Bacterial keratitis

Bacterial keratitis

1. Bacterial Keratitis is a common sight-threatening condition. Some cases have onset and rapidly progressive stromal inflammation. If Untreated, leads to progressive tissue destruction with corneal perforation or extension of infection to adjacent tissue. frequently associated with risk factors that disturb corneal epithelial integrity. Common predisposing factors include contact lens wear Trauma contaminated ocular medications impaired defense mechanisms altered structure of the corneal surface

2. Bacteriology : The bacterial keratitis can be causesd by Gram+ve cocci Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Gram + ve bacilli Corynebacterium diphtherioids C. xerosis Gram- ve bacilli Pseudomonas aeruginosa Acinetobacter species Enterobacteriaceae— Klebsiella , Serratia, Proteus, Escherichia coli

3. Gram- ve diplocooci Neisseria gonorrhoeae, Neisseria meningitidis Gram- ve diplobacillus - Moraxella lacunata Gram- ve coccobacillus Hemophilus influenza, Hemophilus aegyptius Gram + ve filaments Nocardia asteroides , Nocardia brasiliensis Non-tuberculous mycobacterium Mycobacterium fortuitum , Mycobacterium chelonae . Coagulase negative Staphylococcus is identified more often recently.

4. Common causes Staph aureus Staph epidermidis Strept pnumoniae n other strept species P aeruginosa(MCC in soft contact lens wearers) Enterobacteriaceae Causes of bacterial keratitis

5. Risk Factors Break in the barrier function: An intact corneal epithelium is an important defence factor. Only few bacteria like Neisseria gonorrhoeae , Corynebacterium diphtheriae , Hemophilus aegyptius and Listeria monocytogenes can penetrate an intact corneal epithelium

6. External risk factors : An epithelial defect following a trauma is a major risk factor for infection. Corneal abrasion, foreign body or erosion may precipitate development of bacterial keratitis. Ocular surface pathologies: Chronic inflammatory ocular surface diseases cause tear film instability and structural changes of the epithelium which will invite infections Lacrimal passage obstruction is another important source of bacterial infection. Iatrogenic: Contaminated eye drops preparations, Preservative free formulations which are used for long term like artificial tear substitutes and anti glaucoma agents are important source of Pseudomonas keratitis.

7. Contact lens use: In developed countries, this is MC risk factor for bacterial keratitis. Microorganisms can get attached to the contact lenses. Mechanical abrasions render the hypoxic cornea susceptible to infections. Infections are more common with soft and extended wear lenses. Pseudomonas is the most common isolate of bacterial keratitis associated with contact lens use. Corneal foreign body removal without strict sterility precautions is an important source for devastating bacterial infections like Pseudomonas keratitis.

8. Contact lens induced Pseudomonas keratitis

9. Pathogenesis : determined by: Microbial factors Host factors Therapy effects Microbial factors consist of virulence, Bacterial load and sensitivity to commonly used antimicrobial agents.

10. Factors Determining Bacterial Virulence Bacterial adherence: Bacteria adhere to the wounded corneal surface and avoid clearance by tear film. This is aided by adhesins, a protein moiety which attaches to protein or carbohydrate specific host cell components. The glycocalyx, a biological slime produced by bacteria not only helps in adhesion to host cell but also helps them to resist phagocytosis.

11. Bacterial invasion: Bacterial capsule and other surface components are important in bacterial invasion. Lipopolysaccharides, the subcapsular constituents of bacteria are major mediators of corneal inflammation. Bacteria also release many proteases, which damage basement membrane and facilitate invasion. After inoculation, bacteria infiltrate the surrounding epithelium and into deeper stroma. Viable bacteria tend to be found at peripheral margins and deep within the ulcer crater.

12. Pseudomonas aeruginosa produce enzymes like alkaline protease elastase which exotoxins like hemolysin exotoxin A Phospholipidase C Gram-positive bacteria also secrete distinct toxins. Coagulase positive Staphylococci produce staphylokinase , lipase, hyaluronidase, coagulase and lysozyme degrade basement membrane & extracellular matrix stromal necrosis

13. Streptococcal enzymes are streptokinases , streptolysin O and S and streptodornase . Streptococcus pneumoniae produce collagenase for invasion Corneal inflammatory response: Recruitment of acute inflammatory cells occurs within a few hours of bacterial inoculation. Vascular dilatation and limbal vessels are associated withincreased permeability, resulting in an inflammatory exudation into tear film and peripheral cornea. Polymorphonuclear neutrophils can enter injured cornea anteriorly via tear film, but most migrate from the limbus. Influx of neutrophils is directed by bacterial proteins via chemotaxis toward the area of infection.

14. Collagenase released from PMNs, matrix metallo proteases by host tissues, proteases produced by the pathogen lead to rapid tissue lysis. Macrophages subsequently begin to migrate to cornea to ingest invading bacteria. Once the infection is controlled with treatment, the healing process leads to scaring. Uncontrolled infective and inflammatory reactions may lead to corneal perforation

15. CLINICAL PRESENTATION In bacterial infections the outcome depends upon the virulence of organism, its toxins and enzymes, and the response of host tissue. Broadly bacterial corneal ulcers may manifest as: i . Purulent corneal ulcer without hypopyon; or ii. Hypopyon corneal ulcer. Symptoms In general Pain and foreign body sensation occurs due to mechanical effects of lids and chemical effects of toxins on the exposed nerve endings. Watering from the eye occurs due to reflex hyperlacrimation . Photophobia, i.e., intolerance to light results from stimulation of nerve endings. Blurred vision results from corneal haze. Redness of eyes occurs due to congestion of circumcorneal vessels.

16. Signs : Lids are swollen. Marked blepharospasm may be there Conjunctiva is chemosed & shows conjunct hyperaemia & ciliary congestion. Corneal ulcer usually starts as an epithelial defect associated with greyish-white circumscribed infiltrate (seen in early stage). The epithelial defect & infiltrate enlarges & stromal oedema develops. A well established bacterial ulcer is characterized by : Yellowish-white area of ulcer which may be oval or irregular in shape. Margins of the ulcer are swollen and over hanging. Floor of the ulcer is covered by necrotic material. Stromal oedema is present surrounding the ulcer area

17. Hypopyon corneal ulcer Many pyogenic organisms (staphylococci, streptococci, gonococci, Moraxella) may produce hypopyon Most dangerous are pseudomonas pyocyanea and pneumococcus. The characteristic hypopyon corneal ulcer caused by pneumococcus is called ulcus serpens Source of infection for pneumococcal infection is usually the chronic dacryocystitis . Factors predisposing to development of hypopyon. Two main factors which predispose to development of hypopyon in a paitent with corneal ulcer are, the virulence of the infecting organism and the resistance of the tissues. Hence, hypopyon ulcers are MC in old debilitated or alcoholic subjects

18. Mechanism of development of hypopyon Corneal ulcer is often associated with some iritis owing to diffusion of bacterial toxins. When the iritis is severe the outpouring of leucocytes from the vessels is so great that these cells gravitate to the bottom of the anterior chamber to form a hypopyon. Thus, the hypopyon is sterile since the outpouring of polymorphonuclear cells is due to the toxins and not due to actual invasion by bacteria. Once the ulcerative process is controlled, the hypopyon is absorbed

19. Symptoms are the same as described above During initial stage of ulcus serpens there is remarkably little pain. As a result the treatment is often undully delayed. Signs In general the signs are same as described above Typical features of ulcus serpens are : a greyish white or yellowish disc shaped ulcer occuring near the centre of cornea The ulcer has a tendency to creep over the cornea in a serpiginous fashion. One edge of the ulcer which the ulcer spreads shows more infiltration. The other side of the ulcer may be undergoing simultaneous cicatrization and the edges may be covered with fresh epithelium. Violent iridocyclitis is commonly associated with a definite hypopyon. Hypopyon increases in size very rapidly & often results in 2 glaucoma. Ulcer spreads rapidly and has a great tendency for early perforation.

20. Streptococcus pneumoniae ulcer serpens One edge (active and leading) with hypopyon

21. Suppurative ulcerative keratitis

22. Evaluation of ocular surface and adnexa in keratitis : Eyelid margins Meibomian gland dysfunction, Margin ulceration, eyelash abnormalities, Punctal abnormalities Tear film -Dry eye, debris Conjunctiva Discharge, inflammation, follicles, papillae, cicatrization , keratinization, membrane, foreign bodies, limbal health, filtering blebs

23. Sclera inflammation Ulceration Scarring thinning Nodules Cornea Epithelial defect – location,size,shape,satellite lesions,punctate defects Stroma – chr of infiltrate margin , colour of infiltrate, thinning/perforation Status of endothelium Lacrimal apparatus Regurgitation of purulent material on pressure on lacrimal sac area

24. Clinical features of diff bacterial keratitis Gram-positive Cocci Staphylococcus aureus Seen in compromised corneas such as bullous keratopathy, chronic herpetic keratitis, dry eyes, ocular rosacea. May present with marked suppuration, deep stromal abscess. Staphylococcus epidermidis - Indolent course, may also lead onto stromal abscess. Streptococcus pneumoniae Presents with a deep, oval, central stromal ulceration having a progressive edge while the other edge is healing. Posterior corneal abscess and hypopyon

25. Gram- ve bacilli Pseudomonas aeruginosa Severe inflammatory signs with greenish yellow discharge. Rapid progression, marked stromal melt, ring infiltrate, and later descemetocele formation or perforation. Surrounding stroma shows ground glass appearance, diffuse greying of epithelium. stromal necrosis with a shaggy surface and adherent mucopurulent exudate An endothelial inflammatory plaque, marked anterior chamber reaction, and hypopyon frequently occur Proteus -Similar to pseudomonas Klebsiella -More often associated chronic epithelial disease

26. Pseudomonas keratitis with greenish pus

27. Moraxella Produces keratitis after trauma in debilitated, alcoholic, malnourished or diabetic patients. An indolent ulceration with mild to moderate anterior chamber reaction Neisseria gonorrhea Rapidly progressive, hyperpurulent conjunctivitis, with marked chemosis with stromal infiltration Nocardia Indolent ulcerations after minor trauma particularly exposure to contaminated soil. Characteristically, raised, superficial, pinhead like infiltrates in a wreath like configuration, brush fire like border with multifocal lesions

28. Nocardia keratitis showing wreath like arrangement of dot like infiltrates

29. Non-tuberculous mycobacteria ( M.chelonae M.fortuim ) Causes a slowly progressive keratitis, usually by contaminated sharp instruments (atypical like knife, blade and sutures. Occurs after mycobacteria) corneal trauma or corneal surgery, particularly after LASIK. Lesions can be, solitary or multifocal infiltrates with spoke M.chelonae like margins. They tend to heal very slowly. Bacillus cereus (Gram + ve bacillus) keratitis usually follows trauma or wound contamination. Keratitis characterized by a distinctive stromal ring infiltrate remote from the site of injury, with rapid progression to stromal abscess.

30. Early mycobacterial infiltration Mycobacterial stromal infiltration

31. Infectious crystalline keratopathy (ICK) was first reported in 1983, characterized by white crystalline conglomerate of bacterial colony within the corneal stroma with branching linear extensions with almost absent host inflammatory reaction. A low virulent or nutritionally different micro-organism gains entry through a suture track or other injury and starts proliferating along the stromal lamellae but fails to incite inflammatory response. Most commonly reported in corneal grafts adjacent to sutures, local or systemic immunocompromised conditions and even after post LASIK procedure. Risk factors include corticosteroid use, contact lens wear, Previous corneal surgery.

32. MCC is alpha- hemolytic Streptococci. Others organisms include Streptococcus pneumoniae, Staphylococcus epidermidis, Peptostreptococcus , Hemophilus aphrophilus , enterococci, Pseudomonas, Mycobacterium and fungi like Candida and Alternaria.

33. The biofilm glycocalyx produced by these organisms is thought to be the reason for failure of host reaction as well as ineffectiveness of topical therapy to eradicate the infection Definitive diagnosis requires isolation of the causative organisms, either with use of corneal biopsy or 25 gauge needle. Polymerized chain reaction and DNA typing is a recently added advanced tool to diagnose the infective etiology

34. Infectious crystalline keratopathy in a corneal graft caused by α-haemolytic Streptococcus species.

35. HISTOPATHOLOGY OF MICROBIAL KERATITIS Stage 1: Stage of progressive infiltration: Includes adherence and entry of the organism, diffusion of toxins and enzymes, and resultant tissue destruction. Shortly after the bacterial adherence, polymorphonuclear leukocytes arrive at the site. Stromal damage caused by bacterial and neutrophil enzymes facilitates progressive bacterial invasion. Stage 2: Stage of active ulceration: There is progressive tissue necrosis with subsequent sloughing of the epithelium and stroma, resulting in a sharply demarcated ulcer with surrounding neutrophilic infiltration. If organisms penetrate deeper into the stroma with progressive tissue necrosis, it may result in descemetocele formation or perforation

36. Stage 3: Regressive stage: Characterized by improvement in clinical signs and symptoms. Natural host defence mechanisms predominate and humoral and cellular immune defence mechanisms together with antibacterial therapy try to retard bacterial replication, promote phagocytosis of the organism and cellular debris. Vascularization may start if the ulceration is of long duration. Stage 4: Healing stage : Characterized by epithelialization of ulcerated area, replacement of necrotic stroma with scar tissue, which is produced by fibroblasts.

37. Complications of corneal ulcer Toxic iridocyclitis It is usually associated purulent corneal ulcer due to absorption of toxins in the anterior chamber. Secondary glaucoma due to fibrinous exudates blocking the angle of anterior chamber (inflammatory glaucoma). Descemetocele Some ulcers caused by virulent organisms extend rapidly up to Descemet's membrane,which gives a great resistance, but due to the effect of intraocular pressure it herniates as a transparent vesicle called the descemetocele or keratocele This is a sign of impending perforation and is usually associated with severe pain

38. Perforation of corneal ulcer Sudden strain due to cough, sneeze or spasm of orbicularis muscle may convert impending perforation into actual perforation Following perforation, immediately pain is decreased and the patient feels some hot fluid (aqueous) coming out of eyes. Sequelae of corneal perforation include : Prolapse of iris. It occurs immediately following perforation in a bid to plug it. Subluxation or anterior dislocation of lens may occur due to sudden stretching and rupture of zonules . Anterior capsular cataract. It is formed when the lens comes in contact with the ulcer following a perforation in the pupillary area.

39. 4 .Corneal fistula. It is formed when the perforation in the pupillary area is not plugged by iris and is lined by epithelium which gives way repeatedly. There occurs continuous leak of aqueous through the fistula. 5 .Purulent uveitis, endophthalmitis or even panophthalmitis may develop due to spread of intraocular infection. 6 .Intraocular haemorrhage in the form of either vitreous haemorrhage or expulsive choroidal haemorrhage may occur in some patients due to sudden lowering of intraocular pressure. Corneal scarring . It is the usual end result of healed corneal ulcer. Corneal scarring leads to permanent visual impairment ranging from slight blurring to total blindness.

40. Management of a case of corneal ulcer Thorough history taking to elicit mode of onset, duration of disease and severity of symptoms General physical examination - built, nourishment, anaemia immune status Ocular examination should include: Diffuse light examination for gross lesions of the lids, conjunctiva and cornea including testing for sensations. Regurgitation test and syringing to rule out lacrimal sac infection. Biomicroscopic examination after staining of corneal ulcer with 2% fluorescein to note site, size, shape, depth, margin, floor and vascularization of corneal ulcer. presence of keratic precipitates at the back of cornea, depth and contents of anterior chamber, colour and pattern of iris and condition of crystalline lens

41. bacterial ulcer stained with flourescein

42. Laboratory investigations of microbial keratitis Routine laboratory investigations such as HB, TLC, DLC, ESR, RBS, complete urine and stool examination Microbiological investigations Corneal scraping to obtain specimens for microbiological staining and cultures. cultures are indicated in cases with large corneal infiltrates, infiltrates that extend into deeper stroma, that is chronic in nature or is unresponsive to empirical therapy or that has clinical features of fungal, amoebic or mycobacterial keratitis. Corneal specimen is usually obtained by heat sterilized platinum [Kimura] spatula or 15 number blade. In cases with primary involvement of deep stroma, a small trephine may be used to obtain a corneal biopsy

43. Stains The material for smear is applied on a clean glass slide to make a thin, even film. Gram's stain: sensitivity of 55 to 79 percent. It can also identify fungal filaments and amoebic cysts. Grampositive bacteria appear bluish-purple Gram-negative bacteria appear pink. It can also identify filamentary bacteria like Nocardia Giemsa stain: It is primarily used to distinguish the types of inflammatory cells and intracytoplasmic inclusions. It can distinguish bacteria from fungi. Chlamydia inclusion bodies may be identified with Giemsa stain.

44. Gram+ve fine filaments of nocardia Gram+ve diplococci Gram- ve bacteria

45. Ziehl-Neelsen acid fast staining: This is done for identification of suspected mycobacterium, Actinomyces or Nocardia. Mycobacterium is acid fast, Nocardia variably stained while Actinomyces is not acid fast. Acridine orange and calcofluor white stains are fluorochromatic dyes which stain micro-organisms and fluoresce. Culture As corneal scraping specimens are usually very small in quantity, they should be inoculated directly onto the culture plates directly. While plating the culture media, specimen should be inoculated in C streaks to distinguish valid bacterial growth from plating contamination. Antimicrobial susceptibility - Standard disc diffusion or microdilution techniques

46. TREATMENT primary goal of therapy is preservation of sight and corneal clarity. Bacterial pathogens can produce irreversible corneal scarring over a period of hours because of their rapid growth, keratolytic enzymes, and stimulation of destructive host immune responses. Therefore, therapy must be initiated before definitive diagnosis is obtained in order to rapidly reduce the bacterial load and minimize later visual disability

47. Initial therapy is empirical with topical broad-spectrum coverage. Topical Monotherapy : Topical FQ initially be given every 30–60 minutes and then tapered in frequency according to the clinical response. In severe cases, administration of antibiotics every 5 min for 30 min as a loading dose can more rapidly achieve therapeutic concentrations in the corneal stroma. 2 nd gen FQ (cipro, ofloxacin) has excellent Pseudomonas coverage but lack useful gram-positive activity. 3 rd & 4 th gen FQ ( eg , moxi , gati , levo , besifloxacin)have improved gram-positive and atypical mycobacterial coverage but limited activity against MRSA.

48. Topical combination therapy One agent active against gram+ve bacteria & another agent active against gram- ve bacteria Indications : if monotherapy fails or if at initial presentation the ulcer is large, vision threatening, or atypical in nature

49. Sub-conjunctival injections of antibiotics are reserved for non-compliant patients. Cycloplegics are used to relieve pain due to ciliary spasm. Homatropine 1% is preferable, since atropine can increase anterior chamber inflammation cyclopentolate can be more irritative. Systemic analgesics and anti-inflammatory such as paracetamol and ibuprofen relieve the pain and decrease oedema. Vitamins (A, B-complex and C) help in early healing Physical and general measures (a) Hot fomentation. Local application of heat (preferably dry) gives comfort, reduces pain and causes vasodilatation. (b) Dark goggles may be used to prevent photophobia. (c) Rest, good diet and fresh air may have a soothing effect

50. Fortified antibiotics compounded at increased concentrations compared to their commercial formulations in order to achieve therapeutic levels in the corneal stroma are more difficult to obtain have a greater toxic effect on the ocular surface, should consider using especially in combination with vancomycin for gram+ve coverage when MRSA is suspected with large or vision-threatening ulcers, or with prior antibiotic failure.

51. organism Antibiotic Preparation Gram+ve Cefazolin 5% Cefuroxime 5% 500 mg IV preparation mixed in 10 ml of artificial teras (AT) Multidrug resistant Gram + ve Vancomycin 2–5% Amikacin 2–5% IV vancomycin in AT Gram- ve Ceftazidime 5% Amikacin 2–5% 500 mg in 10 ml AT Multidrug resistant Gram- ve Tobramycin 14 mg/ml Cefotoxime 5% Diluted in AT Nocardia 4 th gen FQ ,0.3% Clarithromycin ,4 mg/ml Amikacin Atypical Mycobateria 4 th gen FQ

52. Most infectious keratitis is culture- ve after 48–72 hours if treated effectively Treatment should be continued until substantial control of the infection is seen. A prophylactic broad-spectrum antibiotic (not a fortified antibiotic) may be given at a therapeutic dose until the corneal epithelium is healed

53. Systemic antibiotics FQ -have excellent ocular penetration Intensive topical antibiotics are indicated in cases with suspected scleral and/or intraocular extension of infection clinical parameters are useful to monitor clinical response to antibiotic therapy: blunting of the perimeter of the stromal infiltrate decreased density of the stromal infiltrate makes the fuzzy infiltrate margin to become more defined and demarcated. reduction of stromal edema and endothelial inflammatory plaque reduction in anterior chamber inflammation reepithelialization cessation of corneal thinning

54. Treatment of non-healing corneal ulcer Removal of any known cause of non-healing ulcer like Local causes: Associated raised intraocular pressure, concretions, misdirected cilia, impacted foreign body, dacryocystitis , inadequate therapy, wrong diagnosis, lagophthalmos and excessive vascularization of ulcer. Systemic causes: Diabetes mellitus, severe anaemia, malnutrition, chronic debilitating diseases and patients on systemic steroids. Mechanical debridement of ulcer to remove necrosed material by scraping floor of the ulcer with a spatula under LA may hasten healing. Cauterisation with pure carbolic acid or 10-20 % trichloracetic acid. Bandage soft contact lens may also help in healing. Peritomy, i.e., severing of perilimbal conjunctival vessels may be performed when excessive corneal vascularization is hindering healing.

55. Treatment of impending perforation 1. No strain. The patient should be advised to avoid sneezing, coughing and straining during stool etc.strict bed rest. 2. Pressure bandage should be applied to give some external support. 3. Lowering of IOP by acetazolamide 250 mg QID orally, intravenous mannitol (20%) drip stat, Oral glycerol twice a day, 0.5% timolol eyedrops twice a day, and paracentesis 4. Tissue adhesive glue such as cynoacrylate is helpful in preventing perforation. 5. Conjunctival flap: The cornea may be covered completely or partly by a conjunctival flap to give support to the weak tissue. 6. Bandage soft contact lens may also be used. 7. Penetrating therapeutic keratoplasty (tectonic graft)

56. Role of corticosteroid therapy for bacterial keratitis remains controversial. 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 about steroid therapy used concomitantly with antibiotic therapy or after it is initiated

57. Penetrating keratoplasty 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.