Considering Keratitis: Critical Questions in Disease Management
Your approach to these four clinical challenges will influence the course of therapy and its outcome.
This course reviews the cause, presentation, test and treatment methods of bacterial keratitis.
Rachel Wozniak, MD, PhD, and James Aquavilla, MD
This course is COPE approved for 1 hour of CE credit. COPE ID 46966-AS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Joint Sponsorship Statement:
This continuing education course is jointsponsored by the Pennsylvania College of Optometry.
Dr. Wozniak and Dr. Aquavella have no financial interest in any products mentioned.
|Bacterial corneal infections, like the Pseudomonas ulcer pictured here, can lead to severe consequences if not handled properly.
Photo: Christine W. Sindt, OD
Bacterial keratitis is a rare yet potentially devastating ophthalmic disease. Acute infections can present with dense corneal infiltrates, edema and subsequent ulceration, which, despite aggressive treatment, may result in long-term, vision-threatening sequelae including corneal scarring, glaucoma and cataract.1,2 In fact, corneal opacification due to ulceration is a leading cause of vision loss contributing approximately two million new cases of blindness worldwide each year.3,4
Past research has noted an incidence of ulcerative bacterial keratitis as approximately 11 per 100,000 person-years in the United States, while more recent studies report rates ranging from 20.9 to 27.6 per 100,000 person-years.5-7 Unsurprisingly, there is a significant increase in incidence among contact lens wearers, up to 130.4 per 100,000 person-years; in fact, wearing contact lenses, especially overnight, is the greatest risk factor for bacterial keratitis in developed nations.6,8–10 With 40 million contact lens wearers in the United States and the increasing popularity of toric and multifocal lenses, the incidence of bacterial keratitis may well continue to rise.11
Aside from contact lens wear, other significant risk factors for bacterial keratitis include surgical and non-surgical trauma; ocular surface disease such as exposure keratopathy, tear-film deficiencies, neurotrophic keratopathy, bullous keratopathy and blepharitis; and systemic conditions such as diabetes, graft-versus-host disease, mucous membrane disorders or immunosuppression.12-15 Often, patients exhibit several of these risk factors.
1. WHAT'S THE CAUSE?
In general, it is extremely rare for a healthy eye to develop a spontaneous infection; generally, one or more predisposing factors can be identified in most cases. Recording a thorough contact lens history—including wear time, type of solution, lens hygiene and replacement habits—is critically important. Understanding the nature of the disease course including duration of symptoms, degree of pain, redness, presence of discharge and change in vision can indicate severity as well as help distinguish rapidly evolving infections from those with a more indolent course. Taking a thorough medical and ocular history can also help uncover underlying issues such as immunosuppression, recent illness, prior ocular disease, infections or trauma. Of particular importance is a history of prior herpetic eye disease, which can often leave the cornea neuro-trophic and thus more susceptible to bacterial keratitis.
Though causes of bacterial keratitis vary depending on geography and patient population, most reflect the normal flora of the ocular surface and are largely due to gram-positive organisms such as coagulase-negative Staphylococci, Staphylococcus aureus and Corynebacterium.6,14,16-18Pseudomonas aeruginosa is generally the most likely causative organism in cases of gram-negative infections.14 Contact lens wear in particular tends to be associated with Pseudomonas, although significant numbers of Serratia marcescens and Moraxella sp. infections have also been reported.14,18-21 Generally, gram-negative organisms result in a rapidly evolving, highly virulent infection that can lead to ocular perforation in just 24 to 48 hours. While certain gram-positive organisms, such as S. aureus or Streptococcus pneumoniae may behave similarly, other gram-positive species such as Streptococcus viridans may have a more indolent course with less dramatic clinical presentations.
2. HOW TO TEST?
Stains and cultures allow for early identification of non-bacterial organisms and provide the basis for eliminating either gram-positive or gram-negative coverage in order to reduce patient eye drop burden and avoid overuse and misuse of antibiotics. However, variations in ability and availability of culture materials and reagents result in the empiric treatment of many cases of community bacterial keratitis.22,23 In fact, the 2013 published preferred practice pattern of bacterial keratitis from the American Academy of Ophthalmology recommends pursuing stains and cultures only in cases in which the ulcer: is particularly large; is centrally located; involves the mid or deep stroma; is an infection that has not been responsive to initial treatment; or has atypical features which may indicate fungal, amoebic or myco-bacterial keratitis.24
While traditional culture methods successfully identify a causal organism in only 40% to 60% of cases, in the era of emerging antibiotic resistance it may be prudent to attempt Gram stain and culture of all cases of bacterial keratitis in order to tailor treatment appropriately when possible.18,22,25,26 Of importance, prior treatment with antimicrobials does not necessarily decrease culture yields, although it may take longer to recover pathogens.18,27 Thus, there can be utility in delayed cultures particularly in refractory or chronic cases.
A corneal tissue biopsy is an additional diagnostic approach, particularly when initial results from corneal scrapings are unrevealing.28-30 A recent study identified a causal agent in 42% of cases, either with culture or histopathologic examination of the tissue. Of note, 44% of patients in this series had initial negative cultures from corneal scrapings.30 The advantage of biopsy is that the tissue can be used both for culture and histopathology; the latter of which may have added benefit in identifying Acanthamoeba or fungi, which are more difficult to culture with traditional methods. While biopsy may have some inherent risk to the patient (i.e., corneal perforation), this technique may be most useful in the setting of recalcitrant disease with no clear causal organism. As mentioned above for delayed cultures, corneal biopsy can still be an effective means for identifying organisms, even after treatment has been initiated.
3. WHICH ANTIBIOTIC?
Ideally, treatment should be tailored to the causal organism; however, in the case of a rapidly progressive disease process, patients cannot afford to wait until Gram stain results return prior to initiating treatment. Gram stain may take up to 24 hours to return from the lab while culture data will take several days. In the absence of details from the history or unusual features on clinical exam that could indicate a fungal, amoebic or viral process, first-line empiric treatment should provide broad coverage against both gram-positive and gram-negative organisms.
Fourth-generation fluoroquinolones are considered by many to be mainstays of corneal ulcer treatment, as they provide excellent gram-negative coverage while offering strong protection against gram-positive organisms such as S. aureus and coagulase-negative Staphylococcus sp. In general, fluoroquinolones are readily available, well tolerated, and effectively penetrate the ocular surface, making these agents an attractive first line choice in treating keratitis. Gatifloxicin and moxiflox-acin, in particular, are often popular choices for initial empiric treatment of bacterial keratitis.
However, increasing rates of antibiotic resistance, particularly among gram-positive organisms, should be considered when initiating treatment. Studies like the Ocular Tracking Resistance in US Today (TRUST) and Antibiotic Resistance Monitoring in Ocular MicRorganisms (ARMOR) have shown that while methicillin-sensitive S. aureus (MSSA) susceptibility to all fluoroquinolones is approximately 80%, methicillin-resistant S. aureus (MRSA), susceptibility is only roughly 15%.31,32 In addition to MSSA and MRSA, many other gram-positive organisms have developed significant resistance to most commonly used ophthalmic antibiotics, with the efficacy of third generation fluoroquinolones the most affected.17,20,33 Regarding gram-negative organisms, fluoroquinolones continue to provide excellent coverage in most geographic areas, but reports of emerging resistance are on the rise.34,35
Fortified antibiotics offer an increased concentration of drug over commercially available antibiotics and provide more complete coverage of both gram-positive and gram-negative organisms including MRSA and Pseudomonas. A fortified antibiotic regimen typically includes a cephalosporin or vancomycin combined with an aminoglycoside such as tobramycin or gentamycin. Though effective in many cases, there are also obvious disadvantages, including access to specialized compounding pharmacies, reduced shelf life, the need for multiple drops and possible increased risk of ocular toxicity.36,37 While several studies highlight similar outcomes between fluoroquinolone monotherapy and fortified antibiotics, in an era of significant antibiotic resistance, practioners should consider either combining a fluoroquinolone with fortified vancomycin or cefazolin, or using a combination fortified regimen for complete coverage, particularly in severe cases.37–40 Antibiotic resistance patterns can vary significantly by geography. Thus, local antibiograms should be used to inform treatment choices.
4. WHAT ABOUT STEROIDS?
Debate over whether or not to use steroids in the treatment of bacterial keratitis is ongoing—on one hand, they suppress inflammation, which may in turn reduce the risk of subsequent corneal scarring; on the other, there are a number of disadvantages including higher risk of corneal melting, an increase in infection burden due to local immunosuppression and elevated IOP.
A recent review analyzed four randomized control trials (including the Steroids for Corneal Ulcer Trial (SCUT)) comparing groups treated with antibiotics and topical corticosteroids against antibiotics alone.41 As three of the four trials were underpowered to detect treatment effect differences, it is difficult to draw definitive conclusions. Nonetheless, there did not appear to be a difference in visual acuity, re-epithelialization time, quality of life or adverse affects between the treatment and control groups.
However, the timing of steroid initiation may be an important consideration. Participants in the Steroids for Corneal Ulcer Trial (SCUT) received steroids anywhere from two to 34 days after starting antibiotic therapy. In a recently published sub-analysis, patients who were given steroids within two to three days of starting antibiotic therapy showed a statistically significant gain in visual acuity at three months, particularly those with severe or moderately severe ulcers.42 Additionally, the data suggests steroids may actually be detrimental with respect to visual acuity if initiated after four days of antibiotic therapy.42 Long-term follow-up data from the SCUT also supports corticosteroid use, showing a one-line improvement in visual acuity at 12 months for ulcers not caused by Nocardia species.43
There are a number of differing approaches and unanswered questions in the diagnosis and management of bacterial keratitis. A thorough history with particular attention to contact lens use, combined with subsequent culture data can help tailor treatment regimens. When possible, cultures and smears should be obtained on initial presentation, although delayed cultures can still be beneficial. Antibiotic resistance is an important consideration when treating empirically, and it is necessary to understand local antibiograms to make rational decisions. In cases where ulcers are large, centrally located and have begun to invade and destroy the corneal stroma, fortified antibiotics provide the necessary robust gram-positive and gram-negative coverage for adequate treatment. Finally, steroids may provide some benefit with respect to visual acuity if initiated early.
Rachel Wozniak, MD, PhD, is a senior ophthalmology resident at the Flaum Eye Institute, with a reasearch background in microbiology and molecular genetics. She will be pursuing a cornea and external disease fellowship after graduation.
Dr. Aquavella is the Catherine E. Aquavella Distinguished Professor of Ophthalmology and director of the Ocular Surface Laboratory at the University of Rochester Flaum Eye Institute. His most recent activity has been in the development of techniques for keratoprosthesis surgery in infants and objective technology for the evaluation of the ocular surface.
- Lotti R, Dart J. Cataract as a complication of severe microbial keratitis. Eye (Lond). 1992;6(Pt4):400-3.
- Zarei-Ghanavati S. et al. Elevated intraocular pressure is a common complication during active microbial keratitis. Am. J. Ophthalmol. 2011 Oct;152(4):575-581.
- Resnikoff S. et al. Global data on visual impairment in the year 2002. Bull. World Health Organ. 2004; 82:844–51.
- Whitcher JP, Srinivasan M, and Upadhyay MP. Corneal blindness: a global perspective. Bull. World Health Organ. 2001;79:214–21.
- Erie JC, Nevitt MP, Hodge DO, Ballard DJ. Incidence of ulcerative keratitis in a defined population from 1950 through 1988. Arch. Oph-thalmol. 1993 Dec;11(12):1665-71.
- Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern Califor-nia. Arch. Ophthalmol. 2010 Aug:128(8):1022-8.
- Ibrahim, Boase & Cree. Incidence of Infectious Corneal Ulcers, Portsmouth Study, UK. J Clin Exp Ophthalmol (2012). doi:10.4172/2155-9570.S6-001
- Dart JK, Radford CF, Minassian D, et al. Risk factors for microbial keratitis with contemporary contact lenses: a case-control study. Ophthalmology 2008 Oct:115(10):1647-54.
- Yildiz EH, Airiani S, Hammersmith KM, et al. Trends in contact lens-related corneal ulcers at a tertiary referral center. Cornea 31, 1097–102 (2012).
- Dart JK, Stapleton F and Minassian D. Contact lenses and other risk factors in microbial keratitis. Lancet 338, 650–3 (1991).
- Efron N, Nichols J, Woods C and Morgan P. Trends in US Contact Lens Prescribing 2002 to 2014. Optometry & Vision Science. 2015 Jul:92(7):758-67.
- Ng A. et al. Predisposing Factors, Microbial Characteristics, and Clinical Outcome of Microbial Keratitis in a Tertiary Centre in Hong Kong: A 10-Year Experience. Journal of Ophthalmology 2015.
- Green M, Apel A, Stapleton F. A longitudinal study of trends in keratitis in Australia. Cornea 2008 Jan;27(1):33-9.
- Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea 2008 Jan;27(1)22–7.
- Lam DS, Houang E, Fan DS, et al. Incidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America. Eye (Lond). 12002 Sep;16(5):608-18.
- Hsu HY, Lind JT, Tseng L, Miller D. Ocular flora and their antibiotic resistance patterns in the midwest: a prospective study of patients undergoing cataract surgery. Am. J. Ophthal-mol. 2013 Jan;155(1):36-44.
- Lichtinger A, Yeung SN, Kim P, et al. Shifting trends in bacterial keratitis in To-ronto: an 11-year review. Ophthalmology 2012 Sep;119(9):1785-90.
- Ni N, Nm EM, Hammersmith KM, et al. Seasonal, geographic, and antimicrobial resistance patterns in microbial keratitis: 4-year experience in eastern Pennsylvania. Cornea. 2015 Mar;34(3):296-302.
- Stapleton F, Carnt N. Contact lens-related microbial keratitis: how have epidemiology and genetics helped us with pathogenesis and prophylaxis. Eye (Lond) 26, 185–93 (2012).
- Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology. 2000 Aug;107(8):1497-502.
- Pandita A, Murphy C. Microbial keratitis in Waikato, New Zealand. Clin. Experiment. Oph-thalmol. 2011 Jul:39(5):393-7.
- McLeod SD, Kolahdouz-Isfahani A, Rosta-mian K, et al. The role of smears, cultures, and antibiotic sensitivity testing in the management of suspected infectious keratitis. Ophthalmology. 1996 Jan;103(1):23-8.
- Hsu HY, et al. Community opinions in the management of corneal ulcers and ophthalmic antibiotics: a survey of 4 states. Eye Contact Lens. 2010 Jul;36(4):195-200.
- American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern® Guidelines. Bacterial Keratitis. San Francisco, CA: American Academy of Ophthalmology; 2013.Available at: www.aao.org/ppp.
- Levey SB, Katz HR, Abrams DA, et al. The role of cultures in the management of ulcerative keratitis. Cornea 1007 Jul;16(4):383-6.
- Knox CM, Cevellos V and Dean D. 16S ribosomal DNA typing for identification of pathogens in patients with bacterial keratitis. J. Clin. Microbiol. 1998 Dec;36(12):3492-3496.
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- Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. Am. J. Ophthalmol. 2011 Oct;152(4):567-574.
- Chang VS, Dhaliwal DK, Raju L, Kowalski RP. Antibiotic Resistance in the Treatment of Staphylococcus aureus Keratitis: a 20-Year Review. Cornea 2015 Jun;34(6):698-703.
- Oldenburg CE, Lalitha P, Srinivasan M, et al. Emerging moxifloxacin resistance in Pseudomonas aeruginosa keratitis isolates in South India. Ophthalmic Epidemiol. 2013 Jun;20(3):155-8.
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- Constantinou M, Daniell M, Snibson GR,et al. Clinical eﬃ cacy of moxifloxacin in the treatment of bacterial keratitis: a randomized clinical trial. Ophthalmology 2007 Sep;114(9):1622–9.
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- Ray KJ, Srinivasan M, Mascarenhas J. Early addition of topical corticosteroids in the treatment of bacterial keratitis. JAMA Ophthalmol. 2014 Jun;132(6):737-41.
- Srinivasan M, Mascarenhas J, Rajaraman R, et al. The steroids for corneal ulcers trial (SCUT): secondary 12-month clinical outcomes of a randomized controlled trial. Am. J. Oph-thalmol. 2014 Feb;157(2):327-333.