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KERATITIS
Bacterial , fungal , viral &
parasitic
Indoredrishti.wordpress.com
DR DINESH MITTAL DR SONALEE MITTAL
DRISHTI EYE HOSP VIJAYNAGAR INDORE
Normal Ocular Flora
• Bacterial colonization of the eyelid margin and conjunctiva is
normal and can be beneficial by compe...
Normal Ocular Flora
• Although gram-negative bacteria become more commonly isolated
over time, S epidermidis and other coa...
Few bacteria can overcome intact
epithelium
• Few bacteria can overcome intact epithelium. Those that can,
include
• Neiss...
Pseudomonas keratitis with soft contact lens. A
paracentral corneal infiltrate with surrounding corneal
edema and hypopyon
Culture of contact lens from a pt with Pseudomonas keratitis.
Confluent growth of Pseudomonas around contact lens on a
blo...
Common etiologic agents of
bacterial keratitis in the USA
• Pearly-white colonies of
Staphylococcus aureus in C
streaks on a blood agar plate
from a corneal ulcer.
Diminishing numb...
A large peripheral corneal ulcer of Staphylococcus aureus with
several smaller infiltrates in a pt with marked blepharitis.
• A Streptococcus pneumoniae
corneal ulcer in an
immunocompromised patient
with deep stromal infiltrates
and dense hypopyon
Heavy growth of
nonhemolytic
Streptococcus
pneumoniae on a
chocolate agar
plate.
Bacterial Keratitis
Bacteriology
• A basic understanding of bacteriology is important in the diagnosis of
external eye infections and for effe...
Bacteriology
• Classification of bacteria is based on microscopic morphology
(round or elongated) and colony morphology, e...
Bacteriology
• Thick gram positive bacterial cell walls contain predominantly
peptidoglycan, the primary target of penicil...
Gram-positive cocci (Streptococcus
pneumoniae).
Gram-negative cocci (Neisseria
gonorrhoeae
Gram-positive rods (Propionibacterium
acnes).
Gram-negative rods (Pseudomonas
aeruginosa).
FUNGUS
Septate hyphae of filamentous fungus
(Fusarium solani).
Yeasts (Candida albicans).
Acanthamoeba cyst. Diff-Quick stain
×100
Introduction
• Microbial keratitis or infectious corneal ulcer is due to the
proliferation of microorganisms (including ba...
Introduction
• predisposing factors including contact lens wear, trauma,
corneal surgery, ocular surface disease, systemic...
Introduction
• When there is strong suspicion for a possible infectious
keratitis, laboratory investigations should be con...
Introduction
• Medical therapy with appropriate antibiotics is the mainstay of
treatment. The outcome usually depends on t...
Natural History
• While some bacteria (e.g. Gonococcus) can invade an intact corneal
epithelium, most cases of bacterial k...
Natural History
• Bacterial keratitis can occur in any part of the cornea, but
infections involving the central cornea hav...
Presentation
• The clinical signs and symptoms of microbial keratitis are
variable and they depend on the virulence of the...
Presentation
• Nonetheless, clinical diagnosis is possible when a pertinent
history is available or the organisms present ...
DIAGNOSIS
• The presumptive diagnosis of infectious keratitis is based primarily on
the clinical history and physical exam...
DIAGNOSIS
• Since approximately 95% of suspected bacterial ulcers respond
favorably to a well-chosen initial antibiotic re...
Corneal Infections
• There are four basic classes of organisms responsible for
infectious keratitis: bacterial, viral, fun...
Corneal specimen collection
(A) Different
instruments can be
used to collect
corneal specimens.
Because corneal
infiltrates are often
small, care must...
(B) A conjunctival culture can be obtained
with a cotton-tipped applicator
(C) The specimen is inoculated directly
on to a culture plate.
(D) The specimen can be brought directly
to the lab or transported through the mail.
(E) Antibiotic sensitivity testing with the
disk diffusion method.
(F) This Gram stain specimen from corneal
tissue shows Gram-negative diplobacilli
(Moraxella sp.).
Giemsa stain cytolology
Giemsa stain cytolology. (A)
Polymorphonuclear cells
(B) mononuclear and epithelial cells;
(C) plasma cell in center
(D) Acanthamoeba cyst in the center
(E) dark purple chlamydial inclusion caps
peripheral to nucleus of epithelial cell;
(F) corneal multinucleated epithelial cell
from HSV keratitis.
Laboratory diagnosis of bacterial,
fungal and parasitic infections
(A) Routine culture agar plates
(B) microsporidia spores from stained
corneal specimen;
(C) mold growing on agar plates
(D) Acanthamoeba sp. hexagonal cysts on
nonnutrient agar with Enterobacter aerogenes
overlay;
(E) Candida albicans pseudohyphae on
giemsa-stained corneal specimen
(F) Actinomyces sp. on giemsa-stained
corneal tissue.
Laboratory Investigations
• Cultures and smears
• Laboratory investigations of microbial keratitis include corneal
scrapin...
Laboratory Investigations
• In addition, cultures are helpful to guide modification of therapy
in patients with a poor cli...
Culture
• Obtaining corneal materials for microbial culture is most easily
performed with slit lamp magnification under to...
Culture
• Corneal material is obtained by scraping corneal tissues from
the advancing borders of the infected area using e...
Culture
• Multiple samples from the advancing borders of representative
areas of the ulcer are often required to achieve m...
Stains
• Microbial pathogens may be categorized by examining stained
smears of corneal scrapings. The material for smear i...
Gram stain
• Gram stain is used routinely to stain the corneal specimens.
This stain can confirm the presence of a microor...
Giemsa stain
• Giemsa stain is primarily used to distinguish the types of
inflammatory cells and intracytoplasmic inclusio...
Acridine orange stain
• Acridine orange stain is also a useful screening test. It is a
fluorochromatic dye that binds to r...
Specific Therapeutic Agents
Cephalosporins
• Like penicillins, cephalosporins contain a β-lactam ring that is
necessary for bactericidal activity. The...
Cephalosporins
• Ceftazidime is a third-generation cephalosporin with
antipseudomonal activity. It is used in Pseudomonas ...
Glycopeptides
• Vancomycin is a glycopeptide antibiotic with activity against
penicillin-resistant staphylococci. Its bact...
Glycopeptides
• Vancomycin should be reserved for cephalosporin-resistant
staphylococci. Streptococci (including penicilli...
Aminoglycosides
• Aminoglycosides have a selective affinity to the bacterial 30-S
and 50-S ribosomal subunits to produce a...
Aminoglycosides
• For severe Pseudomonas keratitis, aminoglycosides may be
combined with an antipseudomonal cephalosporin....
Macrolides
• Macrolides such as erythromycin inhibit bacterial protein synthesis
by reversibly binding to the 50-S ribosom...
Macrolides
• Erythromycin ointment is one of the best-tolerated and least toxic
topical ophthalmic antibiotics, commonly u...
Fluoroquinolones
• The bactericidal action is due to inhibition of bacterial DNA
gyrase and topoisomerase IV, which are en...
Fluoroquinolones
• Among those pathogens tested, Streptococcus pneumoniae
was noted to respond less to fluoroquinolone tha...
Fluoroquinolones
• The wide use of fluoroquinolone monotherapy has imposed a
risk of emergence of resistant strains of mic...
Fluoroquinolones
• The latest fourth-generation fluoroquinolones such as
gatifloxacin and moxifloxacin have been developed...
Fluoroquinolones
• Side effects of fluoroquinolone are minimal. The incidence of
ocular discomfort for patients receiving ...
fourth-generation fluoroquinolones
• The greater potency and resistance-thwarting capabilities of the
fourth-generation fl...
Sulfonamide and trimethoprim
• Sulfonamides have a structure similar to that of para-aminobenzoic
acid (PABA). The mechani...
Sulfonamide and trimethoprim
• Trimethoprim is a 2,4-diamino-pyrimidine that also inhibits
bacterial folic acid synthesis....
clinical response to antibiotic therapy:
• blunting of the perimeter of the stromal infiltrate
• decreased density of the ...
progressive ulcer
• In progressive ulcer with a prior positive culture and proper
therapy, the existence of a resistant st...
continuity of the epithelium
• Although disruption of the continuity of the epithelium is the most
common event that allow...
Modification of Therapy
• The clinical response to treatment is multifactorial, taking into
account the severity of the in...
Modification of Therapy
• In general, the initial therapeutic regimen should be modified
when the eye shows a lack of impr...
Modification of Therapy
• Progression after 48 hours of treatment implies that organisms
are not sensitive to selected age...
Review after 1 week
• After 1 week of specific treatment, the clinical findings and
response to antibiotics should be revi...
Corticosteroid Therapy
• Topical corticosteroid therapy may have a beneficial role in treating
some cases of bacterial ker...
Corticosteroid Therapy
• In prospective studies, no difference was found between the patients
with microbial keratitis tre...
Corticosteroid Therapy
• The objective in topical corticosteroid therapy is to use the
minimum amount of corticosteroid re...
Corticosteroid Therapy
• In cases where the corneal infiltrate compromises the visual axis,
topical corticosteroid therapy...
Corticosteroid Therapy
• Tissue destruction results from a combination of the direct effects of the
bacteria and an exuber...
Corticosteroid Therapy
• The indiscriminate or universal use of corticosteroids is, therefore,
unsupported but does not ap...
criteria for instituting corticosteroid therapy for
bacterial keratitis:
• The patient must be able to return for frequent...
Steroids
• Steroids reduce host inflammation, improve comfort, and
minimize corneal scarring. However, they promote replic...
Steroids
• Evidence that they improve the final visual outcome is mainly
empirical, but the recent Steroids for Corneal Ul...
Steroids
• Epithelialization may be retarded by steroids and they should be
avoided if there is significant thinning or de...
Steroids
• Regimens vary from minimal strength preparations at low
frequency to dexamethasone 0.1% every 2 hours; a reason...
Penetrating keratoplasty (PK)
• Penetrating keratoplasty (PK) for treatment of bacterial keratitis is
indicated if the dis...
Therapy for Complicated Cases
• Coexisting risk factors, such as eyelid abnormalities, should be
corrected for optimal res...
Cyanoacrylate tissue adhesives
• Cyanoacrylate tissue adhesive (N-butyl-2-cyanoacrylate) is
approved for dermatologic use ...
Cyanoacrylate application
• Necrotic tissue and debris should be removed from the ulcer
bed prior to application of the gl...
Therapeutic soft contact lenses
• After eradication of the causative bacteria, therapeutic contact
lenses may be applied t...
Surgical Management
Conjunctival flap
• Conjunctival flap has been used to treat recalcitrant microbial
keratitis. The fla...
Penetrating keratoplasty
• Major factors that can necessitate penetrating keratoplasty for
patients with bacterial keratit...
Penetrating keratoplasty indications
• The indications for emergency therapeutic penetrating
keratoplasty are uncontrolled...
Fungal Keratitis
• Fungal keratitis represents one of the most difficult forms of
microbial keratitis for the ophthalmolog...
Fungal Keratitis
• There has been an increase in the number of reported cases of
fungal keratitis. The increasing use of b...
Pathogenesis
• Fungi are eukaryotic and heterotrophic organisms. That is, they
have a membrane-bound nucleus within which ...
Pathogenesis
• Fungi are ubiquitous, saprophytic, and/or pathogenic organisms.
Saprophytic fungi obtain their nutrients fr...
Fungi
• Fungi gain access into the corneal stroma through a defect in
the epithelial barrier. This defect may be due to ex...
Fungi
• It is thought that once organisms gain access into the anterior
chamber or to the iris and lens, eradication of th...
Fungal Keratitis
Aspergillus infection,
shown by
lactophenol cotton
blue stain. Septate
hyphae with phialides
are seen on top of
swollen ve...
Anti fungal drugs
• Among the azoles, the most commonly used compounds have
been topical voriconazole and oral ketoconazol...
Anti fungal drugs
• Most patients were treated with a combination of topical, oral, and
intravenous voriconazole. However,...
Anti fungal drugs
• The echinocandins (caspofungin and micafungin) have also been
used in the treatment of fungal keratiti...
Anti fungal drugs
• Likewise, experimental models have demonstrated the potential
antagonism between antifungals such as a...
Anti fungal drugs
• Clinically, commercially available natamycin 5% suspension is
the initial drug of choice for fungal ke...
Anti fungal drugs
• The average length of treatment with topical treatment was 39
days. In general, the length of treatmen...
Anti fungal drugs
• Subconjunctival injections of antifungal agents are not routinely
used in the treatment of fungal kera...
Anti fungal drugs
• The use of systemic antifungal agents is generally not indicated in
the management of fungal keratitis...
Debridement of the corneal epithelium
• The corneal epithelium serves as a barrier to the penetration of
most topical anti...
Acanthamoeba and Other Parasitic
Corneal Infections
• Acanthamoeba keratitis is a chronic, primarily contact lens-
related...
Acanthamoeba and Other Parasitic
Corneal Infections
• Commonly mistaken for noninfectious as well as bacterial,
fungal, or...
Laboratory diagnosis of viral infection
(A) In the Adenoclone test the presence of
andenovirus antigen causes a blue color
change in the reaction well.
(B) In the shell vial test, infected cells are
stained with monoclonal antibodies
conjugated with fluorescein isothiocyana...
(C) When adenovirus is inoculated onto A549
monolayer cells, cell rounding is seen.
Adenovirus is confirmed with the Adeno...
(D) when Herpes
simplex virus is
inoculated onto
A549 monolayer
cells, cell rounding is
seen. Herpes
simplex virus is
conf...
(E) In the enzyme-
linked virus
induced system
(ELVIS) test, the
presence of
herpes simplex
virus is indicated
by a blue c...
(F) A positive
enzyme-linked
immunosorbent
assay (ELISA) test
for chlamydial
DNA after
polymerase chain
reaction (PCR)
amp...
Primary herpes
simplex infection of
the facial skin. There
are multiple vesicular
lesions, some of which
are crusted over....
Recurrent herpes simplex vesicles
around the mouth
Herpes simplex virus.
Same patient as in
Figure 12.13. Note the
diffuse conjunctivitis.
With primary herpes
infections, th...
A magnified
view of herpes
blepharitis. An
ulcerative lesion
is present on
the skin.
Herpes simplex keratitis with a large
geographic ulcer. These ulcers take
longer to heal than dendritic ulcers
Anterior
stromal scars.
“Footprints” in a
pattern of
herpetic
ulceration
indicate
previous
herpetic
infection
Herpes simplex scars with typical
“ground glass” appearance.
Herpes simplex. Advanced scarring and
vascularization are seen
A slit beam
view of
disciform
keratitis.
There is
central
corneal
edema.
Chronic herpes simplex
keratitis with secondary
bacterial infection. Eyes
with this disorder are more
susceptible to secon...
Subepithelial infiltrates in herpes zoster
ophthalmicus. These infiltrates probably
represent an immunologic reaction to v...
THANK
YOU
DR DINESH
DR SONALEE
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Keratitis 2016

  1. 1. KERATITIS Bacterial , fungal , viral & parasitic Indoredrishti.wordpress.com
  2. 2. DR DINESH MITTAL DR SONALEE MITTAL DRISHTI EYE HOSP VIJAYNAGAR INDORE
  3. 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. 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. 5. 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
  6. 6. Pseudomonas keratitis with soft contact lens. A paracentral corneal infiltrate with surrounding corneal edema and hypopyon
  7. 7. Culture of contact lens from a pt with Pseudomonas keratitis. Confluent growth of Pseudomonas around contact lens on a blood agar plate
  8. 8. Common etiologic agents of bacterial keratitis in the USA
  9. 9. • 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
  10. 10. A large peripheral corneal ulcer of Staphylococcus aureus with several smaller infiltrates in a pt with marked blepharitis.
  11. 11. • A Streptococcus pneumoniae corneal ulcer in an immunocompromised patient with deep stromal infiltrates and dense hypopyon
  12. 12. Heavy growth of nonhemolytic Streptococcus pneumoniae on a chocolate agar plate.
  13. 13. Bacterial Keratitis
  14. 14. 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
  15. 15. 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 .
  16. 16. 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.
  17. 17. Gram-positive cocci (Streptococcus pneumoniae).
  18. 18. Gram-negative cocci (Neisseria gonorrhoeae
  19. 19. Gram-positive rods (Propionibacterium acnes).
  20. 20. Gram-negative rods (Pseudomonas aeruginosa).
  21. 21. FUNGUS
  22. 22. Septate hyphae of filamentous fungus (Fusarium solani).
  23. 23. Yeasts (Candida albicans).
  24. 24. Acanthamoeba cyst. Diff-Quick stain ×100
  25. 25. 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.
  26. 26. 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 .
  27. 27. 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.
  28. 28. 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.
  29. 29. 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.
  30. 30. 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.
  31. 31. 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.
  32. 32. 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
  33. 33. 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.
  34. 34. 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 .
  35. 35. 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
  36. 36. Corneal specimen collection
  37. 37. (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.
  38. 38. (B) A conjunctival culture can be obtained with a cotton-tipped applicator
  39. 39. (C) The specimen is inoculated directly on to a culture plate.
  40. 40. (D) The specimen can be brought directly to the lab or transported through the mail.
  41. 41. (E) Antibiotic sensitivity testing with the disk diffusion method.
  42. 42. (F) This Gram stain specimen from corneal tissue shows Gram-negative diplobacilli (Moraxella sp.).
  43. 43. Giemsa stain cytolology
  44. 44. Giemsa stain cytolology. (A) Polymorphonuclear cells
  45. 45. (B) mononuclear and epithelial cells;
  46. 46. (C) plasma cell in center
  47. 47. (D) Acanthamoeba cyst in the center
  48. 48. (E) dark purple chlamydial inclusion caps peripheral to nucleus of epithelial cell;
  49. 49. (F) corneal multinucleated epithelial cell from HSV keratitis.
  50. 50. Laboratory diagnosis of bacterial, fungal and parasitic infections
  51. 51. (A) Routine culture agar plates
  52. 52. (B) microsporidia spores from stained corneal specimen;
  53. 53. (C) mold growing on agar plates
  54. 54. (D) Acanthamoeba sp. hexagonal cysts on nonnutrient agar with Enterobacter aerogenes overlay;
  55. 55. (E) Candida albicans pseudohyphae on giemsa-stained corneal specimen
  56. 56. (F) Actinomyces sp. on giemsa-stained corneal tissue.
  57. 57. 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.
  58. 58. 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.
  59. 59. 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 .
  60. 60. 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.
  61. 61. 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.
  62. 62. 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.
  63. 63. 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.
  64. 64. 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 .
  65. 65. 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.
  66. 66. Specific Therapeutic Agents
  67. 67. 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.
  68. 68. 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.
  69. 69. 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.
  70. 70. 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.
  71. 71. 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.
  72. 72. 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 .
  73. 73. 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.
  74. 74. 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.
  75. 75. 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.
  76. 76. 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.
  77. 77. 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.
  78. 78. 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.
  79. 79. 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.
  80. 80. 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.
  81. 81. 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.
  82. 82. 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
  83. 83. 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
  84. 84. 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
  85. 85. 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 .
  86. 86. 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
  87. 87. 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 .
  88. 88. 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
  89. 89. 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.
  90. 90. 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.
  91. 91. 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.
  92. 92. 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.
  93. 93. 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
  94. 94. 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.
  95. 95. 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:
  96. 96. 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.
  97. 97. 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.
  98. 98. 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.
  99. 99. 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.
  100. 100. 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.
  101. 101. 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.
  102. 102. 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.
  103. 103. 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
  104. 104. 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.
  105. 105. 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.
  106. 106. 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.
  107. 107. 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.
  108. 108. 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.
  109. 109. 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.
  110. 110. 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.
  111. 111. 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.
  112. 112. 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 .
  113. 113. 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.
  114. 114. 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).
  115. 115. Fungal Keratitis
  116. 116. 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
  117. 117. 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.
  118. 118. 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 .
  119. 119. 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.
  120. 120. 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.
  121. 121. 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
  122. 122. 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 .
  123. 123. 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.
  124. 124. 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 .
  125. 125. 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.
  126. 126. 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 .
  127. 127. 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
  128. 128. Laboratory diagnosis of viral infection
  129. 129. (A) In the Adenoclone test the presence of andenovirus antigen causes a blue color change in the reaction well.
  130. 130. (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
  131. 131. (C) When adenovirus is inoculated onto A549 monolayer cells, cell rounding is seen. Adenovirus is confirmed with the Adenoclone test;
  132. 132. (D) when Herpes simplex virus is inoculated onto A549 monolayer cells, cell rounding is seen. Herpes simplex virus is confirmed with an antigen test.
  133. 133. (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.
  134. 134. (F) A positive enzyme-linked immunosorbent assay (ELISA) test for chlamydial DNA after polymerase chain reaction (PCR) amplification is seen.
  135. 135. 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.
  136. 136. Recurrent herpes simplex vesicles around the mouth
  137. 137. 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
  138. 138. A magnified view of herpes blepharitis. An ulcerative lesion is present on the skin.
  139. 139. Herpes simplex keratitis with a large geographic ulcer. These ulcers take longer to heal than dendritic ulcers
  140. 140. Anterior stromal scars. “Footprints” in a pattern of herpetic ulceration indicate previous herpetic infection
  141. 141. Herpes simplex scars with typical “ground glass” appearance.
  142. 142. Herpes simplex. Advanced scarring and vascularization are seen
  143. 143. A slit beam view of disciform keratitis. There is central corneal edema.
  144. 144. 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.
  145. 145. 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.
  146. 146. THANK YOU DR DINESH DR SONALEE

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