The emergence and spread of antimicrobial resistance among ocular pathogens has received widespread attention and raised concern among ophthalmic clinicians and surgeons. Escalating methicillin and multidrug resistance to ocular antibiotics documented among bacterial isolates causing conjunctivitis (Figure 1), keratitis, and endophthalmitis means that cataract and refractive surgeons must contemplate alternative agents for use in the prevention and treatment of the aforementioned ocular infections.^1-5 Prevention, however, is not the same as the treatment of an established methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE) ocular infection.

NEW VERSUS OLD ANTIBIOTIC AGENTS
Gatifloxacin and Moxifloxacin
Microbiology laboratory susceptibility data show a correlation between methicillin and fluoroquinolone resistance in S aureus (and S epidermidis) clinical isolates from patients with ocular infection.⁴ Although 8-methoxy-fluoroquinolones such as gatifloxacin and moxifloxacin have greater potency than earlier fluoroquinolones, their susceptibility to MRSA and MRSE isolates has gradually declined,⁶ a change requiring ophthalmologists to consider other agents. Interestingly, older antibiotic compounds, especially those that have not been utilized extensively by the systemic route, offer possible alternatives to advanced-generation fluoroquinolones.

Bacitracin
Bacitracin demonstrates efficacy against many gram-positive ocular pathogens, including the common streptococci and staphylococci. This antibiotic is indicated for the treatment of superficial ocular infections involving the conjunctiva and/or cornea caused by bacitracin-susceptible organisms. The prolonged use of a low-dose antibiotic may result in an overgrowth of organisms that are not susceptible.

Sulfamethoxazole, Trimethoprim, and Polymyxin B
Sulfamethoxazole inhibits the bacterial synthesis of dihydrofolic acid by competing with PABA. Trimethoprim blocks the production of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. Their combination blocks two consecutive steps in the bacterial biosynthesis of essential nucleic acids and proteins and is usually bactericidal. A topical preparation of trimethoprim and polymyxin B has been widely used for the treatment of bacterial conjunctivitis and, more recently, as a possible agent for perioperative prophylaxis against infection during and after cataract and refractive surgery.

Mupirocin
Mupirocin is an antibacterial agent that is active against a wide range of gram-positive bacteria, including MRSA.⁷ It is also active against certain gram-negative bacteria. Mupirocin inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl transfer-RNA synthetase. Due to this unique mode of action, mupirocin demonstrates no in vitro cross-resistance with other classes of antimicrobial agents. Mupirocin is bactericidal at the concentrations achieved by topical administration. The minimum bactericidal concentration against relevant pathogens, however, is generally eight- to 30-fold higher than the minimum inhibitory concentration. Mupirocin is somewhat insoluble, and it is available only as a skin ointment and nasal gel, not in an ophthalmic formulation.

Vancomycin
For decades, vancomycin has been the mainstay of therapy for ocular infections with gram-positive bacteria resistant to methicillin, but an alarming resistance to even vancomycin has emerged that has prompted the development of antibiotics that are effective against vancomycin-resistant pathogens. A variety of antibiotics to treat resistant gram-positive infections have been approved or are being investigated for approval.

OTHER AGENTS
Agents with variable activity against MRSA, MRSE, and other resistant strains in addition to vancomycin include teicoplanin, quinupristin-dalfopristin, linezolid, daptomycin, tigecyline, dalbavancin, telavancin, ceftobiprole, and oritavancin. Vancomycin, a glycopeptide antibiotic, is the first line of treatment for MRSA and MRSE ocular infections, but the agent is not recommended for use in a prophylactic fashion.⁸ Although not available in the United States, teicoplanin, another glycopeptide antibiotic, has simpler dosing and monitoring requirements than vancomycin. Quinupristin-dalfopristin shows positive in vitro activity against resistant staphylococcal strains, but the agent has no record of efficacy in treating established ocular infections due to MRSA or MRSE. Daptomycin is effective against all strains of Staphylococcus. Linezolid is approved to treat community-acquired and nosocomial pneumonia and infections caused by MRSA. Tigecycline, a glycylcycline derived from minocycline, has been approved by the FDA to treat complicated staphyloccal skin infection, but it has not been widely studied for ocular infections. Dalbavancin, effective against MRSA, has coverage similar to vancomycin, but again, it has not been widely tested for efficacy in ocular infections. Telavancin deploys multiple mechanisms of action and is effective against MRSA and gram-positive bacteria resistant to vancomycin, but it has not been studied extensively for ocular disease. Ceftobiprole, a cephalosporin effective against MRSA, has few side effects but also has not been systematically tested in eyes with infection. Oritavancin demonstrates similar activity to vancomycin but possesses extended activity against vancomycin-resistant Staphylococcus and enterococci.

CONCLUSION
Ophthalmologists should exercise caution when selecting agents empirically for the treatment of established MRSA or MRSE infections of the eye, despite the agents' suggested or apparent in vitro activity. Vancomycin continues to be the most commonly used treatment for ocular MRSA and other gram-positive infections resistant to methicillin. This antibiotic has a favorable pharmacokinetic profile that allows for topical dosing with concentrations of 25 to 50 mg/mL. Intravitreal therapy with vancomycin is recommended at a concentration of 1 mg/0.1 mL. The agent has a good safety profile and is structurally dissimilar to beta-lactam and other antimicrobials, which makes it useful and useable in patients who are allergic to such antibiotics.

A variety of agents are in development to address the emerging resistance to contemporary antibacterial agents in ocular infections. Some of these drugs may be useful in the prevention and treatment of MRSA and/or MRSE ocular infections, but none is omnipotent. A reappraisal of preventive strategies in ophthalmic surgeries that combine antiseptics, such as povidone-iodine 5%, with various antibacterial agents that maintain MRSA/MRSE activity requires evidence-based updates. Vancomycin will likely continue to be the first-line agent recommended for the treatment of established MRSA or MRSE ocular infection.

Terrence P. O'Brien, MD, is a professor of ophthalmology and the Charlotte Breyer Rodgers distinguished chair in ophthalmology at the Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, in Palm Beach, Florida. Dr. O'Brien may be reached at (561) 515-1544; tobrien@med.miami.edu.

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