BACTERIAL KERATITIS

Signs and Symptoms

A patient with bacterial keratitis will present with a typically unilateral, painful, photophobic, injected eye. Visual acuity may be reduced, and profuse tearing is common. There will be a focal stromal infiltrate with an overlying area of epithelial excavation. Often, there will be a history of contact lens wear, corneal trauma, or other corneal defects as common precipitating conditions.1-3

Mucopurulent discharge may emanate from the eye. The cornea is often edematous. The conjunctival and episcleral vessels will be deeply engorged and inflamed, often greatly out of proportion to the size of the corneal defect. In bacterial keratitis, bulbar conjunctival injection is typically 360 degrees rather than sectoral as seen in noninfectious corneal infiltrates. A pronounced anterior chamber reaction, occasionally with hypopyon, is present in severe cases. IOP may be either reduced due to secretory hypotony of the ciliary body, or elevated due to blockage of the trabecular meshwork by the inflammatory cells. Often, the eyelids may also be edematous.1,4

Pathophysiology

Once defenses are breached, the cornea is prone to colonization by pathogenic bacteria, either a virulent invading organism or part of the normal ocular flora. Factors known to compromise defenses include direct corneal trauma, chronic lid disease (including poor lid congruity and misdirected lashes), systemic immune disease, tear film abnormalities affecting the ocular surface and hypoxic trauma from contact lens wear.1-4

Bacteria colonizing the corneal stroma immediately become antigenic, both directly and indirectly, by releasing enzymes and toxins. An antigen-antibody immune reaction with chemotactic factors induces an inflammatory reaction where polymorphonuclear leukocytes (PMNs) mobilize and aggregate at the area of infection, creating an infiltrate. The PMNs phagocytize and digest the bacteria, but also damage stromal tissue by releasing numerous collagenolytic enzymes that directly degrade stromal tissue.1,4 The collagen of the corneal stroma is poorly tolerant of the bacterial and leukocytic enzymes and undergoes degradation, necrosis and thinning, leading to scarring of the cornea. As thinning advances, the cornea may perforate, thus introducing bacteria into the eye with ensuing endophthalmitis.

The most commonly occurring organisms in bacterial keratitis vary depending on the precipitating factors of the ulcer and the geographic location of the patient. In cases involving contact lens wear, the most common infective organism is Pseudomonas aeruginosa.1,5 Throughout North America, the most common infective organism in bacterial keratitis is Staphylococcus aureus. It appears that there is an increased incidence of gram-positive colonizaton in infectious keratitis.1,5

Management

Proper diagnosis and prompt therapy are essential to preserve vision in bacterial keratitis. Microbial identification, as well as antibiotic sensitivity studies, will aid in management. The first step should be to obtain samples from the corneal lesion for microbiologic studies. Traditional culturing involves scraping the cornea with a platinum spatula and plating directly onto blood or chocolate agar medium. An alternative for culturing of less threatening keratitis involves a mini-tip calcium alginate culturette and transport-media-containing carrier. However, the effectiveness of the fluoroquinolone antibiotics has led many practitioners away from routine microbiologic culturing. Microbiologic identification is most crucial for central lesions that threaten vision, for ulcerations presenting a risk of perforation, in cases also involving scleral tissue, injury with vegetative matter, and in institutionalized patients in nursing homes and hospitals where methicillin-resistant S. aureus infections are possible.6

Empirical broad-spectrum antibiotic therapy must be initiated prior to obtaining culture results. Monotherapy with fluoroquinolone eye drops has been shown to result in shorter duration of intensive therapy and shorter hospital stay when compared to combined fortified therapy (tobramycin-cefazolin). This finding may have resulted from quicker clinical response of healing as a result of less toxicity found in the patients treated with fluoroquinolones. In large, deep ulcers seen in the elderly, some poor outcomes due to resistance were encountered. Here, caution should be exercised regarding empirical use of single-agent topical fluoroquinolones.7,8

Despite the clear efficacy of fluoroquinolones in the management of bacterial keratitis, consideration must be given to increasing resistance.4,9-11 There has been a rise in the incidence of bacterial isolates in keratitis that exhibit resistance to the early generation fluoroquinolones, especially among the gram-positive organisms.4,5,12-15 Even cephazolin has seen increasing bacterial resistance.14

One method of combating the increasing problem of fluoroquinolone resistance and rising level of gram-positive infections is use of the later generation fluoroquinolones. Two fourth-generation formulations—moxifloxacin (Vigamox, Moxeza, Alcon) and gatifloxacin (Zymar, Zymaxid, Allergan)—have a greatly lowered resistance rate while providing much greater gram-positive activity than previous generation fluoroquinolones.15-21 Gatifloxacin has a significantly better action against gram-positive cocci both in vitro and in vivo when compared with ciprofloxacin.22 Gatifloxacin 0.3% ophthalmic solution, due to its strong activity against various gram-positive and gram-negative microbes, is strongly effective in the treatment of acute bacterial keratitis.23 Monotherapy with later generation fluoroquinolones such as moxifloxacin have seen equivalent efficacy to fortified therapy with aminoglycosides and cephalosporins with much better tolerability.24,25

Levofloxacin 1.5% (Iquix, Santen) offers the highest concentration available for any ocular antibiotic for the treatment of bacterial keratitis.26 Manufacture of this product in the United States has recently been discontinued. Additionally, Besivance (besifloxacin, Bausch + Lomb) is an effective and well tolerated option for the management of bacterial keratitis. Besivance has no oral formulation, so development of resistance is theoretically lower.27

Strong cycloplegia is also recommended adjunctively in the form of homatropine 5%. If this is insufficient, then atropine 1% is indicated. Adjunctive use of cold compresses will also help to reduce inflammation.

The patient should be followed daily until the infection shows improved status. If the results of cultures and sensitivities show that the initially-prescribed antibiotic is appropriate for the infective organism, or if the patient shows signs of clinical improvement (the ulcer does not worsen and pain and photophobia are reduced) at the 24 to 48 hour follow-up visit, a topical corticosteroid such as prednisolone acetate 1%, difluprednate 0.05% or loteprednol etabonate 0.5% can be added to speed resolution and decrease corneal scarring. While steroids have historically been avoided in the management of infectious keratitis, judicious use can be beneficial. Antibiotics will suppress the infective organism while corticosteroids can inhibit the corneotoxic inflammatory response. It has been feared that the immunosuppressive effects of steroids could enhance bacterial replication and worsen infection. However, if the chosen antibiotic is effective against the organism, the concurrent use of steroids will not inhibit the bactericidal effect.28-34

Steroids should not be employed until the antibiotic has been given enough time to kill bacteria. A minimum 24-hour antibiotic-only loading period is recommended. Be sure that the infection is not of herpetic, fungal or protozoan origin prior to initiating topical steroids. Steroids should only be used with true bactericidal antibiotics such as fluoroquinolones or fortified antibiotics.

More recently, controlled clinical trials have given mixed results on the adjunctive use of corticosteroids along with topical antibiotics in the management of bacterial keratitis. The most notable research comes from the Steroids for Corneal Ulcer Trial (SCUT) study, which examined the adjunctive use of prednisolone phosphate 1% to eyes treated with moxifloxacin 0.3%. The results showed no detrimental effects of adjunctive steroid use, but also failed to show an improvement in vision at three months; thus, the study did not advocate for the addition of topical steroids.35 However, later analyses indicated that there was a potential benefit and that adjunctive topical corticosteroid therapy may be associated with improved long-term clinical outcomes in bacterial corneal ulcers not caused by Nocardia species.36 Additionally, sub-analyses of the original data showed that larger, more central ulcers with very poor initial visual acuity may benefit from adjunctive steroid use.37 It was noted that eyes treated adjunctively with topical steroids within two to three days of antibiotic therapy fared better visually than those treated after four days or more with antibiotics alone, thus advocating for early use.38

Newer treatments for resistant or non-resolving cases of bacterial keratitis include laser thermal ablation, corneal crosslinking and amniotic membrane therapy. Argon laser phototherapy may be useful, though not universally accepted at this point, as an adjunctive treatment for resistant infected corneal ulcers.39 In one report, during the first four weeks after laser treatment, all patients showed complete healing of the epithelial defect and resolution of stromal infiltration with no adverse effects.39 Corneal crosslinking has been seen as an adjunctive therapy for both early and severe non-healing bacterial keratitis.40,41

Clinical Pearls

If a patient presents with a corneal infiltrate without overlying epithelial staining, it is likely not infectious bacterial keratitis.

The use of strong bactericidal antibiotics will eliminate the infective organisms and sterilize the infectious keratitis, but will do nothing to quell the inflammatory reaction. In this instance, the inflammatory reaction is as damaging to the cornea as is the infective organism. If there is evidence that the antibiotic is suppressing the infective organism, then corticosteroid use will inhibit the inflammatory reaction and speed healing and reduce the potential for corneal scarring.

For steroids to be most beneficial, prescribe them while the ulcer bed is still open, usually within the first 24 to 48 hours after you initiate antibiotic therapy. If you wait until the ulcer re-epithelializes before adding a steroid, its beneficial effects will be reduced. A cautionary note: Be comfortable that the antibiotic has had time to sterilize the lesion before instituting the steroid.

Oral doxycycline and high-dose vitamin C have some potential to reduce stromal damage in bacterial keratitis.

Despite recent research showing possibly only marginal benefits from the adjunctive use of topical steroids, we have practiced in times where only antibiotics were used and other times when steroids were added adjunctively. We can clearly state that patients treated with both antibiotics and adjunctive steroids had faster recovery and better quality of life compared to antibiotic therapy alone.

1. Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea. 2008;27(1):22-7.

2. Keay L, Edwards K, Naduvilath T, et al. Microbial keratitis predisposing factors and morbidity. Ophthalmology. 2006;113(1):109-16.

3. Bourcier T, Thomas F, Borderie V, et al. Bacterial keratitis: predisposing factors, clinical and microbiological review of 300 cases. Br J Ophthalmol. 2003;87(7):834-8.

4. Schaefer F, Bruttin O, Zografos L, et al. Bacterial keratitis: a prospective clinical and microbiological study. Br J Ophthalmol. 2001;85(7):842-7.

5. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology. 2000;107(8):1497-502.

6. Sotozono C, Inagaki K, Fujita A, et al. Methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis infections in the cornea. Cornea. 2002;21(7 Suppl):S94-101.

7. Gangopadhyay N, Daniell M, Weih L, et al. Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers. Br J Ophthalmol. 2000;84(4):378-84.

8. Prajna NV, George C, Selvaraj S, et al. Bacteriologic and clinical efficacy of ofloxacin 0.3% versus ciprofloxacin 0.3% ophthalmic solutions in the treatment of patients with culture-positive bacterial keratitis. Cornea. 2001;20(2):175-8.

9. Wilhelmus KR, Abshire RL, Schlech BA. Influence of fluoroquinolone susceptibility on the therapeutic response of fluoroquinolone-treated bacterial keratitis. Arch Ophthalmol. 2003;121(9):1229-33.

10. Parmar P, Salman A, Kalavathy CM, et al. Pneumococcal keratitis: a clinical profile. Clin Experiment Ophthalmol. 2003;31(1):44-7.

11. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999;106(7):1313-8.

12. Afshari NA, Ma JJ, Duncan SM, et al. Trends in resistance to ciprofloxacin, cefazolin, and gentamicin in the treatment of bacterial keratitis. J Ocul Pharmacol Ther. 2008;24(2):217-23.

13. Sharma V, Sharma S, Garg P, et al. Clinical resistance of Staphylococcus keratitis to ciprofloxacin monotherapy. Indian J Ophthalmol. 2004;52(4):287-92

14. Leibovitch I, Lai TF, Senarath L, et al. Infectious keratitis in South Australia: emerging resistance to cephazolin. Eur J Ophthalmol. 2005;15(1):23-6

15. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136(3):500-5.

16. Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133(4):463-6.

17. Oliveira AD, D’Azevedo PA, Francisco W. In vitro activity of fluoroquinolones against ocular bacterial isolates in São Paulo, Brazil. Cornea. 2007;26(2):194-8.

18. Duggirala A, Joseph J, Sharma S, et al. Activity of newer fluoroquinolones against gram-positive and gram-negative bacteria isolated from ocular infections: an in vitro comparison. Indian J Ophthalmol. 2007;55(1):15-9.

19. Caballero AR, Marquart ME, O’Callaghan RJ, et al. Effectiveness of fluoroquinolones against Mycobacterium abscessus in vivo. Curr Eye Res. 2006;31(1):23-9.

20. Lee SB, Oliver KM, Strube YN, et al. Fourth-generation fluoroquinolones in the treatment of mycobacterial infectious keratitis after laser-assisted in situ keratomileusis surgery. Can J Ophthalmol. 2005;40(6):750-3.

21. Callegan MC, Ramirez R, Kane ST, et al. Antibacterial activity of the fourth-generation fluoroquinolones gatifloxacin and moxifloxacin against ocular pathogens. Adv Ther. 2003;20(5):246-52.

22. Parmar P, Salman A, Kalavathy CM, et al. Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis. Am J Ophthalmol. 2006;141(2):282-6.

23. Afzal Junejo S, Ali Lodhi A, Ahmed M, et al. Efficacy of gatifloxacin in acute bacterial corneal ulcer. Pak J Med Sci. 2013;29(6):1375-80.

24. Sharma N, Goel M, Bansal S, et al. Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial. Ophthalmology. 2013;120(6):1173-8.

25. McDonald EM, Ram FS, Patel DV, McGhee CN. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials. Br J Ophthalmol. 2014;98(11):1470-7.

26. McDonald MB. Research review and update: IQUIX (levofloxacin 1.5%). Int Ophthalmol Clin. 2006;46(4):47-60.

27. Schechter BA, Parekh JG, Trattler W. Besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial keratitis: a retrospective safety surveillance study. J Ocul Pharmacol Ther. 2014 Nov 19. [Epub ahead of print].

28. Engel LS, Callegan MC, Hobden JA, et al. Effectiveness of specific antibiotic/steroid combinations for therapy of experimental Pseudomonas aeruginosa keratitis. Curr Eye Res. 1995;14(3):229-34.

29. Hobden JA, Hill JM, Engel LS, et al. Age and therapeutic outcome of experimental Pseudomonas aeruginosa keratitis treated with ciprofloxacin, prednisolone, and flurbiprofen. Antimicrob Agents Chemother. 1993;37(9):1856-9.

30. Hobden JA, Engel LS, Hill JM, et al. Prednisolone acetate or prednisolone phosphate concurrently administered with ciprofloxacin for the therapy of experimental Pseudomonas aeruginosa keratitis. Curr Eye Res. 1993;12(5):469-73.

31. Hobden JA, O’Callaghan RJ, Hill JM, et al. Ciprofloxacin and prednisolone therapy for experimental Pseudomonas keratitis. Curr Eye Res. 1992;11(3):259-65.

32. Carmichael TR, Gelfand Y, Welsh NH. Topical steroids in the treatment of central and paracentral corneal ulcers. Br J Ophthalmol. 1990;74(9):528-31.

33. Wilhelmus KR. Indecision about corticosteroids for bacterial keratitis: an evidence-based update. Ophthalmology. 2002;109(5):835-42.

34. Stern GA, Buttross M. Use of corticosteroids in combination with antimicrobial drugs in the treatment of infectious corneal disease. Ophthalmology. 1991;98(6):847-53.

35. Srinivasan M, Mascarenhas J, Rajaraman R, et al. Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012;130(2):143-50.

36. 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 Ophthalmol. 2014;157(2):327-33.

37. Tuli SS. Topical corticosteroids in the management of bacterial keratitis. Curr Ophthalmol Rep. 2013 Dec;1(4).

38. Ray KJ, Srinivasan M, Mascarenhas J, et al. Early addition of topical corticosteroids in the treatment of bacterial keratitis. JAMA Ophthalmol. 2014;132(6):737-41.

39. Khater MM, Selima AA, El-Shorbagy MS. Role of argon laser as an adjunctive therapy for treatment of resistant infected corneal ulcers. Clin Ophthalmol. 2014;23;8:1025-30.

40. Shetty R, Nagaraja H, Jayadev C, et al. Collagen crosslinking in the management of advanced non-resolving microbial keratitis. Br J Ophthalmol. 2014;98(8):1033-5.

41. Said DG, Elalfy MS, Gatzioufas Z, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology. 2014;121(7):1377-82.