Moxifloxacin HCl 0.5% ophthalmic solution (VIGAMOX; Alcon Laboratories, Inc., Fort Worth, TX), a recent addition to the fluoroquinolone family, features properties that exceed those of the earlier generation of fluoroquinolone antibiotics, which include ofloxacin, levofloxacin, and ciprofloxacin. Moxifloxacin is one of the newer designer “smart bombs” in the war against ocular infection. The eighth position of the basic fluoroquinolone nucleus is substituted with a methoxy group (OCH3), which has expanded the activity of moxifloxacin against gram-positive organisms. This methoxy group addition expands the spectrum of activity to include the majority of ocular infections today. Almost 80% of ocular infections are due to gram-positive pathogens.1
THE IMPORTANCE OF GRAM-POSITIVE COVERAGE
Although there is considerable fear regarding the virulence of gram-negative organisms such as Pseudomonas, especially among contact lens wearers, in actuality, gram-positives have recently been isolated with the greatest frequency. The possibility that these organisms have evolved to develop resistance to earlier generations of fluoroquinolone antibiotics is of increasing concern. Moxifloxacin accomplishes two important objectives: (1) it provides an expanded spectrum of coverage against gram-positive bacteria, and (2) it offers increased activity against resistant organisms. Ophthalmologists must be aware that this revolutionary compound possesses far greater in vitro and in vivo bactericidal activity against gram-positives than its earlier cousins.
EFFICACY OF A HIGHER CONCENTRATION
VIGAMOX is formulated at a higher concentration than gatifloxacin (ZYMAR; Allergan, Inc., Irvine, CA), another newer fluoroquinolone. In fact, at 0.5%, its concentration is the highest of any fourth-generation fluoroquinolone and translates into greater concentrations of the drug in various ocular tissues including the cornea, aqueous humor, and tear film. Although gatifloxacin is formulated at a concentration of 0.3% for topical administration, this slight difference could be significant in some cases, owing to the concentration-dependent mechanism of killing bacteria that fluoroquinolone agents employ. The more highly concentrated fluoroquinolones deliver more available drug into the ocular tissues for effective bactericidal action. Other antibiotics are concentration-independent and rely on factors such as exposure time to work.
Moxifloxacin is approved for the topical therapy of the indication of acute bacterial conjunctivitis. During clinical FDA phase III trials, the agent was assigned a slightly less frequent regimen than has been traditionally used q.i.d. for 7 days. VIGAMOX received approval for t.i.d. dosing for 7 days, a total of 21 drops (Table 1). In contrast, gatifloxacin received approval for q2h day 1 to 2 and q.i.d. days 3 to 7, a 36-drop regimen that is similar to that of earlier-generation fluoroquinolones. VIGAMOX's convenient dosing of t.i.d. for 7 days could help improve patients' compliance. Researchers have not yet determined the dosing regimen for more serious infections such as acute bacterial keratitis, but perhaps the 5-mg/mL concentration would also allow a slightly less frequent dosing while maintaining equivalent efficacy than a 3-mg/mL concentration solution.
Moxifloxacin's designer chemical structure was synthesized to be less prone to the development of bacterial resistance in an effort to help ophthalmologists in that battle. Moxifloxacin binds to both of the enzymes that bacteria rely upon for replication, bacterial DNA gyrase and topoisomerase IV. As a result, bacteria must acquire a double-hit mutation in order to develop resistance to either moxifloxacin or gatifloxacin, compared with only a single mutation for resistance against ciprofloxacin, ofloxacin, and levofloxacin. Because moxifloxacin and gatifloxacin have a high affinity for binding to both enzymes necessary for bacterial DNA replication, these agents still remain effective, even against bacteria that have demonstrated resistance to the earlier generations of fluoroquinolones. In addition, moxifloxacin has a bulky chemical substitution at the C7 position that reduces the likelihood of bacterial efflux, another important mechanism of bacterial resistance (Figure 1). I therefore encourage the use of these new fluoroquinolone agents in place of the earlier generations. If ophthalmologists continue to use earlier-generation agents, they will contribute to a single-bacterial mutation, after which the bacteria will require only one additional mutation to develop resistance to the newer-generation compounds.
Moxifloxacin and gatifloxacin are newer-generation fluoroquinolones with novel properties that distinctly separate them from levofloxacin, ofloxacin, and ciprofloxacin. Moxifloxacin is formulated at a higher concentration than other newer-generation fluoroquinolones, and by virtue of the 8-methoxy substitution, has fundamentally superior intrinsic antibacterial activity against gram-positive species, including resistant staphylococci and streptococci. The combination of a higher concentration and greater potency translates into superior pharmacodynamics. The agent's high binding affinity to DNA gyrase and topoisomerase IV preserves activity against ocular strains resistant to levofloxacin, ofloxacin, and ciprofloxacin and discourages the development of bacterial resistance by requiring two-step mutations.
Terrence P. O'Brien, MD, serves as Director of Ocular Infectious Diseases and Ocular Microbiology Laboratory at The Wilmer Ophthalmological Institute at Johns Hopkins University School of Medicine. He holds no direct financial interest in any of the products discussed herein but serves as an ad hoc consultant to Alcon Laboratories, Inc., Allergan, Inc., Novartis Ophthalmics, Inc., Pfizer Inc., and Santen, Inc. Dr. O'Brien may be reached at (410) 583-2842; firstname.lastname@example.org.
1. Durand M. Microbiologic factors and visual outcome in endophthalmitis vitrectomy study. Am J Ophthalmol. 1997;124:127-130.