Treatment of Microbial Keratitis- Indian Guidelines

Microbial keratitis is an important cause of avoidable monocular blindness in India. Young adults in their prime working age group are most commonly affected and hence the loss of man years of productivity is extremely high. The therapeutic results are less than satisfactory even in the most optimistic situations. Even the so called successfully treated cases end up with a corneal scar which might impair vision. The cost of treatment is compounded by the long treatment schedules and frequent follow ups to the hospital A significant percentage of patients fail medical treatment, and will require corneal transplantation. The availability of donor corneas in India is extremely low. Currently only 5% of the requirement is being met. Under these circumstances, it becomes very clear that adequate and appropriate therapy at all levels and more importantly preventive strategies at the primary level will go a long way in preventing this unnecessary catastrophe.

The Ministry of Health and Family Welfare has issued the standard treatment Ophthalmology Guidelines for Microbial Keratitis. Following are the major recommendations:

Case definition:

A theoretical definition of a corneal ulcer is a loss of the overlying epithelium with underlying infiltration. However, for all practical purposes, microbial keratitis includes any condition which causes suppurative infection of the cornea. Further progress of the disease can cause necrosis of the deeper stromal tissue, resulting in perforation and loss of intraocular contents.

Incidence of the condition in Our Country

It is an extremely common condition causing significant ocular morbidity in our country. In fact, an editorial in the British Journal of Ophthalmology called it as an silent epidemic. Gonzales et al found that the annual incidence of corneal ulceration in Madurai district in South India was 113 per 1,00,000 people. By applying the 1993 corneal ulcer incidence rate in Madurai district to whole of India, about 8,40,000 people are likely to develop a corneal ulcer in a year. Even this figure is quoted as an under estimation when compared to other SAARC countries. This figure is thirty times more than the number of corneal ulcers seen in the United States.

Differential Diagnosis

The term microbial keratitis is often reserved for conditions caused by microorganisms which results in suppuration. The common causative organisms can be bacteria, fungi or, parasites. Other conditions which can mimic a suppurative keratitis includes

• Viral keratitis


• Marginal keratitis caused by hypersensitivity reactions


• Ulcerative keratitis secondary to inherent connective tissue disorders


• Toxic keratitis


• Exposure and neurotrophic keratitis


• Corneal ulceration secondary to Vitamin A deficiency in children.

Prevention and Counselling

Avoiding exposure to predisposing factors may minimize the risk of microbial keratitis. The majority of corneal ulcers follow trivial corneal abrasions. The use of traditional eye medicines (TEMs) is an important risk factor for corneal blindness, since they are often contaminated and provide a vehicle for the growth of pathogenic organisms. The common TEM's used in our country includes breast milk, castor oil and leaf extracts. Training traditional healers in asepsis, banning harmful medicines and directing patients to appropriate health care facilities would be the first rewarding approach in preventing corneal blindness due to red eye and corneal injuries. Ocular surface disease such as Trachoma, dry eye, lagophthalmos and Vitamin A deficiency should be treated. Routine use of prophylactic topical antibiotics in this setting is controversial because their efficacy has not been established and may promote growth of resistant organisms. Even though keratomalacia is rare, still we see children going blind due to Vitamin A deficiency. Proper diet counseling and Vitamin A supplementation will totally eradicate keratomalacia from our country.

Optimal Diagnostic Criteria, Investigations, Treatment and Referral Criteria

At Secondary Hospital

Clinical Diagnosis:

An adequate history taking, coupled with a comprehensive evaluation goes a long way in establishing a clinical diagnosis which can then be confirmed by microbiological examination. Patients come with varying degrees of pain, photophobia, watering and redness of eyes and may also complain of defective vision, especially if the visual axis is involved.

History

Eliciting a proper history with regards to nature of trauma and use of TEM is crucial step in the management of microbial keratitis. Trauma with vegetable matter such as paddy husks or onions are more likely to cause a fungal keratitis. Contact with contaminated or brackish water is likely to produce Acanthamoeba keratitis. In cases of contact lens wearers, it is imperative to take history of wearing schedule and lens care.

Examination

The ocular examination includes recording visual acuity, an external eye examination and slit-lamp biomicroscopy of affected and normal eye.

Visual Acuity measurement

Due to acute infection of the involved eye, it is difficult to record visual acuity accurately. However, an approximate visual acuity with or without optical correction will give a baseline data to aid in the appropriate management strategy and also to monitor the healing process.

External Examination

An external examination should be performed with particular attention to the following:

• General appearance of the patient


• Facial examination


• Eyelids and lid closure


• Conjunctiva


• Nasolacrimal apparatus


• Corneal sensation

Slit-lamp Biomicroscopy

Should include evaluation of the following:

Eyelid margins: Inflammation, ulceration, eyelash, and abnormalities including trichiasis, irregularities, and lacrimal punctal anomalies.

Conjunctiva: Discharge, inflammation, morphologic alterations (e.g. follicles, papillae, cicatrization, keratinization, membrane, pseudomembrane, ischemia, and foreign bodies).

Sclera: Inflammation, (e.g. infectious, versus autoimmune), ulceration, scarring / thinning, nodules, ischemia.

Cornea: Epithelium, including defects and punctate keratopathy, edema Stroma, including ulceration, thinning, perforation, and infiltrate (location [central, peripheral, perineural, surgical, or traumatic wound], density, size, shape [ring], number [satellite], depth, character of infiltrate margin [suppuration, necrosis, feathery, soft, crystalline], color), edema

Signs of corneal dystrophies (e.g., epithelial basement membrane dystrophy)

Previous corneal inflammation (thinning, scarring, or neovascularization)

Signs of previous corneal or refractive surgery

Fluorescein (or, occasionally, rose bengal staining) of the cornea is usually performed and may provide additional information about other factors, such as the presence of dendrites, pseudodendrites, loose or exposed sutures, foreign body, and any epithelial defect.

Clinical features suggestive of bacterial keratitis include dense suppurative stromal infiltrate with distinct edges and edema. The symptoms are typically more prominent than the signs. Fungal keratitis presents with dry raised surface and feathery indistinct margins. Accompanying satellite lesions may be present in few cases. Acanthamoeba keratitis usually presents with a ring shaped stromal infiltrate, as a late clinical feature and commonly it is misdiagnosed as viral keratitis. It has to be emphasized however that all these features are only suggestive of the organism and microbiological confirmation should be sought for proper identification.

Investigations:

Microbiological investigations:

While characteristic clinical features have been described for ulcers caused by different microorganisms, it is difficult to confirm these, especially after the disease has become well established. Patients present late in our country and by this time, the clinical demarcation between the ulcers caused by bacteria and fungi are usually lost. Since bacteria and fungi cause an almost equal proportion of keratitis in our country, it is highly essential to perform at least a smear test before initiating the treatment. Corneal infective material is obtained by scraping after instilling a topical anesthetic agent (4% lignocaine) and using a flame sterilized platinum spatula, blade or other similar sterile instrument. The material is obtained from the advancing borders; ulcer base and edges. Two smears are initially prepared – one with Gram's stain (for identifying bacteria, fungi, and Acanthamoeba) and the other with 10% potassium hydroxide (for fungus).

Biochemical investigations: A baseline evaluation for diabetes mellitus should be performed. Some of these patients have undiagnosed diabetes, which might hinder with the healing of the ulcer.

Treatment:

The treatment for suppurative keratitis is often prolonged. The importance of a regular follow up should be adequately emphasized to the patient before the initiation of the appropriate anti microbial therapy. A careful counseling of the dosages of the individual medicine should be adequately explained to the patient and an accompanying person so that it will be applied in the right manner. The treatment strategy should be guided by the microbiological investigations and the clinical appearance of the ulcer.

Bacterial Keratitis: Topical antibiotics are capable of achieving high tissue levels and are the preferred route in most cases. Ointments may be useful in children and at bedtime. Routine subconjunctival antibiotics are not necessary unless the compliance of the patient is doubtful or poor

For severe keratitis (ulcer more than 5mm and deep), a loading dose at every 5 to 15 minutes during the first hour, followed by applications every 15 minutes to 1 hour during waking hours is recommended. It is ideal to treat the patient as inpatient. For non-severe keratitis, a regimen with less frequent dosing is appropriate. Cycloplegic agents may be used to prevent synechia formation and to decrease pain. Small ulcers less than 2 mm and away from the visual axis do not need cycloplegics. Gram positive cocci are the most important cause of bacterial keratitis in our country. Topical eye drops of Chloramphenicol (0.5%) and Cefazolin (5 to 10%) are ideal for gram positive cocci. S. pneumoniae, which is the most common bacterial isolate in our country, has variable susceptibility to fluoroquinolones and hence fluoroquinolones may not be the ideal antibiotic for monotherapy for gram positive organisms in our country . Gram negative bacilli respond very well to fluoroquinolones and aminoglycosides. Single drug therapy using a fluoroquinolone has shown to be as effective as combination therapy utilizing topical antibiotics that are commercially available. But recent reports do not recommend this in view of more drug resistance. The following table gives the dosage schedule of commonly used antibacterial agents.

Antibiotic Therapy of Bacterial Keratitis

Note: Systemic antibiotics are recommended only when the ulcer involves sclera or perforates. Fortified antibiotic therapy is a good armament to treat bacterial keratitis. The preparation and the indication for such a therapy is described in the following paragraph

Preparation of fortified antibiotics:

Gentamicin and Tobramycin

Add 2 ml of injectable Gentamicin or Tobramycin to 5 ml commercial topical preparation in a sterile set up using disposable syringe.

5 ml commercial has - 15 mg

Added drug - 80 mg

Total in 7 ml - 95 mg

1 cc contains 13.5 mg or 1.35%

Cefazolin:

Add 5 ml or 10 ml of distilled water or sterile saline to 500 mg vial of cefazolin to obtain 10% or 5% solution. Use a dropper, which is available in the pharmacy or other source.

Vancomycin:

Add 10 ml distilled water or saline to 500mg vial of Vancomycin and obtain a 5% solution.

Amikacin:

1% would be sufficient. Add 10cc distilled water to 100mg of Amikacin. Use a sterile empty Xylocaine vial and place the cap for ready use. All these solutions could be safely used for a week. If it is applied frequently as recommended it will not last more than a week.

The treatment of fungal keratitis remains as a challenge. All the available antifungal agents are fungistatic and not fungicidal. The penetration of the drugs is poor particularly when the epithelial defect is small. It leads to prolonged treatment, often leading to poor compliance with antifungal therapy. Natamycin (5%) and Amphotericin -B(0.15%-0.5%) are the most efficacious among the available topical antifungal agents against filamentous fungi. Voriconazole 1% is a recent addition in the treatment of filamentous fungi. A recently published randomized clinical trial demonstrated that the safety and efficacy of Natamycin and Voriconazole are comparable when used for fungal keratitis .Use of systemic antifungals like imidazoles and triazoles are reserved for deep keratitis associated with scleritis and endophthalmitis. The following table gives the dosage schedule of commonly used antifungal agents.

Therapy of fungal Keratitis

Other Drugs

• Itraconazole – oral – 300 mg daily (only 55 to 60 % efficacy) Several clinical features suggest the response to antimicrobial therapy.


• Decreased pain.


• Consolidation and sharper demarcation of the periphery of the stromal infiltrate.


• Decreased density of the stromal infiltrate.


• Reduction of stromal edema and endothelial inflammatory plaque.


• Dilatation of the pupil.


• Re-epithelialization.


• Reduction in congestion of bulbar conjunctiva


• Visual improvement

Topical therapy is tapered according to the clinical response, taking into account the baseline clinical picture and the virulence of the pathogen.

Standard Operating Procedure

In Patient

• Severe keratitis (ulcer more than 5mm and deep)


• No response to initial management


• Doubtful compliance

Out Patient

• Small ulcers


• Patients who can come for frequent follow up and those who understand the importance of compliance

Referral criteria:

Immediate referral on presentation if there is

• Immediate threat to vision


• Ulcer involved in the only seeing eye


• Pediatric patients needing anesthesia


• Impending or actual perforation

Referral following initial treatment if,

Non healing or progressive ulcer inspite of adequate and appropriate anti microbial therapy, apart from all the points mentioned above.

At Super Specialty Hospital

Clinical Diagnosis:

Apart from the regular history taking, care should be exercised to fully understand the treatment history of the patient, including all the medications along with the dosage schedules which were prescribed at the secondary centre. This will avoid unnecessary wastage of medicines and help in formulating an ideal treatment strategy. A fresh comprehensive clinical examination, as detailed in the previous section should be performed without being biased by the referral report.

Investigations:

Microbiology: Since the patient has been referred for a potentially serious condition, a comprehensive microbiological evaluation including additional culture, antibiotic sensitivity testing and if necessary, a corneal biopsy should be performed. A repeat smear examination should be ordered for and carefully looked for mixed organisms. Routine culture examinations are useful for the following reasons.

1. Gold standard that confirm gram stain microscopy (GSM)


2. Provide sensitive data, including antibiotic sensitivity measurement to enable modification of initial therapy


3. It will serve as an useful tool to understand the causative organisms prevalent in the region

The cultures should be selected to identify common organisms like fungi and bacteria. An ideal minimal culture tests would use blood agar and Sabouraud's dextrose agar. Special culture medial such as non nutrient agar should be reserved for non responsive cases or cases which show clinical suspicion of Acanthamoeba. Ocular bacterial cultures usually grow within 48 hours while the fungi from the ocular specimens grow within 7 days.

Recommended Stains and Culture media for Microbial Keratitis

Note: Acridine orange – GMS – if facilities available, use it.

Corneal biopsy:

53 It may be performed in the following conditions

• Deeper stromal lesions which are non accessible to routine corneal scrapings


• Ulcers which show a negative culture, probably because of inadequate specimen

Treatment:

The treatment strategies should be revisited to check for adequacy, appropriateness and affordability. If the culture grew a different organism, then the treatment regimen should be modified appropriately as recommended in the previous table. If the ulcers continue to worsen in spite of correct treatment, then surgical options should be considered.

Surgical Procedure may include:

Ulcer Debridement:

• Enhance penetration of topical medication


• Debulking of infective material

Tissue adhesive

• Microperforation


• Peripheral corneal ulcer with descematocoele

Dacryocystectomy if lacrimal sac infection in same eye

Penetrating Keratoplasty

Therapeutic keratoplasty has to be performed when the ulcer progresses despite specific anti-microbial therapy leading to descemetocele or perforation. The microperforation could be diagnosed by noticing a decrease in the size of the hypopyon, radial folds from the base of the ulcer and relief from pain. Sometimes it may seal spontaneously and healing will be faster. If the anterior chamber is formed within 48 hours with bandage or other supportive therapy therapeutic keratoplasty could be avoided or postponed. The goals of the therapeutic keratoplasty are to eliminate the infection and restore the integrity of the globe. The size of the graft should be decided on the basis of the size of the ulcer and should include the infected edges. Fresh donor corneas give better results in Phakic eyes. Steroid in any form should be avoided post operatively in fungal ulcers.

Tarsorrhaphy: can be considered in neurotrophic and exposure keratitis

Standard Operating Procedure

In Patient

• Immediate threat to vision


• Ulcer involved in the only seeing eye


• Pediatric patients needing anesthesia


• Impending or actual perforation


• Any patients requiring surgery

Out Patient

• If the patient requires only modification of the topical antibiotics, then he/she can be treated as outpatients.

Who Does What and Timelines

Doctor

• Patient History is taken and a Clinical Examination performed


• Corneal infective material is obtained by scrapping and smear are prepared and also materials are inoculated directly onto culture media


• Documenting the medical record


• Plan treatment guidelines and perform surgery if necessary.


• Monitoring, publication and reporting to department of health if there is an epidemic of drug resistant pathogen and iatrogenic corneal ulcer (Contact lens, refractive Surgery related)

Nurse/Technician

• Prepare Slide, Media for smear and culture


• To monitor the patients who are admitted regarding application of eye drops and ensure compliance


• To maintain separate inpatient and outpatient record


• To maintain lab reports

Resources Required

Situation	Human Resources	Investigation	Drug and Consumables	Equipment
1) Secondary level	1)Ophthalmologist - 1 2)OP Nurse – 1 3)Refraction nurse - 1(shared )	1) Smear test 2) Gram stain microscopy 3) KOH smear 4) Blood sugar 5) Lacrimal syringing	1) Antibiotics eye drops 2) Antifungal eye drops 3) Systemic antibiotics and anti fungal 4) Vitamin A 5) Cyclopiegics	1)Slit lamp - biomicroscope -1 2)Light microscope -1
2) Tertiary level	1)Cornea specialist - 1 2)Refraction nurse - 1(shared ) 3)OP Nurse - 1 4)lab technician – 1 5)Scrub nurse – 1 6)OT nurse – 1 7)Ward nurse - 1	1) Smear test 2) Culture medium 3) Antibiotic sensitivity 4) Corneal biopsy 5) AC tap 6) PCR 7) Blood sugar 8) Lacrimal syringing	1) Antibiotics eye drops/ointment 2) Antifungal eye drops/Ointment 3) Systemic antibiotics and anti fungal 4) Vitamin A 5) Topical and systemic steroids 6) Suture materials 7) Needles and syringes	1)Slit lamp - biomicroscope -1 2)Light microscopy -1 3)Confocal microscope -1 4)Specular microscope -1 5) OT microsurgical instruments including trephines. 6)Well equipped microbiological laboratory for smear, culture and PCR) 7)Eye Bank equipment

Guideline developed by Ministry of health and family Welfare-

Group Head Coordinator of Development Team Dr. Venkatesh Prajna Chief- Dept of Medical Education, Aravind Eye Hospitals, Madurai