Bacterial corneal ulcers

1. Central ulcer. Predominant causes of central bacterial keratitis are Staphylococcus, e.g., S. aureus, and S.
epidermidis; Streptococcus, such as S. pneumococcus and groups AG Streptococcus; other Gram-positive organisms,
such as Bacillus and Propionibacterium sp; the Gram-negative organisms Haemophilus, Pseudomonas, and Moraxella;
and other Enterobacteriaceae (Proteus, Serratia, E. coli, and Klebsiella). Mycobacterium chelonae keratitis may follow
laser-assisted in situ keratomileusis (LASIK) surgery. Gram-negative diplococci are an uncommon cause of corneal
ulceration except in inadequately treated cases of hyperacute gonococcal conjunctivitis. Infection of the cornea usually
tends to occur after injury to the epithelium or in compromised hosts, except for Neisseria and Corynebacterium, which
may invade intact epithelium. Stromal infiltration in an area of an epithelial defect with surrounding edema and folds
associated with endothelial fibrin plaques or anterior chamber reaction is usually indicative of microbial infection.
Staphylococcal ulcers are often more localized, whereas pneumococcus may produce a shaggy undermined edge of an
ulcer that is associated with a hypopyon. A destructive keratitis with rapid necrosis and adherent mucopurulent discharge
is highly suggestive of Pseudomonas, Streptococcus, or anaerobic infection. Infectious crystalline keratopathy is an
indolent, noninflammatory branching crystalline growth commonly associated with Streptococcus viridans, but also
reported with Peptostreptococcus sp, S. epidermidis, H. influenzae, and two fungal species. There is also often a history
of local ocular trauma, contact lens use, steroid use, and/or chronic antibiotic administration. Response to antibiotic
therapy is very slow and may fail. Surgical intervention with neodymium:yttrium, aluminum, garnet (Nd:YAG) laser
disruption, e.g., 3.2 mJ 30, creates diffuse haze of the protective glycocalyx matrix within the intrastromal crystals
making the bacteria drug-susceptible. This should be considered before more extensive surgical steps are taken.
2. Marginal ulcers. Ulceration with superficial white infiltrates in the corneal periphery is seen most commonly with
staphylococcal bacterial disease. There is concurrent blepharoconjunctivitis. The ulceration may be caused by
hypersensitivity reaction, because culture of the ulcer is often sterile. The ulceration must be distinguished from Mooren
ulcer and the peripheral ulceration seen with collagen vascular diseases such as rheumatoid arthritis. Moraxella sp has
been described as producing ulcers that extend to the limbus, especially inferiorly.
3. Laboratory tests are similar to those for hyperacute conjunctivitis (see sec. III.C., above) apply also to bacterial corneal
disease.
a. Cultures are performed after instillation of topical proparacaine 0.5% (tetracaine, benoxinate, and cocaine are more
likely to interfere with recovery of the organisms) and should obtain as much material as feasible, particularly from
the deeper areas and the margin of the ulcer, using a sterile broth or saline-moistened calcium alginate or dacron
rayon swab. Organism recovery is much higher when alginate swabs are used rather than spatulas. Cultures are
done on meat broth, blood agar plates (at room temperature and 38C), chocolate agar, thioglycolate broth, and
Sabouraud agarbroth (fungus), and Page medium (Acanthamoeba), if suspected. Scrapings taken from a
nonnecrotic area may be examined microscopically with Gram and Giemsa stains. Because 30% to 40% will be
negative even if infection is present, these scrapings may be judiciously omitted.
b. Corneal biopsy is often diagnostic in cases that progress despite seemingly adequate treatment; even if an
organism has been identified, another may have been missed. In the minor operating room or at the slitlamp, after
local anesthesia (drops or xylocaine block), a 2 to 3 mm sterile disposable dermatologic trephine is advanced to
partial depth into the anterior corneal stroma, taking both clinically infected and adjacent clear cornea. The base is
then undermined with a surgical blade to complete the lamellar keratectomy.
4. Initial treatment is based on clinical impression and results, if any, of the scraping. Coverage should be broad,
intensive, and amenable to change when final culture and sensitivity reports are available. Contact lens wearers with
central corneal ulcers should particularly be covered for Pseudomonas (tobramycin, netilmicin, and/or a quinolone).
Antibiotic treatment of infectious corneal ulcers must be aggressive using fortified solutions, and patients should be kept
under close observation to prevent serious scarring or frank perforation. Initial antibiotic therapy may be guided by the
results of the Gram stain of the corneal scraping, but broad-spectrum therapy should be used ( see Table 5.5, Table 5.6,
and Table 5.7 and Appendix B for detailed lists of drug indications, dosage, and routes of administration).
a. Gram-positive cocci. In mild to moderate infections, frequent topical therapy alone may be used, but it may be
advisable to give subconjunctival therapy as well in severe infections, or apply a collagen contact lens soaked 10
minutes in fortified antibiotic solution (see sec. IV.B.6.).
1. fortified cephalosporinaminoglycoside therapy is common. Topical cefazolin solution, 100 mg per mL, should be
used q1min for 5 doses to achieve high stromal levels quickly and then q60min 24 hours per day or 16 times per day
with a polymyxinbacitracin ointment HS depending on severity of disease. Tobramycin is often effective against
Staphylococcus, but poorly effective against pneumococcus or other Streptococcus. Fortified drops of one of these
aminoglycosides are used in the same regimen as cefazolin to cover any Gram-negative organisms that may be
revealed only by culture. Vancomycin (14 to 25 mg per mL) or bacitracin (10,000 units per mL) is effective in Grampositive coccal and bacillus infections, and especially methicillin-resistant Staphylococcus, where cephalosporins
would fail. Drops are tapered over a 1- to 2-week period to qid for 3 weeks more as indicated. For methicillinresistant organisms, vancomycin is the drug of choice.
2. Single-agent broad-spectrum drops of the quinolones, (ciprofloxacin, ofloxacin, levofloxacin, or norfloxacin) are
commercially available. More severe ulcers should probably be treated at least initially with double agents (sec.
IV.B.), but either quinolone may be substituted when the situation is under control and organism(s) known.
Organisms covered are similar to those for cefazolin or vancomycin and an aminoglycoside, and include the
microbes listed in sec. III.B.1., above.
3. Subconjunctival therapy is usually used only in severe cases, or for uncooperative or unreliable patients. Because a
10% cross sensitivity between cephalosporins and penicillin has been reported in penicillin-allergic patients, it is
usually safer to proceed with vancomycin therapy. Subconjunctival injections are painful and are best preceded by
topical anesthetic (or general anesthetic when treating children) and adequate postinjection analgesics.

b. Gram-negative cocci (N. meningitidis, N. gonorrhoeae) and Haemophilus require systemic and topical therapy and are
discussed under hyperacute conjunctivitis (see sec. III.D.2., above). Topical therapy should be q1h for 2 to 4 days with
taper over 2 to 4 weeks.hyperacute conjunctivitis (see sec. III.D.2., above). Topical therapy should be q1h for 2 to 4 days
with taper over 2 to 4 weeks.
c. Gram-positive rods. These uncommon agents of ocular infection usually respond to systemic penicillin (see Appendix
B). Bacillus sp are susceptible to moderate doses of penicillin; clostridial organisms require higher doses. Bacillus cereus
infections may be extremely hard to treat, even using gentamicin, ofloxacin, norfloxacin, ciprofloxacin, or clindamycin.
Topical drops and subconjunctival injections are used q1h. Tetracycline topically and orally is a useful adjunctive.
d. Gram-negative rods
1. Topical therapy initially should be fortified tobramycin ophthalmic solution q1min for 5 doses, then q60min for 3 to 6
days before starting slow taper. Important adjunctive therapy is topical ticarcillin 6 mg per mL, or carbenicillin 4 mg
per mL, q60min. Treat Pseudomonas at least 1 month or rebound infection may occur. Aminoglycoside-resistant
strains are increasing. If Pseudomonas is gentamicin-resistant, a quinolone drop should be coupled with ticarcillin or
carbenicillin, as above. If the strain is quinolone-resistant, amikacin is often effective.
2. Subconjunctival therapy, if used, should include tobramycin or amikacin 40 mg, and carbenicillin 100 mg, each
injected in a different area of the conjunctiva.
e. Anaerobic Gram-positive filaments (Actinomyces, Nocardia [formerly Streptothrix]) are sensitive to penicillins and
tetracyclines.
f. Mycobacterium chelonae ulcers are treated with a combination of topical amikacin (50 mg per mL, commercial
ciprofloxacin, and either clarithromycin (10 mg per mL) or azithromycin (2 mg per mL) hourly around the clock to start
with, then taper over weeks. Oral doxycycline 100 mg bid is additive therapeutically.
g. When no organisms are identified, but bacterial etiology is strongly suspected on clinical grounds:
1. Topical therapy should be with fortified cefazolin q1min for 5 doses, then coupled with tobramycin 14 mg per mL q60
min, for 36 days before taper over 46 weeks. Use vancomycin in severe cases and suspected methicillin-resistant
or penicillin-allergic patients.
2. Subconjunctival therapy, if used, should be cefazolin 100 mg, plus tobramycin 40 mg, until culture results are
available. A fortified-antibiotic-soaked collagen lens (see sec. IV.B.6.) may also be effective adjunctively.
h. Systemic antibiotics are used if there is scleral extension of the infection or a threatened perforation. Levofloxacin 500
mg p.o. q24h or ofloxacin 200 to 400 mg p.o. q12h for 7 days both have excellent aqueous and vitreous penetration after
oral dosing. A cephalosporin or vancomycin and an aminoglycoside may also be used p.o. or i.v., with doses given as in
Appendix B. In cases of vancomycin resistance, which is an emerging problem, linezolid 600 mg i.v. or p.o. q12h may be
indicated. Table 5.5, Table 5.6 and Table 5.7, and Appendix B summarize the recommended therapy. Therapy may be
refined when culture and sensitivities return.
i. The antibiotic regimen is altered, if necessary, when final culture and sensitivity information is available. Fortified
vancomycin and bacitracin are used if methicillin-resistant staphylococci are recovered. In the event that a suspected
Gram-negative coccus infection was initially treated with penicillin and the subsequent culture results disclose
Acinetobacter sp, penicillin should be discontinued because these organisms are often not sensitive to penicillin.
5. Other treatment modalities
a. Dilation. Long-acting cycloplegics such as atropine 1% or scopolamine 0.25% should be used if significant anterior
chamber reaction is present. Initial instillation is usually required at least three times a day. If significant synechiae
are forming at the pupillary margin, one or two doses of topical 2.5% phenylephrine are often indicated to ensure
mobility of the pupil.
b. Corticosteroid use in treatment of infectious corneal ulcers is less controversial than in past years. It is probably
unwise to use steroids until at least 24 to 48 hours of antibacterial treatment has been completed, or until the
etiologic agent has been identified and shown to be sensitive to the antibiotics being used. Corticosteroid use is
contraindicated if fungus is at all suspected. Low-dose topical corticosteroids (e.g., prednisolone 0.12% qid) have a
place in limiting the inflammatory reaction once the clinician is satisfied that the antibiotic treatment is effective.
6. Collagen shields (Surgilens, Bausch & Lomb), are contact lenses initially developed to enhance corneal epithelial
healing after surgery, trauma, or dystrophic erosions and filaments, but are also used as effective high-dose drug delivery
systems (the lenses are not FDA approved as drug delivery systems). The lenses come in two sizes and dissolve
spontaneously over 24 to 72 hours. Soaking the lenses in antibiotics, such as tobramycin 40 mg solution for 10 minutes,
results in a 30-fold increase in antibiotic penetration into the aqueous compared to subconjunctival injection or a regular
therapeutic soft contact lens (TSCL) and q1h drops. The high level of drug may be maintained with q4h drops using the
collagen shields.
7. Special pediatric considerations. Subconjunctival therapy is usually not feasible unless the child is under general
anesthesia at the time of a corneal culture and scraping. Should systemic medication be considered necessary, it is best
done with the consultation of a pediatrician or internist. See Appendix B for dosages and organism indications.

ULKUS KORNEA-WILLS
Symptoms
Red eye, mild-to-severe ocular pain, photophobia, decreased vision, discharge.
Critical Signs
Focal white opacity (infiltrate) in the corneal stroma. An ulcer exists if there is also stromal loss with an overlying
epithelial defect that stains with fluorescein.
Note An examiner using a slit beam cannot see through an infiltrate/ulcer to the iris, whereas stromal edema and
inflammation are more transparent.
Other Signs
Conjunctival injection, corneal thinning, stromal edema and inflammation surrounding the infiltrate, folds in Descemets
membrane, anterior-chamber reaction, hypopyon, mucopurulent discharge, upper eyelid edema. Posterior synechiae,
hyphema, and glaucoma may occur in severe cases.
Etiology
Bacterial (Most common infectious etiology. In general, corneal infections are assumed to be bacterial until proven
otherwise by laboratory studies or until a therapeutic trial is unsuccessful.)
Fungal [Must be considered after any traumatic corneal injury, particularly from vegetable matter (e.g., a tree
branch). Infiltrates commonly have feathery borders and may be surrounded by satellite lesions. Candida infections
tend to occur in diseased eyes. Hyphae or yeast may be evident on Giemsa stain, although they are also seen with
Gomori methenamine silver stain. Most fungi grow on Sabourauds dextrose agar. See Section 4.13, Fungal
Keratitis.]
Acanthamoeba [An extremely painful stromal infiltrate usually in a soft contact lens wearer who practices poor lens
hygiene or has a history of swimming while wearing contact lenses. In the late stages, the infiltrate becomes ringshaped. Acanthamoeba cysts may be seen with periodic acidSchiff (PAS), Giemsa stain, or calcofluor white. This
fastidious organism requires nonnutrient agar with Escherichia coli overlay for culture. See Section 4.14,
Acanthamoeba.]
Herpes simplex virus (HSV) (May have eyelid vesicles or corneal epithelial dendrites. A history of recurrent eye
disease or known ocular herpes is common. Patients with chronic herpes simplex keratitis may develop bacterial
superinfections. See Section 4.15, Herpes Simplex Virus.)
Atypical mycobacteria (Usually follows ocular injuries or corneal grafts. Culture plates must be kept for 8 weeks.)
Differential Diagnosis

Sterile ulcer (Not infectious; dry-eye syndrome, rheumatoid arthritis or other collagen-vascular diseases, vernal
keratoconjunctivitis, neurotrophic keratopathy, vitamin A deficiency, others. Cultures are negative, anterior-chamber
inflammation is minimal to none, and the eye may be white and comfortable.)
Staphylococcal hypersensitivity [Peripheral corneal infiltrate(s), sometimes with an overlying epithelial defect, usually
multiple, often bilateral, with a clear space between the infiltrate and the limbus. There is minimal-to-no anteriorchamber reaction. Often with coexisting blepharitis. See Section 4.22, Staphylococcal Hypersensitivity.]
Sterile corneal infiltrates from an immune reaction to contact lenses or solutions (Generally, multiple, small
subepithelial infiltrates with an intact overlying epithelium and minimal-to-no anterior-chamber reaction. Usually a
diagnosis of exclusion after ruling out an infectious process.)
Residual corneal foreign body or rust ring (May be accompanied by corneal stromal inflammation, edema, and
sometimes, a sterile infiltrate. There may be a mild anterior-chamber reaction. The infiltrate and inflammation
generally clear after the foreign body is removed.)

Workup
a.
b.
c.
d.

History: Contact lens wear and lens-care regimen? Swim with lenses? Trauma or corneal foreign body? Eye care
before visit (e.g., antibiotics or topical steroids)? Previous corneal disease? Systemic illness?
Slit-lamp examination: Stain with fluorescein to determine if there is epithelial loss overlying the infiltrate; document
the size, depth, and location of the corneal infiltrate; assess the anterior-chamber reaction; and measure the
intraocular pressure (IOP).
Corneal scrapings for smears and cultures are performed as described later for infiltrates considered to be infectious
and for all ulcers. Small, nonstaining infiltrates are sometimes treated empirically with regular-strength broadspectrum antibiotics without prior scraping.
In contact lens wearers suspected of having an infectious ulcer, the contact lenses and case are cultured if at all
possible. Explain to the patient that the cultured contact lenses can never be worn again.

Culture Procedure
EQUIPMENT
Slit lamp; sterile Kimura spatula, knife blade, or moistened calcium alginate swab (i.e., with thioglycolate or trypticase soy
broth); culture media; microscopy slides; alcohol lamp.
PROCEDURE
Anesthetize the cornea with topical drops (proparacaine is best, as it appears to be less bacteriocidal than others.)

At the slit lamp, scrape the base and the leading edge of the infiltrate firmly with the spatula, blade, or swab, and place
the specimen on the culture medium or slide. Sterilize the spatula over the flame of the alcohol lamp between each
separate culture or slide. Be certain that the spatula-tip temperature has returned to normal before touching the cornea
again.
MEDIA
Routine:
Blood agar (most bacteria)
Sabourauds dextrose agar without cyclohexamide; place at room temperature (fungi)
Thioglycolate broth (aerobic and anaerobic bacteria)
Chocolate agar; place into a CO2 jar (Haemophilus species, Neisseria gonorrhoeae)
Optional:
LowensteinJensen medium (mycobacteria, Nocardia species)
Nonnutrient agar with E. coli overlay (acanthamoeba)
Trypticase soy broth
SLIDES
Routine:
Grams stain (bacteria, fungi)
Giemsa stain (bacteria, fungi, acanthamoeba)
Optional:
Gomori methenamine silver stain, PAS stain (acanthamoeba, fungi)
Acid-fast stain (mycobacteria, Nocardia species)
Calcofluor white; a fluorescent microscope is needed (acanthamoeba, fungi)
Note When a fungal infection is suspected, deep scrapings into the base of the ulcer are essential. Sometimes a corneal
biopsy is necessary to obtain diagnostic information.
Treatment
a. As mentioned earlier, ulcers and infiltrates are generally treated as bacterial initially unless there is a high index of
suspicion of another form of infection (see Fungal Keratitis, Section 4.13; Acanthamoeba, Section 4.14; and Herpes
Simplex Virus, Section 4.15).
a.
b.
a.

Cycloplegic (e.g., scopolamine, 0.25%, t.i.d., or atropine, 1%, t.i.d.).

Topical antibiotics according to the following algorithm:
Low risk of visual loss
i. Small nonstaining peripheral infiltrate with at most minimal anterior-chamber reaction and minimal
discharge:
ii. Noncontact lens wearer Broad-spectrum topical antibiotics (e.g., polymyxin B/bacitracin ointment
q.i.d. or fluoroquinolone [ciprofloxacin or ofloxacin] drops q 2 to 6 h).
iii. Contact lens wearer Tobramycin or fluoroquinolone (ciprofloxacin or ofloxacin) drops q 2 to 6 h;
can add tobramycin or ciprofloxacin ointment qhs.

b.

Borderline risk
o Medium (1- to 1.5-mm diameter) peripheral infiltrate, or any smaller infiltrate with an associated
epithelial defect, mild anterior chamber reaction, or moderate discharge:
o

c.

b.
c.
d.
e.
f.

Fluoroquinolone (ciprofloxacin or ofloxacin) every hour around the clock.

Vision threatening
Large (>1.5-mm diameter) staining infiltrate/ulcer, or any infiltrate with moderate-to-severe
anterior-chamber reaction, purulent discharge, or involving the visual axis:
Fortified tobramycin or gentamicin (15 mg/ml) every hour alternating with fortified cefazolin (50
mg/ml) or vancomycin (25 mg/ml) every hour. (This means that the patient will be placing a drop in
the eye every one-half hour around the clock.) (See Appendix 9 for directions on making fortified
antibiotics.)
An alternative choice for smaller (<1.5 mm), peripheral staining infiltrates/ulcers is intensive topical
fluoroquinolone therapy (ciprofloxacin or ofloxacin) 1 drop every 5 minutes for 3 doses, then every
15 minutes for 2 to 6 hours, then every 30 minutes around the clock.

Consider subconjunctival antibiotics [e.g., gentamicin (20 to 40 mg) and cefazolin (100 mg) or vancomycin (25 mg)]
in very severe cases or when fortified antibiotics cannot be started within a short time. (See Appendix 7 for the
injection technique.)
Eyes with corneal thinning should be protected by a shield without a patch (a patch is never placed over an eye
thought to have an infection).
No contact lens wear.
Oral pain medication as needed (e.g., acetaminophen with or without codeine).
Oral fluoroquinolones (e.g., ciprofloxacin, 500 mg p.o., b.i.d.) penetrate the cornea well, and these may have added
benefit for patients with scleral extension of infection or extremely deep ulcerations.

g.

h.

Admission to the hospital may be necessary if:

There is a sight-threatening infection.
The patient is unable to give him or herself the antibiotics at that frequency without difficulty.
There is a likelihood of noncompliance.
The patient is unable or unwilling to return daily.
Systemic antibiotics are needed (e.g., corneal perforation, scleral extension of the infection, gonococcal or
Haemophilus infection)
For atypical mycobacteria, consider amikacin, 10 mg/ml drops, q 2 h for 1 week and then q.i.d. for 2 months
(kanamycin or cefoxitin may be substituted).

Follow-up
Daily evaluation at first, including repeated measurements of the size of the infiltrate and ulcer. The most important
criteria in evaluating the response to treatment include the degree of eye pain, the size of the epithelial defect over the
infiltrate, the size and depth of the infiltrate, and the anterior-chamber reaction. Less pain, a smaller epithelial defect and
infiltrate, and a less-inflamed eye are all favorable responses. The IOP must be checked and glaucoma treated if present
(see Section 10.4, Inflammatory Open-Angle Glaucoma).
If the ulcer is improving, the antibiotic regimen is gradually tapered. Otherwise, the antibiotic regimen is adjusted
according to the culture and sensitivity results.
If the infiltrate or ulcer was not cultured originally and subsequently worsens, cultures, stains, and treatment with fortified
antibiotics are needed. Hospitalization is considered.
Reculture the ulcer (with the addition of optional media and stains) if it does not seem to be responding to the current
antibiotic regimen and the original cultures are negative.
A corneal biopsy may be required if the condition is worsening and infection is still suspected despite negative cultures.
In an impending or completed corneal perforation, a corneal transplant or patch graft is considered. Cyanoacrylate tissue
glue may also work in a treated corneal ulcer.
Note Outpatients are told to return immediately if the pain increases or the vision decreases.