Therapy for acute bacterial keratitis

ByTerrence P. O'Brien, MD

Bacterial keratitis affects more than 500,000 patients annually worldwide and more than 30,000 patients per year in the United States.¹ When acute bacterial keratitis is suspected, the clinical situation is often urgent, given the rapid pace and destructive effects of the infectious process. Complications resulting from bacterial keratitis, primarily corneal opacification, limit the vision of approximately 100,000 people in North America and more than 1 million people globally.¹ Approximately 50% of contact lens-related keratitis results in poor vision, and corneal opacification with perforation accounts for 330 corneal transplants per year in the United States. In developing parts of the world, bacterial keratitis is an even greater problem, with an epidemic of corneal blindness, especially monocular blindness, resulting from infectious corneal ulcerations.²

Microbial keratitis can be caused by bacteria, fungi, parasites or viruses. The principal gram-positive bacterial organisms involved in microbial keratitis are Staphylococcus and Streptococcus. Pseudomonas and other Enterobacteriaceae are the primary gram-negative pathogens involved in microbial keratitis. Gram-positive infections often cause an ulceration of the corneal epithelium followed by a worsening suppurative keratitis. On the other hand, gram-negative infection has a rapid pace of inflammation, often leading to severe corneal abscess and perforation with hypopyon.

Risk factors

“Bacteria readily bind to contact lenses of all types and materials and to the corneal epithelium, initiating the pathogenesis of bacterial keratitis.”
— Terrence P. O’Brien, MD

Several risk factors can predispose patients to bacterial keratitis, including contact lens use, surgical procedures, ocular trauma or injury, epithelial defects, ocular surface disease and systemic conditions.3 A brief overview of a patient’s medical history can identify risk factors and aid prompt diagnosis of bacterial keratitis.

Although refractive surgery is popular, approximately 35 to 40 million people in the United States continue to wear contact lenses, which remain a primary risk factor for the development of severe bacterial keratitis with ulceration. Despite physicians’ efforts to educate patients on appropriate contact lens hygiene measures, not all patients follow the recommendations. If contact lenses are not handled and cleaned properly, a biofilm can form. Bacteria readily bind to contact lenses of all types and materials and to the corneal epithelium, initiating the pathogenesis of bacterial keratitis. Presence of a biofilm potentiates the possibility of infection by binding to the contact lens and the contact lens storage case. The biofilm blocks antibiotics from working uniformly, which can result in unchecked bacterial proliferation and, ultimately, severe keratitis.

Studies have shown that among patients who wear contact lenses, approximately 54% of bacterial keratitis cases are caused by gram-negative bacteria and approximately 40% of cases are caused by gram-positive bacteria. Gram-negative organisms may bind more efficiently to contact lenses, accounting for their increased connection with contact lens-associated keratitis. Fungal keratitis may develop in patients who wear soft contact lenses, especially when they use multipurpose solutions. Studies at the Bascom Palmer Eye Institute show that the incidence of fungal keratitis among patients who wear soft contact lenses has increased sharply compared to past decades.^4-9

Treatment goals

“Fluoroquinolones offer broad-spectrum potency, and the bioavailability and penetration into the ocular tissue to achieve increased concentrations in the corneal stroma.”
— Terrence P. O’Brien, MD

Obtaining material from the cornea suspected of infection for diagnostic testing is an essential step, especially in cases judged to be severe. Microbial culture identifies the pathogen and directs appropriate treatment, especially in cases of severe bacterial keratitis. These cultures confirm the diagnosis, aid in modifying therapy, and help determine susceptibility to the treatment agents.

When treating bacterial keratitis, the primary goal is to eliminate the pathogens by rapidly halting organism replication. The secondary goal is to prevent host tissue destruction by collagenolysis, which can lead to scarring, neovascularization, corneal opacification and vision loss. The traditional treatment approach for bacterial keratitis is to use a “saturation bombing” with extemporaneously prepared fortified antibiotics administered hourly. Typically, a broad-spectrum antibiotic is used to cover likely pathogens early in the course of infection. I suggest using a culture to identify the pathogens and guide optimal therapy.

There has been a shift toward empirical monotherapy, which can be appropriate, especially with less severe cases and with certain antibiotics. Fluoroquinolones have been useful in successfully treating bacterial keratitis alone or in combination with another antibiotic. A multicenter trial compared single-agent fluoroquinolone therapy with a combination of fortified cefazolin and tobramycin, and the findings showed equivalency of therapeutic efficacy with less cytotoxicity compared with fortified antibiotics.¹⁰

Initial therapy is based on the severity of the bacterial keratitis, and the American Academy of Ophthalmology has a preferred practice program that enables ophthalmologists to assign a severity assessment (Figure 1). For severe cases, cultures are obtained and antibiotic therapy begins immediately. For nonsevere cases, ophthalmologists first assess the likelihood that the patient is suspected of having bacterial keratitis. If the patient has bacterial keratitis, fluoroquinolones may be an effective treatment option. If a diagnosis cannot be confirmed, the physician may not use an antibiotic and may consider other causes of keratitis in the differential diagnosis.

Table: Initial Therapy Based on Severity

Figure 1. Ophthalmologists must follow guidelines set forth by the Aamerican Aacademy of Ophthalmology for the initial treatment of corneal infection. Once physicians assess the severity of patients’ symptoms, they can determine the appropriate course of treatment.

Source: O’Brien T.

Increasing resistance

Drug-resistant strains of bacteria are typically rare, but with increasing antimicrobial exposure, resistant strains can emerge and proliferate in the population. Increasing drug resistance has been reported among keratitis isolates. A number of studies show the shift in susceptibility patterns among ocular isolates.^11-13 A study at the Bascom Palmer Eye Institute found approximately 40% to 50% of Staphylococcus aureus strains recovered from acute corneal infections are now methicillin-resistant (E. Alfonso, MD, D. Miller, MD, T. O’Brien, MD, unpublished data, 2008). Goals for Therapy

These susceptibility patterns have caused physicians to reconsider initial treatment with fortified antibiotics to cover both gram-positive and gram-negative bacteria and to select an antibiotic wisely. In some cases, a combination of two or more antibiotics may be required. Fluoroquinolones offer broad-spectrum potency, and the bioavailability and penetration into the ocular tissue to achieve increased concentrations in the corneal stroma. Fluoroquinolones maintain low minimal inhibitory concentrations based on bacterial susceptibility testing, thus preventing surviving bacteria from mutating and developing resistance if sufficiently high tissue concentrations are achieved.

Some fluoroquinolones can act as fortified fluoroquinolones with high concentrations. Levofloxacin ophthalmic solution 1.5% has an active concentration of 15 mg/mL and is effective against both gram-positive and gram-negative infections. For patients with small, peripheral corneal ulcerations less than 2 mm in diameter without progressive keratolysis, empirical therapy using a fortified fluoroquinolone such as levofloxacin ophthalmic solution 1.5% is a viable option. However, if a patient has an ulceration larger than 2 mm in the central mid to deep stroma that is fulminating and sight-threatening, it must be cultured to obtain material for staining, organism identification and susceptibility testing. In this case, initial therapy may include a combination of vancomycin 2.5% and levofloxacin ophthalmic solution 1.5% with frequent administration early in the course of treatment. However, levofloxacin 1.5% is the only newer fluoroquinolone indicated for the treatment of bacterial keratitis. Physicians must stress patient compliance, and adjunctive measures, such as cycloplegic agents and judicious application of topical corticosteroids, must be used to prevent destruction of the stromal tissue.

Initial therapy for severe, central, sight-threatening keratitis has improved over the years. Having fortified fluoroquinolones for both severe and mild cases allows ophthalmologists to be more successful in their approach to treatment on behalf of patients with corneal infections. Combined therapy is still an option, especially for severe cases. More research on strategies to prevent tissue destruction associated with microbial keratitis is needed, and research into basic pathogenesis and identifying new targets is ongoing.

Editor’s Note: Iquix solution is indicated for the treatment of corneal ulcer.

Terrence P. O’Brien, MD, is a professor of ophthalmology at the Ocular Microbiology Laboratory at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Palm Beach, Florida, and a Cornea/External Disease Section member of the Ocular Surgery News Editorial Board. Dr. O’Brien can be reached at 561-515-1544; fax: 561-515-1588; e-mail: tobrien@med.miami.edu.

References:

Wilhelmus KR. Indecision about corticosteroids for bacterial keratitis. An evidence-based update. Ophthalmology. 2002;109:835-844.
Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79:214-221.
Prepared by the American Academy of Ophthalmology Cornea/External Disease Panel. Preferred practice pattern: bacterial keratitis. San Francisco, CA: American Academy of Ophthalmology; 2005.
Liesegang TJ, Forster RK. Spectrum of microbial keratitis in South Florida. Am J Ophthalmol. 1980;90:38-47.
Alfonso E, Mandelbaum S, Fox MJ, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol. 1986;101:429-433.
Wilhelmus KR, Robinson NM, Font RA, Hamill MB, Jones DB. Fungal keratitis in contact lens wearers. Am J Ophthalmol. 1988;106:708-714.
Rosa RH Jr, Miller D, Alfonso EC. The changing spectrum of fungal keratitis in south Florida. Ophthalmology. 1994;101:1005-1013.
Tanure MA, Cohen EJ, Sudesh S, Rapuano CJ, Laibson PR. Spectrum of fungal keratitis at Wills Eye Hospital, Philadelphia, Pennsylvania. Cornea. 2000;19:307-312.
Alfonso EC, Cantu-Dibildox J, Munir WM, et al. Insurgence of Fusarium keratitis associated with contact lens wear. Arch Ophthalmol. 2006;124:941-947.
O’Brien TP, Maguire MG, Fink NE, Alfonso E, McDonnell P. Efficacy of ofloxacin vs cefazolin and tobramycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research Group. Arch Ophthalmol. 1995;113:1257-1265.
Mah FS. New antibiotics for bacterial infections. Ophthalmol Clin North Am. 2003;16:11-27.
Marangon FB, Miller D, Romano A, Alfonso EC. Emergence of quinolone resistance among methicillin sensitive Staphylococcus aureus keratitis and conjunctivitis isolates. Presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; May 5, 2002; Ft. Lauderdale, Fla. Abstract.
Kowalski RP, Karenchak LM, Romanowski EG, Mah FS, Ritterband DC and Gordon YJ. An in vitro comparison of 2nd, 3rd, and 4th generation fluoroquinolones against bacterial keratitis isolates. Presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; May 6, 2002; Ft. Lauderdale, Fla. Abstract.