Fluoroquinolone efficacy depends on both potency and penetration

ByTerry Kim, MD

In the past, ophthalmologists have considered fluoroquinolone potency—as determined by in vitro minimum inhibitory concentration data—its primary measure of efficacy. Penetration, however, is also an important factor in determining the efficacy of a fluoroquinolone.

Newer-generation fluoroquinolones moxifloxacin 0.5% (Vigamox, Alcon Laboratories, Inc.) and gatifloxacin 0.3% (Zymar, Allergan) have been in use for approximately 5 years in the United States, and ophthalmologists who use them find them beneficial.

Terry Kim

In 2002, Mather and colleagues¹ published a study evaluating the potency of these newer fluoroquinolones and older-generation agents such as ofloxacin (Ocuflox, Allergan), ciprofloxacin (Ciloxan, Alcon Laboratories, Inc.), and levofloxacin (Quixin, Santen). Median minimum inhibitory concentration (MIC) data from human endophthalmitis isolates showed that newer-generation fluoroquinolone MICs for gram-positive organisms Streptococcus pneumoniae, Staphylococcal aureus, and Staphylococcal epidermis were significantly lower than MICs for older fluoroquinolones. Because the majority of cases of infectious keratitis and postcataract surgery infections are caused by gram-positive organisms, it is clinically relevant that newer-generation fluoroquinolones are more efficacious against gram-positive organisms because they inhibit two bacterial enzymes, DNA gyrase and topoisomerase IV.^2,3

Newer-generation fluoroquinolones moxifloxacin 0.5% and gatifloxacin 0.3% have been in use for approximately 5 years in the United States, and ophthalmologists who use them find them beneficial.
—Terry Kim, MD

Mather’s study also examined the potency of fluoroquinolones against fluoroquinolone-resistant endophthalmitis isolates. Moxifloxacin and gatifloxacin demonstrated significantly greater potency, or lower median MICs, compared with the older fluoroquinolones.

Concentration equally important

Potency is only one determinant of fluoroquinolone efficacy, however. Fluoroquinolone antibiotics are concentration-dependent medications. If the drug cannot reach the target tissue, then potency is meaningless. To protect against infection, the antibiotic must reach the target tissue in sufficient concentrations, specifically, above the drug’s MIC, preferably above the minimum bactericidal concentration (MBC), and ideally, above the mutation prevention concentration (MPC). Superior clinical activity, in terms of eradicating the organisms, is likely once MBC and MPC concentrations are reached. Reaching the MBC will kill 99.9% of bacteria, and reaching the MPC will kill 100% of bacteria. Surgeons should therefore consider both potency and penetration to truly evaluate the efficacy of a fluoroquinolone.

In study results published in 2005, Wagner and colleagues⁴ evaluated several fluoroquinolone concentrations in human conjunctival tissue after administration of topical drops. In this randomized study of 66 patients, patients received one drop of moxifloxacin, gatifloxacin, levofloxacin, ofloxacin, or ciprofloxacin. A human conjunctival biopsy was taken 20 minutes after the dose, and moxifloxacin demonstrated a statistically significant higher concentration than the other fluoroquinolones. Moxifloxacin reached a concentration of 18.0 µg per gram, which was much higher than that for gatifloxacin (2.54 µg/g), levofloxacin (2.34 µg/g), ofloxacin (1.23 µg/g), and ciprofloxacin (2.65 µg/g).

In another study, Holland and colleagues⁵ evaluated human corneal concentrations of newer-generation fluoroquinolones. The study was carried out in corneas from 48 patients undergoing corneal transplantation. Before surgery, patients were randomized to receive either moxifloxacin or gatifloxacin, with two drops administered 5 minutes apart. Corneal endothelium, stroma, and epithelial samples were assayed for concentrations of moxifloxacin and gatifloxacin, using a validated, simultaneous high-performance liquid chromatography fluorescence method. The results showed that for all epithelial, stromal, and endothelial samples, the concentration of moxifloxacin exceeded that of gatifloxacin. Most significantly, in the stroma, moxifloxacin reached a concentration of 48.5 µg per gram compared with 15.7 µg per gram for gatifloxacin, representing a threefold difference.

In a 2005 study, Kim and colleagues⁶ evaluated the ocular penetration of newer-generation fluoroquinolones moxifloxacin 0.5% and gatifloxacin 0.3% in the aqueous humor. This study included 50 patients undergoing routine cataract surgery. The patients were divided into two groups, and each group received either moxifloxacin or gatifloxacin. One antibiotic drop was administered every 10 minutes; patients received a total of four drops, with the last drop administered 30 minutes before surgery. Samples of aqueous humor were taken at the start of surgery. The mean concentration of moxifloxacin in the aqueous humor was 1.8 µg per milliliter compared with 0.48 µg per milliliter for gatifloxacin, which is almost a fourfold, statistically significant difference (Figure).

Moxifloxacin and Gatifloxacin:
Gram-positive MICs and human aqueous concentrations

Figure. The data show median minimum inhibitory concentrations (MICs) for gatifloxacin and moxifloxacin against various gram-positive organisms compared with the mean aqueous concentration levels achieved in a study by Kim and colleagues at the Wilmer Eye Institute. The data show that moxifloxacin penetrated into the aqueous at concentrations that meet and exceed the agent’s mutant prevention concentration for the most common endophthalmitis-causing susceptible pathogens. In addition, moxifloxacin met its MIC against fluoroquinolone-resistant Staphylococcus aureus.

Adapted from data published in:
Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133(4):463-466.
Kim DH, Stark WJ, O’Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology. 2005;112(11):1992-1996.

The goal is to achieve the highest possible concentration of antibiotic in the target tissue, not only to exceed MICs, but also to reach MBCs and MPCs. Typically, MBC values are three to four times higher than MIC values, and MPC values are approximately 10 times higher than MIC values. The aforementioned studies are based on human data that have consistently shown that concentrations of newer-generation fluoroquinolone in human ocular tissue exceed concentrations of the older fluoroquinolones. Furthermore, data show that moxifloxacin concentrations exceeded that of gatifloxacin in all human conjunctival, corneal, and aqueous humor samples studied.

Strategies for Limiting Resistance

Reducing the risk of resistance

Drug resistance is a concern in all medical specialties. Mah and colleagues⁷ demonstrated that over the past several years, the percentage of fluoroquinolone-susceptible bacterial isolates such as S. aureus from ocular infections including keratitis, endophthalmitis, and blepharitis/conjunctivitis has been decreasing.

Ophthalmologists are observing emerging resistance to fluoroquinolones, primarily by the Staphylococcal organisms, and these cases are usually found in postcataract and refractive surgery patients. For these patients, I think that newer-generation fluoroquinolones are beneficial. Studies indicate that three basic factors promote resistance to antibiotics: prolonged use, subtherapeutic dosing, and total antibiotic use, such as total kilograms of the antibiotic used annually.⁸ Studies have shown that bacterial resistance develops primarily during systemic use of antibiotics and also from exposure to antibiotics through other routes such as in animal feed.^8-10 Topical fluoroquinolone use for surgical prophylaxis, however, is minimal compared with overall systemic use. Ophthalmic use of fluoroquinolones likely represents a relatively insignificant selection pressure for promoting resistant bacteria.

In traditional medical practice, the use of stronger antibiotics was reserved for the worst infections. Surgeons are now urged to use newer-generation fluoroquinolones because developing resistance to them is more difficult. One of the mechanisms of newer-generation fluoroquinolones is that they have more balanced activity against both DNA gyrase and topoisomerase IV in gram-positive organisms. Bacteria must develop mutations against both of these enzymes to develop resistance against the newer-generation fluoroquinolones, whereas they need to develop mutations against only one enzyme to develop resistance to the older fluoroquinolones.

Physicians will always be concerned about the emergence of resistant organisms, and antibiotic therapy must be adjusted continually as resistance patterns emerge. At this time, surgeons can follow several strategies for topical antibiotic use to limit resistance. One strategy is appropriate antibiotic use. Newer-generation fluoroquinolones should be used for acute (ie, corneal ulcer) and not chronic (ie, blepharitis) infections, as well as for short-term prophylaxis (ie, after cataract surgery). Another strategy is to follow the appropriate dosing and scheduling regimens as specified on the package insert. For prophylaxis after cataract surgery, I typically use a newer-generation fluoroquinolone such as moxifloxacin for 1 week postoperatively and then stop the antibiotic administration. I do not recommend tapering antibiotics because this practice increases the likelihood of developing resistance. Strategies for limiting resistance also include switching to newer-generation fluoroquinolones, because by avoiding lower dosing of the older or less potent fluoroquinolone antibiotics, the risk of forming mutations is reduced. In addition, because newer-generation fluoroquinolones remain in ocular tissue in higher concentrations, the rate of random mutations in bacterial organisms is minimized.

In summary, ophthalmologists now have human data to demonstrate the enhanced penetration of newer-generation fluoroquinolones such as moxifloxacin, which inevitably should lead to enhanced efficacy of antibiotic therapy. With the increasing trend toward using premium IOLs in elective cataract surgery as well as the continued growth of lens-based and cornea-based refractive procedures, surgeons can use newer fluoroquinolones to reach the target tissues in sufficient concentrations to minimize the risk of potentially devastating ocular infections after these procedures.

References

Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133(4):463-466.
Tankovic J, Bachoual R, Ouabdesselam S, Boudjadja A, Soussy CJ. In-vitro activity of moxifloxacin against fluoroquinolone-resistant strains of aerobic gram-negative bacilli and Enterococcus faecalis. J Antimicrob Chemother.1999;43 (suppl B):19-23.
Schedletzky H, Wiedemann B, Heisig P. The effect of moxifloxacin on its target topoismerases from Escherichia coli and Staphylococcus aureus. J Antimicrob Chemother. 1999;43 (suppl B):31-37.
Wagner RS, Abelson MB, Shapiro A, Torkildsen G. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue. Arch Ophthalmol. 2005;123(9):1282-1283.
Holland EJ, Lane SS, Kim T, Raizman M, Dunn S. Ocular penetration and pharmacokinetics of topical gatifloxacin 0.3% and moxifloxacin 0.5% ophthalmic solutions after keratoplasty. Cornea. In press.
Kim DH, Stark WJ, O’Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology. 2005;112(11):1992-1996.
Mah F. New antibiotics for bacterial infections. Ophthalmol Clin North Am. 2003;16(1):11-27.
Gordon YJ. Vancomycin prophylaxis and emerging resistance: are ophthalmologists the villains? The heroes? Am J Ophthalmol. 2001;131:371-376.
Levy SB. The challenge of antibiotic resistance. Sci Am. 1998;278(3):46-53.
McDermott PF, Zhao S, Wagner DD, Simjee S, Walker RD, White DG. The food safety perspective of antibiotic resistance. Anim Biotechnol. 2002;13(1):71-84.