Besifloxacin: Fluoroquinolone developed expressly for ophthalmic use

September 15, 2009

Besifloxacin is the first chlorinated fluoroquinolone developed especially for use in the eye.

Key Points

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 or more years, 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

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 success, however, also led to widespread use globally, not only for treatment of systemic infections but also for livestock and agricultural purposes. As a result, an 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 Tracking Resistance in U.S. Today3 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 to note 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 Staphylococcus epidermidis, and fluoroquinolone- or ciprofloxacin-resistant strains.

Clinafloxacin, chlorinated at C8, was more potent than three respiratory fluoroquinolones against many Gram-positive, Gram-negative, and resistant strains. Another chlorinated fluoroquinolone, sitafloxacin, which showed strong potency against multi-drug resistant Gram-positive pathogens, was used systemically in the treatment of infections due to MRSA or vancomycin-resistant strains of Enterococcus.5–8 Commercial development of both agents was curtailed, however, due to effects such as phototoxicity associated with high systemic doses. Such phototoxic reactions were linked primarily to high serum levels attained after systemic administration and not with the low levels of drug delivered after topical drops. Still, phototoxic reactions generally were limited to skin, resembling overexposure to ultraviolet light.

Levofloxacin and ciprofloxacin both have been associated with phototoxicity after systemic adminstration,9,10 although ciprofloxacin eye drops have had extensive use over the years without any reports of phototoxic effects to the eye. Animal studies and human trials exploring this potential with besifloxacin showed no phototoxic effects after topical use.11,12