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The latest generation fluoroquinolone antibiotics formulated for topical ophthalmic use - gatifloxacin and moxifloxacin - are increasing our ability to provide broader and more effective antibacterial prophylaxis and treatment.

Ofloxacin and ciprofloxacin, the first commercially available topical antibiotics to be used for monotherapy for corneal infections maintained a very broad spectrum for antibacterial activity against ocular pathogens for over a decade. Soon after my initial evaluation of the efficacy of those second generation fluoroquinolones for corneal ulcers for the FDA clinical trials in the early 1990's, they became my antibiotics of choice for topical antibacterial prophylaxis in corneal, refractive and cataract surgery. My preferences for ciprofloxacin in the late 1990's and oflaxacin more recently - until the availability of the fourth generation fluoroquinolones - were based on the latest data from comparative studies of potency, ocular tissue penetration, maintenance of therapeutic concentrations and resistance trends at my hospitals.

Over the past decade, fluoroquinolone resistance has become an increasing concern. The vast systemic use of ciprofloxacin and levofloxacin led to varying degrees of resistance to second and third generation fluoroquinolones in the United States and Europe-particularly in Gram-positive species, which became the most common pathogens in endophthalmitis and infectious keratitis.

In 1993 Chen and I documented the changing trends and increasing prevalence of Gram-positive organisms in corneal ulcers. In 1998 Han and collaborators in the Endophthalmitis Vitrectomy Study reported that 94% of pathogens causing endophthalmitis were Gram-positive. The 2002 ASCRS survey of infectious keratitis after LASIK demonstrated a comparable predominance of Gram-positive organisms (including some methicillin - and second generation fluoroquinolone resistant bacteria) in cases not caused by opportunistic organisms. Multiple reports over the last three years have documented atypical mycobacteria as frequent pathogens in opportunistic infections after LASIK.

Gatifloxacin and moxifloxacin, fourth generation C8-methoxy fluoroquinolones, are demonstrating increased activity against Gram-positive bacteria and atypical mycobacteria when compared to ciprofloxacin, Ofloxacin and levofloxacin in vitro and in vivo. Multiple studies were presented at the 2003 ARVO meeting. Long et al documented minimal inhibitory concentrations (MIC90) that are four- to 16-fold greater for gatifloxacin than for ciprofloxacin and levofloxacin.

Efficacy depends not only on potency but also on penetration. In a study comparing ocular pharmacokinetics of gatifloxacin 0.3% and ciprofloxacin 0.3% following topical application four times daily for three days in rabbits, Batoosingh et al reported significantly greater penetration with higher aqueous humour concentrations (p<0.001) with gatifloxacin than with ciprofloxacin.

Formulating a fluoroquinolone at a higher concentration can provide higher drug concentrations in target ocular tissues. Poor solubility of a fluoroquinolone can preclude the possibility of developing such a concentrated formulation. Ciprofloxacin, for example, has poor solubility and cannot be effectively formulated at much higher concentrations than the current 0.3%. Levofloxacin, however, is much more soluble that ciprofloxacin.

A new formulation of topical levofloxacin (1.5%) is being developed to contain active drug concentrations three-fold higher than those in the currently available 0.5% formulation. This approach aims to increase ocular levels for more effective bacterial killing and prevent the emergence of resistant organisms.

The results of several in vitro studies presented at the 2003 ARVO meeting, demonstrated that gatifloxacin and moxifloxacin have comparable activity against Gram-positive bacteria but that gatifloxacin is more effective against atypical mycobacteria, Nocardia and Gram-negative bacteria. In direct comparisons of MICs as reported by Ramirez et al. and Callagan et al., gatifloxacin has two- to six-fold stronger activity than moxifloxacin against Gram-negative ocular isolates.

The available formulations of gatifloxacin (Zymar, Allergan, Inc.) and moxifloxacin (Vigamox, Alcon Inc) are 0.3% and 0.5% respectively. The higher concentration and the higher solubility of the moxifloxacin formulation could theoretically lead to higher tissue levels. However, the absence of the preservative benzalkonium chloride (BAK), in the moxifloxacin formulation and the presence of 0.005% BAK - which increases antibiotic penetration through epithelial cells - in the gatifloxacin formulation could balance out the higher concentration and solubility.

The advantages and disadvantages of preservation with BAK vs self preservation remain controversial and depend on the patient's ocular condition. Possible adverse effects of epithelial toxicity in patients with compromised epitheliums and the beneficial effects of BAK antisepsis also must be considered.

The antiseptic effect of BAK has been well documented to kill bacteria, viruses, yeast and fungi, thereby preventing bottle contamination - as well as synergistically adding to sterilisation of the ocular surface. Without BAK, the moxifloxacin formulation was demonstrated to suppress growth of aspergillus and yeast. Suppression of other fungi and viruses has not been documented. The chemical structures of the C8-methoxy fluoroquinolones add protection from bacterial resistance in addition to enhancement of bactericidal properties. The substitution of the methoxy group at the eighth carbon on the basic ring in both gatifloxacin and moxifloxacin reduces the likelihood of ocular pathogens developing resistance to these fluoroquinolones. The methoxy group allows binding of the antibiotics to two bacterial enzymes - DNA gyrase and topoisomerase IV.

As a result, C8 methoxy fluoroquinolones are hypothesised to require two simultaneous mutations for development of resistance. Previous generations of fluoroquinolones required only a single mutation. Moreover, a bulky side chain at the C7 position of these antibiotics makes it even more difficult for bacterial cells to get rid of antibiotics.
Based on data to date, gatifloxacin is my current preference for antibacterial prophylaxis in cataract, refractive and corneal surgery - except in some patients with compromised epitheliums. However, widespread clinical experience and head-to-head comparison studies will teach all of us much more about the indications for gatifloxacin and moxifloxacin.

Both gatifloxacin (Zymar, Allergan, Inc) and moxifloxacin (Vigamox, Alcon, Inc.) are commercially available in the United States. Gatifloxacin received the first FDA approval for treatment of bacterial conjunctivitis in March 2003. Approval for moxifloxacin for the same indication followed one month later.

In the Unites States where health insurance companies cover very variable and limited amounts of medication costs and where Congress still has not passed a bill to cover even a portion of Medicare prescription drug costs, pricing influences choice, pricing influences choice of antibiotics. For about US$60 a patient can buy a 5ml bottle of gatifloxacin but only a 3 ml bottle of moxifloxacin.

Neither gatifloxacin nor moxifloxacin are commercially available yet in Europe. It is hoped that marketing approvals of these antibiotics will be forthcoming, so that patients can benefit from their increased potency, their increased penetration into ocular tissues and their broader coverage of pathogenic organisms. This newer generation of fluoroquinolones should decrease postoperative infection rates - until widespread systemic use and abuse leads to new resistance trends.

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