therapeutic insights
Old Problem, New Remedy
Zymar is designed to effectively treat infection while deterring bacterial resistance.
Calvin Roberts, M.D.

Editor's note: This month "Therapeutic Insights" begins it coverage of fourth-generation fluoroquinolones. In July we will cover moxifloxacin 0.5% (Vigamox by Alcon).

Bacterial resistance is quickly becoming a concern for health professionals worldwide. While bacterial conjunctivitis is one of the most common and prevalent eye conditions, increasing bacterial resistance to the current class of anti-infectives has decreased the efficacy of the current generation of therapy. In addition to looking for therapeutic options that reduce the risk of bacterial resistance, doctors seek new therapies that have a broader spectrum of activity, allowing for greater patient success rates.

Allergan's Zymar (gatifloxacin ophthalmic solution 0.3%) could provide the answer. It recently became the first fourth-generation fluoroquinolone approved by the U.S. Food and Drug Administration.

What is Zymar?

Indicated for "the treatment of bacterial conjunctivitis caused by susceptible strains of bacteria," Zymar is a highly efficacious fluoroquinolone with complete solubility, effective tissue penetration and low minimal inhibitory concentrations (MIC) 90s (concentration at which 90% of isolates of a given bacteria are killed) against a broad spectrum of organisms, says Allergan.

Zymar takes advantage of a dual mechanism of action to slow the development of bacterial resistance, ultimately providing a higher success rate for patients. Its molecular structure contains an 8-methoxy group that's been attributed to its dual mechanism of action, affording it an enhanced inhibition of both DNA-gyrase and Topoisomerase IV, the company says.

Meet your familiar foe

Bacterial conjunctivitis is the inflammation of the conjunctiva caused by bacterial infection. This form of conjunctivitis is characterized by a thick, white or creamy discharge. The eyelid may swell and itch intensely; there is redness, tearing and often a gritty feeling. Bacterial conjunctivitis usually affects only one eye but may spread easily to the other. A swab culture can identify the type of bacteria that caused the eye infection.

While many cases of conjunctivitis are allergic or viral in etiology, bacterial conjunctivitis may present as:

Staphylococcus or Streptococcus conjunctivitis. These are highly contagious forms that are characterized by a sudden reddening of the eye, pain, itching, puffiness of the eyelids and purulent discharge.

Gonorrheal conjunctivitis. This is usually transmitted by sexual contact and may also occur in newborn infants during passage through the birth canal. Thus most states require that all newborns receive eye drops that kill the causing bacteria.

Chlamydial conjunctivitis. This may also be contracted by sexual contact, but the use of contaminated eye make-up is another common way of spreading this disease. Newborns may acquire it by passing through the birth canal.

Corroborating Zymar's story

A study conducted by Michelle C. Callegan, Ph.D.; Harold Jensen Ph.D.; Scott T. Kane and D. Clay Cochran compared antibacterial activity of the fourth generation fluoro-quinolones gatifloxacin and moxifloxacin against gram-negative and gram-positive bacterial species typically encountered in ocular infections. Investigators determined minimal inhibitory concentrations (MICs) for gatifloxacin and moxifloxacin in triplicate against six clinical ocular isolates of each species (four for Klebsiella pneumoniae and Enterobacter aerogenes) and computed mean MIC values.

Gatifloxacin and moxi-floxacin exhibited similar mean MIC values for isolates of the gram-positive species, Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus cereus and Enterococcus faecalis, ranging from 0.08 µg/mL to 0.57 µg/mL. These were comparable to previously published values.

The mean MIC of gati-floxacin for Pseudomonas aeruginosa was 1.28 µg/mL, as compared to 2.60 µg/mL for moxifloxacin. Mean MIC values against Klebsiella pneumoniae and Enterobacter aerogenes favored gatifloxacin over moxifloxacin by four- to six-fold. The two drugs achieved similar MICs against Serratia marcescens.

Scrutinizing susceptibility

Monica Monica, M.D., and Harold Jensen, Ph.D., evaluated susceptibility of ocular isolates from bacterial conjunctivitis patients to gatifloxacin, using levofloxacin and ciprofloxacin as comparator antimicrobials. Conjunctival swabs were taken prior to antibacterial therapy from patients diagnosed with bacterial conjunctivitis participating in a clinical trial of gatifloxacin. MICs for independent bacterial isolates from the swabs were classified using National Committee for Clinical Laboratory Standards susceptibility breakpoints. All gram-positive ocular isolates (n=170) were susceptible to gatifloxacin, except for one strain of Staphylococcus haemolyticus that displayed intermediate susceptibility.

In contrast, 2.9% of gram-positive isolates were resistant to levofloxacin and 7.6% were resistant to ciprofloxacin. All isolates of Staphylococcus epidermidis (n=38), a species frequently encountered in ocular infections, were susceptible to gatifloxacin. However, 10.5% of S. epidermidis ocular isolates were resistant to levofloxacin and 15.8% to ciprofloxacin. Another 5.3% showed intermediate resistance to levofloxacin. The gatifloxacin MIC 90 for S. epidermidis ocular isolates was 2.0 µg/mL, compared to 8.0 µg/mL for levofloxacin and 32 µg/mL for ciprofloxacin.

For Streptococcus pneumoniae (n=30), the gatifloxacin MIC 90 was 0.25 µg/mL, compared to 1.0 µg/mL for levofloxacin and ciprofloxacin. All gram-negative isolates (n=65) were susceptible to all three antibacterials. In the end, substantial percentages of gram-positive species isolated from bacterial conjunctivitis patients in this study were resistant or partially resistant to levofloxacin and ciprofloxacin; however, the same isolates were susceptible to gatifloxacin. MIC 90 values for the most commonly encountered species of gram-positive ocular pathogens favored gatifloxacin by four-fold to 16-fold. Compared with older fluoroquinolones, gatifloxacin displays clearly improved activity against gram-positive ocular bacteria in vitro.

Looking to the future

During its pivotal FDA study, Zymar outperformed Ocuflox (ofloxacin ophthalmic solution 0.3%, Allergan), a third generation fluoroquinolone, in eradicating bacteria. Fourth-generation fluoroquinolones represent a therapeutic improvement over the second and third-generation versions that have been the market leaders for anti-infective therapy in the U.S. In the interest of the public health, doctors should begin transitioning from second and third-generation agents to this fourth-generation agent in order to accomplish these two major goals:

• First, to slow the development of bacterial resistance via Zymar's mechanism of action.
• Second, to treat those fluoroquinolone-resistant and atypical pathogens that have already developed and mutated to the first step in the replication process. By making this transition immediately, doctors will also hinder other bacteria from mutating and becoming resistant. This action will extend the life of fourth-generation fluoroquinolones and provide more effective treatments for patients.

References available upon request.

Dr. Calvin Roberts is a Professor of Ophthalmology at Weill Medical College of Cornell University. Contact him at RobertsMD1@aol.com.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.