Clinical Updates on Managing Infectious Keratitis
Corneal infections and subsequent opacities, largely caused by infectious keratitis, are the 4th leading cause of blindness worldwide. In the United States, infectious keratitis is especially seen with extended contact lens wear, though in developing countries ocular trauma remains the leading etiology. Typically, bacterial keratitis develops when the ocular surface has been compromised. However, some bacteria are able to penetrate an intact epithelium, i.e.- Neisseria gonorrhea, Neisseria meningitis, Corynebacterium diphtheria, and Haemophilis influenza.
Proper diagnosis is paramount to initiating adequate treatment protocols and achieving clinical resolution. Currently, corneal cultures are the mainstay in identifying the underlying pathogen. Below are common cultured stains used to identify pathogens:
Gram and Giemsa stains: bacterial and fungal cases
Blood and chocolate agar: bacterial (most commonly used) and some fungi
Sabouraud’s agar: fungal
Non-nutrient agar with Escherichia coli overlay: Acanthamoeba
Polymerase chain reaction: viral (rarely used, often diagnosed on history/examination)
As mentioned, keratitis can be segregated into one of three categories: bacterial, fungal, and viral keratitis (though bacterial and fungal infection can coexist). We will now describe each pathogen with preferred therapeutic options from scientifically supported clinical trials.
Treatment with Antibiotics
Treatment with topical antibiotics is the preferred therapy in achieving resolution of an infection. Antibiotic monotherapy has an advantage over duotherapy in lowering the risk of ocular surface toxicity as well as increasing patient compliance. Commercially available fluoroquinolones are typically preferred agents to treat bacterial keratitis and are regarded as being as effective as duotherapy.
In very aggressive diseases, duotherapy may be desired and usually involves a combination of two fortified antibiotics (i.e.- a cephalosporin and an aminoglycoside) to cover for Gram-positive and Gram-negative pathogens respectively. Fortified antibiotics have several disadvantages including cumbersome compounding, higher cost, risk of contamination, limited availability, short shelf life, and the need for refrigeration.
In a recent study, bacterial keratitis was managed in 16 trials over the period of 7 days that compared moxifloxacin vs. ofloxacin vs. tobramycin/cefazolin (fortified antibiotic). The research showed that while there was occasionally mild ocular discomfort when instilling the aminoglycoside-cephalosporin antibiotic compared to the fluoroquinolones, there was no significant difference on the time to re-epithelialize the cornea or on time to cure. Of note, moxifloxacin demonstrated superior corneal penetration.
Antibiotic resistance is a growing concern when treating infections. Not only are 2 million people infected with drug resistant microbes annually, 80% of methicillin-resistant Staphylococcus aureus in the United States are resistant to the fluoroquinolones, the most commonly prescribed antibiotic class. As previously stated, in patients diagnosed with bacterial keratitis who are not improving on fluoroquinolones, switching to fortified broad-spectrum antibiotics is advised.
Implications: Fortified antibiotics are rarely preferred to commercially available fluoroquinolones. In patients who truly need fortified antibiotics, consider starting them on fluoroquinolones until the compounded antibiotics can be obtained.
In an acute infection, fibroblasts, keratocytes, and other inflammatory cells can result in corneal melting and potential corneal perforation, increasing the incidence of severe infectious keratitis. Tetracyclines, well known to inhibit matrix metalloproteinase-9 responsible for protein degradation and keratolysis, reduce the rate of corneal perforation. In two rabbit studies, high-dose systemic tetracycline reduced corneal ulceration from 85% to 9%; a separate study systemic doxycycline reduced the rate of cornea perforation from pseudomonas by 50%. We recommend prescribing 100mg of doxycycline at the initial encounter (along with topical therapy as previously discussed).
Treatment with Steroids
The large, randomized, controlled Steroids for Corneal Ulcers Trial (SCUT) study compared adjuvant topical corticosteroids with placebo for treating bacterial corneal ulcers. While steroids did not show any significant benefit overall, they did prove advantageous in ulcers that were central, deep, large, non-Nocardia, or in cases of Pseudomonas. Nocardia, an atypical bacterium, was seen in 10% of all ulcers in SCUT. Subjects randomized to corticosteroids with Nocardia fared far worse than placebo, as a larger infiltrate or scar was present at 3-month follow up.
Implications: Based on the results of SCUT, adjuvant topical steroids in non-Nocardia cases are recommended after 48 hours of selective antibiotic therapy.
Treatment with Topical Anti-Fungals
Due to their unique microbiological structure and physiology, fungal ulcers are more difficult to treat, and have worse outcomes than bacterial ulcers. Also, fungal keratitis diagnosis is typically delayed as the offending pathogen is usually presumed bacterial. Since natamycin was FDA-approved in the 1960s, no other topical eye drop to treat fungal keratitis has been developed. As with bacterial keratitis, contact lens wear is also an important risk factor for developing fungal keratitis.
Though natamycin 5% is the preferred topical treatment option in fungal infections, its efficacy is somewhat hindered by its poor corneal stromal penetration. Amphotericin B 0.3% to 0.5% are viable alternatives but require a compounding pharmacy that are not always readily available.
In the Mycotic Ulcer Treatment Trial I (MUTT I), topical 5% natamycin and topical (compounded) 1% voriconazole were studied in the treatment of filamentous fungal ulcers. The results of natamycin compared with voriconazole was so astounding that the Data Safety Monitoring Committee urged to cease treating those taking voriconazole due to a statistically significant increase in corneal perforation and severe complications. Patients taking natamycin had a better BCVA and smaller scar size at the 3-month follow up than those treated with voriconazole. Further evidence showed that on day 6 of treatment, a higher percentage of patients still cultured positive for fungal infection with voriconazole compared to natamycin.
Implications: Topical voriconazole is inferior to topical natamycin in the treatment of all fungal infections as evidenced by the MUTT I.
Treatment with Oral Voriconazole
The Mycotic Ulcer Treatment Trial II (MUTT II), sought to investigate potential benefits of oral voriconazole compared to oral placebo. The shortcomings of topical voriconazole were exposed once again, with oral voriconazole providing higher and more constant doses than topical voriconazole. In a study comparing oral and topical voriconazole, testing after topical administration showed large variability in aqueous concentrations “with troughs well below the minimum inhibitory concentration at which 90% of fungal isolates are inhibited (MIC90).” MUTT II discovered no major advantage to treating with oral voriconazole compared to placebo, with significantly more adverse effects when oral voriconazole was employed.
Implications: Topical natamycin remains first-line therapy over oral and topical voriconazole in the treatment of filamentous fungal keratitis as evidenced by MUTT I and MUTT II. Additionally, there was no benefit of adjuvant oral voriconazole.
Unlike bacterial and fungal keratitis, viral keratitis has the ability to be both chronic and recurrent. The leading cause of corneal blindness in the world, herpes simplex virus keratitis (HSV-K) affects 500,000 individuals in the United States alone. In developing countries, 60% of all corneal ulcers are noted to be the result of the herpes simplex virus. Globally, the lifetime risk of developing HSK is 1%.
Because of the virus’ ability to relapse, a persistent impairment on the quality of life for individuals who have been affected is well documented. Forty percent of patients will experience 2 to 5 relapses in their lifetime, with 11% of those experiencing 6 to 15 relapses. Even during the quiescent phases of the disease, psychological impairment is similar to that of sight-threatening diseases like glaucoma and macular degeneration.
Treatment with Topical Antivirals
There are two FDA-approved topical agents to treat HSK: trifluridine (Viroptic) and ganciclovir (Zirgan). Trifluridine is more commonly prescribed due to its generic availability, though it does carry a higher propensity for ocular surface toxicity.
Implications: While ganciclovir is a newer drug with enhanced broad-spectrum antiviral coverage, its use it somewhat prohibitive due to cost. Thankfully, there are coupons available to make Zirgan more affordable.
Treatment with Topical Steroids
In the Herpetic Eye Disease Study I (HEDS I), the efficacy of adjuvant corticosteroids to treat HSV stromal keratitis was researched over a 10-week period. While visual acuity was similar with those treated with topical corticosteroids compared to placebo after 6-months, the placebo group paled in comparison when analyzing HSK time to resolution.
Implications: HEDS I showed faster resolution of infection by adding topical corticosteroids with trifluridine compared to trifluridine alone when stromal keratitis was present.
Treatment with Oral Steroids
The adjuvant use of oral acyclovir was also analyzed as a treatment protocol for HSV stromal keratitis. In this study, 104 patients taking topical trifluridine and corticosteroids were randomized to receive oral acyclovir or the placebo. The addition of oral acyclovir resulted in a significantly significant increase in vision after 6-months compared to placebo.
Implications: Oral acyclovir provided improved vision after 6-months of use to decrease stromal keratitis.
Oral valacyclovir, a prodrug of acyclovir, has an enhanced ability to penetrate the cornea with a less-frequent dosing schedule compared to acyclovir.
Implications: To avoid ocular surface toxicity, oral antivirals are often preferred to topical antivirals, and work equally as well. Further, oral acyclovir at 400mg 5xD or valacyclovir 500mg TID is the least expensive medical therapy.
In the Herpetic Eye Disease Study II (HEDS II), prolonged use of oral acyclovir was researched to examine rate of recurrent ocular HSV. In those taking oral acyclovir, the risk of HSV recurrence was 45% lower compared to placebo.
Implications: A long-term, low dose of oral acyclovir decreases the risk of developing recurrent HSV stromal keratitis. The dosage is either acyclovir 400mg BID or valacyclovir 500mg QD for “5-disease free years.”
New Treatments on the Horizon
Collagen Cross-Linking (CXL)
Collagen cross-linking is gaining popularity to help treat a spectrum of corneal ulcers. In CXL, photochemically activated riboflavin strengthens collagen bonds and molecules in the cornea, improving the resistance to enzymatic degradation while providing antimicrobial effects.
In a small case study, 16 patients with bacterial keratitis were treated only by CXL. Out of this sampling, 14 of the patient’s ulcers resolved with out any adjuvant therapy. Only 2 required topical antibiotics to resolve the infection. If more research can prove the effectiveness on CXL, perhaps this model will help address the current drug-resistant therapies that plaque millions of affected patients worldwide.
Austin, et al. Update on the Management of Infectious Keratitis. Ophthalmology. Vol 124, Number 11, Nov 2017.
Bowling, Brad. Kanski’s Clinical Opthalmology.
Reynaud, et al. Persistent Impairment of Quality of Life in Patients with Herpes Simplex Keratitis. Ophthalmology. Article in Press.