
individuals has been largely associated with the
use of soft contact lenses.
Rapid progression, dense stromal infiltrate,
marked suppuration, liquefactive necrosis, and
descemetocele formation or corneal perforation
are the characteristics of this pathogen .
Despite appropriate treatment, the keratitis may
progress rapidly into a deep stromal abscess and
stromalkeratolysis with perforation may occur.
A corneal ring infiltrate, which is a dense
accumulation and aggregation of
polymorphonuclear leukocytes, can also be
Staphylococcus, the most common Gram-positive
organism, is usually present in normal ocular
Staphylococcus keratitis occurs more frequently
in compromised cornea cases.
S. aureus tends to produce a rapidly progressive
corneal infiltration and moderate anterior
chamber reactions with endothelial plaques or
The corneal lesions usually are round or oval
with dense infiltration and a distinct border .
Coagulase-negative staphylococci usually cause
opportunistic infection in the compromised
cornea. More than 85% of eyelid cultures from
the normal population are positive for
The infection tends to progress slowly and the
infiltrates are usually superficial, localized with
the surrounding cornea clear. However, severe
ulcers with dense infiltrates can occur if
pneumoniae keratitis usually
occurs after corneal
trauma, dacryocystitis, or
filtering bleb infection.
The ulcer tends to be
acute, purulent, and rapidly
progressive with a deep stromal
The anterior chamber reaction is
usually severe with marked
hypopyon and retrocorneal
Perforation secondary to ulcer is
This is a class of rapidy growing and acid-
The most common pathogens
are Mycobacterium fortuitumand M.
chelonei, which may be found in soil and
These organisms tend to cause a slowly
progressive keratitis, and usually occur after
a corneal foreign body, corneal trauma or
following corneal surgery, particularly after
Keratitis from nontuberculousmycobacteria
is often associated with delayed onset of
symptoms, and severe ocular pain can
develop from 2 to 8 weeks after exposure to
Infiltrates are typically nonsuppurative and
can be solitary or multifocal, with variable
anterior chamber reactions.
Delay in diagnosis is common due to the
protracted clinical course and difficulty of
isolating the organism from culture.
Include corneal scraping to obtain
specimens for microbiological stainings and
cultures to isolate the causative
organismand determine sensitivity to
The majority of community-acquired cases
of bacterial keratitis resolve with empirical
therapy and are managed without smears or
Prior to initiating antimicrobial therapy,
smears and cultures are indicated in cases
where the corneal infiltrate is central, large,
deep, is chronic in nature, or has atypical
clinical features suggestive of fungal,
amoebic, or mycobacterialkeratitis.
In addition, cultures are helpful to guide
modification of therapy in patients with a
poor clinical response to empirical
treatment and to decrease toxicity by
eliminating unnecessary drugs.
Corneal material is
obtained by scraping
corneal tissues from the
advancing borders of the
Obtaining only purulent
material usually results in
Cultures of contact lenses,
lens case, and contact lens
solution may provide
additional information to
Media Common isolates
Blood Agar Aerobic and facultative, anaerobic bacteria,
including P. aeruginosa, S. aureus, S.
epidermidis, S. pneumoniae
Chocolate Agar Aerobic and facultative, anaerobic bacteria,
including H. influenzae, N. gonorrhoeae,
and Bartonella species
Thyoglicollate broth Aerobic and facultative, anaerobic bacteria
Lowenstein-Jensen medium Mycobacterium species
Thayer-Martin agar Pathologic Neisseria
Sabouraud's dextrose agar Fungi
Microbial pathogens may be categorized by examining
stained smears of corneal scrapings.
Stain Organisms visualized
Gram stain Best for bacteria; can also
Giemsa stain Bacteria,
Acid fast Mycobacterium, Nocardia
Calcofluor white Fungi, Acanthamoeba
Corneal biopsy may be indicated if there has been a lack of response to
treatment or if cultures have been negative on more than one occasion and the
clinical picture continues to suggest strongly an infectious process.
It may also be indicated if the infiltrate is located in the mid or deep stroma
with overlying uninvolved tissue that yield little material with scraping.[
Using topical anesthesia, a 2–3-mm circular trephine can be used to outline the
area to be biopsied.
Femtosecond laser has been recently used to perform lamellar corneal biopsies
The biopsy may also help ulcer healing by debulking or debridement of
An option for a deep corneal abscess may be to use a suture that can be passed
through the abscess without disturbing the overlying intact corneal epithelium
Topical antibiotic eye drops are capable of achieving high levels of tissue
concentration and are the preferred method of treatment in most cases.
Ointments may be useful adjunctive therapy and for use at bedtime in less
severe cases, but may impair the penetration of concomitant topical eye
Subconjunctival antibiotics may be helpful where there is imminent
scleral spread or perforation or in cases where compliance with the
treatment regimen is questionable.
Systemic antibiotics may be considered in severe cases with scleral or
intraocular extension of infection.
Systemic therapy is necessary in cases of gonococcalkeratitis due to its
fulminant nature and systemic involvement.
This approach is based on the pre-existing culture and sensitivity
data without specifically obtaining corneal specimens from the
Clinicians use broad-spectrum antibiotics to cover potential
causative organisms. Fortified antibiotics such as cefazolin or
vancomycin for Gram-positive organisms and tobramycin or
ceftazidime for Gram-negative organisms are used.
However, prolonged and nonelective use of these fortified
antibiotics may cause ocular discomfort and epithelial toxicity.
The important breakthrough in this empirical approach is the
introduction of fluoroquinolone antibiotics, which have been
shown by clinical trials to have an efficacy for common ocular
pathogens equivalent to that of the fortified antibiotics.
However, there are potential gaps in the antibacterial spectrum
In the past, monotherapy with fluoroquinolone was generally
recommended for contact lens-related Pseudomonas keratitis;
however, increasing emergence of ciprofloxacin-resistant P.
aeruginosa has been reported, and this treatment strategy
should be exercised with caution.
In this traditional approach, corneal scrapings for staining and
microbiological culture are performed in all cases of microbial
keratitisbefore treatment is started.
The initial therapy is based on the clinical and epidemiological
information and may be modified according to microbiological
These patients are more likely to have severe corneal ulcers or
infections caused by atypical pathogens.
The major disadvantage of this approach is the inconvenience
Cultures from routine corneal scrapings are positive in only 60%
In addition, discrepancy between in vitro antibiotic sensitivity
and clinical response is often encountered.
Topical antibiotics are used initially in the treatment
of bacterial keratitis
For central or severe keratitis, a loading dose every 5 to
15 minutes for the first hour, followed by applications
every 15 minutes to 1 hour around the clock to achieve
a sustained therapeutic level, is recommended.
For less severe keratitis, a regimen with less frequent
dosing is appropriate.
Cycloplegic agents may be used to decrease synechia
formation and to decrease pain and ciliary spasm in
more severe cases.
Single-drug therapy using a fluoroquinolone (e.g. third or
fourth generation) has been shown to be as effective as
combination therapy utilizing antibiotics that are fortified.
Although the prevalence of resistance to the
fluoroquinolones appears to be increasing.
Combination fortified antibiotic therapy is an alternative to
consider for severe infection and for eyes unresponsive to
Frequency of reevaluation of the patient with bacterial
keratitis depends on the extent of disease, but severe cases
(e.g. deep stromal involvement or larger than 2 mm with
extensive suppuration) initially should be followed at least
daily until clinical improvement is documented.
The clinical response is best assessed after 48 hours of
treatment, as earlier evaluation is usually inconclusive and not
helpful in assessing the efficacy of antibiotic treatment.
In general, the initial therapeutic regimen should be modified
when the eye shows a lack of improvement or stabilization
within 48 hours.
Several clinical features suggestive of a positive response to
antibiotic therapy include reduction in pain, reduced amount of
discharge, less eyelid edema or conjunctival injection,
consolidation and sharper demarcation of the perimeter of the
stromal infiltrate, decreased density of the stromal infiltrate,
reduced stromal edema and endothelial inflammatory plaque,
reduced anterior chamber inflammation, and reepithelialization.
Despite aggressive therapy, bacterial keratitis can
advance causing progressive corneal thinning,
descematocele formation and corneal perforation.
Cyanoacrylate tissue adhesive (N-butyl-2-
cyanoacrylate) has been used to treat
progressive corneal thinning,
descemetocele, and corneal perforation
with satisfactory results.
In addition to its tectonic support and
bacteriostatic effects, the tissue glue can
arrest keratolysis by blocking leukocytic
proteases from the corneal wound.
Perforations up to 2–3 mm in diameter can
be sealed by the tissue adhesive.
Necrotic tissue and debris should be
removed from the ulcer bed prior to
application of the glue.
Due to potential corneal toxicity, only the
minimum amount of glue required to cover
the defect should be used.
The adhesive is usually left in place until it
dislodges spontaneously or a keratoplasty is
Collagen cross linking (CXL) of the cornea has been developed
recently as a new treatment for multidrug-resistant infectious
keratitis, as documented by several recent case reports.
This technique has showed promising results specially in
patients with corneal melting and impending perforation.
Corneal melting has been arrested and complete
epithelialization achieved in several cases.
The success rate was higher for bacterial infections than fungal
Although randomized controlled trials are needed, the available
evidence supports the use of CXL in the treatment of infectious
Conjunctival flap has been
used to treat recalcitrant
The flap can bring blood
vessels to the infected
area, promote healing, and
provides a stable surface
A conjunctival flap is
particularly useful in cases
of nonhealing peripheral
corneal ulcer, where the
flap can be placed without
Therapuetickeratoplasty should be considered
in cases medically unresponsive, extensive or
full-thickness, and/or nearing perforation.
Recently, deep anterior lamellar keratoplasty
(DALK) has been suggested as an alternative to
therapeutic PK in some cases of infectious
A primary advantage of DALK in this setting is
the reduction of organism entry into the
The specimen should be submitted to
pathology and microbiology for evaluation.
Topical antibiotic therapy should be continued
Corticosteroids should be used judiciously
postoperatively with the primary goal of surgery
being eradication of infection.
Careful postoperative evaluation is required as
multiple recurrences in the graft have been
Patients with bacterial keratitis should be referred to
an ophthalmologist, because the disease has the
potential to cause visual loss or blindness.
The majority of patients can be treated on an
Patients and care providers should be educated about
the destructive nature of bacterial keratitis and the
need for strict adherence to the therapeutic regimen.
The possibility of permanent visual loss and need for
future visual rehabilitation should be discussed.
Remember: “Prevention is better than cure”
Early detection and appropriate treatment are imperative in
order to prevent permanent visual loss from bacterial keratitis.
The risk may be reduced by avoiding or correcting predisposing
For example educating them about the risks of extended-wear
lensesand the importance of adherence to techniques that
promote contact lens hygienemay reduce the incidence of
bacterial keratitis in contact lens users.
Most ocular trauma can be avoided by using protective eyewear
for sports and other high-risk activities.
Ocular surface disease such as corneal epithelial defects, severe
tear deficiency, or lagophthalmos should be treated.
Patients should be acquainted with the signs and symptoms of
infection, and be informed that they should consult an eye
specialist promptly if they experience these.