2. DR DINESH MITTAL DR SONALEE MITTAL
DRISHTI EYE HOSP VIJAYNAGAR INDORE
3. Normal Ocular Flora
• Bacterial colonization of the eyelid margin and conjunctiva is
normal and can be beneficial by competitively inhibiting
pathogenic strains. The spectrum of normal ocular flora varies
with the age and geographic locale of the host. In the eye of an
infant delivered vaginally, multiple bacterial species
predominate, including Staphylococcus aureus, Staphylococcus
epidermidis, streptococci, and Escherichia coli; streptococci and
pneumococci predominate during the first 2 decades of life.
4. Normal Ocular Flora
• Although gram-negative bacteria become more commonly isolated
over time, S epidermidis and other coagulase-negative
staphylococci, S aureus, and diphtheroids remain some of the most
common species . Nonpathogenic colonization of the eyelid margin
with Demodex folliculorum and Demodex brevis also becomes
more common with age, with these parasites becoming almost
ubiquitous. The use of topical antibiotics or corticosteroids for
conditions such as ocular surface disease may alter the spectrum
of eyelid and conjunctival flora.
5.
6.
7.
8.
9. Few bacteria can overcome intact
epithelium
• Few bacteria can overcome intact epithelium. Those that can,
include
• Neisseria gonorrhoeae
• Neisseria meningitidis
• Corynebacterium diphtheriae
• Shigella spp
• Haemophilus influenzae biotype III (formerly Haemophilus
aegyptius)
• Listeria monocytogenes
10.
11.
12.
13.
14.
15.
16. Pseudomonas keratitis with soft contact lens. A
paracentral corneal infiltrate with surrounding corneal
edema and hypopyon
17. Culture of contact lens from a pt with Pseudomonas keratitis.
Confluent growth of Pseudomonas around contact lens on a
blood agar plate
19. • Pearly-white colonies of
Staphylococcus aureus in C
streaks on a blood agar plate
from a corneal ulcer.
Diminishing numbers of
colonies are noted in the
consecutive C streaks,
indicating the organisms are
from bona fide infection rather
than contamination of the
plate
20. A large peripheral corneal ulcer of Staphylococcus aureus with
several smaller infiltrates in a pt with marked blepharitis.
21. • A Streptococcus pneumoniae
corneal ulcer in an
immunocompromised patient
with deep stromal infiltrates
and dense hypopyon
24. Bacteriology
• A basic understanding of bacteriology is important in the diagnosis of
external eye infections and for effective, appropriate use of antibiotics.
Bacteria are prokaryotes, defined as organisms in which the genetic
material is not separated from the cytoplasm by a nuclear membrane.
Rather, DNA, RNA, and protein in an amorphous matrix are enclosed in a
single cytoplasmic compartment without membrane-bound cellular
organelles, surrounded by a plasma membrane. Most bacterial genes
exist as part of a single circular chromosome, but some are present on
smaller extrachromosomal circles called plasmids, which typically
determine inheritance of 1 or a few characteristics. Plasmid DNA is
passed between bacterial strains and species more easily than is
chromosomal DNA and represents an important mechanism in the rapid
proliferation of mutations such as antibiotic resistance
25. Bacteriology
• Classification of bacteria is based on microscopic morphology
(round or elongated) and colony morphology, enzyme activity,
biochemical tests, DNA fingerprinting, and genomic sequence
(when known).
• The prokaryote cell wall imparts shape and rigidity to the cell and
also mediates interactions with other bacteria, bacterial viruses,
and the environment, including therapeutic drugs. The reaction of
a bacterium to the Gram stain classifies the bacterial cell wall as
either gram-positive (blue) or gram negative (red) and provides
critical information on the structure and biochemical composition of
the cell wall that can be predictive of the bacteria’s antibiotic
susceptibility .
26. Bacteriology
• Thick gram positive bacterial cell walls contain predominantly
peptidoglycan, the primary target of penicillin, and teichoic acid,
whereas gram-negative cell walls have a thin peptidoglycan
layer that is covered by an external lipopolysaccharide
membrane (endotoxin), which excludes certain antibiotics.
Some bacteria stain poorly with Gram stain, including
Mycobacteria and Nocardia asteroides, but they can be
visualized with acid-fast stain.
42. Introduction
• 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 corneal tissue. It is a potentially sight-
threatening condition and frequently presents as an ocular
emergency. However, it is often challenging to distinguish
microbial keratitis from other noninfectious or inflammatory
corneal conditions resulting from trauma or immune-mediated
reactions. 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.
43. Introduction
• predisposing factors including contact lens wear, trauma,
corneal surgery, ocular surface disease, systemic diseases, and
immunosuppression may alter the defense mechanisms of the
ocular surface and permit bacteria to invade the cornea. There
are no specific clinical signs to help confirm a definite bacterial
cause in microbial keratitis, but clinicians should identify the risk
factors for ocular infection and assess the distinctive corneal
findings to determine potential etiologies .
44. Introduction
• When there is strong suspicion for a possible infectious
keratitis, laboratory investigations should be considered in order
to identify and confirm the causal organisms. Based on the
clinical and laboratory findings, a therapeutic plan can then be
initiated.[2] It is sometimes necessary to modify the therapeutic
plan based on clinical response and tolerance of the
antimicrobial agents. The goals for treating bacterial keratitis
are to treat the corneal infection and associated inflammation,
and to restore corneal integrity and visual function.
45. Introduction
• Medical therapy with appropriate antibiotics is the mainstay of
treatment. The outcome usually depends on the preceding
pathology and the extent of ulceration at the time of
presentation. Surgery may be considered if medical therapy
fails to eradicate the pathogens or if the vision is markedly
threatened by the infection or resultant scar.
46.
47. Natural History
• While some bacteria (e.g. Gonococcus) can invade an intact corneal
epithelium, most cases of bacterial keratitis develop at the site of an
epithelial abnormality or defect in the corneal surface. The rate of
disease progression is dependent on the virulence of the infecting
organism and on host factors. For example, highly virulent
organisms such as Pseudomonas, Streptococcus pneumoniae, or
Gonococcus cause rapid tissue destruction, while other organisms
such as nontuberculous Mycobacterium and Streptococcus viridans
are usually associated with a more indolent keratitis. Some bacteria
that are considered to be normal conjunctival flora (e.g.
Corynebacterium) may become opportunistic pathogens in the
compromised eye.
48. Natural History
• Bacterial keratitis can occur in any part of the cornea, but
infections involving the central cornea have a worse prognosis.
Scarring in this location is likely to cause visual loss, even if the
causal organism is successfully eradicated. Untreated or severe
bacterial keratitis may result in corneal perforation and has the
potential to develop into endophthalmitis and result in loss of
the eye. Because the destruction of corneal tissues can take
place rapidly (within 24 hours by a virulent organism), optimal
management requires rapid recognition, timely institution of
therapy, and appropriate follow-up.
49. Presentation
• The clinical signs and symptoms of microbial keratitis are
variable and they depend on the virulence of the organism,
duration of infection, pre-existing corneal conditions, immune
status of the host, and previous use of antibiotics or
corticosteroids. Severe bacterial keratitis usually has a history
of rapid onset of pain, photophobia, decreased vision,
conjunctival injection, anterior chamber reaction, and/or
hypopyon. However, keratitis caused by nontuberculous
Mycobacterium may present with an insidious onset or indolent
course. The clinical findings usually cannot readily distinguish
the causing organism.
50. Presentation
• Nonetheless, clinical diagnosis is possible when a pertinent
history is available or the organisms present with characteristic
features, such as a rapidly progressive stromal necrosis with
mucopurulent discharge in Pseudomonas aeruginosa keratitis
in a young patient with extended contact lens wear. However,
many microorganisms such as fungi or Acanthamoeba can
cause masquerading syndromes mimicking bacterial keratitis
51.
52.
53.
54.
55.
56.
57.
58. DIAGNOSIS
• The presumptive diagnosis of infectious keratitis is based primarily on
the clinical history and physical examination, but confirmation of
infectious infiltration and definitive identification of the offending
organism can be achieved only by examining stained smears of
corneal scrapings and laboratory cultures of these scrapings. In
practice, specific identification of the offending organism and antibiotic
sensitivity data are necessary only insofar as they advise modification
of antibiotic treatment if the initial antibiotic regimen fails.
59. DIAGNOSIS
• Since approximately 95% of suspected bacterial ulcers respond
favorably to a well-chosen initial antibiotic regimen, treatment
modification is rarely necessary. Many practitioners therefore defer
diagnostic stains and cultures for selected cases of suspected bacterial
keratitis. There is some evidence that small infiltrates that are not
associated with advanced suppuration or severe intraocular
inflammation respond favorably to this approach. There is no debate
that scrapings are mandatory if the infection is advanced or central, or if
history or examination is at all suggestive of filamentous bacterial,
nontuberculous mycobacterial, gonococcal, mycotic, or protozoal
infection .
60.
61.
62.
63.
64.
65.
66.
67. Corneal Infections
• There are four basic classes of organisms responsible for
infectious keratitis: bacterial, viral, fungal and parasitic.
Whenever possible, the exact diagnosis should be established
by direct examination of corneal material and/or culture
techniques. However, the clinical appearance of some of these
disorders can establish a definitive diagnosis (e.g., herpes
simplex epithelial keratitis) or guide treatment until the exact
diagnosis is known
69. (A) Different
instruments can be
used to collect
corneal specimens.
Because corneal
infiltrates are often
small, care must be
taken to obtain an
adequate specimen.
70. (B) A conjunctival culture can be obtained
with a cotton-tipped applicator
89. Laboratory Investigations
• Cultures and smears
• Laboratory investigations of microbial keratitis include corneal
scraping to obtain specimens for microbiological stainings and
cultures to isolate the causative organism and determine
sensitivity to antibiotics. The majority of community-acquired
cases of bacterial keratitis resolve with empirical therapy and
are managed without smears or cultures. 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 mycobacterial keratitis.
90. Laboratory Investigations
• 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. The
hypopyon that occurs in eyes with bacterial keratitis is usually
sterile and aqueous or vitreous taps should not be performed in
order to avoid intraocular inoculation of the microorganisms,
unless there is a high suspicion of microbial endophthalmitis.
91. Culture
• Obtaining corneal materials for microbial culture is most easily
performed with slit lamp magnification under topical anesthesia.
Proparacaine hydrochloride 0.5% is the preferred anesthetic
agent because of its minimal inhibitory effects on organism
recovery. Use of other topical anesthetics, such as tetracaine,
may significantly reduce organism recovery due to their
bacteriostatic effects. Culture yield may be improved by
avoiding anesthetics with preservatives .
92. Culture
• Corneal material is obtained by scraping corneal tissues from
the advancing borders of the infected area using either a wet
Dacron/calcium alginate or sterile cotton swab, a heat-sterilized
platinum (Kimura) spatula, a No. 15 Bard-Parker blade, a
jeweler's forceps, a large-gauge disposable needle, or a Mini-tip
Culturette. A small trephine may be necessary to obtain an
adequate corneal biopsy specimen for ulcers with primary deep
stromal involvement.
93. Culture
• Multiple samples from the advancing borders of representative
areas of the ulcer are often required to achieve maximal yield of
organisms. Obtaining only purulent material usually results in
inadequate yield. Corneal specimens obtained from corneal
scrapings are usually small in quantity and should be inoculated
directly onto appropriate culture media in order to maximize
culture yield . If this is not feasible, specimens should be placed
into a broth culture medium prior to transportation. This has
been reported to generate satisfactory yields of causative
organisms. Cultures of contact lenses, lens case, and contact
lens solution may provide additional information to guide
therapy.
94.
95. Stains
• Microbial pathogens may be categorized by examining stained
smears of corneal scrapings. The material for smear is applied
to a clean glass microscope slide in an even, thin layer for
microbial staining . Immersion of the slide in methanol 95% or
cold acetone in a Coplin jar for 5 to 10 minutes is preferable to
heat fixation because this preserves a better morphology of
cells and microorganisms.
96. Gram stain
• Gram stain is used routinely to stain the corneal specimens.
This stain can confirm the presence of a microorganism with a
sensitivity of 55–79%. It can also distinguish bacteria from fungi.
• Gram-positive bacteria retain the gentian violet–iodine complex
and appear bluish-purple.
• Gram-negative bacteria lose the gentian violet–iodine complex
by decolorization with acid alcohol and appear pink when
counterstained with safranin.
97. Giemsa stain
• Giemsa stain is primarily used to distinguish the types of
inflammatory cells and intracytoplasmic inclusions, and can
distinguish bacteria from fungi. Bacteria appear dark blue and
fungi appear purple or blue. Acanthamoeba and Chlamydia
inclusion bodies may be identified with Giemsa stains .
98. Acridine orange stain
• Acridine orange stain is also a useful screening test. It is a
fluorochromatic dye that binds to ribonucleic acid. Microorganisms
fluoresce orange whereas epithelial cells and polymorphonuclear
leukocytes fluoresce green. An epifluorescence microscope is
needed to visualize organisms and cells. The organisms that can be
visualized by acridine orange include bacteria, fungi, Acanthamoeba,
and Mycobacterium (weakly staining). The acridine orange stain
accurately predicts culture results in 71–84% of the cases and has
been reported to be more sensitive than Gram stain. Calcofluor
white, another fluorochromatic dye, binds to chitin and cellulose in
the cell wall of fungi and Acanthamoeba cysts. These organisms
stain bright green under epifluorescence microscopy.
101. Cephalosporins
• Like penicillins, cephalosporins contain a β-lactam ring that is
necessary for bactericidal activity. The nucleus of
cephalosporins is 7-aminocephalosporanic acid, which is
resistant to the action of penicillinases produced by
staphylococci.
• Cefazolin, with an excellent activity against Gram-positive
pathogens and minimal toxicity after topical administration, has
been the most commonly used first-generation cephalosporin
for bacterial keratitis. It is most frequently used in combination
with other agents against Gram-negative bacteria to provide a
broad spectrum of coverage for polymicrobial keratitis, or if the
causative organisms are unknown.
102. Cephalosporins
• Ceftazidime is a third-generation cephalosporin with
antipseudomonal activity. It is used in Pseudomonas keratitis
with resistance to aminoglycosides or fluoroquinolones.
Ceftazidime also has some activity against Gram-positive
organisms.
• Topical β-lactam antibiotics have never been available
commercially because they are somewhat unstable in solution
and tend to break down in days or weeks. A fresh preparation
must be provided every 4–5 days.
103. Glycopeptides
• Vancomycin is a glycopeptide antibiotic with activity against
penicillin-resistant staphylococci. Its bactericidal effect is related
to the inhibition of biosynthesis of peptidoglycan polymers
during bacterial cell wall formation. It is primarily active against
Gram-positive bacteria and remains one of the most potent
antibiotics against methicillin-resistant S. aureus and
coagulase-negative staphylococci.
104. Glycopeptides
• Vancomycin should be reserved for cephalosporin-resistant
staphylococci. Streptococci (including penicillin-resistant
strains) are also highly susceptible to vancomycin. Vancomycin
has excellent activity against a variety of other Gram-positive
bacilli including Clostridium, Corynebacterium, Bacillus, L.
monocytogenes, Actinomyces, and Lactobacillus.
105. Aminoglycosides
• Aminoglycosides have a selective affinity to the bacterial 30-S
and 50-S ribosomal subunits to produce a nonfunctional 70-S
initiation complex that, in turn, facilitates the inhibition of
bacterial protein synthesis. Aminoglycosides have a bactericidal
effect against aerobic and facultative Gram-negative bacilli.
However, there is emergence of Pseudomonas resistance to
gentamicin, tobramycin, and to a lesser extent, amikacin.
106. Aminoglycosides
• For severe Pseudomonas keratitis, aminoglycosides may be
combined with an antipseudomonal cephalosporin. For
Nocardia keratitis, amikacin has also been reported to be
effective and remains the drug of choice. Although commercially
prepared aminoglycosides are adequate for mild to moderate
keratoconjunctivitis, many ophthalmologists prefer to use more
concentrated preparations for severe bacterial keratitis .
107.
108.
109. Macrolides
• Macrolides such as erythromycin inhibit bacterial protein synthesis
by reversibly binding to the 50-S ribosomal subunit, thereby
preventing elongation of the peptide chain in susceptible bacteria.
Erythromycin has a relatively broad spectrum of activity, especially
against most Gram-positive and some Gram-negative bacteria. S.
pneumoniae and S. pyogenes are both highly susceptible to
erythromycin with occasional resistant strains. Erythromycin also has
generally good activity against most S. viridans and anaerobic
streptococci. It has variable activity against Enterococcus,
Actinomyces, Nocardia, Chlamydia, and certain nontuberculous
mycobacteria. Many S. aureus and coagulase-negative
staphylococci are susceptible, although there may be increasing
resistance. Most strains of N. gonorrhoeae and N. meningitides are
susceptible to erythromycin. Many strains of H. influenzae are only
moderately susceptible.
110. Macrolides
• Erythromycin ointment is one of the best-tolerated and least toxic
topical ophthalmic antibiotics, commonly used for blepharitis.
However, its penetration into the cornea is suboptimal secondary to
its relative lack of solubility and bioavailability.
• Newer macrolides including azithromycin, clarithromycin, and
roxithromycin have higher tissue levels and are more favorable for
treating intracellular pathogens, including C. trachomatis and
nontuberculous mycobacteria. Topical suspensions of clarithromycin
and azithromycin have been used to treat of nontuberculous
mycobacterial infections. Because of their poor solubility and limited
corneal penetration, topical preparations of these newer macrolides
may have a limited role for bacterial keratitis.
111. Fluoroquinolones
• The bactericidal action is due to inhibition of bacterial DNA
gyrase and topoisomerase IV, which are enzymes essential for
bacterial DNA synthesis. The second and third generation of
fluoroquinolones, such as ciprofloxacin, ofloxacin, and
levofloxacin, are commercially available for ophthalmic use and
have similar antimicrobial spectra, including most Gram-
negative and some Gram-positive bacteria.
112. Fluoroquinolones
• Among those pathogens tested, Streptococcus pneumoniae
was noted to respond less to fluoroquinolone than to
conventional fortified cefazolin. Other organisms that responded
less favorably to fluoroquinolone monotherapy include S.
viridans, anaerobic Streptococcus in crystalline keratopathy,
methicillin-resistant Staphylococcus aureus, non-aeruginosa
Pseudomonas, and anaerobes.
113. Fluoroquinolones
• The wide use of fluoroquinolone monotherapy has imposed a
risk of emergence of resistant strains of microorganisms.
Increasing resistance of Pseudomonas aeruginosa and Gram-
positive organisms such as Staphylococcus aureus and
streptococcus species to fluoroquinolones has been reported.
There is also growing evidence for resistance of
Staphylococcus aureus to third-generation fluoroquinolones,
from 5.8% in 1993 to 35% in 1997.
114. Fluoroquinolones
• The latest fourth-generation fluoroquinolones such as
gatifloxacin and moxifloxacin have been developed with an
expanded antimicrobial spectrum to combat these resistant
strains. The fourth-generation fluoroquinolones have been
reported to have better coverage of Gram-positive pathogens
as compared to earlier-generation fluoroquinolones in head-to-
head in vitro studies.
115. Fluoroquinolones
• Side effects of fluoroquinolone are minimal. The incidence of
ocular discomfort for patients receiving topical fluoroquinolone
is significantly less when compared with patients receiving
fortified antibiotics (5.7% vs 13.4%). Crystalline corneal
deposits after use of ciprofloxacin, norfloxacin, and ofloxacin
have been reported. These deposits occur with higher
frequency in ciprofloxacin-treated eyes, consistent with the pH
solubility profile of fluoroquinolone compounds in that
ciprofloxacin is less soluble at physiological pH. However, these
deposits are precipitates of the antibiotics and do not appear to
diminish the antimicrobial effect.
116.
117.
118. fourth-generation fluoroquinolones
• The greater potency and resistance-thwarting capabilities of the
fourth-generation fluoroquinolones is due to strategic modifications
to the molecule that have allowed it to overcome several bacterial
defenses effectively. The third-generation fluoroquinolones only
target DNA gyrase for Gram-negative organisms and topoisomerase
IV for Gram-positive organisms. In contrast, the methoxy group
(OCH3) substitution at the eighth carbon on the basic ring of the
fourth-generation quinolones enhances their antibacterial potency.
The C8-methoxy group can tightly bind to both the bacterial enzymes
DNA gyrase and topoisomerase IV. All bacteria contain at least one
and usually both of these enzymes, which allows bacterial DNA to
supercoil during replication. The C8-methoxy fluoroquinolones block
the bacteria's ability to supercoil and cause DNA gyrase to nick
bacterial DNA.
119. Sulfonamide and trimethoprim
• Sulfonamides have a structure similar to that of para-aminobenzoic
acid (PABA). The mechanism of action is to competitively inhibit the
bacterial synthesis of folic acid. The sulfonamides are primarily
bacteriostatic at therapeutic concentrations.
• Sulfonamides are active against Gram-positive and Gram-negative
bacteria, although susceptibilities often are variable, even among
susceptible pathogens. Many bacteria become highly resistant to
sulfonamides during therapy because of chromosomal or plasmid-
mediated transference. Topical sulfonamides are not first-line
medications for most bacterial keratitis. However, they are
conventionally used for Nocardia keratitis, although a combination of
trimethoprim and sulfamethoxazole (Bactrim) is proven to be more
effective against Nocardia.
120. Sulfonamide and trimethoprim
• Trimethoprim is a 2,4-diamino-pyrimidine that also inhibits
bacterial folic acid synthesis. Trimethoprim is often combined
with a sulfonamide to produce a synergistic antibacterial effect.
Trimethoprim may be bacteriostatic or bactericidal, depending
on the clinical situation. Trimethoprim is active against many
Gram-positive cocci in vitro, although increasing resistance is
observed among staphylococci. Trimethoprim has only minimal
activity against enterococci. P. aeruginosa and most anaerobes
are resistant to it
121. clinical response to antibiotic therapy:
• blunting of the perimeter of the stromal infiltrate
• decreased density of the stromal infiltrate
• reduction of stromal edema and endothelial inflammatory
plaque
• reduction in anterior chamber inflammation
• Re epithelialization
• cessation of corneal thinning
122. progressive ulcer
• In progressive ulcer with a prior positive culture and proper
therapy, the existence of a resistant strain should be suspected.
Polymicrobial infection, which has been observed in 6–56% of
the overall cases, should also be considered. The antibiotic
sensitivity should be reevaluated and the therapy modified if
necessary. For an unresponsive keratitis on seemingly
appropriate treatment, one should consider possible drug
toxicity or underlying ocular surface problems. Promotion of
epithelial healing is the mainstay for a nonhealing sterile ulcer.
The indolent, nonhealing ulcer sometimes can be improved by
debridement of necrotic corneal stroma, frequent lubrication,
and/or temporary tarsorrhaphy
123. continuity of the epithelium
• Although disruption of the continuity of the epithelium is the most
common event that allows the establishment of a corneal infection,
a few organisms such as Corynebacterium diphtheriae,
Haemophilus aegyptius, Neisseria gonorrhoeae, Neisseria
meningitidis, and Shigella and Listeria species can penetrate an
intact epithelium. Occasionally,keratitis can be established via the
corneoscleral limbus by hematogenous spread .
124. Modification of Therapy
• The clinical response to treatment is multifactorial, taking into
account the severity of the initial clinical picture, the virulence of
the pathogen, and the presence of systemic or ocular
immunocompromise. 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. Keratitis due to Pseudomonas and other
Gram-negative organisms may exhibit increased inflammation
during the first 24 to 48 hours despite appropriate therapy
125. Modification of Therapy
• 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. The culture/sensitivity data should only
be used as a guide to modify therapy for patients with definite
worsening of the clinical findings .
126.
127. Modification of Therapy
• Progression after 48 hours of treatment implies that organisms
are not sensitive to selected agents or the patient is not
compliant. For nonresponsive cases, one should consider
stopping the antibiotics for at least 24 hours (prior to corneal
scraping) to increase the yield for microbiology cultures. Topical
therapy is tapered according to clinical response, taking into
account the severity of the initial clinical picture and the
virulence of the pathogen. More prolonged therapy may be
mandated by the presence of virulent or indolent organisms or
ocular immunocompromise
128. Review after 1 week
• After 1 week of specific treatment, the clinical findings and
response to antibiotics should be reviewed . If complete
resolution is noted, the medication can be discontinued. In this
nonurgent phase, if the ulcer is still progressing and the
previous culture remains negative, the medication should be
stopped for at least 24 hours prior to repeating the
microbiological work-up. Special staining/culture media or
corneal biopsy may be required. Noninfectious causes or
atypical organisms such as nontuberculous mycobacteria,
Nocardia, or Acanthamoeba should be suspected. The
antibiotic should be modified accordingly.
129.
130. Corticosteroid Therapy
• Topical corticosteroid therapy may have a beneficial role in treating
some cases of bacterial keratitis; however, its use remains
controversial, as there is no conclusive scientific evidence that
corticosteroids alter clinical outcome. The potential advantage of
corticosteroids is the possible suppression of inflammation, which
may reduce subsequent corneal scarring and associated visual loss.
Potential disadvantages include recrudescence of infection, local
immunosuppression, inhibition of collagen synthesis presdisposing
to corneal melting, and increased intraocular pressure or cataract
formation. Topical corticosteroids, used without antibiotics, worsen
experimental Pseudomonas keratitis and may promote recurrence of
apparently healed Pseudomonas keratitis after discontinuing
antibiotics.
131. Corticosteroid Therapy
• In prospective studies, no difference was found between the patients
with microbial keratitis treated with or without corticosteroids in terms
of time to cure, final visual acuity, and complications. In other
studies, patients who received corticosteroids before being
diagnosed with microbial keratitis had a significantly greater chance
of antibiotic treatment failure and related complications. Despite the
risks involved, many experts believe that the judicious use of topical
corticosteroids in the treatment of bacterial keratitis can reduce
morbidity. Patients being treated with topical corticosteroids at the
time of presentation with suspected bacterial keratitis should have
their topical steroids reduced or eliminated until the infection has
been controlled. Inflammation may temporarily worsen as the
corticosteroid is reduced.
132. Corticosteroid Therapy
• The objective in topical corticosteroid therapy is to use the
minimum amount of corticosteroid required to achieve control of
inflammation. Successful treatment requires optimal timing,
careful dose regulation, use of adequate concomitant
antibacterial medication, and close follow-up. Corticosteroids
should not be part of initial treatment of presumed bacterial
ulcers, and ideally they should not be used until the organism
has been determined by cultures. The use of corticosteroids in
the initial treatment of corneal ulcers has been determined to be
a risk factor for requiring a penetrating keratoplasty.
133. Corticosteroid Therapy
• In cases where the corneal infiltrate compromises the visual axis,
topical corticosteroid therapy may be added to the regimen following
at least 2 to 3 days of progressive improvement with topical antibiotic
treatment. Topical antibiotics, which are generally administered more
frequently than corticosteroids during treatment of active infection,
are continued at high levels with gradual tapering. Patient
compliance is essential, and the intraocular pressure must be
monitored frequently. The patient should be reexamined within 1 to 2
days after initiation of topical corticosteroid therapy. Corticosteroids
should not be used in eyes with significant corneal thinning or
impending perforation due to their adverse effects of activating
collagenolytic enzymes and suppressing collagen synthesis
134. Corticosteroid Therapy
• Tissue destruction results from a combination of the direct effects of the
bacteria and an exuberant host inflammatory response consisting of
polymorphonuclear leukocytes and proteolytic enzymes, which predominate
even after corneal sterilization. Corticosteroids are effective at modifying this
response, but they also inhibit the host response to infection. The literature
strongly suggests that corticosteroid therapy administered prior to
appropriate antibiotic therapy worsens prognosis. The literature is
inconclusive, though, about steroid therapy used concomitantly with
antibiotic therapy or after it is initiated, as demonstrated recently 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, but a trend toward improved
outcomes was noted in those patients with the worst initial vision who
received corticosteroids.
135. Corticosteroid Therapy
• The indiscriminate or universal use of corticosteroids is, therefore,
unsupported but does not appear to increase the general risk of poor
outcomes or complications in treated bacterial keratitis. In fact, selected
patients may benefit from the addition of corticosteroids to antibiotic
therapy. Future study of the appropriate timing and dosage may further
refine the indications for corticosteroid use.
• As there is still significant risk associated with corticosteroid use in
patients with bacterial or other forms of infectious keratitis not
appropriately treated, following are recommended criteria for instituting
corticosteroid therapy for bacterial keratitis:
136. criteria for instituting corticosteroid therapy for
bacterial keratitis:
• The patient must be able to return for frequent follow-up
examinations and demonstrate adherence to appropriate
antibiotic therapy.
• No other associated virulent or difficult-to-eradicate organism is
found or suspected.
• Corticosteroid drops may be started in moderate dosages
(prednisolone acetate or phosphate 1% every 6 hours), and the
patient should be monitored at 24 and 48 hours after initiation of
therapy. If the patient shows no adverse effects, the frequency
of administration may be adjusted based on clinical response.
137. Steroids
• Steroids reduce host inflammation, improve comfort, and
minimize corneal scarring. However, they promote replication of
some microorganisms, particularly fungi, herpes simplex and
mycobacteria and are contraindicated if a fungal or
mycobacterial agent is suspected (beware prior refractive
surgery and trauma involving vegetation). By suppressing
inflammation, they also retard the eye’s response to bacteria
and this can be clinically significant, particularly if an antibiotic is
of limited effect or bacteriostatic rather than bactericidal.
138. Steroids
• Evidence that they improve the final visual outcome is mainly
empirical, but the recent Steroids for Corneal Ulcers Trial
(SCUT) found no eventual benefit in most cases, though severe
cases (counting fingers vision or large ulcers involving the
central 4 mm of the cornea) tended to do better; a positive
culture result was an inclusion criterion, and steroids were
introduced after 48 hours of moxifloxacin.
139. Steroids
• Epithelialization may be retarded by steroids and they should be
avoided if there is significant thinning or delayed epithelial
healing; corneal melting can occasionally be precipitated or
worsened.
• ○ Many authorities do not commence topical steroids until
evidence of clinical improvement is seen with antibiotics alone,
typically 24–48 hours after starting treatment. Others delay their
use at least until the sensitivity of the isolate to antibiotics has
been demonstrated, or do not use them at all.
140. Steroids
• Regimens vary from minimal strength preparations at low
frequency to dexamethasone 0.1% every 2 hours; a reasonable
regimen is prednisolone 0.5–1% four times daily.
• ○ Early discontinuation may lead to a rebound recurrence of
sterile inflammation.
• ○ The threshold for topical steroid use may be lower in cases of
corneal graft infection, as they may reduce the risk of rejection.
141. Penetrating keratoplasty (PK)
• Penetrating keratoplasty (PK) for treatment of bacterial keratitis is
indicated if the disease progresses despite therapy, descemetocele
formation or perforation occurs, or the keratitis is unresponsive to
antimicrobial therapy. The involved area should be identified
preoperatively, and an attempt 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.
142. Therapy for Complicated Cases
• Coexisting risk factors, such as eyelid abnormalities, should be
corrected for optimal results. Additional treatment is necessary
in cases where the integrity of the eye is compromised, such as
when there is an extremely thin cornea, impending or frank
perforation, progressive or unresponsive disease, or
endophthalmitis. Application of tissue adhesive, therapeutic
contact lens, penetrating keratoplasty, and, rarely, lamellar
keratectomy are among the treatment options.
143. Cyanoacrylate tissue adhesives
• Cyanoacrylate tissue adhesive (N-butyl-2-cyanoacrylate) is
approved for dermatologic use but not for ophthalmic use. It 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
144. Cyanoacrylate application
• 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. A bandage contact lens is then placed to
ensure patient comfort and proper placement of the glue. The
adhesive is usually left in place until it dislodges spontaneously
or a keratoplasty is performed.
145. Therapeutic soft contact lenses
• After eradication of the causative bacteria, therapeutic contact
lenses may be applied to facilitate epithelial healing. Antibiotic
administration should continue over the therapeutic soft contact
lens. Caution should be exercised, as recurrent infection may
occasionally complicate the use of a therapeutic contact lens. A
therapeutic lens may also provide some tectonic support for
impending or microscopic corneal perforation.
146. Surgical Management
Conjunctival flap
• Conjunctival flap has been used to treat recalcitrant microbial
keratitis. The flap can bring blood vessels to the infected area,
promote healing, and provides a stable surface covering. A
conjunctival flap should not be placed over a necrotic area with
active infection because the flap can become infected and
necrotic. A conjunctival flap is particularly useful in cases of
nonhealing peripheral corneal ulcer, where the flap can be
placed without compromising vision.
147. Penetrating keratoplasty
• Major factors that can necessitate penetrating keratoplasty for
patients with bacterial keratitis include older age, delay in
referral, injudicious steroid treatment, past ocular surgery, large
size of ulcer, and central location of the ulcer. A therapeutic
penetrating keratoplasty performed at the acute stage of
microbial keratitis is difficult and is associated with a higher
complication rate and lower graft survival, as compared to
perfoming an optical keratoplasty for corneal scarring.
148. Penetrating keratoplasty indications
• The indications for emergency therapeutic penetrating
keratoplasty are uncontrolled progression of the infiltrates ,
limbal involvement with impending scleritis, or corneal
perforation. Intensive antibiotics should be administered for 48
hours before surgery to minimize the risks of recurrent infection
or development of endophthalmitis. It is preferable to defer
penetrating keratoplasty at an acute stage of bacterial keratitis
to avoid potentially incomplete excision of infected tissues or
intraocular extension of the infection. After complete resolution
of the corneal infection, optical penetrating keratoplasty can be
used to remove corneal scarring and to rehabilitate vision.
149.
150. Fungal Keratitis
• Fungal keratitis represents one of the most difficult forms of
microbial keratitis for the ophthalmologist to diagnose and treat
successfully. Difficulties arise in making the correct diagnosis,
establishing the clinical characteristics of fungal keratitis, and
obtaining confirmation from the microbiology laboratory. Other
problems relate to treatment. It is difficult to obtain topical
antifungal preparations, they do not work as effectively as
antibiotics for bacterial infections, and the infection is often
more advanced because of delays in making the correct
diagnosis. Medical or surgical success, therefore, may be
limited.
151. Fungal Keratitis
• There has been an increase in the number of reported cases of
fungal keratitis. The increasing use of broad-spectrum topical
antibiotics may provide a noncompetitive environment for fungi to
grow. In addition, the use of topical corticosteroid enhances the
growth of fungi while suppressing host immune response. There has
also been an increase in fungal keratitis related to the use of soft
contact lenses. The increasing laboratory capability for recovery of
fungi from infected corneas has increased our awareness of fungal
keratitis. The treatment of fungal keratitis can be quite challenging,
often requiring prolonged and intensive topical and systemic
antifungal therapy, with surgical intervention in the form of
penetrating keratoplasty, conjunctival flap, or cryotherapy required
when medical treatment fails.
152. Pathogenesis
• Fungi are eukaryotic and heterotrophic organisms. That is, they
have a membrane-bound nucleus within which the genome of
the cell is stored as chromosomes of DNA, and they require
organic compounds for growth and reproduction. They are
nonphotosynthetic and typically form reproductive spores. Many
fungi exhibit both sexual and asexual forms of reproduction.
Some fungi are unicellular, but most form filaments of
vegetative cells known as mycelia. The mycelia usually exhibit
branching and are typically surrounded by cell walls containing
chitin or cellulose.
153. Pathogenesis
• Fungi are ubiquitous, saprophytic, and/or pathogenic organisms.
Saprophytic fungi obtain their nutrients from decaying organic matter,
whereas pathogenic fungi feed on living cells. Pathogenic fungi are
actually saprobes, which are known to cause disease in humans.
Many of the fungi associated with ocular infections are saprophytic
and have been reported as causes of infection only in the ophthalmic
literature. A convenient method of classifying fungal isolates has
been reported in the ophthalmic literature. It includes four
diagnostic/laboratory groups: yeasts which include Candida spp.;
filamentous septated fungi, which include both nonpigmented
hyphae (Fusarium spp. and Aspergillus spp.) and pigmented hyphae
(Alternaria spp. and Curvularia spp.); filamentous nonseptated fungi,
which include Mucor spp.; and other fungi .
154.
155. Fungi
• Fungi gain access into the corneal stroma through a defect in
the epithelial barrier. This defect may be due to external trauma,
including epithelial trauma caused by wearing contact lenses, a
compromised ocular surface, or previous surgery. Once in the
stroma, they multiply and can cause tissue necrosis and a host
inflammatory reaction. Organisms can penetrate deep into the
stroma and through an intact Descemet's membrane.
156. Fungi
• It is thought that once organisms gain access into the anterior
chamber or to the iris and lens, eradication of the organism
becomes extremely difficult. Likewise, organisms that extend
from the cornea into the sclera become difficult to control.
Blood-borne, growth-inhibiting factors may not reach the
avascular tissues of the eye such as the cornea, anterior
chamber, and sclera, which may explain why fungi continue to
grow and persist despite treatment. It also may be the reason
why a conjunctival flap helps control fungal growth (i.e. by
bringing to avascular tissue blood-borne, growth-inhibiting
factors).
162. Aspergillus infection,
shown by
lactophenol cotton
blue stain. Septate
hyphae with phialides
are seen on top of
swollen vesicles. The
phialides produce
chains of round conidia
spores
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177. Anti fungal drugs
• Among the azoles, the most commonly used compounds have
been topical voriconazole and oral ketoconazole and
itraconazole. Vemulakonda et al. analyzed the aqueous and
vitreous penetration of topically administered voriconazole 1%
(1 drop every 2 hours for 1 day) in noninflamed human eyes
undergoing planned vitrecomy.[139] The aqueous and vitreous
levels exceeded or met the MIC90 for most pathogens,
demonstrating that voriconazole can be suitable as an
ophthalmic drop. Several clinical case reports have reported on
the successful use of voriconazole on fungal keratitis which
failed to respond to conventional agents.
178. Anti fungal drugs
• Most patients were treated with a combination of topical, oral, and
intravenous voriconazole. However, there is ongoing debate on
whether voriconazole's in vivo effect is as good as predicted by in
vitro studies. Marangon et al. reported that while voriconazole had
good in vitro susceptibility, it was not effective as a topical 1%
solution in two patients with keratitis, one with Fusarium species and
the other with Colletotrichum. Voriconazole (50 µg/0.1 mL) has also
been used successfully as an intrastromal injection in three patients
with deep fungal keratitis recalcitrant to topical therapy alone. Data
on the use of posaconazole in the treatment of fungal keratitis is
limited; a few case reports described rapid resolution of infection
after oral posaconazole was used as salvage therapy. Miconazole is
the drug of choice for Paecilomyces spp .
179. Anti fungal drugs
• The echinocandins (caspofungin and micafungin) have also been
used in the treatment of fungal keratitis. Topical caspofungin 0.5% in
conjunction with intrastromal voriconazole successfully treated a
patient with Alternaria keratitis. Likewise, micafungin 0.1%, used as
a single agent, successfully treated three patients with Candida
keratitis.[146]
• Several topical antifungal medications may act synergistically
against a particular fungal organism. Amphotericin B 0.15% and
subconjunctival rifampin were more effective than amphotericin
alone. Amphotericin B and flucytosine (5-flurocytosine) have
synergistic effects. Natamycin and ketoconazole have been used
effectively in an animal model of Aspergillus keratitis.
180. Anti fungal drugs
• Likewise, experimental models have demonstrated the potential
antagonism between antifungals such as amphotericin B and
the imidazoles. Antagonism also has been described when
amphotericin B and the imidazoles have been used
systemically. Clinically, it is difficult to interpret these studies
because they are performed in vitro or in animals. Resistance to
an antifungal is rare except in the case of flucytosine, in which
resistance has been documented when used for systemic
mycoses and could potentially occur if used alone for the topical
treatment of yeast keratitis. Competition for volume in the
precorneal tear film and washout may be of more concern when
using two topical antifungals.
181. Anti fungal drugs
• Clinically, commercially available natamycin 5% suspension is
the initial drug of choice for fungal keratitis. If worsening of the
keratitis is observed on topical natamycin, topical amphotericin
B 0.15% can be substituted in cases of Candida spp. keratitis
and Apergillus keratitis. An oral or topical azole can be
substituted or added in cases Fusarium spp. keratitis. The
length of time required for topical treatment has not been firmly
established clinically or experimentally. Guidelines have been
derived from retrospective clinical reviews. Jones et al.[135]
reported an average of 30 days of treatment for Fusarium
keratitis with natamycin
182. Anti fungal drugs
• The average length of treatment with topical treatment was 39
days. In general, the length of treatment is longer than that for
cases of bacterial keratitis. The clinician must determine the
length of treatment for each individual based on clinical
response. Problems that can arise from prolonged treatment
are due to toxicity. The inflammatory response from this toxicity
can be confused with persistent infection. If toxicity is suspected
and if adequate treatment has been given for at least 4 to 6
weeks, treatment should be discontinued and the patient
carefully observed for evidence of recurrence .
183. Anti fungal drugs
• Subconjunctival injections of antifungal agents are not routinely
used in the treatment of fungal keratitis because of toxicity and
the intense pain induced. Miconazole is perhaps the least toxic
and best-tolerated antifungal agent (5–10 mg of 10 mg/mL
suspension). Subconjunctival injections should be reserved for
cases of severe keratitis, scleritis, and endophthalmitis. Corneal
intrastromal injections of agents such as voriconazole are used
when the infiltrate is recalcitrant to topical treatment or due to its
depth into the cornea. Likewise, intraocular injections into the
anterior chamber are now more commonly used.
184. Anti fungal drugs
• The use of systemic antifungal agents is generally not indicated in
the management of fungal keratitis, but can be considered for deep
lesions that do not respond adequately to topical therapy. Several
clinical and experimental studies have reported favorable results in
the treatment of fungal keratitis with systemic ketoconazole,
itraconazole, miconazole, fluconazole, voriconazole, and
posaconazole. A commonly used first choice for an oral antifungal
agent is voriconazole as it has a favorable side-effect profile.
Treatment with a systemic antifungal agent is recommended in
cases of severe deep keratitis, scleritis, and endophthalmitis.
Systemic antifungals also may be used as prophylactic treatment
after penetrating keratoplasty for fungal keratitis .
185. Debridement of the corneal epithelium
• The corneal epithelium serves as a barrier to the penetration of
most topical antifungal agents. Debridement of the corneal
epithelium is an essential component of the medical
management of fungal keratitis, especially early in the course of
treatment. O'Day et al. have demonstrated experimentally that
corneal debridement significantly increases the antifungal effect
of topical antifungals.
186. Acanthamoeba and Other Parasitic
Corneal Infections
• Acanthamoeba keratitis is a chronic, primarily contact lens-
related, infection caused by a free-living amoeba found
ubiquitously in water and soil. Although classically presenting
with radial keratoneuritis, a corneal ring infiltrate and/or
disproportionate, incapacitating pain, most patients will initially
present with less characteristic signs and symptoms frequently
contributing to diagnostic delay .
187. Acanthamoeba and Other Parasitic
Corneal Infections
• Commonly mistaken for noninfectious as well as bacterial,
fungal, or viral causes of chronic keratitis, the amoebic infection
is resistant to commonly utilized ophthalmic antimicrobial
agents, but may become transiently asymptomatic with the use
of corticosteroids. Excellent outcomes are probable when the
infection is diagnosed and treatment initiated before deep
infiltration. Medical cure requires the specific use of biguanides
alone or in combination with a diamidine for weeks to months or
longer. Clinical resistance does occur and may require more
aggressive medical or surgical therapy
201. (A) In the Adenoclone test the presence of
andenovirus antigen causes a blue color
change in the reaction well.
202. (B) In the shell vial test, infected cells are
stained with monoclonal antibodies
conjugated with fluorescein isothiocyanate
that appears apple-green using a
fluorescent microscope
203. (C) When adenovirus is inoculated onto A549
monolayer cells, cell rounding is seen.
Adenovirus is confirmed with the Adenoclone
test;
204. (D) when Herpes
simplex virus is
inoculated onto
A549 monolayer
cells, cell rounding is
seen. Herpes
simplex virus is
confirmed with an
antigen test.
205. (E) In the enzyme-
linked virus
induced system
(ELVIS) test, the
presence of
herpes simplex
virus is indicated
by a blue color
within the cells.
207. Primary herpes
simplex infection of
the facial skin. There
are multiple vesicular
lesions, some of which
are crusted over. A
blepharoconjunctivitis
is present in the right
eye.
209. Herpes simplex virus.
Same patient as in
Figure 12.13. Note the
diffuse conjunctivitis.
With primary herpes
infections, there may be
a follicular response and
preauricular adenopathy
210. A magnified
view of herpes
blepharitis. An
ulcerative lesion
is present on
the skin.
211.
212.
213.
214. Herpes simplex keratitis with a large
geographic ulcer. These ulcers take
longer to heal than dendritic ulcers
225. A slit beam
view of
disciform
keratitis.
There is
central
corneal
edema.
226.
227.
228.
229.
230.
231.
232.
233.
234.
235. Chronic herpes simplex
keratitis with secondary
bacterial infection. Eyes
with this disorder are more
susceptible to secondary
infection. Here there is an
extensive corneal ulcer
caused by Moraxella
organisms.
236.
237.
238.
239.
240.
241. Subepithelial infiltrates in herpes zoster
ophthalmicus. These infiltrates probably
represent an immunologic reaction to viral
proteins. Similar to the subepithelial
infiltrates in epidemic keratoconjunctivitis,
these occur 10 to 14 days after the onset of
active disease and respond to treatment
with topical corticosteroids. They can recur
many months to years after active infection.