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Clinical Trials of Topical Antibiotics for Ocular Surface Infection

ByGary N. Faulks, MD, FACS

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It is well established that the bacterial pathogens that commonly cause ocular surface infection are developing resistance to available antibiotics. This has occurred with penicillins and aminoglycoside antibiotics. When fluoroquinolones originally emerged, there were high expectations that they would not cause resistance due to the fact that they target 2 enzymes. However, resistance to both old and newer generation fluoroquinolones is increasing. Thus, research is focused on the development of new antibiotics and the modification of existing agents to “confuse” bacteria and slow resistance.

Besifloxacin Clinical Trials

Besifloxacin is a new fluoroquinolone currently under FDA review (Figure).¹ Many studies have evaluated its efficacy and safety. In a randomized, double-masked, parallel group clinical trial conducted by Karpecki and colleagues, the efficacy of besifloxacin was investigated. Two hundred sixty-nine patients with bacterial conjunctivitis, both children and adults, were enrolled.² Clinical resolution and bacterial eradication rates against gram-negative and gram-positive organisms were examined. At day 8 or 9 following treatment, clinical resolution of infection occurred in 61.7% of patients treated with besifloxacin, compared with 35.7% of patients treated with vehicle. Moreover, bacterial eradication was observed in approximately 90% of patients in the besifloxacin group compared with 60.3% of those in the control group. Thus, it appears as though besifloxacin was superior to control treatment according to both clinical and microbiological parameters.

Another study enrolled 957 patients with bacterial conjunctivitis, 390 of whom had culture-proven bacterial organisms that were available to include in a modified intent to treat analysis. Besifloxacin was again compared to vehicle. On day 5, the rate of clinical resolution of conjunctivitis in the besifloxacin group was 45.2% compared with 33% for the vehicle group. Although the clinical resolution rate in this study was not as high as the rate in the Karpecki study the bacterial eradication rate was, with 91.5% of cases in the besifloxacin group displaying bacterial eradication compared with 59.7% for the vehicle group.²

McDonald and colleagues compared the effectiveness of besifloxacin to that of moxifloxacin in a multicenter, randomized, double-masked, parallel group noninferiority study of 1,161 patients with bacterial conjunctivitis.³ The clinical resolution and bacterial eradication rates were comparable, with minimal differences (Table 1, page 12).³ When the MIC₉₀ of besifloxacin toward a variety of organisms was compared to that of other fluoroquinolones, it was found that besifloxacin had the best MICs for gram-positive organisms and comparable levels for gram-negative organisms. The superiority of besifloxacin to placebo was comparable to the superiority of other fluoroquinolones over placebo observed in clinical trials.⁴

The safety of besifloxacin was also investigated by McDonald and Karpecki. Of the 1,192 patients receiving topical agents, there were comparable adverse events between besifloxacin, its vehicle, and moxifloxacin. All adverse events were predominantly ocular and all were of mild severity and transient (Table 2).^2-4

In summary, although a limited number of clinical trials of besifloxacin exist, the available data demonstrate clinical and microbiological effectiveness of this agent in the treatment of bacterial conjunctivitis. Head-to-head trials comparing besifloxacin with moxifloxacin demonstrate equivalency in resolution of clinical and microbial outcomes. In addition, besifloxacin appears to be safe. The above data were presented to the United States FDA advisory panel on December 5, 2008, and the panel recommended the approval of the 0.6% besifloxacin ophthalmic solution for the treatment of bacterial conjunctivitis. If approved, it may reach the market this year and will provide another strategy against the emerging bacterial resistant organisms.

References

1. Zhang JZ, Ward KW. Besifloxacin, a novel fluoroquinolone antimicrobial agent, exhibits potent inhibition of pro-inflammatory cytokines in human THP-1 monocytes. The Journal of Antimicrobial Chemotherapy. 2008 Jan;61(1):111-6. Epub 2007 Oct 25.
2. Karpecki P, Depaolis M, Hunter JA, White EM, Rigel L, Brunner LS, Usner DW, Paterno MR, Comstock TL. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: A multicenter, prospective, randomized, double-masked, vehicle-controlled, 5-day efficacy and safety study. Clinical Therapeutics. 2009 Mar;31(3):514-26.
3. In: Data submitted to FDA panel briefing. www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4397b1-02-BauschLomb.pdf. Accessed May 15, 2009.
4. McDonald M. Clinical and Microbial Efficacy of besifloxacin compared to moxifloxacin in the treatment of bacterial conjunctivitis. Presented at the American Academy of Ophthalmology Annual Meeting. Atlanta, Georgia. November 8-11, 2008.