Novel Fluoroquinolones for the Treatment of Ophthalmic Infections

Proper antibiotic treatment is based on several basic premises. An antibiotic that targets the potential pathogens should be implemented. Moreover, the least toxic, but most effective, agent should be used. Appropriate timing and dosage schedules also should be prescribed. Other factors that affect the selection of the ideal antibiotic include drug solubility and penetration, broad-spectrum activity, rapid onset, low bacterial resistance, and compatibility with other drugs. Inappropriate antibiotic usage can worsen chronic bacterial colonization of the ocular surface and lids and allow resistant pathogens to proliferate. Overall, the goal should be to preserve vision and the integrity of the eye.

Fluoroquinolones

The current fluoroquinolones meet many of these ideal characteristics. They are bactericidal and display broad-spectrum activity, low toxicity, and excellent penetration. Results from noncomparative clinical trials show that eradication rates for existing fluoroquinolones vary in the treatment of bacterial conjunctivitis. Ofloxacin is 65% effective, while the newer fluoroquinolones, levofloxacin, moxifloxacin, and gatifloxacin, are at least 90% effective at microbial eradication (Table 1).

Tracking Resistance in the United States Today

Tracking Resistance in the United States Today (TRUST) is the largest longitudinal susceptibility surveillance program that tests minimum inhibitory concentration (MIC) susceptibility in the United States.¹ The data observed from this study demonstrated that the later generation fluoroquinolones gatifloxacin, levofloxacin, and moxifloxacin are effective against Streptococcus pneumoniae (Table 2). These drugs showed more than 99.5% susceptibility rates. However, ciprofloxacin, an earlier generation fluoroquinolone, showed declining susceptibility data over time. The TRUST data for Haemophilus influenzae showed similar results for the newer generation fluoroquinolones.

On the other hand, methicillin-resistant Staphylococcus aureus (MRSA) is a significant problem. The later generation fluoroquinolones display approximately 15% susceptibility toward this pathogen, while susceptibility toward methicillin-sensitive Staphylococcus aureus (MSSA) was shown to be 80%.2 Thus, even though the new fluoroquinolones require a double mutation to develop resistance, we have seen the emergence of S aureus isolates that are resistant to later generation fluoroquinolones. Research toward new fluoroquinolone development is attempting to address this problem.

Table 2: TRUST: Ocular Isolates Susceptibility of S pneumoniae (2001-2003)

Table 2: TRUST: Ocular Isolates Susceptibility of S pneumoniae (2001-2003)
Source: Sheppard JD, Sahm DF. Invest Ophthalmol Vis Sci. 2005;46:4876.

Current Challenges in Prevention and Treatment of Infections

Fluoroquinolones exhibit concentration-dependent activity. The higher the concentration, the more effective they are. Thus, to improve the management of these pathogens, higher and more sustained antibiotic concentrations at the site of infection must be achieved. This will allow for a more rapid eradication of ocular pathogens associated with external disease of the eye. High concentrations of the antibiotics in the tears and in the cornea if possible should be attained. Structural modifications to the fluoroquinolones will improve delivery of the drug to the site of action. The chemical structure of later generation fluoroquinolones is similar, but differ at the methoxy side chain at the R8 position. Development of new fluoroquinolones stems from substitutions at this methoxy side chain with the goal of decreasing microbial resistance and improving potency against gram-positive and gram-negative organisms. Again, even though resistance to fluoroquinolones requires mutation of target enzymes, it still occurs. Thus the development of new fluoroquinolones is important in the treatment of infections.

Besifloxacin

Besifloxacin is a new fluoroquinolone and the subject of studies presented at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting in 2008. For example, Zhang and colleagues studied besifloxacin efficacy in a prophylactic rabbit model of MRSA-induced endophthalmitis. In this study, the efficacy of besifloxacin was compared to moxifloxacin, gatifloxacin, and levofloxacin. Interestingly, all fluoroquinolones eradicated viable bacteria. Only besifloxacin, however, produced a statistically significant clinical reduction of the signs and symptoms of endophthalmitis versus saline.³

Another study examined the anti-inflammatory effects of besifloxacin in human corneal epithelial cells, as fluoroquinolones also have been shown to decrease the inflammatory immune response through inhibition of cytokine expression. Cytokine expression was stimulated in human corneas using interleukin 1ß (IL-1ß) and the response to besifloxacin versus moxifloxacin was examined. A dose-dependent inhibition of cytokine expression with besifloxacin was observed.⁴ This finding warrants further research.

Granvil and associates studied the pharmacokinetics of besifloxacin in healthy volunteers. They instilled a single drop into the conjunctival sac and examined a single tear sample at a specific time interval over 24 hours. Maximum concentrations were achieved within 10 minutes while concentrations in excess of the MICs required for S aureus and H influenzae eradication were maintained for 24 hours after dosing.⁵

A study of pharmacokinetics by Chappa and colleagues also supported the ongoing clinical development of besifloxacin. This study compared the ocular and systemic pharmacokinetics of besifloxacin with moxifloxacin and gatifloxacin following topical administration in rabbits. After a single instillation of medication, ocular and plasma samples were studied at various intervals up to 24 hours. All of the fluoroquinolones showed rapid absorption. Maximal concentrations in the tears and conjunctiva were higher with besifloxacin while corneal concentrations were equal among the 3 agents. However, systemic concentrations of besifloxacin were considerably lower when compared with the other fluoroquinolones.⁶ These early studies of besifloxacin suggest it has many of the characteristics of a good antibiotic, including broad-spectrum activity, rapid onset, and penetration.

In summary, resistance to fluoroquinolones is increasing, despite the fact that mutation of 2 bacterial enzymes is required for resistance to develop. High doses of antibiotic should be used, as well as a high frequency of doses to avoid the development of resistance. The dose should not be tapered under any circumstances and should be used for a maximum of 2 weeks. Moreover, the antibiotic should be bacteriocidal and highly soluble. Besifloxacin is a promising new fluoroquinolone, but more research is required to discern its efficacy and safety. If antibiotics are used appropriately, their use in ophthalmology will be extended.

References

Sheppard JD, Sahm DF. National Survey of Pathogen Susceptibility After 8 Years of Exposure to Levofloxacin. Investigative Ophthalmology & Visual Science. 2005;46: E-Abstract 4876.
Asbell PA, Colby KA, Deng S, McDonnell P, Meisler DM, Raizman MB, Sheppard JD Jr, Sahm DF. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. American Journal of Ophthalmology. 2008 Jun;145(6):951-958. Epub 2008 Mar 28.
Zhang J, Ward KW. Efficacy of Besifloxacin in a Rabbit Model of Methicillin-Resistant Staphylococcus Aureus-Induced Endophthalmitis. Investigative Ophthalmology & Visual Science. 2008 49: E-Abstract 839.
Cavet ME, VanDerMeid KR, Zhang J, Ward KW. Anti-Inflammatory Effects of Besifloxacin, a Novel Fluoroquinolone, in Primary Human Corneal Epithelial Cells. Investigative Ophthalmology & Visual Science. 2008 49: E-Abstract 2500.
Granvil C, Siou-Mermet R, Comstock T, Jonasse M, Proksch J. Ocular Pharmacokinetics of Besifloxacin, a Novel Fluoroquinolone Antimicrobial Agent for Topical Ophthalmic Use, in Healthy Volunteers. Investigative Ophthalmology & Visual Science. 2008 49: E-Abstract 873.
Chappa AK, Proksch JW, Ward KW. Comparison of the Ocular and Systemic Pharmacokinetics of Besifloxacin, a Novel Fluoroquinolone Antibiotic, With Moxifloxacin and Gatifloxacin in Pigmented Rabbits. Investigative Ophthalmology & Visual Science. 2008 49: E-Abstract 866.