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    Fluoroquinolone is developed expressly for ophthalmic use

    New antibiotic suspension is selected from more than 4 decades of fluoroquinolone research

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    Susanne Gardner, PharmD
    The first specialized, ophthalmic modern fluoroquinolone recently was introduced to market. Besifloxacin ophthalmic suspension 0.6% (Besivance, Bausch & Lomb), approved for the treatment of bacterial conjunctivitis in adults and children aged 1 year or more, is a potent, broad-spectrum, modern fluoroquinolone specially developed for ophthalmic use and formulated in a proprietary base designed to prolong tear retention time.

    Modern fluoroquinolones have evolved over more than 4 decades, from the parent quinolone compound, nalidixic acid (NegGram, Sanofi-Aventis US), patented in 1962. Since then, more than 10,000 derivatives have been patented, all with structural modifications that added features to improve systemic absorption, extend spectrum of action to include Gram-positive microorganisms, and reduce systemic toxicity.

    Notably, in 1973 the first fluoroquinolone antibiotics were identified, with the addition of a fluorine atom at position 6. Norfloxacin followed in 1978, ciprofloxacin in 1983, then ofloxacin and its l-isomer levofloxacin, and most recently, moxifloxacin and gatifloxacin, the latter two containing a methoxy group at position 8, which increased potency and activity against atypical microbes and some anaerobes as well.1, 2

    These stepwise modifications resulted in the modern fluoroquinolones that are considered potent, broad-spectrum, bactericidal antibiotics, particularly useful for the treatment of respiratory infections, with strong activity against Streptococcus pneumoniae. All of these agents had been developed with systemic utility in mind, to maximize their potential for systemic administration while minimizing systemic toxicity. Some agents were also adapted for ophthalmic use by formulation in aqueous vehicles.

    'Respiratory fluoroquinolones'


    Figure 1 The molecular structure of besifloxacin. (Diagram courtesy of Bausch & Lomb.)
    Levofloxacin, gatifloxacin, and moxifloxacin are known as third- and fourth-generation fluoroquinolones, although this terminology is not necessarily derived from differences in molecular structure and mechanism of action. They also have been referred to as "the respiratory fluoroquinolones." These agents successfully achieved the goals of increased systemic absorption, wider tissue distribution, longer half-lives, lower systemic adverse effects, and more activity against Gram-positive bacteria than their predecessors. Their great success, however, also led to widespread use globally, some not only for the treatment of systemic infections, but also for livestock and agricultural purposes. As a result, a striking increase in bacterial resistance has been reported in recent years, with ocular isolates showing reduced susceptibility.

    Chlorinated fluoroquinolones

    Trends in bacterial susceptibilities in ocular isolates should be closely monitored. Data from sources such as Ocular TRUST3 clearly show a change in susceptibilities of ocular isolates in recent years, with reduced bacterial susceptibility to many familiar fluoroquinolones. Although considered broad-spectrum, it is worthwhile noting that many fluoroquinolones had not shown reliable activity against methicillin-resistant Staphylococcus aureus (MRSA) or against microbes that were classified as fluoroquinolone-resistant. Many bacterial isolates that were considered resistant to ciprofloxacin, including S. aureus and some streptococci, were not likely to be susceptible, even to newer-generation agents.4

    In the 1990s, a subgroup of fluoroquinolones was noted to have particularly strong activity against Gram-positive microorganisms and against many resistant strains as well. These were the fluoroquinolones with a halogen atom, either fluorine or chlorine, at the C8 position. The agents were associated with increased potency, lower bacterial minimum inhibitory concentrations, slower development of bacterial resistance mediated by increased DNA gyrase mutations, and increased efficacy against MRSA, methicillin-resistant S. epidermidis, and fluoroquinolone- or ciprofloxacin-resistant strains.

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    Optometry Times A/V