Bacterial Keratitis

Bacterial keratitis is a serious ocular problem that can, if not appropriately treated, lead to sight-threatening complications such as corneal scarring, perforation, endophthalmitis, and, ultimately, blindness. A particular feature of bacterial keratitis is its rapid progression; corneal destruction may be complete in 24-48 hours with some of the more virulent bacteria. Corneal ulceration, stromal abscess formation, surrounding corneal edema, and anterior segment inflammation are characteristic of this disease. (See image below.)

Human eye anatomy.

Bacterial keratitis remains one of the most important potential complications of contact lens use. Keeping this in mind, early diagnosis and treatment are key to minimizing any visual-threatening sequelae. In addition, close follow-up, attention to laboratory data, and changing antimicrobials if no clinical improvement is evident are important elements for successful outcome.

Interruption of an intact corneal epithelium and/or abnormal tear film permits entrance of microorganisms into the corneal stroma, where they may proliferate and cause ulceration. In addition, some bacteria can penetrate an intact corneal epithelium to cause infection. Virulence factors may initiate microbial invasion, or secondary effector molecules may assist the infective process. Many bacteria display several adhesins on fimbriated and nonfimbriated structures that may aid in their adherence to host corneal cells. During the initial stages, the epithelium and stroma in the area of injury and infection swell and undergo necrosis. Acute inflammatory cells (mainly neutrophils) surround the beginning ulcer and cause necrosis of the stromal lamellae.

Diffusion of inflammatory products (including cytokines) posteriorly elicits an outpouring of inflammatory cells into the anterior chamber and may create a hypopyon. Different bacterial toxins and enzymes (including elastase and alkaline protease) may be produced during corneal infection, contributing to the destruction of corneal substance.

The most common groups of bacteria responsible for bacterial keratitis are as follows: Streptococcus, Pseudomonas, Enterobacteriaceae (including Klebsiella, Enterobacter, Serratia, and Proteus), and Staphylococcus species.

Up to 20% of cases of fungal keratitis (particularly candidiasis) are complicated by bacterial coinfection.

Frequency

United States

Approximately 25,000 Americans develop bacterial keratitis annually.

International

Incidence of bacterial keratitis varies considerably, with less industrialized countries having a significantly lower number of contact lens users and, therefore, significantly fewer contact lens-related infections.

Mortality/Morbidity

In cases of severe inflammation, a deep ulcer and a stromal abscess may coalesce, resulting in thinning of the cornea and sloughing of the infected stroma. These processes may create some of the following complications:

Corneal leukoma

Scar tissue formation with the presence of corneal vascularization may be the end result of a bacterial keratitis. Depending on the location and depth of stromal involvement, the resulting corneal leukoma may be visually significant and necessitate corneal surgery for visual rehabilitation (including phototherapeutic keratectomy [PTK] or penetrating keratoplasty [PK]).

Irregular astigmatism

Another possible complication of these infections is uneven healing of the stroma, resulting in irregular astigmatism (that may require a gas-permeable contact lens or PTK to improve vision).

Endophthalmitis

Bacteria can penetrate the cornea and infect the internal contents of the eye, potentially requiring intravitreal injection of antibiotics or surgery for treatment.

Corneal perforation

This is one of the most feared complications of bacterial keratitis that may result in secondary endophthalmitis and possible loss of the eye.

The visual prognosis depends on several factors, as outlined below, and may result in a mild-to-severe decrease in best-corrected visual acuity.

• Virulence of the organism responsible for the keratitis

• Extent and location of the corneal ulcer

• Resulting vascularization and/or collagen deposition

Patients who are contact lens wearers (in particular extended-wear contact lenses) should be instructed not to force the use of contact lenses when they have hyperemia, irritation, or foreign body sensation, and to use sterile contact lens solutions to avoid contamination.

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education article Corneal Ulcer.

Patients with bacterial keratitis usually complain of rapid onset of pain, photophobia, and decreased vision. It is important to document a complete systemic and ocular history in these patients to identify any potential risk factors that would have made them susceptible to develop this infection, including the following:

• Contact lens wear (Note the type of lens, wearing time, and type of disinfection system.)
• Trauma (including previous corneal surgery)
• Use of contaminated ocular medications
• Decreased immunologic defenses
• Use of immunosuppressive agents such as steroid drops that may predispose to infection
• Aqueous tear deficiencies
• Recent corneal disease (herpetic keratitis, neurotrophic keratopathy)
• Structural alteration or malposition of the eyelids

External and biomicroscopic examination of these patients reveals some or all of the following features:

• Ulceration of the epithelium; corneal infiltrate with no significant tissue loss; dense, suppurative stromal inflammation with indistinct edges; stromal tissue loss; and surrounding stromal edema
• Anterior chamber reaction (cells and flare) with or without hypopyon
• Folds in the Descemet membrane
• Upper eyelid edema
• Posterior synechiae
• Surrounding corneal inflammation that is either focal or diffuse
• Conjunctival hyperemia
• Adherent mucopurulent exudate
• Endothelial inflammatory plaque

Any factor or agent that creates a breakdown of the corneal epithelium is a potential cause or risk factor for bacterial keratitis. Furthermore, exposure to some virulent bacteria that may penetrate intact epithelium (eg, Neisseria gonorrhoeae) also may result in bacterial keratitis.

• By far the most common cause of trauma to the corneal epithelium and the main risk factor for bacterial keratitis is the use of contact lenses, particularly extended-wear contact lenses. Of patients with bacterial keratitis, 19-42% are contact lens wearers. Incidence of bacterial keratitis secondary to use of extended-wear contact lenses is about 8,000 cases per year. The annual incidence of bacterial keratitis with daily-wear lenses is 3 cases per 10,000.
• Contaminated ocular medications, contact lens solutions, or contact lens cases ^[1]
• Decreased immunologic defenses secondary to malnutrition, alcoholism, and diabetes ( Moraxella)
• Aqueous tear deficiencies
• Recent corneal disease (including herpetic keratitis and secondary neurotrophic keratopathy)
• Structural alteration or malposition of the eyelids (including entropion with trichiasis and lagophthalmos)
• Chronic dacryocystitis
• Use of topical corticosteroids

A thorough anterior-segment slit-lamp examination in patients with suspected or confirmed bacterial keratitis is essential and should include the following:

• Best corrected visual acuity
• Examination for epithelial defects (seen with fluorescein)
• Examination for corneal infiltrates (whitish opacities in the cornea)
• Examination for other corneal findings such as thinning or corneal edema
• Seidel examination for leak of aqueous humor through a perforated area of cornea, if suspicious
• Anterior chamber examination for cells, flare, and hypopyon

The most feared complication of this condition is thinning of the cornea, secondary descemetocele, and eventual perforation of the cornea that may result in endophthalmitis and loss of the eye.

Scrapings of the corneal ulcer, including the edges, should be obtained using a sterile spatula, blade, or sterile Mini-tip Calcium Alginate Swab, and they should be plated in chocolate, blood, and Sabouraud agar plates.

Microscope slides are used for stained smears with Gram, Giemsa, and acid-fast stain or acridine orange/calcofluor white (if fungi or Acanthamoeba are suspected).

Samples of the eyelids/conjunctiva, topical ocular medications, contact lens cases, and solutions also may be cultured.

In the past, some practitioners considered suspending antibiotic therapy for 12 hours before performing corneal scraping to increase the yield of a positive culture; however, most practitioners now would not recommend this technique for initial management.

In cases of mild keratitis (eg, a peripheral infiltrate < 1-2 mm), some practitioners defer corneal scrapings and treat empirically. This is especially common in community settings where a laboratory and specialized culture plates may not be readily available.

Cotton swabs contain fatty acids, which have an inhibitory effect on bacterial growth. On the other hand, calcium alginate moistened with trypticase soy broth can be used to obtain culture material to inoculate directly onto the culture media.

Topical anesthetic (proparacaine hydrochloride 0.5%) should be used to anesthetize the patient prior to culture scraping because it has the least inhibitory effect. In contrast, tetracaine and cocaine have bacteriostatic effects.

Repeat cultures can be obtained if the original cultures were negative and the ulcer is not improving clinically.

Corneal biopsy using a small trephine or a corneal blade should be considered in cases of deep stromal infiltrates, particularly if cultures are negative and the eye is not improving clinically.

Slit lamp photography can be useful to document the progression of the keratitis, and, in cases where the specific etiology is in doubt, it is used to obtain additional opinions, particularly in indolent and chronic cases not responding to antimicrobial therapy.

A B-scan ultrasound can be obtained in eyes with severe corneal ulcers with no view of the posterior segment where endophthalmitis is being considered.

Corneal biopsy

A deep lamellar excision can be made using a disposable skin punch or a small Elliott corneal trephine. The superficial cornea is incised and deepened with a surgical blade to approximately 200 microns. Then, a lamellar dissection is performed, and the material is plated directly onto culture media. A portion also can be sent for histopathologic evaluation.

During the initial stages, the epithelium and the stroma in the area of injury and infection swell and undergo necrosis. Acute inflammatory cells (mainly neutrophils) surround the beginning ulcer and cause necrosis of the stromal lamellae. In cases of severe inflammation, a deep ulcer and a deep stromal abscess may coalesce, resulting in thinning of the cornea and sloughing of the infected stroma.

As the natural host defense mechanisms overcome the infection, humoral and cellular immune defenses combine with antibacterial therapy to retard bacterial replication. Following this process, phagocytosis of the organism and cellular debris take place, without further destruction of stromal collagen. During this stage, a distinct demarcation line may appear as the epithelial ulceration and stromal infiltration consolidate and the edges become rounded.

Vascularization of the cornea may follow if the keratitis becomes chronic. In the healing stage, the epithelium resurfaces the central area of ulceration and the necrotic stroma is replaced by scar tissue produced by fibroblasts. The reparative fibroblasts are derived from histiocytes and keratocytes that have undergone transformation. Areas of stromal thinning may be replaced partially by fibrous tissue. New blood vessel growth directed toward the area of ulceration occurs with delivery of humoral and cellular components to promote further healing. The Bowman layer does not regenerate but is replaced with fibrous tissue.

New epithelium slowly resurfaces the irregular base, and vascularization gradually disappears. With severe bacterial keratitis, the progressive stage advances beyond the point in which the regressive stage can lead to the healing stage. In such severe ulcerations, stromal keratolysis may progress to corneal perforation. Uveal blood vessels may participate in sealing the perforation, resulting in an adherent vascularized leukoma.

The traditional therapy for bacterial keratitis is fortified antibiotics, tobramycin (14 mg/mL) 1 drop every hour alternating with fortified cefazolin (50 mg/mL) or vancomycin (50mg/mL) 1 drop every hour. In cases of severe ulcers, this is still the recommended initial therapy. These medications are available at special compounding pharmacies or may also be obtained from the in-hospital pharmacy. As the patient heals, it is important to appropriately taper and eventually stop the fortified antibiotics, as they are toxic to the corneal epithelium and inhibit healing.

In current practice, fourth-generation fluoroquinolones are increasingly being used as monotherapy, especially in cases of smaller and less-severe keratitis. While this was once limited to small, peripheral infiltrates, multiple studies have now shown fluoroquinolones to be effective for treatment of bacterial keratitis. Other antimicrobials can also be used, depending on the clinical progress and laboratory findings.

The fourth-generation ophthalmic fluoroquinolones include moxifloxacin (VIGAMOX, Alcon Laboratories, Inc, Fort Worth, TX) and gatifloxacin (Zymar, Allergan, Irvine, CA), and they are now being used for the treatment of bacterial conjunctivitis. Both antibiotics have better in vitro activity against gram-positive bacteria than ciprofloxacin or ofloxacin. Moxifloxacin penetrates better into ocular tissues than gatifloxacin and older fluoroquinolones; in vitro activity of moxifloxacin and gatifloxacin against gram-negative bacteria is similar to that of older fluoroquinolones. Moxifloxacin also has better mutant prevention characteristics than other fluoroquinolones. These findings support the use of the newer fluoroquinolones for the prevention and treatment of serious ophthalmic infections (eg, keratitis, endophthalmitis) caused by susceptible bacteria.

In view of these findings, moxifloxacin or gatifloxacin may be a preferred alternative to ciprofloxacin as the first-line monotherapy in bacterial keratitis. Typically, dosing is every 1 hour, around the clock.

A new fluoroquinolone, besifloxacin ophthalmic suspension, is now approved for treatment of bacterial conjunctivitis. It was specifically developed as an ocular topical preparation and approved by the FDA in 2009. It has been shown to have a higher potency against anaerobes and gram-positive bacteria than other topical antibiotics and equivalent to other fluoroquinolones against gram-negative bacteria. It also has a higher ocular surface retention time, theoretically allowing less-frequent dosing. While not approved by the FDA for the treatment of bacterial keratitis and despite a lack of clinical trials to prospectively study its efficacy, some practitioners use besifloxacin in the treatment of bacterial keratitis.

Additionally, 0.5% moxifloxacin and, to a lesser extent, levofloxacin and ciprofloxacin have demonstrated significant effectiveness for reducing the number of Mycobacterium abscessus in vivo, suggesting the potential use of these agents in prevention of M abscessus keratitis.

Three patients with Acanthamoeba keratitis were successfully treated with a topical application of 0.1% riboflavin solution and 30 minutes of UV irradiation focused on the corneal ulcer.[2]

The frequency of antibiotic administration should be tapered off according to the clinical course using some of the following parameters:

• Blunting of the perimeter of the stromal infiltrate
• Decreased density of the stromal infiltrate
• Decreased stromal edema and endothelial inflammatory plaque
• Decreased anterior chamber inflammation
• Reepithelialization of the corneal epithelial defect
• Improvement in painful symptoms

The most common cause of corneal perforation is infection by bacteria, virus, or fungus, accounting for 24-55% of all perforations, with bacterial infections being the most common. PK, sclerocorneal patch, or application of cyanoacrylate tissue adhesive may be necessary in cases of corneal perforation or imminent perforation, following the guidelines provided below.

• Systemic intravenous antibiotics (alternatively ciprofloxacin 500 mg PO bid) should be started once an infected corneal ulcer has perforated and for 3 days following the PK.
• A clear plastic shield should be placed over the eye.
• The use of general anesthesia usually is preferred for keratoplasty surgery. Topical anesthesia can be used for application of tissue adhesive.
• The size of the transplant should be the smallest trephine capable of incorporating the perforation site and any infected or ulcerated border. Donor generally is oversized by 0.5 mm.
• Cataract removal is left for a subsequent procedure because of the risk of expulsive hemorrhage and endophthalmitis.
• Posterior and anterior synechiae should be lysed gently.
• The anterior chamber should be irrigated to remove any necrotic or inflammatory debris.
• The donor cornea should be secured with 16 interrupted 10-0 nylon sutures.
• Subconjunctival injections of antibiotics can be given without depot steroid injection.
• Postoperative use of frequent topical fortified antibiotics. Corticosteroids 4 times a day can be used immediately after surgery if it is believed that the infection was excised completely. Alternatively, steroids can be withheld for several days to monitor for infection. Once the acute postoperative period is over, long-term care is similar as that for uncomplicated PK.

Consultation with vitreoretinal colleagues may be helpful if the diagnosis of endophthalmitis is considered.

Topical antibiotics are given routinely after traumatic injury to the cornea (including surgery).

Preventing contamination of topical medications and the use of sterile contact lens solutions are critical steps in preventing contact lens-related infections.

Patients with bacterial keratitis need to be monitored closely to make certain the infection is responding to treatment as the medications are tapered.

Severe cases of bacterial keratitis are monitored daily, while-less severe cases may be monitored every few days.

The frequency of antibiotic administration should be tapered off gradually according to the clinical improvement using some of the following parameters:

• Blunting of the perimeter of the stromal infiltrate

• Decreased density of the stromal infiltrate

• Decreased stromal edema and endothelial inflammatory plaque

• Decreased anterior chamber inflammation and reepithelialization of the corneal epithelial defect

Improvement of patient's symptoms

The antibiotic medications are decreased slowly, depending on the culture and sensitivity results and the clinical response. If topical steroids are used, the antibiotic should not be discontinued.

Topical antibiotics constitute the mainstay of treatment in cases of bacterial keratitis, with subconjunctival antibiotics used only under unusual circumstances, and systemic antibiotics used only in cases of perforation or specific organisms (eg, N gonorrhoeae). The use of topical corticosteroids remains controversial; however, when they are used, strict guidelines and close follow-up care are mandatory to ensure the best ultimate outcome of these patients.

Class Summary

Aminoglycosides have a broad range of bactericidal activity against many bacterial species, particularly gram-negative rods. They have a selective affinity to bacterial 30S and 50S ribosomal subunits to produce a nonfunctional 70S initiation complex that results in inhibition of bacterial cell protein synthesis. Unlike other antibiotics that impair protein synthesis, they are bactericidal. Their clinical activity is limited severely in anaerobic conditions. They have a low therapeutic/toxic ratio.

Cephalosporins have a broad spectrum of activity, including effective action against Haemophilus species. They contain a beta-lactam ring similar to penicillins, and a dihydrothiazine ring that makes them resistant to the action of penicillinases produced by staphylococci. They inhibit the third and final stage of bacterial cell wall formation by preferentially binding to one or more penicillin-binding proteins that are in the cytoplasmic membrane beneath the cell walls of susceptible bacteria. They are well tolerated topically.

Chloramphenicol usually is reserved for specific infections such as those associated with H influenzae. Its use has been limited by toxicity, including a dose-dependent bone marrow depression.

Macrolides are bacteriostatic agents (eg, erythromycin, tetracycline) that can suppress the growth of susceptible gram-positive cocci. This class of drugs works by inhibition of bacterial protein synthesis.

Glycopeptides have activity against gram-positive bacteria, and methicillin and penicillin-resistant staphylococci. They inhibit the biosynthesis of peptidoglycan polymers during the second stage of bacterial cell wall formation, at a different site of action from that of the beta-lactam antibiotics. They also have an excellent activity against a variety of gram-positive bacilli.

Sulfonamides have a structure similar to para -aminobenzoic acid (PABA), a precursor required by bacteria for folic acid synthesis. They competitively inhibit the synthesis of dihydropteroic acid, the immediate precursor of dihydrofolic acid from PABA pteridine. This inhibition does not affect mammalian cells because they lack the ability to synthesize folic acid and require preformed folic acid. They are active against gram-positive and gram-negative bacteria, and they are the preferred drugs against Nocardia keratitis.

Fluoroquinolones variably inhibit the action of bacterial DNA gyrase an enzyme essential for bacterial DNA synthesis. They have activity against most aerobic gram-negative bacteria and some gram-positive bacteria. Concern has been generated regarding the emerging resistance to fluoroquinolones among staphylococci. Emerging resistance to these antimicrobials has been reported in nonocular and ocular isolates. A study by Haas et al has revealed that among patients with ocular bacterial pathogens, resistance to 1 or more antibiotics is prevalent.[3] They have limited efficacy against streptococci, enterococci, non-aeruginosa Pseudomonas, and anaerobes. Two multicenter trials compared the efficacy of ciprofloxacin 0.3% and ofloxacin 0.3% solution versus fortified cefazolin and tobramycin showing favorable efficacy for a single agent fluoroquinolone therapy.

They also have a record for low toxicity, good ocular surface penetration, and prolonged tear film penetration. Monotherapy for bacterial keratitis using these classes of antibiotics has been proved to be effective in large clinical trials. However, emerging resistance to the fluoroquinolones is now being reported in nonocular and ocular isolates. One randomized trial of 500 patients with bacterial corneal ulcer who received the fluoroquinolone moxifloxacin found a higher resistance to the agent was associated with worse clinical outcomes. Results show a rate of 1 line of vision loss per 32-fold increase in minimum inhibitory concentration.[4]

Fortified tobramycin 14 mg/mL (AKTob, Tobrex)

Interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits, which results in a defective bacterial cell membrane. Add 2 mL of parenteral tobramycin (40 mg/cc) to 5 mL commercial 0.3% tobramycin solution. Refrigerate (expires in 7 d)

Amikacin 20 mg/mL (Amikin)

When mycobacteria are suspected. Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition.

Cefazolin

First-generation cephalosporin with excellent gram-positive but narrow gram-negative activity. To prepare for topical use, dilute 500 mg parenteral cefazolin powder in sterile water to form 10 mL solution. Refrigerate (preparation expires in 7 d).

Ceftazidime 50 mg/mL (Fortaz, Ceptaz)

Third-generation cephalosporin has slightly less activity against gram-positive pathogens but more activity against gram-negative bacteria compared to a first-generation cephalosporin. To prepare, add 1 g parenteral ceftazidime powder to 9.2 cc of artificial tears. Add 5 cc of dilution to 5 cc of artificial tears, and shake well.

Chloramphenicol ophthalmic (Chloromycetin)

Acts by inhibiting bacterial protein synthesis. Binds reversibly to the 50S subunit of bacterial 70S ribosome and prevents attachment of the amino acid-containing end of the aminoacyl-tran to acceptor site on ribosome. Active in vitro against a wide variety of bacteria, including gram-positive, gram-negative, aerobic, and anaerobic organisms.

Erythromycin ophthalmic (E-Mycin)

Ophthalmic ointment applied hs can be used in combination with a fluoroquinolone to improve coverage against streptococci and other gram-positive bacteria when dealing with small ulcers and outpatient treatment.

Vancomycin 50 mg/mL (Vancocin)

To prepare for topical administration, dilute 500 mg of parenteral vancomycin powder in 10 mL sterile water, artificial tears, or normal saline (0.9%). Refrigerate (preparation expires in 4 d). The 25 mg/mL concentration appears to be just as effective as the 50 mg/mL concentration but is much better tolerated by patients.

Sulfacetamide ophthalmic (Sulfacetamide Ophth, Bleph 10, Bleph 30)

Laboratory diagnosis of Nocardia keratitis. Exerts bacteriostatic action by competitive antagonism of PABA, an essential component of folic acid synthesis.

Ciprofloxacin 0.3% (Ciloxan)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis, and consequently growth.

Ofloxacin ophthalmic (Floxin)

A pyridine carboxylic acid derivative with broad-spectrum bactericidal effect.

Gatifloxacin ophthalmic

Quinolone that has antimicrobial activity based on ability to inhibit bacterial DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Differences in chemical structure between quinolones have resulted in altered levels of activity against different bacteria. Altered chemistry in quinolones result in toxicity differences.

Class Summary

Anti-inflammatory agents that may impair host defenses and enhance microbial proliferation, but can reduce host inflammatory response that contributes to conjunctival or corneal scarring. Should not be used until specific antimicrobial therapy has controlled microbial proliferation, and clear clinical improvement is evident. Judicious corticosteroid use entails dosage adjustment according to severity of ocular inflammation and occurrence of side effects. Discontinuation should be gradual to minimize rebound of inflammation.

Prednisolone acetate 1% (AK-Pred, Pred Forte)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

As the keratitis is controlled with antimicrobials, increase corticosteroids and decrease antibiotics.