AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Bacterial keratitis is a sight-threatening process. 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.

Pathophysiology

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. 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).
• 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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
• Aqueous tear deficiencies
• Recent corneal disease (herpetic keratitis, neurotrophic keratopathy)
• Structural alteration or malposition of the eyelids

Physical

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
• Increased anterior chamber reaction 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

Causes

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 or contact lens solutions
• 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Mooren ulcer

Sterile ulcer secondary to connective tissue disease (including rheumatoid arthritis and Sjögren syndrome)

Catarrhal or marginal ulcer (secondary to staphylococcal hypersensitivity) - Ulcerated phlyctenules, frequently within 1 mm and with a clear space from the limbus, usually multiple and associated with blepharoconjunctivitis

Corneal infiltrates from an immune reaction to contact lens wearing (multiple small subepithelial infiltrates with minimal anterior chamber reaction)

Coat's ring - Resulting from a foreign body or rust in the cornea (likely iron)

Toxic keratitis (from abuse of some topical medications, including anesthetic drops)

Atypical mycobacterial infections of the cornea (caused by an opportunistic acid-fast bacillus Mycobacterium)

Protozoal infection that can be caused by amoebas (All ocular infections have been caused by the genus Acanthamoeba and usually follow contact lens wearing or ocular trauma.)

Ring ulcer - This ulcer results when separate infiltrates or ulcers at the corneal periphery progress circumferentially until they fuse, forming a partial or complete ring (often associated with a systemic connective tissue disease).

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Scrapings of the corneal ulcer, including the edges, should be obtained using a sterile spatula or blade, 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.
• If the patient has been treated partially and the keratitis is mild or moderately severe, antibiotic therapy can be suspended for 12 hours before obtaining corneal/conjunctival samples for culture and sensitivity, to increase the yield of a positive culture.
• 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.

Imaging Studies

• 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.

Procedures

• 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.

Histologic Findings

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

If no organisms are identified on the slide smear, initiate broad-spectrum antibiotics with the following: tobramycin (14 mg/mL) 1 drop every hour alternating with fortified cefazolin (50 mg/mL) 1 drop every hour.

If the corneal ulcer is small, peripheral and no impending perforation is present, intensive monotherapy with fluoroquinolones is an alternative treatment. Other antimicrobials can 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.

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.

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

Surgical Care

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.

Consultations

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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: Antibiotics

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. 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.

Drug Category: Topical corticosteroids

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• 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

Further Outpatient Care

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

In/Out Patient Meds

• 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.

Deterrence/Prevention

• 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.

Complications

• 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.

Prognosis

• 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

Patient Education

• 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 eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Corneal Ulcer.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Early diagnosis and prompt treatment help to reduce the possibility of permanent visual loss.

Special Concerns

• If a presumed bacterial keratitis is not improving clinically despite the use of broad-spectrum antibiotics, suspect an indolent organism (eg, Acanthamoeba, Mycobacteria), perform further laboratory studies to identify the organism, and start specific treatment.
• Be extremely cautious with the use of topical steroids. Close follow-up care of patients started on topical steroids is mandatory.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bower KS, Kowalski RP, Gordon YJ. Fluoroquinolones in the treatment of bacterial keratitis. Am J Ophthalmol. Jun 1996;121(6):712-5. [Medline].
• Caballero AR, Marquart ME, O'Callaghan RJ. Effectiveness of fluoroquinolones against Mycobacterium abscessus in vivo. Curr Eye Res. Jan 2006;31(1):23-9. [Medline].
• Genvert GI, Cohen EJ, Donnenfeld ED. Erythema multiforme after use of topical sulfacetamide. Am J Ophthalmol. Apr 15 1985;99(4):465-8. [Medline].
• Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. Jul 1999;106(7):1313-8. [Medline].
• Hirst LW, Harrison GK, Merz WG. Nocardia asteroides keratitis. Br J Ophthalmol. Jun 1979;63(6):449-54. [Medline].
• Hirst LW, Smiddy WE, Stark WJ. Corneal perforations. Changing methods of treatment, 1960--1980. Ophthalmology. Jun 1982;89(6):630-5. [Medline].
• Hyndiuk RA, Eiferman RA, Caldwell DR. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group. Ophthalmology. Nov 1996;103(11):1854-62; discussion 1862-3. [Medline].
• Knapp A, Stern GA, Hood CI. Mycobacterium avium-intracellulare corneal ulcer. Cornea. 1987;6(3):175-80. [Medline].
• Leibowitz HM. Clinical evaluation of ciprofloxacin 0.3% ophthalmic solution for treatment of bacterial keratitis. Am J Ophthalmol. Oct 1991;112(4 Suppl):34S-47S. [Medline].
• Moore MB, Newton C, Kaufman HE. Chronic keratitis caused by Mycobacterium gordonae. Am J Ophthalmol. Oct 15 1986;102(4):516-21. [Medline].
• Newman PE, Goodman RA, Waring GO 3d. A cluster of cases of Mycobacterium chelonei keratitis associated with outpatient office procedures. Am J Ophthalmol. Mar 1984;97(3):344-8. [Medline].
• Parmar P, Salman A, Kalavathy CM. Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis. Am J Ophthalmol. Feb 2006;141(2):282-286. [Medline].
• Pate JC, Jones DB, Wilhelmus KR. Prevalence and spectrum of bacterial co-infection during fungal keratitis. Br J Ophthalmol. Mar 2006;90(3):289-92. [Medline].
• Poggio EC, Glynn RJ, Schein OD. The incidence of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. N Engl J Med. Sep 21 1989;321(12):779-83. [Medline].
• Schein OD, Glynn RJ, Poggio EC. The relative risk of ulcerative keratitis among users of daily-wear and extended-wear soft contact lenses. A case-control study. Microbial Keratitis Study Group. N Engl J Med. Sep 21 1989;321(12):773-8. [Medline].
• Schlech BA, Alfonso E. Overview of the potency of moxifloxacin ophthalmic solution 0.5% (VIGAMOX). Surv Ophthalmol. Nov 2005;50 Suppl 1:S7-15. [Medline].
• Stern GA, Buttross M. Use of corticosteroids in combination with antimicrobial drugs in the treatment of infectious corneal disease. Ophthalmology. Jun 1991;98(6):847-53. [Medline].
• Stern GA, Schemmer GB, Farber RD. Effect of topical antibiotic solutions on corneal epithelial wound healing. Arch Ophthalmol. Apr 1983;101(4):644-7. [Medline].
• Varma R, eds. Cornea/external diseases. Essentials of Eye Care: The Johns Hopkins Wilmer Handbook. Lippincott Williams & Wilkins;1997:152-203.

Article Last Updated: Apr 18, 2006