Use the lowest amount of drug possible to achieve efficacy with safety

Increasing the concentration of a drug may decrease tolerability without boosting efficacy.

Issue: June 15, 2006

ByTasha Y. Tanhehco, BS

ByRandall J. Olson, MD

When selecting topical anti-infective medications for treatment of infection or for surgical prophylaxis, clinicians must consider the risk-benefit ratio. The available evidence demonstrates that increasing the concentration of active drug does not necessarily increase efficacy but may decrease ocular tolerability and safety and inhibit wound healing.

Randall J. Olson

Patients benefit when their doctors select the lowest amount of effective medication needed to treat or prevent ocular infection.

With the wide selection of topical ocular anti-infective drugs available, clinicians must consider the class of drugs, their dosing regimens and schedules, and the concentrations of active ingredients in making their selection.

All medications have the potential for side effects, and the risk of the side effects must be countered by maximizing efficacy. Specifically, topical antibiotics must eradicate pathogens while limiting the risk of toxic effects.

Duration of treatment also influences the risk-benefit ratio. For patients undergoing cataract surgery, clinicians must determine the impact of a medication’s toxicity on wound healing and the probability that delaying wound healing may increase the risk of endophthalmitis. After refractive procedures, failure to adequately treat with appropriate antimicrobial prophylaxis may increase the risk of corneal infection, thereby increasing the risk of resultant scarring.

Balancing efficacy, safety

Evaluation of the efficacy of antimicrobial drugs often includes review of the minimum inhibitory concentrations (MIC) of the agent against potential ocular pathogens. The MIC is defined as the concentration of a drug required to kill a particular pathogen. A common permutation of the MIC is the MIC₉₀, which is the concentration of drug required to eliminate 90% of a population of a specific microbial species.

MIC and MIC₉₀ levels are most often evaluated using the active molecule but may also include evaluations of commercial preparations. The evaluation of commercial preparations, although less frequently performed, is likely more useful as these preparations may contain preservatives that enhance antimicrobial efficacy and rapidity of kill.

Is achievement of the MIC for a particular agent sufficient to protect patients from ocular infection, or should the target concentration be several or even 10 times the MIC? If there were no attendant risk of side effects or probability of decreased ocular tolerability, achieving concentrations in ocular tissue that are several times greater than the MIC levels might be beneficial, or at least not harmful. However, there is no evidence that concentrations greatly exceeding the MIC levels provide any greater killing efficacy than achieving the MIC₉₀ levels.

Class matters

The class of antibiotic selected should also be considered when evaluating both the risk-benefit ratio and the amount of drug needed for effective therapy. For instance, the newest generation of fluoroquinolones has been shown to provide greater efficacy and a lower rate of resistance than older generations. The superiority of the newest generation compared with older generations is due to molecular differences between the groups and is not dependent only on the concentration of the formulation.

The introduction of a formulation of levofloxacin that contains three times more active drug than the original demonstrates this concept. Increasing the concentration of a fluoroquinolone is unlikely to produce efficacy equivalent to that provided by a newer fluoroquinolone, but it will increase inherent toxicity. In fact, any increase in antimicrobial efficacy resulting from trebling the concentration is difficult to evaluate, as no studies have been published comparing the efficacy of levofloxacin 1.5% against the original 0.5% formulation. Similarly, no data evaluating an increase in side effects and ocular toxicity concurrent with the increase in concentration have been presented. Moreover, no information is available comparing levofloxacin 1.5% against any newer-generation fluoroquinolone.

In the only published study evaluating levofloxacin 1.5%, Walters and Hart compared maximal tear concentration with that of ofloxacin 0.3% in normal subjects. In that report, the mean concentration of levofloxacin in tears was greater than the mean concentration of ofloxacin at all time points, but only the difference at 12 hours after dose on day 0 was statistically significant. The differences at all time points were threefold to tenfold higher for levofloxacin. It is also important to note that the level of ofloxacin exceeded the MIC values for common ocular pathogens at all time points, despite having one-fifth the active ingredient of the levofloxacin solution.

Comfort, tolerability

Ocular comfort and tolerability are also important considerations when selecting topical anti-infective medications, and these variables are likely adversely influenced by increasing the concentration of active ingredient. Ocular tolerability is critical because if a patient is noncompliant with a prescribed treatment regimen, even a highly efficacious drug is worthless.

In a recent study, Donnenfeld and colleagues compared the ocular tolerability of gatifloxacin 0.3% (Zymar, Allergan) with that of moxifloxacin 0.5% (Vigamox, Alcon) in a randomized, paired-eye study. Patients received gatifloxacin in one eye and moxifloxacin in the other. Compared with gatifloxacin, eyes receiving moxifloxacin experienced a significantly greater increase in hyperemia and conjunctival vascularity. Moreover, significantly less pain and irritation were reported with instillation of gatifloxacin than with the higher-concentration moxifloxacin.

A study by Kaufman and colleagues also reported that gatifloxacin was less painful and more biocompatible than moxifloxacin. In that study, gatifloxacin was instilled in one eye and moxifloxacin in the other, and patients graded the discomfort of the administered drops. The degree of conjunctival injection was also graded. Moxifloxacin produced significantly greater discomfort than gatifloxacin (2 points higher on a scale of 1 to 10 for moxifloxacin, P < .05) and significantly greater conjunctival injection (mean score of 0 on a 4-point scale for gatifloxacin vs. 2 for moxifloxacin, P < .05). Confocal microscopy revealed a trend of 1.4 times greater corneal epithelial cell dropout in the moxifloxacin eyes (P = .052).

Surgical challenges

Use of anti-infective agents in surgical patients poses its own set of challenges, as the clinician must consider how the selected medication will influence the delicate healing processes in the wounded eye. After surgery, it is important to rapidly re-establish a normal epithelial barrier and stromal structure to minimize the risk of infection and optimize visual outcomes, and this at-risk period extends until the wound is completely healed. It is critical, therefore, that the selected topical agent does not inhibit wound healing.

Numerous studies have demonstrated that moxifloxacin 0.5% inhibits wound healing more than gatifloxacin 0.3%. Furthermore, a recent evaluation of five fluoroquinolones by Fernandez de Castro and colleagues demonstrated that lower-concentration fluoroquinolones were less disruptive to wound healing. Although some of these differences may be due to differences in concentration, it is likely that inherent toxicity of the active molecules is a contributing factor in the observed rates of reduced corneal healing. In fact, a recent study by Chang-Lin and colleagues reported that moxifloxacin was more toxic to the ocular surface than a gatifloxacin solution of equal concentration, and these differences were consistent when the commercially available ophthalmic solutions were evaluated despite the presence of preservative and lower drug concentration in the gatifloxacin ophthalmic solution.

For more information:

Randall J. Olson, MD, can be reached at John Moran Eye Center, 50 N. Medical Drive, Salt Lake City, UT 84132; 801-585-6622; fax: 801-581-8703; e-mail: randall.olson@hsc.utah.edu. Dr. Olson is a consultant to Allergan.

Allergan Inc., maker of Zymar (gatifloxacin ophthalmic solution 0.3%), can be reached at P.O. Box 19534, Irvine, CA 92623; 714-246-4500; fax: 714-246-4971; Web site: www.allergan.com.

References:

Agrawal VB, Tsai RJ. Corneal epithelial wound healing. Indian J Ophthalmol. 2003;51(1):5-15.

Cellular changes following epithelial abrasion. In: Beuerman RW, Crosson CE, Kaufman HE, eds. Healing Processes in the Cornea. Portfolio Publishing; 1989.

Blondeau JM, Hedlin P, Borsos SD. The antimicrobial activity of gatifloxacin (GAT) with or without benzalkonium chloride (BAK) against ocular bacterial pathogens. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2005.

Chang-Lin JE, Way W, et al. Cytotoxicity comparison of the fourth-generation fluoroquinolones gatifloxacin and moxifloxacin in primary rabbit corneal epithelial cell layers using an ethidium bromide staining assay. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2005.

Donnenfeld E, Perry H, et al. Ocular tolerability of the fourth-generation fluoroquinolones gatifloxacin 0.3% and moxifloxacin 0.5%. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2004.

Fernandez de Castro LE, Sandoval HP, Vroman DT, Solomon KD. Comparison of 5 fluoroquinolones in corneal wound healing rate in an animal model. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2005.

Fukuda H, Kishii R, Takei M, Hosaka M. Contributions of the 8-methoxy group of gatifloxacin to resistance selectivity, target preference, and antibacterial activity against Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45(6):1649-1653.

Kaufman SC, Ahee J, Salahuddin A. Comparison of the biocompatibility of moxifloxacin and gatifloxacin. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2004.

McDonnell PJ, Taban M, et al. Dynamic morphology of clear corneal cataract incisions. Ophthalmology. 2003;110(12):2342-2348.

Schmidt LP, Beuerman RW. Comparison of gatifloxacin and moxifloxacin in healing of a linear incision in the rabbit cornea. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2004.

Stern ME, Gao J, et al. Effects of fourth-generation fluoroquinolones on the ocular surface, epithelium, and wound healing. In press.

Walters TR, Hart W. Tear concentration of 1.5% levofloxacin ophthalmic solution following topical administration in healthy adult volunteers. Presented at: annual meeting of the Association for Research in Vision and Ophthalmology; 2003.