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Microbial keratitis is an ocular emergency that requires prompt and appropriate management to ensure the best visual outcome for the patient. If possible, this means identification of the causative organism(s) and selection of the best antimicrobial agent(s) to treat the patient.
A clinical diagnosis of corneal infection does not give an unequivocal indication of the causative organism because a wide range of organisms can produce a similar clinical picture. The clinical history together with the duration and severity of symptoms and signs may make the clinical diagnosis of one type of organism more likely, but without attempting to identify the causative organism(s) treatment can only be based on clinical judgment.
The identification of organisms responsible for microbial keratitis is desirable because a positive result indicates the appropriate class of antimicrobial agent to use. Knowing the causative organism also gives the treating clinician confidence to pursue a particular line of therapy and avoids the unnecessary use of ineffective and potentially toxic drugs. Culturing allows sensitivity testing to a range of agents so that treatment modification can be made in an informed manner if the clinical response to initial treatment is inadequate.
In urban communities of developed countries the most common bacteria causing keratitis are Staphylococcus, Streptococcus, and Pseudomonas species. For more than 20 years the recommended initial therapy for bacterial keratitis has centred around the use of topical broad spectrum fortified antibiotics that cover these bacteria.1 The usual choice is between a first generation cephalosporin (for example, cefazolin 5%) to cover the Gram positive cocci and an aminoglycoside (for example, gentamicin 1%) to cover the Gram negative organisms. These antibiotics could be used either alone or in combination, depending on the results of laboratory identification.1 This therapy was based on data from the treatment of experimental Pseudomonas keratitis which showed that increasing both the frequency of application and the concentration of topical antibiotics increased the antibiotic concentrations in the cornea and improved the therapeutic response.2–4 Clinical data spanning a 20 year period confirm that this approach has been highly successful.5,6 Over the past decade the most significant variation to this approach has occurred following the introduction of topical fluoroquinolone antibiotics.
Competing manufacturers of topical fluoroquinolone antibiotics were quick to support clinical trials of bacterial keratitis treatment.7–11 These well designed studies were done to compare the efficacy and safety of commercially available fluoroquinolone antibiotics with combination fortified cephalosporin and aminoglycoside antibiotics. The conclusions from these studies, together with other retrospective comparisons,6 show no difference in the treatment success between the two therapies. What these studies do highlight is the difficulty in defining a cure for infectious keratitis. The aim of antibiotic treatment is sterilisation of the cornea, but this does not necessarily equate with healing of the epithelium or resolution of inflammation.12 Closure of the epithelium is, however, used as a significant end point in defining a cure in these comparative studies,7–11 and may lead to an overestimation of treatment failure. The studies also demonstrate that “failures” occur with all therapies and are not necessarily associated with organism susceptibility to the antibiotic given. Clearly, many factors such as disease severity, drug toxicity, stromal inflammation, and dysfunction of the external eye may influence the resolution of an episode of infectious keratitis. Nevertheless, topical fluoroquinolone antibiotics have become popular in the treatment of bacterial keratitis based on the results of these studies.
Fluoroquinolone antibiotic drops have been recommended for bacterial keratitis7,9–11 because of their ease of availability, broad spectrum of activity, and apparent lack of toxicity. There are some concerns however. Clinical and laboratory reports show emerging resistance and gaps in the spectrum of activity for organisms that commonly cause keratitis.13,14 Experimental Streptococcus pneumoniae keratitis has shown that topical penicillin and gentamicin are best for treating keratitis caused by penicillin sensitive and penicillin resistant S pneumoniae, respectively.15 Reviews of antibiotic susceptibilities of bacteria isolated from cases of keratitis have even prompted the recommendation of combining fluoroquinolones with an antibiotic with superior Gram positive activity such as cefazolin.16 The problem with reviewing in vitro susceptibility testing is that is does not relate to treatment success or failure.17 One of the most likely reasons for this discrepancy is the high concentration of antibiotics achievable by topical delivery in the inflamed ulcerated cornea.
A more serious complication reported with the use of topical ofloxacin is an increased incidence of corneal perforation.6,18 This has not been verified in clinical trials but remains a significant concern. The possible mechanism is not understood but experimentally ofloxacin, ciprofloxacin, and norfloxacin have been shown to have significantly higher antiproliferative and cytotoxic effects than gentamicin and tobramycin on rabbit keratocytes in vitro.19
Another potential concern is that the commercial availability of fluoroquinolones has tended to encourage empirical treatment of infectious keratitis and discourage investigation.20 Such an approach is problematic for individual cases that are not caused by bacteria or are non-responsive to initial treatment because it delays diagnosis and exposes the patient to inappropriately prolonged and potentially toxic treatment. This approach also will ultimately limit knowledge related to the epidemiology of organisms causing keratitis and, subsequently, make recommendations on primary therapy difficult.
Both fortified antibiotics and fluoroquinolones are effective for the treatment of bacterial keratitis. Each mode of therapy provides good cover for the most frequently encountered bacteria causing keratitis with combination fortified antibiotics providing a theoretically superior Gram positive cover. The commercial availability and longer shelf life of fluoroquinolone antibiotics make them more convenient to use. Greater short term epithelial toxicity occurs with fortified antibiotics, particularly the aminoglycosides, but the more serious potential for increased rate of corneal perforation with ofloxacin needs to be monitored. I think the best approach to the initial treatment of bacterial keratitis remains combination fortified antibiotics with the use of fluoroquinolones, an approach that is as effective but not superior to fortified antibiotics.
FUNGAL AND ACANTHAMOEBA KERATITIS
There is far less controversy related to the selection of antimicrobial agents for the treatment of fungal and acanthamoeba keratitis. However, because of antimicrobial toxicity and the possible need for prolonged therapy, treatment should not be started until microscopy or culture of samples taken from the cornea identifies organisms.
Clinical and experimental studies have shown that topical natamycin 5% is the drug of choice for filamentous fungal keratitis.21 Topical amphotericin B 0.15% is the preferred initial agent for yeast infection. The triazole fluconazole is also effective topically as a 0.2% solution for candida keratitis.22 Fluconazole and itraconazole can also be administered orally.23,24
Acanthamoeba keratitis should initially be treated with a combination of propamidine isethionate 0.1% (Brolene) and polyhexamethylene biguanide 0.02% (PHMB).25 Brolene is easily obtainable in the United Kingdom and Australia, whereas PHMB needs to be made up on an individual basis and can be difficult to obtain.