Review of Cornea
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How to Manage Bacterial Eye Infections

Bacterial eye infections can have visually devastating consequences. But, the proper use of anti-infectives and antibiotic-steroid combination agents can protect your patients' sight.

By Kimberly K. Reed, O.D.

Release Date: MAy 2011
Expiration Date: April 1, 2014

Goal Statement:

Here, we review the most common types of bacterial infection of the eye—blepharitis, conjunctivitis and keratitis—and discuss the most common causative organisms, pathogenesis, clinical findings and general management strategies for each infection. Additionally, we review the most commonly used antibiotic and combination antibiotic-steroid agents for the treatment of bacterial eye infections.

Faculty/Editorial Board:

Kimberly K. Reed, O.D.

Credit Statement:

This course is COPE approved for 2 hours of CE credit. COPE ID is 31346-AS. Please check your state licensing board to see if this counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Reed has no relationships to disclose.


Bacterial infection of the eye present in several ways, ranging from mild, self-limiting conditions to those that could be extremely serious and visually threatening. The prevalence of these infections and the responsible bacterial organisms varies with the age of the patient and his or her geographic location. For example, bacterial infections are more common in urban hospital settings than in rural hospitals when compared to viral eye infections. Further, children and elderly patients are more susceptible to infection by bacteria than are young and middle-aged adults.

In some instances, management of patients with bacterial eye disease may involve nothing more than supportive and palliative therapy; however, in other instances, it may require aggressive intervention with antimicrobial and anti-inflammatory agents. A wide variety of antibiotic and combination antibiotic-steroid therapeutic topical agents are available to combat bacterial infections. Selecting the best drug for each patient requires a thorough understanding of the properties of each drug and the natural history of the disease.

Here, we review the most common types of bacterial infection of the eye—blepharitis, conjunctivitis and keratitis—and discuss the most common causative organisms, pathogenesis, clinical findings and general management strategies for each infection. Additionally, we review the most commonly used antibiotic and combination antibiotic-steroid agents for the treatment of bacterial eye infections.

Pathogenesis: One Pathway to Infection

Let's look at a hypothetical case of acute bacterial eye infection to illustrate the condition's pathogensis.

A 28-year-old female with no history of contact lens wear presented with small, crusty flakes in her eyelashes. No other ocular symptoms were noted.

If this patient were to present to your office at this stage, you would likely diagnose her with blepharitis. This very common condition can present with scales, flakes, collarettes or "sleeves" of debris on the lashes and at the lash margin. The flakes are comprised primarily of desquamated epithelial cells, sebum and a combination of both live and devitalized bacteria.1

At this stage, simple hygiene with warm compresses and lid cleansing would likely be sufficient to eradicate the clinical signs and symptoms of this conventionally low-grade infection. Many practitioners used to suggest the use of a diluted baby shampoo/water mixture as the cleansing agent, but many now prefer a commercially available lid scrub product. After a few days of non-medical treatment, the homeostatic balance of normal bacterial flora would be restored and the symptoms would resolve without further consequences.

Back to our hypothetical case. Let's assume the patient neglected her condition for a few days. The live bacteria in now higher-thannormal numbers at her lash margins would likely cause irritation, redness, swelling and, if severe, ulceration of the skin at the base of the lashes. Perhaps more importantly, the dead and dying bacteria release powerful chemical stimulants—known as exotoxins—that catalyze our patient's immune system and cause swelling and redness of the lids.

At this stage, even without any ocular surface involvement, therapeutic intervention would be prudent. Antibiotic drops or ointments, or more preferably antibiotic-steroid combination drops or ointments (to address the inflammatory changes), are acceptable therapeutic selections depending upon your findings and the degree of inflammation present.

In some cases, the exotoxin response of the dead bacteria provokes an inflammatory nodule on the ocular surface that is known as a phlyctenule. These are characteristically seen at the limbus, equally impacting the cornea and the conjunctiva, but can more rarely occur on either tissue in isolation. Occasionally, these phlyctenules are found in tuberculosis-infected patients and require systemic treatment, but the far more common phlyctenules—due to Staphylococcal blepharitis—respond especially well to antibiotic-steroid combination drugs.

Remember, in our hypothetical patient, treatment still hasn't been initiated, so the pathological mechanisms continue to progress. The bacteria that are now colonizing the patient's lash margins will have easy access to the ocular surface. And, given the warm, moist environment of the ocular surface and cul-de-sac, they will proliferate there.

This is antigenic to the ocular surface. The immune system will mount a response, beginning with vasodilation of the conjunctival blood vessels. This process brings greater blood flow to the tissue, and appears clinically in the conjunctiva as injection and hyperemia (figure 1).

img1
1. This patient with a bacterial eye infection presented with injection and mild chemosis.

 

At the same time, the vessels themselves become more permeable, allowing the white blood cells and other chemical inflammatory mediators to seep out of the blood vessels into the tissue where they are needed, appearing clinically as chemosis.2 The white blood cells will begin their programmed process of attacking the bacteria that are present on the ocular surface.

Concurrently, conjunctival epithelial cells will slough off, due to an increased cellular replacement rate that is characteristic of the inflammatory response. These cells will mix with the bacteria and white blood cells, creating the well-known mucopurulent discharge associated with bacterial conjunctivitis (figure 2).

img2
2. Note the presence of a mucopurulent
discharge.

 

As this process continues, the discharge reaches a volume that will bring it into regular contact with the cornea. The exotoxins produced by the dead bacteria bring even more specific inflammatory substances to the ocular surface that are visible as collections of white blood cells in the sub-epithelial space. These collections of white blood cells are commonly referred to as "infiltrates," or far less accurately "sterile ulcers" (figure 3).3,4 These white blood cell infiltrates are present to help combat the antigen on the ocular surface.

Remember, in the vast majority of scenarios, the patient's immune system handles low-grade infectious threats. Unfortunately, the "autoinfection-control" process isn't without its faults, and one of those faults is that, along with the proliferation of white blood cells, other chemical mediators are also called to the troubled area in higher-than-usual numbers. In non-infected states, specific substances known as matrix metalloproteinases (MMPs) are responsible for the important function of regulating the programmed breakdown and replacement of corneal cells. When MMPs are over-expressed, this process is accelerated. The result is that the subepithelial corneal infiltrate will begin to exhibit some tiny areas of epithelial loss that are seen clinically as punctate staining with sodium fluorescein (figure 4).

img3 img4
3, 4. This patient presented with superior corneal subepithelial infiltrates (left).
Sodium fluorescein staining revealed trace punctate epithelial keratitis (right).

 

But, it's important to understand that the infiltrate itself, with its MMPs, is the cause of that corneal compromise—and it doesn't qualify as a corneal "ulcer" just because of the overlying punctate staining. At this stage, the best treatment for the patient is an antibiotic-steroid combination drug—NOT a stand-alone antibiotic. Remember, the patient's symptoms are caused by not only the offending bacterial organisms, but also her own immune system reaction. So, use of a combination agent for bacterial conjunctivitis and for corneal infiltrates—even when they exhibit just mild staining—is the treatment of choice.3-5

In this instance, let's assume that our hypothetical patient's condition remains untreated. All of those live bacteria that are still present in everhigher numbers at the ocular surface now have a foothold into the corneal tissue via the areas of epithelial compromise overlying the infiltrate. At this stage, the live organisms can aggressively attack the surrounding corneal epithelium, which can result in a large, confluent area of epithelial loss that stains vividly with fluorescein. The patient now has a true bacterial corneal ulcer, which is more formally called "bacterial keratitis with ulceration."

The patient's immune response remains busy, sending even greater numbers of white blood cells to the affected area, which enlarges the infiltrate and consequently enhances epithelial breakdown. The corneal stroma begins to swell and becomes cloudy, reducing vision. The immune system continues to receive signals that the threat is still present, causing the iris vasculature to send even more white blood cells and chemicals to help fight the threat.

This is when the anterior chamber shows cells and flare, and you may even see a mild to moderate anterior chamber reaction ("irits") in conjunction with moderate to severe cases of bacterial keratitis with ulceration.

Meanwhile, the conjunctiva is dealing with the overwhelming numbers of live and dead bacteria, as well as an increase in injection and chemosis. This is a "hot" eye that requires high doses of strong antibiotics to kill the live bacteria.

But, as you can already predict, killing the live bacteria is just half the battle. So, theoretically, you would include a concurrent steroid to address the damaging effects of the patient's immune system. But at this point in the disease process, the risk/benefit ratio of using a combination antibiotic-steroid drug (or two separate drugs) comes down squarely on the side of patient risk. And at this time, it is too risky to use a steroid.

Although the patient's immune system is definitely causing trouble at the ocular surface, it's also providing much needed infection control services. If you remove that action without being supremely confident that the antibiotic that you chose is going to effectively manage the infectious process, the patient's cornea could be overwhelmed, resulting in adverse visual consequences.

Once you are certain that your chosen antibiotic is working effectively to fight the infection, then adding a corticosteroid is nearly always indicated within 24 to 48 hours after initial presentation.

Of course, this pathogenic process is not the only one that can result in a bacterial eye infection that requires therapeutic intervention. Our patient's troubles began with a simple case of blepharitis that progressed to a corneal ulcer. However, in reality, that is not a typical or expected outcome of blepharitis, nor is it the most common sequence of events leading to bacterial ulceration of the cornea. In fact, contact lens wearers comprise the largest group of patients who present with bacterial corneal ulcers.

In these contact lens-related cases, the gram-negative Pseudomonas species of bacteria tend to predominate. The bacteria may be introduced to the ocular surface with contact lens handling via a contaminated case or solution, or from prolonged contact between the cornea and the back surface of the contact lens where colonies of bacteria may exist in/on the contact lens matrix.6,7

Contact lens patients with associated bacterial infection can, and often do, present with primarily corneal findings, while the conjunctival signs and symptoms are the secondary responses to the infection that first began in the cornea.

Other ocular infections can occur from direct inoculation to the eye. Some examples include a conjunctival abrasion from a pet's claw or using contaminated eye drops. Finally, through extension of infection from surrounding tissues (like the nasolacrimal drainage system), bacteria can migrate to the ocular surface and begin to proliferate.

In all cases—regardless of the way they arrived there—bacteria set in motion the same cascade of pathogenic mechanisms as seen in our example patient (i.e., live bacteria infect and invade the patient's tissues while bacterial exotoxins exacerbate the patient's immune response). In order to effectively manage these patients, both of these aspects must be addressed, with the overarching principle at all stages of diagnosis and management being to protect the cornea.

So now that we know how infection occurs, let's consider the wide variety of therapeutic strategies to treat these patients.

Antibiotics

Antibiotics are classified into different groups based upon their specific mode of action. Some antibiotics act to kill bacteria (bactericidal), while others are intended to reduce bacterial growth (bacteriostatic). Some antibiotics are considered broad-spectrum—they combat a variety of both gram-positive and gram-negative bacteria—while others are more specific for certain types of organisms. Many of the newer antibiotics have been shown to have anti-inflammatory activities in addition to their actions against the bacteria themselves, which is an ideal feature if you desire antiinflammatory action and do not wish to use a combination drug or a separate steroid drop.

Today, newer drugs, such as Besivance (besifloxacin, Bausch + Lomb) and AzaSite (azithromycin, Inspire), exhibit prolonged contact time with the ocular surface due to higher viscosity as well as reduced dosing time as compared to earliergeneration antibiotics.7-10 Some antibiotics, including trimethoprim, have demonstrated significant activity against methicillin-resistant Staphylococcus aureus (MRSA), while others, such as the aminoglycosides, are resistant to this organism.11-13 This is why it is critical to understand the differences in dosing, coverage and approved indications for the medications that are available.

Aminoglycosides. Tobramycin 0.3% and gentamicin 0.3% are available both as a solution and an ointment. The aminoglycosides exhibit excellent coverage against gram-negative organisms and the Streptococcal species. Historically, tobramycin was prepared as a "fortified" solution to combat pseudomonal corneal ulcers associated with contact use. Occasionally, it is still used in this fashion when first-line therapy is ineffective.

Neomycin, a third agent in this class, shows good activity against many gram-positive and gram-negative organisms, except for Pseudo monas. Neomycin is not available as a stand-alone drug, but is available in combination with other antibiotics.

Sulfonamides. Sulfa-based drugs have been around a long time, and despite the relatively high incidence of allergy to this class of drugs, they remain a viable option to treat lid disease in non-allergic patients. Sulfa is effective against many grampositive organisms as well as against Demodex species (recently implicated in the pathogenesis of bacterial blepharitis).

Macrolides. Erythromycin 0.5% is available only as an ointment. It is primarily effective against grampositive organisms and Chlamydia trachomatis, and is safe for use in infants and newborns. In fact, erythromycin ointment is the agent of choice in prophylaxis against ophthalmia neonatorium (conjunctivitis in newborns).

The ophthalmic form of azithromycin 1%, AzaSite, is suspended in a proprietary vehicle known as DuraSite. The thicker viscosity allows the drug to remain in contact with the ocular surface longer than a traditional aqueous-based drop, which facilitates less frequent dosing to treat bacterial conjunctivitis (twice or three times a day for the first day and then once a day for the subsequent five days).

AzaSite is effective against both Staph. and Haemophilus species, making it a good choice for both pediatric and adult infections. Recently, several studies have found AzaSite to be highly effective in combating both anterior and posterior (meibomian-based) forms of blepharitis.8

The viscous fluid also can be used off-label as a lid-scrub of sorts—after instillation of a drop, instruct the patient to gently rub the excess drop across the lid margins.

Fluoroquinolones. For good reason, the fluoroquinolones consistently have been very popular as first-line therapeutic agents for virtually all bacterial eye disease.14,15

Many experts believe this has led to increased resistance to these antibiotics, particularly for earlier generations of fluoroquinolones. The second-generation ciprofloxacin is available in both drops and ointment form, and ofloxacin is available in drops. Third-generation levofloxacin was somewhat overshadowed by the fourth-generation agents, despite the fact that Iquix (Vistakon) is only the third FDAapproved agent for the treatment of bacterial corneal ulcers.

Fourth-generation gatifloxacin and moxifloxacin emerged nearly simultaneously, and were recently joined by besifloxacin 0.6%. These drugs are unquestionably the empirical treatment of choice for most practitioners who manage severe bacterial eye infections, including corneal ulcers (although none of the fourth-generation fluoroquinolones are FDA-approved to treat corneal ulcers).16,17 Overwhelming clinical evidence supports their use, based on clinical superiority, less bacterial resistance and, in the case of gatifloxacin and besifloxacin, additional anti-inflammatory activity.

Other antibiotics. Bacitracin is available as a stand-alone antibiotic ointment, and has a spectrum of activity against many gram-positive organisms. A close clinical equivalent, gramicidin, is used as a stand-in for bacitracin in antibiotic combination solutions.

Polymixin B shows good bactericidal activity against many gramnegative bacteria; however, the drug is only available as part of a combination agent. When mixed with bacitracin, the resulting combination makes an excellent all-around antibiotic ointment that is particularly effective for the treatment of lid disease.

When combined with trimethoprim, polymixin B is a powerful antibiotic agent with a broad spectrum of activity. Its only downside is the frequent dosing regimen (every three hours for conjunctivitis). Nonetheless, trimethoprim was recently found to be significantly more effective against MRSA than several other antibiotics, including the fluoroquinolones.13

In hospital-based or assistedcare living facilities, polymixin B/ trimethoprim is an excellent first choice agent against many infectious diseases. It is also good choice for the pediatric population, because it shows activity against the most common pathogens in children, including Haemophilus.

Available Antibiotic-steriod Combination Agents

 

Combination Agents

In the majority of bacterial eye disease cases, the best approach is to address both the infectious and the inflammatory components of the clinical presentation. Antibioticsteroid combination drugs offer just that—protection against further infection as well as a substantial dose of anti-inflammatory activity to quiet the body's immune response.

Ideal clinical conditions for treatment with an antibiotic-steroid combination drug are blepharitis with lid inflammation; bacterial conjunctivitis without serious corneal involvement (such as a true ulcer); corneal infiltrates; phlyctenular keratoconjunctivitis; and any other inflammatory conditions with clinically significant corneal staining that would be managed prophylactically with an antibiotic.

Antibiotic-steroid agents are available in both drop and ointment form. The ointments are ideal for use on the lid margins or for overnight coverage, but generally should be avoided for frequent daily use due to the induced blurry vision associated with oil-based products (see "Available Antibiotic-steroid Combination Agents," above).

Finally, you should determine the general pricing of the drugs you use most often in your practice. You may be able to find two separate generic drops—one antibiotic and one steroid—that would be significantly less expensive than a brand name combination drug. Because insurance plans vary, it's important to have several options available for patients with financial concerns.

Eye care practitioners can choose from an impressive and effective armamentarium of drugs to combat infectious diseases that are caused by bacteria. In most cases, a combination steroid-antibiotic agent is the best choice to address both the infection (or the threat of infection) and the inflammation that results from bacterial inhabitation. High-dose, potent antibiotic therapy should be reserved only for those serious infectious cases where the cornea is truly threatened and should never be used injudiciously because of the evergrowing risk of antibiotic-resistant organisms.

Exceeding the recommended therapeutic dose for antibiotics is never indicated except in extreme cases, such as corneal ulceration. Likewise, in those very rare cases where such frequent dosing is required, antibiotic therapy should not be tapered below the recommended therapeutic dose, but instead should be continued at the recommended dosing schedule until clinical resolution is seen.

Advanced antibiotic therapies are constantly emerging. New drugs are manufactured and information about modern dosing regimens and/or new formulations of existing medications is made available at a frequent pace. Keeping abreast of these advances is critical to ensure that our patients receive the best available care.

Dr. Reed is an associate professor at Nova Southeastern University, where she teaches ocular disease, ocular pharmacology and nutrition, and primary clinical care.

References

  1. Czepita D, Kuzna-Grygiel W, Czepita M, et al. Demodex folliculorum and Demodex brevis as a cause of chronic mar ginal blepharitis. Ann Acad Med Stetin. 2007;53(1):63-7.
  2. Mondino BJ, Caster AI, Dethiefs B. A rabbit model of Staphyloccal blepharitis. Arch Ophthalmol. 1987 Mar;105(3):409-12.
  3. Ficker L, Seal D, Wright P. Staphylococcal infection and the limbus: study of the cell-mediated immune response. Eye (Lond). 1989;3(pt. 2):190-
  4. Ficker L, Ramakrishnan M, Seal D, et al. Role of cell mediated immunity to Staphylocci in blepharitis. Am J Ophthalmol. 1991 Apr 15;111(4):473-9.
  5. Farpour B, Mcclellan KA. Diagnosis and management of chronic blepharokeratoconjunctivitis in children. J Pediatr Ophthalmol Strabismus. 2001 Jul-Aug;38(4):207-12.
  6. Patel PB, Diaz MC, Bennett JE, et al. Clinical features of bacterial conjunctivitis in children. Acad Emerg Med. 2007 Jan;14(1):1-5.
  7. Szczotka-Flynn L, Lass JH, Sethi A, et al. Risk factors for corneal infiltrative events during continuous wear of silicone hydrogel contact lenses. Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5421-30.
  8. Foulks GN, Borchman B, Yappert M, et al. Topical azithro mycin therapy for meibomian gland dysfunction: Clinical response and lipid alterations. Cornea. 2010 Jul;29(7):781-8.
  9. Haque RM, Torkildsen GL, Brubaker K, et al. Multicenter open-label study evaluating the efficacy of azithromycin oph thalmic solution 1% on the signs and symptoms of subjects with blepharitis. Cornea. 2010 Aug;29(8):871-7.
  10. Karpecki P, Depaolis M, Hunter JA, et al. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial con junctivitis: A multicenter, prospective, randomized, double masked, vehicle-controlled, 5-day efficacy and safety study. Clin Ther. 2009 Mar;31(3):514-6.
  11. Tepedino ME, Heller WH, Usner DW, et al. Phase III effi cacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin. 2009 May;25(5):1159-69.
  12. Adebayo A, Parikh JG, McCormick SA, et al. Shifting trends in in vitro antibiotic susceptibilities for common bac terial conjunctival isolates int eh last decade at the New York Eye and Ear Infirmary. Graefes Arch Clin Exp Ophthalmol. 2011 Jan;249(1):111-9.
  13. Asbell PA, Colby KA, Dent S, et al. Ocular TRUST: Nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008 Jun;145(6):951-8
  14. Callegan MC, Novosad BD, Ramadan RT, et al. Rate of bacterial eradication by ophthalmic solutions of fourth-gener ation fluoroquinolones. Adv Ther. 2009 Apr;26(4):447-54.
  15. Hori Y, Nakazawa T, Maeda N, et al. Susceptibility comparisons of normal preoperative conjunctival bac teria to fluoroquinolones. J Cataract Refract Surg. 2009 Mar;35(3):475-9.
  16. Hyon JY, Eser I, O'Brien TP. Kill rates of preserved and preservative-free topical 8-methoxyfluoroquinolones against various strains of Stpahylococcus. J Cat Refract Surg. 2009 Sep;35(9):1609-13.
  17. Kaye SB, Tuft S, Neal T, et al. Bacterial susceptibility to topical antimicrobials and clinical outcome in bacterial kera titis. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):362-8.

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