Current Concepts in Ocular Surface Infection

BY ARTHUR B. EPSTEIN, OD, FAAO
MARCH 1999

This practitioner provides a basis for understanding, managing and preventing ocular surface infection.

Ocular surface infection can range from benign and self-limited to serious and sight-threatening. Despite a broad array of protective and defensive mechanisms, the ocular surface is fragile, and severe damage from infection can occur in a short amount of time. There have recently been important advances in our understanding of ocular surface infection and new developments in its treatment, but understanding the natural ocular environment is an essential prerequisite to recognizing, managing and ideally, preventing ocular infection.

Background On Bacteria

Microbes are simple organisms capable of adapting to their environment. Some bacteria fill niches and exist in a natural balance with their host; others are opportunistic and cause infection. Shifts in the local environment or other precipitating factors allow benign bacteria to become infective. In most cases, normal flora protect the host tissue from infection by competing with more pathogenic species. It's virtually impossible to eradicate normal bacterial flora. Any attempt to do so can lead to the overgrowth of more pathogenic species until the environmental balance returns to a more natural state.

Treating infection is usually effective, but it's often a trade-off. The goal is to disturb normal flora as little as possible. With systemic infection, antibiotic treatment may successfully eradicate bacterial pathogens, but alterations in normal intestinal flora and bacterial overgrowth can lead to stomach-upset and in rare cases, life-threatening reactions. When treating ocular surface infection, narrowly targeted application minimizes some of this risk. However the lids, and to a lessor extent the ocular surface, are reservoirs of potential pathogens that can become infective if opportunity facilitates their proliferation.

Bacteria and Conjunctivitis

Infectious conjunctivitis generally responds rapidly to a variety of available topical antibiotics. Still, the appropriate treatment of bacterial conjunctivitis remains enigmatic. Some clinicians advocate aggressive but limited use of potent fluoroquinolone antibiotics, while others feel that more traditional drugs, like Polytrim, are safer and also less likely to promote resistant bacterial strains. As long as doses remain above a subinhibitory threshold, resistance is a minor concern and the choice of antibiotic should be based on context rather than reflex. Because of the shift in their normal flora, contact lens wearers should be treated more aggressively.

Conjunctivitis is an important but frequently overlooked diagnostic guide. It can exist in isolation or it can be associated with corneal findings. Contact lens wearers who present with subepithelial infiltrates (SEI) may be misdiagnosed as having an adenoviral infection. However, the majority of cases of epidemic keratoconjunctivitis (EKC) and pharyngo conjunctival fever (PCF) are preceded by a follicular conjunctivitis, which is rarely the case in contact lens related SEI. Bacterial conjunctivitis is usually accompanied by the appearance of a velvety papillary conjunctival response.

Bacteria and Keratitis

If conjunctivitis is usually benign, keratitis is often the exact opposite. Nothing generates more fear in clinicians than microbial keratitis. Major risk factors for microbial keratitis include: corneal abrasion with infected material; extended wear and to a lessor extent, daily wear of contact lenses; refractive surgery; and pre-existing conditions such as dry eye, lid disease and ocular surface disorders. Immune compromise and physical debility also increase risk.

The bacterial species isolated from corneal infections vary demographically, geographically and temporally. While gram-positive bacterial corneal ulcers are more frequently found in the general U.S. population, gram-negative infections are more commonly seen among contact lens wearers. During the 1980s, the increased popularity of overnight soft lens wear combined with poor understanding and management of risk factors fueled a decided shift toward gram-negative corneal infection. More recently, gram-negative isolates recovered from corneal ulcers in lens wearers, particularly Pseudomonas sp., have declined substantially in most areas of the United States.

Appropriate treatment of bacterial corneal infection depends on the site, suspected pathogen, severity and the risk of visual loss or other permanent damage. Recent controversy regarding the utility of culturing suspected bacterial ulcers has given way to the tacit acceptance of empirical treatment in the majority of cases. Exceptions include ulcers affecting the visual axis, ulcers that appear suspicious or threaten penetration and ulcers that are unresponsive to initial therapy.

Current standards of care, as well as common sense, dictate that fluoroquinolone-class antibiotics be used to treat all but the mildest bacterial corneal infections. Fluoroquinolones have almost replaced fortified aminoglycoside antibiotics in treating microbial keratitis. As a class, the fluoroquinolones are relatively non-toxic and are well tolerated by ocular tissues, especially when compared to aminoglycoside antibiotics, which are no more effective but more toxic. Broad spectrum, currently available topical fluoroquinolone antibiotics have some gaps in coverage, especially among gram-positive species. For severe infections, or when gram-positive organisms are suspected, topically applied fortified antibiotics, such as bacitracin, cefazolin and vancymycin, are often combined with a fluoroquinolone. Because of bacitracin's toxicity and discomfort upon application and the resistance issues associated with the overuse of vancomycin, cefazolin is preferred by most cornea specialists. The two most commonly used topical fluoroquinolones are ofloxacin, which has been reported to have a slight advantage in tissue penetration, and ciprofloxacin, which is more effective against Pseudomonas sp.

The inhibitory quotient (IQ) relates the penetration of a specific antibiotic to its relative potency (MIC90) against a specific pathogen at that site. This concept is an important one, demonstrating the critical balance between the effectiveness of an antibiotic against a specific pathogen, and the penetration of the antibiotic to the target site.

Although variability in the presentation and severity of infection make a cookbook approach to treatment inadvisable, several studies have demonstrated the benefit of administering loading doses and when necessary, more frequent supervised antibiotic administration. It's important to remember that bacterial resistance to antibiotics is relative. Increased dosing frequency can raise antibiotic levels to lethal concentrations even with resistant pathogens. Typical fluoroquinolone dosing for a moderate corneal ulcer is one to two drops every 15 minutes for the first hour, every 30 minutes for the next four hours, once every hour for the next 24 hours, then four times a day, depending on the clinical response. Subjective improvement may be the best indicator of treatment effectiveness and often precedes objective improvement.

Resistance

Drug resistance is an important issue of growing concern. A study published in Ophthalmology (January 1999) reported fluoroquinolone resistance in over 30 percent of ocular isolates over a six-year period. The authors also noted a dramatic trend toward increased resistance over time. As more and more microbes develop resistance to available antibiotics, our therapeutic options grow increasingly limited.

Improper treatment can foster resistant strains through genetic selection or mutation. The greatest risk of resistance occurs with systemic therapy because of the large numbers of bacteria exposed to variable doses of antibiotics. Regardless of the type of infection or treatment protocol, it's important to ensure that antibiotic doses remain high enough to prevent emergent resistance. For that reason, antibiotics should never be tapered to less than a sub-inhibitory dose. With most topical antibiotics that is four times a day.

Mechanisms of Infection

Coinciding with renewed interest in overnight wear of contact lenses and refractive surgery, mechanisms of infection have come under increased scrutiny.

Normal flora and refractive surgery -- Normal flora from the lids are a frequent source of infection in refractive surgery, so preoperative treatment of active lid disease with a broad-spectrum antibiotic is prudent. Preoperative treatment is especially important for patients who work in hospitals or nursing homes where they are routinely exposed to more virulent pathogens. As refractive surgery grows in popularity, the dangers of infection will underscore the need to develop strategies for infection prevention.

Contact lenses -- Research into contact lens related infection has progressed over the past decade. It now appears that edema and epithelial surface disturbance are not the only predisposing factors in lens related corneal infection. Fleiszig (1998) recently reported the discovery of a cytotoxic strain of Pseudomonas aeruginosa that can penetrate and infect the intact epithelium. Soft lens wear has also been shown to interfere with PMN migration during the early stages of infection. Normal tear film and healthy tear-surface interaction appear to be critical to infection resistance. With continuous wear lenses on the immediate horizon, better understanding of these mechanisms is critical.

Steroids -- Much of the damage to the cornea occurs secondary to the inflammatory response, rather than to the infection itself. Topical steroids can be extremely helpful in managing secondary inflammation and tissue destruction, however, inappropriate or premature use of steroids can cause infection to flare out of control by eliminating host defenses. Steroids are also potentially dangerous in fungal and parasitic infection. Keep in mind that it's important to sterilize an infection before adding steroids to a treatment regimen.

The immediate future of ocular surface infection management appears mixed. With growing resistance to presently available antibiotics and no new antibiotics on the immediate horizon, the clinical focus will likely shift to risk management and prevention. For now, a cautious approach to treating our patients and the prudent use of antibiotics remain the best way to conserve our treatment options.

FIG. 1: A devastating Pseudomonas corneal ulcer in a contact lens wearer. The patient had been treated with sulfacetamide by a primary care practitioner two days earlier.Arthur B. Epstein, OD, FAAO

FIG. 2: Example of a bacterial corneal ulcer with a hypopyon

 

FIG. 3: A rapidly progressive Streptococcal corneal ulcer with an endothelial plaque and hypopyon.

THE EYESSENTIALS Typical dosing using fluoroquinolone for a moderate corneal ulcer would be 1 to 2 drops every 15 minutes for the first hour, every 30 minutes for the next four hours, once every hour for the next 24 hours, then tapering to four times a day, depending on the clinical response. Antibiotics should never be tapered to less than a sub-inhibitory dose. With most topical antibiotics, that is four times a day. It is important that an infection be sterilized before steroids are added to a treatment regimen.

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Dr. Epstein is the chief optometric editor for Optometric Management and is a contact lens specialist with expertise in complications and anterior segment disease. He is in private practice (limited to contact lenses) in Roslyn, New York