Overview: Initial antimicrobial therapy for microbial keratitis

Abstract

Fluoroquinolones are used as monotherapy in many centres and are highly effective (Table I). Tissue concentration can vary dramatically depending on associated conditions and so can make estimation of the true tissue concentration difficult. The determinants of corneal and aqueous antibiotic concentration are based on a standard concentration of drug and frequent intensive applications. However other factors such as the presence of epithelial defect and the formulation can markedly alter penetration of drug into the cornea. As previously alluded to, despite the theoretical relative resistance of streptococcal species to quinolones, clinical practice has not revealed a poor response to topical quinolones in most cases of streptococcal keratitis. Only in a small group of patients does in vitro resistance translate to poor efficacy in vivo. Both prospective trials such as the Ofloxacin Study and retrospective audit have shown equivalent overall efficacy of combined fortified and quinolone therapies. This lack of in vivo resistance has been explained as being a consequence of higher than predicted local tissue concentrations overwhelming a relative but not absolute resistance to ofloxacin. This has been confirmed in a series of more than 42 patients with culture proved streptococcal keratitis treated with ofloxacin (Proceedings of the International Conference on Ocular Infections, Jerusalem, 1995). However, as ofloxacin resistant organisms become more prevalent in the community, this situation is likely to change. A 5 year review published by Goldstein et al showed a significant increased resistance of Staph aureus to fluoroquinolones over the study period and questioned the use of monotherapy. Despite the increasing in vitro resistance in staphylococcal and streptococcal ulcers, topical therapy still produced corneal concentrations far in excess of the MIC values and therapy was only changed in 10% of cases despite up to 41% resistance rates for these isolates. The methods used to assess in vitro sensitivity, usually the Kirby-Bauer test for bacteria, need to be modified to take into account typical tissue concentrations obtained by topical treatment, and so provide more clinically relevant data. As resistance develops organisms will appear that will not respond even to very high local concentrations currently applied, and treatment failures will increase. The other findings to become apparent from the clinical studies that have a significant input into clinical care are the toxicity of the medications. Aminoglycosides produce well recognised epithelial toxicity. Prolonged intensive treatment leads to marked epithelial toxicity with pain, redness, punctate staining, and eventual retardation of epithelial healing. Non-healing epithelial defects are far more common in aminoglycoside treated keratitis. Retrospective series reveal an incidence of 5.9% of non-healing epithelial defects at 14 days in gentamicin treated eyes versus 0% in fluoroquinolone treated eyes. Ciprofloxacin produces white epithelial deposition in up to 16% of cases. This can mask the underlying signs and will retard epithelial healing until the drug deposits wash out. Retrospective audit found an increased incidence of corneal perforation in cases treated with ofloxacin. Fluoroquinolones are well recognised to cause spontaneous tendon rupture in otherwise well adults taking oral doses. A proposed mechanism of corneal perforation has been an increase in keratocyte apoptosis. Until these findings are refuted, great care should be taken in treating large deep ulcers in the elderly with ofloxacin alone.