In late May, the Foodand Drug Administration approved Besivance (besifloxacin ophthalmic suspension 0.6%, Bausch & Lomb) for the treatment of bacterial conjunctivitis. While Besivance has some distinct differences from the other fluoroquinolones on the market, ophthalmologists do not consider it a fifth-generation fluoroquinolone.
"Just like with anything new, clinicians will slowly try it and see where it fits into the armamentarium," says Francis Mah, MD, assistant professor of ophthalmology and co-director of the Charles T. Campbell Eye Microbiology Laboratory at the
"In many ways, besifloxacin is close to a second-generation fluoroquinolone. It is very similar to ciprofloxacin with one substitution. However, it does seem to have an advantage over ciprofloxacin and ofloxacin with regard to its ability to handle MRSA and MRSE. Unfortunately, if an organism is resistant to gatifloxacin and moxifloxacin, it is also resistant to besifloxacin," says Randall Olson, MD, director of the
Besivance is unique in two ways: It has not been used systemically, and it is a suspension rather than a solution. According to
According to Dr. Olson, besifloxacin was not used systemically because patients are likely to experience photosensitivity. "However, it works well topically," he says. "It appears that besifloxacin does give the advantage of fourth-generation. I see it as another fluoroquinolone choice, and it's an advantage to have something new out there."
Two recent studies have shown that besifloxacin is a safe and effective treatment for bacterial conjunctivitis.1,2 A recent Phase III study included 957 patients age 1 year or older and who were diagnosed with bacterial conjunctivitis.1 Patients were randomized to receive treatment with either besifloxacin ophthalmic suspension 0.6% or vehicle applied topically three times daily for five days. Patients were seen on day four, five or six and on day eight or nine. On day four, five or six, 45.2 percent of the patients receiving treatment with besifloxacin experienced clinical resolution of the infection and 91.5 percent experienced microbial eradication compared with 33 percent and 59.7 percent in the vehicle group, respectively. By day eight or nine, 84.4 percent of the patients receiving treatment with besifloxacin experienced clinical resolution and 88.4 percent experienced microbial eradication, compared with 69.1 percent and 71.7 percent of patients in the vehicle group, respectively. Additionally, only 9.2 percent of eyes receiving besifloxacin experienced adverse events, compared with 13.9 percent of eyes receiving vehicle.
In a separate multicenter, prospective, randomized, double-masked, vehicle-controlled, parallel-group study, the safety population consisted of 269 patients, and the intent-to-treat population included 228 patients.2 Patients received topical besifloxacin ophthalmic suspension 0.6% or vehicle three times daily for five days. By day eight, 73.3 percent of the patients in the besifloxacin group and 43.1 percent of the patients in the vehicle group had clinical resolution of the infection. Approximately half of the patients in both groups (50.4 percent in the besifloxacin group and 53 percent in the vehicle group) experienced adverse events. The most common adverse events were eye pain, blurred vision and eye irritation. All events were mild or moderate in severity.
Another interesting feature of Besivance is that it is a suspension. Its vehicle is DuraSite (InSite Vision), which can provide high drug concentrations in the tear film for a much longer period of time. "However, the concentration is mainly staying inside the tear film rather than getting inside the eye," Dr. Olson says.
He notes that this is a cause of concern for toxicity. "No one has addressed that yet, but typically when you have very high concentrations of antibiotics that remain for a long period of time, then that is a potential toxicity concern. It's not good to leave 100 or 1,000 times more concentration sitting on the eye for a long period of time," he adds.
For this reason, he says that ophthalmologists should use caution when using Besivance in clear corneal surgery. "We know that the risk of a wound leak is very real, which is probably why clear corneal cases have been shown to have a higher incidence of endophthalmitis. If there are higher concentrations of Besivance in the tear film, and the tear film gets inside the anterior chamber from a leaky wound, is there intraocular toxicity? We don't have a clue what DuraSite might do intraocularly, and we don't have a clue what might happen if we get levels that are many times higher inside of the eye," he explains.
John D. Sheppard, MD, agrees. "Obviously, this is an outstanding ocular surface agent.
We're not 100 percent sure yet where this is going to fit into our regimen for ocular surgery. On the other hand, I think it's a promising and versatile new player for therapeutic and prophylactic therapy. Its solubility and its tenacity allow decreased frequency of usage. DuraSite is the vehicle enabling this compliance-enhancing capability. It has a prolonged exposure time to the ocular surface and, therefore, better penetration into the tissues. I have been using besifloxacin twice a day for infectious prophylaxis, to prevent surgical mishaps and to treat conjunctivitis. For conjunctivitis, besifloxacin is indicated three times a day. But if you look at all of the data available, this could clearly be a twice-daily drug," says Dr. Sheppard, who is professor of ophthalmology, microbiology, and molecular biology at
Dr. Sheppard gives patients a topical nonsteroidal, then a topical steroid, and then besifloxacin because it is not known whether the DuraSite vehicle will block the exposure and absorption of the other agents. "It may be that it's just the opposite," he says. "If you put another agent in and then cover it with the besifloxacin, the two may stick around longer, but that remains to be seen."
Dr. Moshirfar also feels that besifloxacin with DuraSite is a unique formulation with potentially advantageous pharmacokinetics but cautions against using besifloxacin immediately before cataract surgery. "If you place a drop of besifloxacin suspension on the ocular surface immediately before cataract surgery, it may create a thick gelatinous film on the ocular surface. This may not be an optimal situation. I don't feel comfortable telling my colleagues to put besifloxacin on the eye immediately before surgery. The suspension may linger on the conjunctiva, and the DuraSite could get inside the eye.
However, I feel very comfortable using this new formulation twice daily for prophylaxis several days prior to cataract surgery," he says.
Other New Fluoroquinolones
The concentrations of the newest generation of fluoroquinolones are 1.5% for levofloxacin (Iquix,), 0.6% for besifloxacin, 0.5% for moxifloxacin (Vigamox), and 0.3% for gatifloxacin (Zymar). "Historically, of these four fluoroquinolones, Iquix was the first one to be introduced both systemically and topically. In fact, as most surgeons know, this is a reformulation of 0.5% levofloxacin (Quixin) with a new indication—acute bacterial keratitis. Although it is by far the highest concentration, it has been shown by our lab and others to have the highest MICs compared to the other three. Higher MICs by definition mean it has the least potency, but because the concentration is 1.5%, you really get high concentrations in the tissues, which is one of the two key characteristics determining clinical efficacy," Dr. Mah says.
Gatifloxacin has a concentration of 0.3%. "In our laboratory, we have found that gatifloxacin has higher potency or lower MICs than levofloxacin against gram-positive and gram-negative bacteria," Dr. Mah adds. "In general, through pharmacokinetic testing, the drug itself seems to have better bioavailability than levofloxacin, but because the concentration of the commercial formulation is lower, gatifloxacin probably does not have the tissue concentrations that levofloxacin 1.5% has. Improved potency, or lower MICs, is the second important characteristic that determines clinical efficacy."
Moxifloxacin has a concentration of 0.5%, and its MICs and, therefore, potency are very similar to gatifloxacin's. "Our lab has shown moxifloxacin, like gatifloxacin, is more potent than levofloxacin," Dr. Mah says. "It has slightly better gram-positive coverage than gatifloxacin, and it tends to have slightly lower potency than gatifloxacin against gram-negative bacteria. The interesting thing about moxifloxacin is that, in multiple studies, it has higher tissue concentrations than gatifloxacin, which may be due primarily to the concentration difference of 0.5% versus 0.3%, but there is also some indication that it could be one of the chemical properties of moxifloxacin versus gatifloxacin. So, with moxifloxacin, there is the improved potency of gatifloxacin, with the increased tissue concentrations of levofloxacin 1.5%."
Besifloxacin is formulated at 0.6%, and some early studies have shown that it is slightly more potent than levofloxacin, gatifloxacin and moxifloxacin based on to its MICs.
"However, in terms of tissue concentrations, we know that besifloxacin is not as soluble as levofloxacin, gatifloxacin, and moxifloxacin," says Dr. Mah. "Besifloxacin is soluble at a pH of around 4. DuraSite helps to keep it soluble at a pH of 7 and increases the contact time. Clinically, this means that besides the surface, there will be poor tissue concentrations."
A recent study compared besifloxacin to moxifloxacin for the treatment of bacterial conjunctivitis.3 In this multicenter, randomized, double-masked, parallel-group, active-controlled study, patients who were 1 year or older with bacterial conjunctivitis were randomized to receive either besifloxacin or moxifloxacin three times a day for five days.
The study included 1,161 patients. By day five, 58.3 percent of the patients in the besifloxacin group and 59.4 percent of the patients in the moxifloxacin group had clinical resolution of the infection, and 93.3 percent and 91.1 percent, respectively, had microbial eradication. On day eight, 84.5 percent of patients in the besifloxacin group and 84 percent of those in the moxifloxacin group had clinical resolution of the infection, and 87.3 percent and 84.7 percent, respectively, had microbial eradication. Both drugs were well-tolerated, and the frequency of ocular adverse events was similar. However, eye irritation occurred more often in eyes in the moxifloxacin group. The researchers concluded that besifloxacin was not inferior to moxifloxacin and provided similar safety and efficacy.
Future of Fluoroquinolones
According to Dr. Olson, there is no dramatic fluoroquinolone breakthrough on the horizon. Dr. Mah says there may never be.
Dr. Sheppard agrees: "I don't think you'll see a lot of new antibiotics coming to market. It's going to be difficult to improve upon the drug classes that we now have available."
According to Dr. Mah, of the more than 10,000 fluoroquinolones discovered and reported in the literature, only a few have come to market; the biggest downside to the majority of fluoroquinolones has been toxicity. "You can continue to get stronger and more potent fluoroquinolones, but the problem is that they start affecting the host organism, he says. "In terms of [next generations], I think we have probably come to the end of the line in terms of fluoroquinolones. My thought is that we are probably going to move on to a different class of antibiotic or we're going to go to a combination of antibiotics because almost everything that you can do to the base fluoroquinolone molecule has been done. Without increasing toxicity, the agents that we have are as strong as anything out there."
1. Tepedino ME, Heller WH, Usner DW, et al. Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin 2009;25(5):1159-1169.
2. Karpecki P, Depaolis M, Hunter JA, et al. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: A multicenter, prospective, randomized, double-masked, vehicle-controlled, 5-day efficacy and safety study. Clin Ther 2009;31(3):514-526.
3. McDonald MB, Protzko EE, Brunner LS, et al. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis. Ophthalmology 2009 July 28. [Epub ahead of print].