Fluoroquinolones. Fluoroquinolones are broad-spectrum, bactericidal anti-infective agents with potent balanced activity against gram-positive and gram-negative pathogens.14,45 Fluoroquinolones are administered less frequently than many of the older agents. The fluoroquinolones used in the treatment of bacterial conjunctivitis can be divided into two groups: older agents (i.e., ofloxacin [Ocuflox], ciprofloxacin [Ciloxan], and levofloxacin [Iquix]) and newer agents (i.e., gatifloxacin [Zymar, Zymaxid], moxifloxacin, and besifloxacin [Besivance]). Clinical resolution and bacterial eradication rates were significantly higher with each of the fluoroquinolones than with vehicle in double-masked, randomized, vehicle-controlled studies.12,15,19,29,31,33 The newest fluoroquinolone, besifloxacin, was noninferior to moxifloxacin when administered t.i.d. for five days46 and was shown to be safe and effective when administered b.i.d. for only three days.47 Thus, besifloxacin, which is formulated with DuraSite, may be useful in patients with a history of poor compliance or in children who are in nursery or school settings in which administering a midday dose would be difficult.

Fluoroquinolones have fewer adverse events than the aminoglycosides and polymyxin B combinations. Ocular adverse events are typically mild and self-limited and have included conjunctivitis, pruritus, ocular discharge, discomfort, transient burning, stinging, pain, edema, and photo­phobia.19,34,31,32,48-51 In the moxifloxacin-besifloxacin comparative study, eye irritation, although infrequent, was observed in significantly more eyes treated with moxifloxacin.46


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Bacterial resistance among ocular pathogens

Bacterial resistance to all classes of ophthalmic antibiotics has been increasing steadily in recent decades, with each class exhibiting varying degrees of resistance to different organisms. The increase in resistance can be attributed to excessive use of oral antibiotics, prophylactic use of antibiotics, extended dosing, prolonged duration of treatment, use of subtherapeutic dosages by noncompliant patients, treatment of viral and other nonbacterial infections with antibiotics, and agricultural use.52

Aminoglycosides have shown decreased activity against S. aureus and Streptococcus and Pseudomonas species. Thus, S. pneumoniae and methicillin-resistant S. aureus (MRSA) have exhibited high rates of resistance to tobramycin and gentamicin.53-56 A Brazilian study found that there was no resistance among S. pneumoniae cultures obtained from the cornea or conjunctiva from 1989 through 1992 for either tobramycin or gentamicin. However, by 1997 through 2000, resistance to these antibiotics had increased in corneal and conjunctival infections to 43.6% and 46% for tobramycin and 42.3% and 56% for gentamicin, respectively.55

The majority of penicillin-susceptible and nonsusceptible S. pneumoniae isolates demonstrated resistance to polymyxin B and polymyxin B/neomycin in a study with isolates from 250 pediatric patients with bacterial conjunctivitis.56 Similarly, the Ocular TRUST longitudinal surveillance study conducted from 1999 to 2006 in 19 states found that 100% of S. pneumoniae isolates were resistant to polymyxin B.53

An increase in resistance by S. aureus and H. influenzae to the macrolide antibiotics has been attributed partially to their bacteriostatic effect and, especially for azithromycin, to frequent prescribing for other infections and prolonged elimination half-life.57-59

A 10-year surveillance study identified a doubling of resistance to erythromycin by gram-positive isolates from 22.1% (1994-1995) to 45.1% (2002-2003) and by S. aureus isolates from 23.8% to 48.9%.60 In studies in the United States and Israel, resistance to azithromycin and erythromycin was observed in 76% and 78%, respectively, of H. influenzae isolates.57,61

Resistance to fluoroquinolones

Development of resistance to fluoroquinolones is related to their mechanism of action. The primary targets of these medications in susceptible species are the bacterial DNA replication enzymes DNA gyrase and topoisomerase IV. Ciprofloxacin and ofloxacin preferentially target one replication enzyme over the other, and resistance, especially among gram-positive organisms, is increasing to both of those fluoroquinolones.62

Structural modifications of the newer fluoroquinolones help provide more balanced binding to both enzymes. As a result, newer fluoroquinolones are more active than older ones against gram-positive bacteria associated with bacterial conjunctivitis, including staphylococci and streptococci strains that are not susceptible to other antibiotics.14,63,64 Of the newer fluoroquinolones, besifloxacin has been found to have balanced inhibitory activity at concentrations that are much lower than the concentrations needed for ciprofloxacin and moxifloxacin.65