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Antibiotic potency and penetration define protection

ByTerry Kim, MD

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Newer-generation fluoroquinolones demonstrate excellent penetration into the aqueous humor and corneal stroma, helping to ensure against post-surgical ocular tissue infection. Adequate penetration is of particular concern to cataract and refractive surgeons.

The incidence of infectious keratitis after LASIK procedures may be rising. Recent peer-reviewed literature suggests the incidence is as high as 1 in 1,000 to 1 in 5,000. Unlike patients with diffuse lamellar keratitis (DLK) who are usually asymptomatic, patients with LASIK-associated infections usually have anterior chamber reaction, inflammatory cells in the stroma, and eventually the formation of a distinct infiltrate.

In 2001, a survey of American Society of Cataract and Refractive Surgery (ASCRS) members conducted by the Cornea Clinical Committee found approximately 50% of post-LASIK infections derived from atypical organisms such as mycobacteria, and one-third of infections stemmed from staphylococcus.

A follow-up survey in 2004 revealed a slight increase in the incidence of infections (1 in 2,919 in 2001 to 1 in 2,131 in 2004), as well as a marked decrease in the percentage of infections caused by atypical organisms, with atypical mycobacteria causing only 5% of infections. The survey also revealed a significant rise in the percentage of infections caused by resistant strains of staphylococcus, a jump from 33% to 61%. Based on these numbers, the introduction and arrival of newer-generation fluoroquinolones, as well as improvements in sterile technique, have probably contributed to the decline of potentially devastating atypical mycobacterial infections following LASIK.

LASIK-associated infection

Literature has examined the minimum inhibitory concentrations (MICs) of moxifloxacin and gatifloxacin against various species of atypical mycobacteria.¹ Mycobacterium chelonae is the most common species involved in LASIK-associated infections and is therefore of primary concern to ophthalmologists.

I presented a study to the Ocular Microbiology and Immunology Group at the 2005 Annual Meeting of the American Academy of Ophthalmology in which my colleagues and I investigated the human corneal stromal concentrations of commercial preparations of 0.5% moxifloxacin (Vigamoxophthalmic solution, Alcon) and 0.3% gatifloxacin (Zymar, Allergan) following topical ocular dosing.²

The controlled, randomized, open-label, parallel study used human corneas from 48 patients undergoing penetrating keratoplasty. Before surgery, study eyes were treated with two doses (one drop each) of commercial preparations of either moxifloxacin or gatifloxacin given 5 minutes apart. We administered the last preoperative dose 15 minutes, 30 minutes, 1 hour or 2 hours prior to sampling corneal tissue. The corneal stroma samples were then assayed for these concentrations using a validated HPLC-fluorescence method.

Study results were encouraging. Peak stromal concentrations of moxifloxacin and gatifloxacin occurred early, within 15 minutes to 30 minutes after topical administration. The results show corneal penetration of newer-generation agents occurs rapidly, which is desirable for LASIK surgery prophylaxis in order to have the antibiotics present in the target tissue at the time of surgery and potential inoculation. Additionally, moxifloxacin achieved a higher level in the corneal stroma, with a peak concentration of 48.5 µg per gram, compared with gatifloxacin’s 15.7 µg per gram concentration (Figure 1).

Results of this study show an approximate three-fold difference in the corneal concentrations of moxifloxacin when compared with gatifloxacin following topical dosing in human patients undergoing corneal transplantation. When comparing the corneal concentrations to the MICs of various atypical mycobacterial species, the concentration of moxifloxacin far exceeds the MICs for the organisms, but the concentration of gatifloxacin barely exceeds the MICs for some of the organisms.¹ The higher concentration of moxifloxacin suggests a greater level of protection because it exceeds minimal bactericidal concentration (MBC) and mutant prevention concentration (MPC) levels.

Combating endophthalmitis

Human data also confirms the excellent penetration of topical newer-generation fluoroquinolones into the aqueous humor. A study conducted at Wilmer Eye Institute demonstrates a four-fold difference between moxifloxacin and gatifloxacin concentrations.³ Maximum aqueous humor concentration was 1.80 µg/mL for moxifloxacin and 0.48 µg/mL for gatifloxacin (Figure 2). The difference was found to be statistically significant (P = .00003).

In a similar evaluation, the MIC for human endophthalmitis pathogens are well covered based on the levels of moxifloxacin in the aqueous humor but not based on the levels of gatifloxacin in the aqueous humor.⁴ Because fluoroquinolones are concentration-dependent antibiotics, achieving a higher concentration in the target tissue should translate into better clinical efficacy. Reaching the higher concentrations can also help eradicate bacteria, as opposed to just inhibiting bacterial growth, because MBCs are typically 3 times to 4 times higher than the MICs.

Potent penetration

The high potency and penetration of moxifloxacin into the human aqueous humor and corneal stroma provide key characteristics for clinical efficacy against infectious keratitis and endophthalmitis. The combination of high tissue concentrations and low MICs allow newer-generation agents such as moxifloxacin to achieve a significantly high therapeutic index (C_max:MIC ratio). Achieving a high therapeutic index can not only lead to the inhibition of bacterial growth, but more ideally, the eradication of bacterial growth, as well as the prevention of mutations. With patient data now available, ophthalmologists can feel comfortable using moxifloxacin because the agent should provide patients superior protection in the prevention and treatment of potentially devastating infections following cataract and refractive surgery.

References

1. Abshire R, et al. Topical antibacterial therapy for mycobacterial keratitis: Potential for surgical prophylaxis and treatment. Clinical Therapeutics. 2004;26:191-196.
2. Kim T, Lane S, Holland E, et al. Human corneal stroma and epithelium concentrations of moxifloxacin and gatifloxacin following topical ocular dosing with Vigamox and Zymar. Presented at: Annual Meeting of the Ocular Microbiology and Immunology Group; October 15, 2005; Chicago, Il.
3. Kim DH, Stark WJ, O’Brien TP, et al. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% ophthalmic solution in cataract surgery patients. Ophthalmology. 2005;112:1992-1996.
4. Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: New weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.

Dr. Kim is associate professor of ophthalmology at Duke University School of Medicine and associate director of the corneal and external disease and refractive surgery services at Duke University Eye Center in Durham, N.C.