Cycloplegics, fluoroquinolones primary treatment for bacterial keratitis
Harold R. Katz, MD: Bacterial keratitis is characterized by an epithelial defect with a stromal infiltrate. Predisposing factors include contact lens use, corneal epithelial defects, lid malposition, chronic herpetic keratitis, corneal edema, trauma and immunosuppression. The most common organisms are Staphylococcus, Streptococcus and Pseudomonas aeruginosa. P. aeruginosa causes a devastating ocular infection with liquifactive necrosis of the cornea. It is the most common organism cultured from contact lens-related bacterial keratitis.
The initial therapy of bacterial keratitis should consist of broad-spectrum antibiotics. In the past, formulated drops such as cefazolin and fortified tobramycin or gentamicin were used. Because fortified drops need to be compounded by a pharmacy, they are not always easily available. The drops can also be contaminated during the compounding process, and they have a limited shelf life.
More recently, the fluoroquinolone antibiotics have been shown to be as effective as fortified drops for treating bacterial keratitis. The fluoroquinolones are broad spectrum and are effective against gram-positive and gram-negative organisms. They penetrate into the cornea and have minimal corneal toxicity. The advantage of monotherapy with a fluoroquinolone compared to fortified drops is a lower incidence of toxicity and easier access to the antibiotics.
The two most common fluoroquinolone antibiotics in use today are ciprofloxacin 0.3% and ofloxacin 0.3%. Both antibiotics are approved by the Food and Drug Administration to treat bacterial keratitis. There are significant differences between these antibiotics. Ciprofloxacin is more potent than ofloxacin against most organisms, especially P. aeruginosa. Studies show that ciprofloxacin eradicates bacteria more rapidly than ofloxacin both on the ocular surface of the human eye (J Cataract Refract Surg. 2000;26:1620-1625) and in an animal model of bacterial keratitis (Ann Ophthalmol. 2001;33(1):48-52). Ciprofloxacin also has the advantage of availability as an ointment, which has also been shown to be effective in the treatment of bacterial keratitis.
My therapeutic regimen for severe bacterial keratitis is the use of a cycloplegic agent and frequent use of ciprofloxacin 0.3% antibiotic drops. I instruct the patient to use the drops every 15 minutes for 4 hours followed by every 30 minutes for 4 hours and then every hour around the clock for at least 24 hours. Depending on the severity of the ulcer and the clinical response, ciprofloxacin ointment can be substituted for the drops at a lower frequency during the night after 1 to 2 days of therapy. In a severe ulcer, 1 to 2 weeks of therapy may be required for a complete therapeutic response.
Depends on severity
Scot Morris, OD, FAAO: Most pathogens usually require some type of chemical or mechanical damage to the corneal epithelium in order to gain entry. Once the bacteria gain access and conditions continue to remain favorable for bacterial replication, corneal infection is likely. The four most common pathogens are the Staphylococcus species, Streptococcus species, Pseudomonas species and the various Enterobacteriaceae. Neiserria gonorrhoeae, Corynebacterium diptheriae and Hemophilus can penetrate an intact corneal epithelium.
Proper identification and correct diagnosis is key to the treatment of bacterial keratitis. Once the causative agent has been identified, proper management of both the primary infection and subsequent inflammatory events is indicated. In theory, all corneal ulcers should be cultured and Gram’s stained. However, in the “real” clinical setting, culturing is rare, and treatment should be initiated prior to waiting for lab results. Treatment modalities should be based on the location, depth and rate of progression.
Lesions affecting the central corneal axis or presenting with significant stromal thinning must be treated aggressively with both topical antibiotics and possibly other agents to prevent permanent vision loss. A more peripheral location may be as serious, but is often less of an initial threat to vision.
Lesions that are focal, discrete and confined are typically gram-positive agents. There is also likely associated lid or conjunctival disease. Gram-positive lesions typically start as superficial defects, but the secondary inflammatory cascade may lead to deeper tissue damage.
The gram-negative bacteria, Pseudomonas, typically is much more aggressive both in depth of the defect and circumference. The goal is to promote healing with minimal scarring and effect on vision.
In visually threatening keratitis, I use a fluoroquinolone such as Ciloxan (ciprofloxacin HCl, Alcon), Ocuflox (ofloxacin, Allergan) or Quixin (levofloxacin, Santen). They have been proven to be highly effective and convenient bactericidal agents. They are well tolerated, with relatively low toxicity. I begin with one drop every 30 minutes for the first 24 hours and every hour on the second day, with an appropriate taper based on the clinical findings. Daily follow-up is mandated until the epithelium has covered the defect and inflammation appears to be under control. The epithelial defect and underlying infiltrate size should be measured daily.
I use Polytrim (trimethoprim sulfate, polymyxin B sulfate, Allergan) for more peripheral, slow progressing lesions due to its effectiveness against most pathogens with low toxicity to the corneal epithelium. Despite their effectiveness, I typically avoid the aminoglycosides as a primary agent because of their high toxicity level, with Pseudomonas infections being the notable exception. If compliance is an issue, antibiotic ointments may also be used. If the infection is a severe threat to vision or there is a high risk of noncompliance, hospital admission may be necessary for fortified or intravenous antibiotics.
When evaluating the best proper treatment, the degree of secondary damage from inflammation must also be considered. Significant pain, photophobia, anterior chamber reaction, stromal infiltrate or edema and conjunctival injection all indicate secondary inflammation. The normal inflammatory response to pathogens is stromal infiltration by polymorphonuclear neutrophils (PMN) and subsequent collagenase release that in turn may lead to stromal thinning or corneal scarring.
Cycloplegia with 5% homatropine is also indicated in all corneal ulcers to control inflammation and subsequent pain and photophobia. I typically advise the use of over-the-counter pain medications, such as 800 mg of ibuprofen four times daily to control somatic pain. In severe cases, more potent analgesics may be necessary and recommended only for short-term use.
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids are indicated if moderate inflammation is present or there is a threat to vision. However, the resultant delay in epithelial healing must also be considered. In severe ulcers, ascorbic acid or oral doxycycline may be used to inhibit collagenase and decrease PMN chemotaxis.
If the intraocular pressure is elevated, a glaucoma medication, such as an alpha-adrenergic or one of the beta-blockers, may also be used.
Infectious keratitis management is heavily based on the risk to vision or potential for corneal damage, with various treatment options available. Always err on the side of being too cautious and never be afraid of referring any infectious ulcer that appears to be progressive and unresponsive to treatment.
Robert Wooldridge, OD: Let’s begin by discussing the diagnostic work-up of such patients. A careful history, along with a thorough examination, should always be performed. Patients should be questioned regarding use of contact lenses, including wearing schedule and cleaning regimen. A history of trauma should be ruled out. In the event of trauma, the nature of the trauma should be investigated, and you need to think about the pathogen that was likely induced by such trauma.
The question of whether or not to culture corneal lesions is a reasonable one. With the advent of such effective topical antibiotics as the fluoroquinolones, many corneal lesions are treated without obtaining cultures and sensitivities.
Let’s then consider the nature of the corneal lesion. Corneas with little or no overlying epithelial defect are usually safely treated with topical fluoroquinolones on an hourly basis without the benefit of cultures and sensitivities. However, I would still advise the use of cultures and sensitivities in the case of a large or fairly central corneal ulcer. These ulcers are often treated without the benefit of cultures, but one may have quite a dilemma on hand if the lesion does not respond to the initial therapeutic regimen and neither the identity of the offending microbe nor the antibiotic to which it is sensitive is known.
Traditionally, corneal ulcers have been treated with fortified aminoglycosides and cephalosporins. However, more recently, use of the newer topical fluoroquinolones has been shown to be equally effective.
Hyndiuk and colleagues have shown that ciprofloxacin ophthalmic solution 0.3% monotherapy is equivalent clinically and statistically to standard therapy (fortified tobramycin-cefazolin) for the treatment of bacterial corneal ulcers and produces significantly less discomfort (Hyndiuk RA, Eiferman RA, et al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ophthalmology. 1996;103:1854-1863.
In a similar fashion, O’Brien and colleagues showed that ofloxacin was equally effective as cefazolin and tobramycin in the treatment of bacterial keratitis (O’Brien TP, Bacterial Keratitis Study Group. Comparative clinical efficacy of topical ofloxacin vs. combined fortified cefazolin plus tobramycin in therapy of acute bacterial keratitis. Arch Ophthalmol. 1995;113:1257-1265.
The use of the topical fluoroquinolones has the advantages of commercially prepared agents that are more readily available, often less expensive and generally less toxic to the corneal and conjunctival epithelium.
Ciprofloxacin and ofloxacin have become the mainstay agents for bacterial keratitis in recent years. A new fluoroquinolone, levofloxacin, has recently been approved in the United States for treatment of bacterial conjunctivitis, but it has not been approved for the treatment of bacterial corneal ulcers.
With the availability of the wonderfully effective topical fluoroquinolones ciprofloxacin and ofloxacin, it is easy to take for granted that all bacterial corneal ulcers will respond positively to these agents. However, there is evidence of increasing bacterial resistance, even to these drugs.
Fluoroquinolones are still my first drug of choice for managing bacterial keratitis. However, studies indicating possible bacterial resistance to fluoroquinolones in addition to other anti-bacterial agents should remind each clinician of the value of obtaining cultures and sensitivities in cases of significant bacterial ulcers. We cannot take for granted that all bacteria will be sensitive to any antibiotic.
A common dosage regimen for a severe ulcer would be one drop every 30 to 60 minutes for the first 24 hours, followed by hourly drops while awake and one or two doses during the night for the next 48 to 72 hours. Tapering of the doses should be guided by the clinical response of the keratitis to the treatment regimen.
In most cases, topical treatment is adequate. The additional use of subconjunctival antibiotics is advised in some cases, as in the threat of corneal perforation. The use of subconjunctival injection may be especially helpful in cases where compliance or inability to self-administer topical drops is an issue. Treatment with intravenous antibiotics is also proposed, although, in my experience, most corneal ulcers respond well to topical treatment alone.
In addition to intense topical antibiotic treatment, cycloplegia aids in patient comfort and helps prevent the development of posterior synechiae. Cycloplegia may be given by the use of homatropine 5% or atropine 1% once or twice daily.
The use of topical steroids should usually be withheld until the corneal epithelial surface has been re-established and the ulcer has been treated with antibiotics for up to 5 days. The later use of topical steroids in these cases is somewhat controversial. Some clinicians feel that the addition of a topical steroid, after the infectious agent has been controlled, may decrease the inevitable corneal scarring and thus help preserve vision. Needless to say, the decision to use topical steroids after the infectious microbe is felt to be under control should be made with caution.
We are very fortunate to have the highly effective fluoroquinolones available. Most patients will respond positively to these agents. Careful patient education and frequent follow-up evaluation to ascertain response to treatment remain critical aspects in the care of these patients.