THERAPEUTIC INSIGHTS

Beat Balky Bacteria

Antibiotic provides sustained high concentration, broad coverage and low toxicity.

John D. Sheppard, MD, MMSc, Norfolk, Va.

Recently, Vistakon Pharmaceuticals introduced a 1.5% concentration of levofloxacin (IQUIX) — a preservative-free ophthalmic antibiotic, Food and Drug Administration (FDA)-approved for the treatment of corneal ulcers.

Here, I discuss the reasons I believe you should strongly consider making 1.5% levofloxacin your clear choice for significant ocular-surface infections.

1. Maximized drug exposure

An antibiotic's concentration through time determines its exposure to the bacteria, often referred to as the "area under the curve" (AUC), and therefore its clinical activity.

To kill the offending bacteria and prevent mutations, an antibiotic must exceed the pathogen's minimal inhibitory concentration (MIC) continuously through time. MIC is the lowest concentration required of an antibiotic to preclude the bacteria's growth after incubation over-night. Therefore, the higher the overall drug exposure, the greater the likelihood of bacteria eradication.

Given this fact, our goal with topical-fluoroquinolone dosing should be to maximize drug exposure (AUC) relative to MIC without causing toxicity to ocular tissues. The drug 1.5% levofloxacin has enabled me to accomplish this goal.

In clinical trials and other studies leading up to FDA approval, 1.5% levofloxacin was compared with 0.3% ofloxacin (Ocuflox, Allergan) as a control drug. Tear concentrations of 1.5% levofloxacin, following topical administration in healthy adult volunteers, were very high. In fact, even as long as six hours after administration, 1.5% levofloxacin tear concentrations were 50 to 200 times higher than the median MIC₉₀ for common ocular pathogens.¹

Levofloxacin: The next generation.

The high solubility of 1.5% levofloxacin makes this continuously high concentration possible, penetrating the conjunctiva and adnexae, which, in turn, replenish the tear film in an exchange equilibrium with the ocular-surface tissues. The conjunctiva acts as a high-volume capacitor for this highly soluble agent, then slowly releases it back into the tear film.

In animal models, 1.5% levofloxacin didn't delay re-epithelialization or wound healing, nor did it cause inflammation or adverse changes to the corneal epithelium or endothelium in humans, even with frequent dosing as high as 218 doses in two weeks.^2,3

In addition, in randomized controlled clinical trials in patients with painful corneal ulcers, 1.5% levofloxacin was well tolerated, as it was infrequently associated with ocular discomfort and irritation (1% to 2% incidence).

The most common non-ocular events (8% to 10% incidence) were headache and taste disturbance, none of which caused discontinuation of treatment.⁴

As the leading recruiter for this FDA-approved clinical trial, I saw first hand the ease with which patients tolerated this potent medication, despite their highly irritating keratitis.

2. Proven efficacy

Much of what we know about antibiotic resistance has come from a large, national surveillance program known as TRUST (Tracking Resistance in the United States Today). For more than a decade, infectious-disease specialists and microbiologists have relied on this highly standardized program to monitor trends in infection sources and susceptibility to systemic antibiotics.

Ocular TRUST is a new program that specifically evaluates pathogen susceptibility in ocular infections to antibiotics. Initially, the program included just a small ocular subset from the main TRUST database. Now, however, it also pools specimens from 10 well-known, dedicated ocular-microbiology labs around the country.

Researchers test these isolates against a panel of nine different antibiotics via a central, independent laboratory to provide insight into ocular-disease pathogens, such as Staphylococcus aureus and Staphylococcus epidermidis.

S. aureus, for example, is often associated with blepharitis, conjunctivitis and corneal ulcers. S. epidermidis, while less virulent than S. aureus, is the leading pathogen implicated in endophthalmitis.

In 2006 through 2007, participating centers submitted 155 ocular S. aureus isolates for in-vitro susceptibility testing. More than half (84/155) were methicillin-resistant S. aureus (MRSA), in contrast to the previous year when methicillin-susceptible S. aureus (MSSA) strains predominated.

The fluoroquinolones (ciprofloxacin [Ciloxan, Alcon], gatifloxacin [Zymar, Allergan], 1.5% levofloxacin and moxifloxacin [Vigamox, Alcon]) had between 89% and 93% MSSA susceptibility.⁵

The MRSA pathogens unfortunately showed high-level resistance to all the evaluated antibiotics except for trimethoprim (Polytrim, Allergan). (See "When to Culture," below.)

A total of 57% of the coagulase-negative Staphylococci (CNS) isolates submitted to Ocular TRUST in the same period were methicillin-susceptible; the most common CNS species was S. epidermidis (N=51; 55%).

The methicillin-resistant S. epidermidis (MRSE) was less susceptible to all antimicrobials compared with the MSSA phenotype.

All (100%) of the 198 S. pneumoniae isolates were susceptible to gatifloxacin, 1.5% levofloxacin and moxifloxacin; fifteen isolates (7%) showed intermediate susceptibility, and one isolate ciprofloxacin resistant.

The 144 Hemophilus influenzae isolates were 100% susceptible to all antibiotics tested except trimethoprim (85% susceptibility).

3. Preservative-free

Although, we typically don't use ophthalmic fluoroquinolones for a long enough time to be concerned about preservative-induced cumulative toxicity, those eyes with infections are already exposed to a wide variety of toxic agents, including the hostimmune response and agents secreted or contained within the infectious organism. Therefore, the fact that 1.5% levofloxacin is preservative-free is important to me, as it enables me to reduce surface toxicity as much as possible.

I use 1.5% levofloxacin for treating corneal ulcers, severe bacterial conjunctivitis and trabeculectomy infections, such as blebitis. I also use it as a prophylactic treatment for several ocular-surface surgical procedures, such as phototherapeutic keratectomy. This is because this drug offers patients sustained concentration levels, broad-spectrum activity and low toxicity. OM

1. Walters TR, Hart W. Tear concentration of 1.5% levofloxacin ophthalmic solution following topical administration in healthy adult volunteers. Invest Ophthalmol Vis Sci. 2003;44:E-Abstract 445.
2. Clark L, Bezwada P, Hosoi K, et al. Comprehensive evaluation of ocular toxicity of topical levofloxacin in rabbit and primate models. J Toxicol Cutan Ocul Toxicol 2005 Jan; 23 (1):1-18.
3. Data on file, Vistakon Pharmaceuticals.
4. Package insert, IQUIX® (levofloxacin ophthalmic solution) 1.5%, Vistakon Pharmaceuticals.
5. McDonnell PJ, Sahm DF. Longitudinal nationwide surveillance of antimicrobial susceptibility in ocular isolates (Ocular TRUST 2). Presented at the American Academy of Ophthalmology 2007 annual meeting, New Orleans, November 10-13, Poster PO052.

Dr. Sheppard is a professor of ophthalmology, microbiology and immunology at Eastern Virginia Medical School, where he also serves as clinical director of the Thomas R. Lee Center for Ocular Pharmacology. He is in private practice with Virginia Eye Consultants in Norfolk, Va. Contact him at (757) 622-2200 or at jsheppard@vec2020.com.