Bacterial Keratitis

Defense of the Ocular Surface

Bacterial keratitis usually occurs in patients with predisposing risk factors that compromise normal ocular surface defenses. These defenses include the eyelid, tear film, corneal epithelium, and normal ocular flora.

The eyelids provide the ocular surface with a physical barrier against exogenous microorganisms. Normal blinking also distributes the tear film, which washes away potential pathogens via the nasolacrimal drainage system. Eyelid trauma, poor Bell reflex, or an abnormality of lid closure can compromise this defense mechanism, especially in obtunded or debilitated patients with poor blinking. Chronic infection and inflammation of the eyelid margin can predispose the cornea to bacterial infection.

Tear film constituents provide additional protective factors. Abnormalities of tear volume, tear film distribution, tear components, or tear drainage system threaten ocular surface health. The lipid layer of the tear film possesses surfactant or detergent-like properties that destabilize microbial cell membranes. Aqueous tear deficiency and corneal or conjunctival scarring may lead to poor or uneven corneal wetting. Loss of mucin on tear film or ocular surface may result in loss of corneal integrity and epithelial damage, which allow pathogens to invade the cornea. Many tear proteins, such as secretory immunoglobulin A, lipocalin, surfactant, complement components, and various enzymes including lysozyme, lactoferrin, betalysins, orosomucoid, secretory phospholipase A ₂ , and ceruloplasmin have antibacterial effects. ^, A recent study also correlated tear cytokine changes in bacterial keratitis, which result in adaptive immune responses against pathogens. Nasolacrimal duct obstruction can lead to reduced concentrations of certain antibacterial substances and bacterial pooling in the tear film, predisposing the ocular surface to infection.

An intact corneal epithelium is a critical mechanical barrier. Few bacteria are capable of penetrating an intact epithelium. Compromised corneal epithelial integrity caused by contact lens wear, corneal trauma, or corneal surgery is an important factor predisposing to the development of bacterial keratitis. Furthermore, corneal epithelial cells are capable of phagocytosis and intercellular transport of ingested particles, potentially providing additional defenses to eradicate the invading microorganisms. Both planktonic bacteria suspended in the tears and sessile bacteria adherent to the ocular surface constitute normal flora, which helps to prevent overgrowth of exogenous organisms. Inappropriate use of topical antibiotics could alter the natural protection by normal flora and predispose the cornea to development of opportunistic infections or antibiotic-resistant pathogens. In addition, the conjunctiva contains subepithelial mucosa-associated lymphoid tissue (MALT)—a collection of lymphoid cells—and can provide specific immune-mediated defenses to the ocular surface.

External Risk Factors

Corneal trauma, including chemical and thermal injuries, foreign bodies, and local irradiation, can predispose to infectious keratitis. Agricultural injuries may lead to Nocardia keratitis or other unusual infectious etiologies. Exposure to contaminated water or other solutions may also lead to bacterial keratitis. Preservatives are now routinely added to multiuse topical ophthalmic medications to prevent contamination. Nonetheless, the antimicrobial profile of various ophthalmic preservatives may vary due to a lack of standardized antimicrobial effectiveness testing regimens across countries.

Chronic topical anesthetic abuse disrupts the corneal epithelium and neural pathways, rendering the cornea at risk for microbial infection ( Fig. 76.1 ). Crack cocaine smoking also disrupts the corneal epithelium and is associated with vigorous eye rubbing in the setting of a relatively hypoesthetic cornea. Nosocomial corneal infections have occurred in unconscious or sedated patients as a result of lagophthalmos or inadvertent trauma by the tubing or solutions used for airway aspiration. Geographic and climatic factors can also influence the prevalence of bacterial keratitis. The variation of habitats, antibiotic usage, and microorganism exposure, such as in rural versus urban areas, can lead to differences in infectious keratitis profile.

Contact Lens Use

Contact lens wear has been identified as the most common risk factor for bacterial keratitis in developed countries. There are an estimated 38 million contact lens wearers in the United States and 125 million worldwide. Microbial keratitis affects 5–10 per 10,000 contact lens users and accounts for nearly 1 million clinic visits annually in the United States. The incidence of contact lens–related microbial keratitis has been well established at 2–4 per 10,000 wearers per year for daily soft lens wearers and 20 per 10,000 for overnight soft lens wearers. Bacterial infections represent nearly 90% of all contact lens-related microbial keratitis cases, with Pseudomonas aeruginosa being the most common pathogen, followed by Staphylococcus aureus .

All types of contact lenses, including hard, gas-permeable, soft, disposable, orthokeratology, and cosmetic, have been implicated in microbial keratitis. ^, On average, contact lens users have a 1.5% chance of developing infectious keratitis during a lifetime of contact lens wear. The incidence of microbial keratitis is lowest with rigid gas-permeable lenses. Although daily disposable contact lenses can circumvent storage and cleansing steps and are associated with less severe disease, the risk of microbial keratitis has not been significantly reduced. ^, The two major risk factors associated with contact lens–induced infectious keratitis are overnight wear and poor lens hygiene, which account for 43% and 33% of the population-attributable risk of microbial keratitis. ^, Although there is less corneal hypoxia associated with the use of silicone hydrogel lenses, the severity and overall incidence of keratitis are comparable between extended wear of silicone hydrogel lenses and overnight wear of hydrogel lenses.

Pseudomonas spp. are the most common contact lens-associated pathogen in bacterial keratitis ( Fig. 76.2 ). ^, P. aeruginosa and other microorganisms have been frequently recovered from tap and bottled water used to prepare contact lens saline solutions. Bacteria can adhere to a contact lens regardless of lens materials, and microbes can survive in the moist chamber of a contact lens case. Worn contact lenses with surface protein and mucin deposits are more susceptible to bacterial adhesion. The biofilm, a slimy layer composed of organic polymers produced by bacteria embedded on contact lenses, can protect pathogenic bacteria from antibiotics and provides a nidus for infection.

A seasonal variation in the incidence of contact lens-associated bacterial keratitis might be due to activities such as swimming in the summer. Contact lens wear does not necessarily affect normal conjunctival flora, but some lens disinfectants may influence the microbial milieu of the ocular surface. Although healthcare workers wearing contact lenses do not necessarily have altered conjunctival flora, they are prone to develop bacterial keratitis caused by antibiotic-resistant strains.

Contact lens use can adversely affect the healthy cornea by causing hypoxia and altering epithelial hemostasis. Corneal hypoxia and related endothelial dysfunction can result in acute epithelial edema and compromise epithelial integrity. Contact lens wear slows corneal epithelial hemostasis by suppressing cell proliferation, impairing cell migration, and reducing the rate of cell exfoliation. Corneal abrasion may occur during lens insertion or removal.

Ocular Surface Abnormalities

Ocular surface diseases such as mucus membrane pemphigoid, Stevens-Johnson syndrome, atopic keratoconjunctivitis, radiation and chemical injury, and vitamin A deficiency can lead to squamous metaplasia of the ocular surface epithelium and cause an unstable tear film.

Dysregulation of the host immune system and alteration of host flora may also play an important role. Disruption of the epithelial glycocalyx may encourage bacterial adherence and subsequent keratitis. Bacterial keratitis can complicate corneal epithelial erosions associated with epithelial basement membrane dystrophy, lattice corneal dystrophy, and vernal or atopic keratoconjunctivitis.

Microbial keratitis is an uncommon but serious complication after corneal transplantation that threatens the viability of corneal grafts and jeopardizes the posttransplant visual outcome. The incidence of microbial keratitis following penetrating keratoplasty ranged from 1.76% to 4.9% in developed countries versus 7.4% to 12.6% in developing countries. Newer keratoplasty techniques, including endothelial and anterior lamellar keratoplasty, may have a lower rate of postoperative infectious keratitis, but retrospective data are currently limited. In general, risk factors for the development of post-keratoplasty infectious keratitis have three sources: the host environment, surgical technique, and donor tissue. The most commonly cited risk factors are suture-related problems ( Fig. 76.3 ) and suboptimal ocular surface conditions, including epithelial defect, postoperative contact lens use, topical antibiotics, and topical corticosteroids. Gram-positive bacteria native to the normal ocular flora are the most common microorganisms after penetrating keratoplasty, with S. aureus in developed countries versus Streptococcus pneumoniae and coagulase-negative Staphylococcus (CNS) in developed countries. The most commonly identified gram-negative bacterium after penetrating keratoplasty is P. aeruginosa .

Microbial keratitis following refractive surgery is an increasingly recognized sight-threatening complication. The incidence of post-LASIK (laser in situ keratomileusis) infectious keratitis is variable among reports with estimates ranging from 0% to 1.5%. The incidence of infectious keratitis was found to be 0.02%–0.2% after primary surface ablation, with Staphylococcus as the most commonly reported etiology. ^, A recent survey from the American Society of Cataract and Refractive Surgery (ASCRS) indicates the incidence of infections following refractive surgery appears to be declining, including those by atypical Mycobacterium ( Fig. 76.4 ). Methicillin-resistant Staphylococcus aureus (MRSA) is becoming an increasingly common etiologic agent. Pathogenesis may occur through colonization of bandage contact lenses and a postoperative persistent epithelial defect. Systemic conditions such as malnutrition, diabetes, collagen vascular diseases, or chronic alcoholism may also compromise the ocular surface and increase the risk of microbial keratitis caused by unusual organisms such as Moraxella ( Fig. 76.5 ). In patients with HIV, the incidence of microbial keratitis was generally thought to be comparable to the general population, but an analysis in northern California suggests that HIV may be an independent risk factor. Furthermore, infectious keratitis tends to be more severe and more resistant to therapy in these patients. ^, A study with a high HIV prevalence setting in rural South Africa found a high occurrence of bacterial superinfection in viral keratitis in HIV patients, with Staphylococcus epidermidis as the most common detected bacterium.

Bacterial Adherence

The smallest inoculum that can produce infection in the human cornea remains undetermined. Animal models of bacterial keratitis show that only about 50 P. aeruginosa or 100 S. aureus are needed to initiate corneal infection. ^,

Shortly after a corneal injury, viable bacteria adhere to the damaged edges of corneal epithelial cells and to the basement membrane or the bare stroma near the wound edge. The glycocalyx of injured epithelium is particularly susceptible to attachment by microorganisms.

Microbial attachment is initiated by the interaction of bacterial adhesins with glycoprotein receptors of the ocular surface. ^, The ability of certain bacteria to adhere to an epithelial defect may account for the frequent occurrence of S. aureus , S. pneumoniae , and P. aeruginosa infection. Biofilm production enhances bacterial aggregation, protects adherent microorganisms, and promotes growth during these early stages of infection. Pili (fimbriae) are thin (4–10 nm in diameter) protein filaments located on the surfaces of many bacteria. Pili facilitate adherence of P. aeruginosa and Neisseria spp. to epithelium.

Bacterial Invasion

The bacterial capsule and other surface components are important in corneal invasion. For example, some bacteria avoid activation of the alternate complement pathway because of their capsular polysaccharide. Lipopolysaccharides, the subcapsular constituents of bacteria, and endotoxin induce an inflammatory response. Bacterial invasion of surface epithelial cells is partially mediated by the interactions between the bacterial cell-surface proteins, integrins, epithelial cell-surface proteins, and the release of proteases by bacteria. Few microorganisms such as Neisseria gonorrhoeae , Neisseria meningitidis , Corynebacterium diphtheriae , Haemophilus aegyptius , and Listeria monocytogenes can penetrate the intact corneal epithelial surface via these types of mechanisms.

Without antibiotics or other intervening factors, bacteria continue to invade and replicate in the corneal stroma. Keratocytes are also capable of phagocytosis, but the exposed, avascular stroma provides little protection to the cornea. Microorganisms in the anterior stromal lamellae produce proteolytic enzymes ^, that destroy stromal matrices and collagen fibrils. Bacterial invasion begins within hours after exogenous contamination of a corneal wound or after the application of a heavily contaminated contact lens. The largest increase in a bacterial population usually occurs within the first 2 days of stromal infection.

After inoculation, bacteria infiltrate the surrounding epithelium and invade the deeper stroma around the initial site of infection. Viable bacteria tend to be found at the peripheral margins of the infiltrate or deep within a central ulcer crater.

Corneal Inflammation and Tissue Damage

Various inflammatory cells and soluble mediators can be induced by bacterial invasion and cause corneal inflammation with eventual tissue destruction. Soluble mediators of inflammation include the kinin-forming system, the clotting and fibrinolytic systems, immunoglobulins, complement components, vasoactive amines, eicosanoids, neuropeptides, and cytokines. The complement cascade can be triggered to kill bacteria, but complement-dependent chemotaxins also initiate focal inflammation.

The production of cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1, results in the adherence and extravasation of neutrophils in limbal blood vessels. This process is mediated by cell adhesion glycoproteins such as integrins and selectins and members of the immunoglobulin superfamily such as intercellular adhesion molecules (ICAMs) on vascular endothelial cells and on leukocytes.

Vascular dilation of the conjunctival and limbal blood vessels is associated with increased permeability, resulting in an inflammatory exudate into the tear film and peripheral cornea. Polymorphonuclear neutrophils (PMNs) can enter the injured cornea anteriorly via tear film through an epithelial defect, but most migrate from the limbus.

Recruitment of acute inflammatory cells occurs within a few hours after bacterial inoculation. As neutrophils accumulate at the infected site, more cytokines such as leukotrienes and complement components are presumably released to attract additional leukocytes. Macrophages subsequently begin to migrate to the cornea to ingest invading bacteria and degenerating neutrophils. Extensive stromal inflammation eventually leads to proteolytic stromal degradation and liquefactive tissue necrosis. The regulation of various immune response components such as Toll-like receptors (TLRs) and ILs is a subject of active investigation and may provide further insight into the mechanism of infectious keratitis as well as opportunities for novel therapies.

Staphylococci

Staphylococcus , the most common gram-positive organism, is usually present in normal ocular flora. The bacteria grow easily as pearly-white colonies on routine culture media such as blood agar plate ( Fig. 76.8 ). Staphylococcus keratitis occurs more frequently in the compromised corneal surface such as in bullous keratopathy, chronic herpetic keratitis, keratoconjunctivitis sicca, ocular rosacea, or atopic keratoconjunctivitis.

S. aureus tends to produce a rapidly progressive corneal infiltration and moderate anterior chamber reaction with endothelial plaques or hypopyon. The corneal lesions are usually round or oval with dense infiltration and a distinct border ( Fig. 76.9 ), but occasionally a stromal microabscess with an ill-defined border may develop.

MRSA has been isolated with increasing frequency from patients with bacterial keratitis, ^, although the regional incidence varies widely from 1.3% in Toronto to 45% in Los Angeles. High rates of MRSA have been observed in conjunctival flora studies. ^, Several recent studies suggested an increasing trend of fluoroquinolone resistance among MRSA. ^{, ,} Increasing rates of MRSA from 18% to 55% across a 25-year period have also been observed in culture-proven postoperative endophthalmitis cases. The common predisposing factors for MRSA colonization include preexisting ocular surface disease, ^, advancing age, local immunocompromised status, and recent antibiotic usage. Interestingly, recent exposure to a healthcare setting or being a healthcare worker have not been identified as risk factors for conjunctival colonization. ^, Isolated postoperative MRSA infections have also been reported following keratorefractive surgery. ^,

CNS usually causes opportunistic infection in the compromised cornea. More than 85% of eyelid cultures from the normal population are positive for CNS. The infection tends to progress slowly, and the infiltrates are usually superficial and localized with a clear surrounding cornea. However, severe ulcers with dense infiltrates can occur if untreated. Methicillin-resistant CNS rates have been reported as high as 53.7% of CNS isolates recently.

Streptococci

S. pneumoniae keratitis usually occurs after corneal trauma, dacryocystitis, or filtering bleb infection. The ulcer tends to be acute, purulent, and rapidly progressive with a deep stromal abscess. The anterior chamber reaction is usually severe with marked hypopyon ( Fig. 76.10 ) and retro-corneal fibrin coagulation. A culture appears nonhemolytic on a blood or chocolate agar plate ( Fig. 76.11 ). Perforation secondary to ulcer is common. A distinct, indolent crystalline keratopathy has also been reported.

Nocardia

Nocardia asteroides grows slowly as small white colonies on the culture plate ( Fig. 76.12 ) and is a variably acid-fast and gram-positive bacillus in branching filaments ( Fig. 76.13 ). It tends to produce an indolent ulcer after minor trauma, particularly with exposure to contaminated soil. The keratitis usually waxes and wanes. Nocardia can survive within neutrophils and macrophages associated with production of superoxide dismutase. The characteristic features of Nocardia keratitis include raised, superficial pinhead-like infiltrates in a wreath-like configuration ( Fig. 76.14 ), brush fire border, cracked windshield appearance, and multifocal or satellite lesions. The keratitis may simulate mycotic infection and microbiologic confirmation is crucial for appropriate therapy. Nocardia keratitis with early diagnosis and therapy typically have good visual recovery. Despite aggressive and prompt surgical intervention, the prognosis for Nocardia scleritis and endophthalmitis is more guarded.

Nontuberculous Mycobacteria

Previously known as “atypical mycobacteria,” this is a class of rapidly growing and acid-fast mycobacteria, in contrast to the slow-growing and better known Mycobacterium tuberculosis . The most common pathogens are Mycobacterium fortuitum and Mycobacterium chelonae , which may be found in soil and water. These organisms tend to cause a slowly progressive keratitis and usually occur after a corneal foreign body, corneal trauma ( Fig. 76.15 ), or following corneal surgery, particularly after LASIK (see Fig. 76.4 ). ^,

Keratitis from nontuberculous mycobacteria is often associated with delayed onset of symptoms, topical corticosteroid use, and severe ocular pain, which can develop 2–8 weeks after exposure to the organism. Infiltrates are typically nonsuppurative and can be solitary or multifocal, with variable anterior chamber reactions. Delay in diagnosis is common due to the protracted clinical course and difficulty of isolating the organism from culture. The diagnosis may be challenging in LASIK patients because infection can be confused with diffuse lamellar keratitis (DLK). The diagnosis may be confirmed with acid-fast stain or culture on Löwenstein-Jensen medium ( Fig. 76.16 ). Lack of response to conventional antibiotic therapy is usually a clue to the diagnosis of this unusual keratitis.

Pseudomonas

P. aeruginosa is the most common gram-negative pathogen isolated from severe keratitis. The increasing prevalence of Pseudomonas keratitis in otherwise healthy individuals has been largely associated with the use of soft contact lenses. Rapid progression, dense stromal infiltrate, marked suppuration, liquefactive necrosis, and descemetocele formation or corneal perforation are the characteristics of this pathogen (see Fig. 76.2 ). The remaining uninvolved cornea usually has a ground-glass appearance and diffuse graying of epithelium. Despite appropriate treatment, the keratitis may progress rapidly into a deep stromal abscess, and stromal keratolysis with perforation may occur. A corneal ring infiltrate, which is a dense accumulation and aggregation of polymorphonuclear leukocytes, can also be present (see Fig. 76.17 ). The other, less common clinical presentation of Pseudomonas keratitis associated with contact lens use is an indolent course of multiple elevated granular opacities caused by less virulent species. ^, Severe disease caused by P. aeruginosa results from the specific virulence factors of the organism and an extreme host inflammatory response with PMNs. ^, Pseudomonas strains can be categorized genotypically into either cytotoxic or invasive types based on the expression of different toxins. Cytotoxic strains secrete a phospholipase exoU that induces rapid necrosis of host cell membrane and causes overwhelming inflammation and host tissue damage ; whereas invasive strains secrete a different toxin, exoS, and are capable of invading host epithelial cells and producing cell death through disruption of the host cell actin cytoskeleton. Invasive strains are more frequently found in the isolates from contact lens–related keratitis, and associated with greater overall disease severity but better response to topical corticosteroids than cytotoxic strains. Treatment of P. aeruginosa eye infections often becomes a challenge due to the resistance of this bacterium to antibiotics via intrinsic and acquired mechanisms. Transfer of resistance due to interchangeable genetic elements is an important mechanism for the rapid transfer of antibiotic resistance in this pathogen.