Therapeutic Insights
Quixin: The New Contender

A new fluoroquinolone enters the mix. See how it compares to other treatments in this class.
By Larry R. Henry, Edmond, Okla.

Topical fluoroquin-olones have been an exceptional addition to our anti-microbial armament. Originally FDA-approved for treating bacterial conjunctivitis, their efficacy quickly made them a first choice for treating bacterial keratitis, peripheral corneal ulcers and for post-op care following cataract surgery.

Fluoroquinolones exert anti-bacterial effects by binding to and interfering with two specific enzymes: DNA gyrase and topoisomerase IV, both of which are required for DNA replication. DNA gyrase is the primary target for Gram-negative bacteria and topoisomerase IV is the target for Gram-positive bacteria.

The early fluoroquinolones ofloxacin (Ocuflox), ciproflox-acin (Ciloxan) and norfloxicin (Chibroxin) are ophthalmic solutions especially effective against Gram-negative organisms such as Haemophilus, Pseudomonus and Acinetobacter. Their major downfall has been their variable coverage of Gram-positive organisms such as Streptococcus and Staphylococcus.

Second- and third-generation oral fluoroquinolones, such as trovafloxacin, grepafloxacin, sparfloxacin, levofloxacin (Quixin) and moxifloxacin, are effective against Gram-negative organisms too, and their Gram-positive and anaerobic spectrums are broader. This is noticeable when combating methicillin-susceptible strains of Staphylococcus, such as S. aureus and S. epidermidis, and methicillin-susceptible strains of Streptococcus, such as S. pneumoniae.

The new contender

Until recently, third-generation fluoroquinolones were available only in oral form. Santen Pharmaceutical received FDA approval of its sterile levoflox-acin 0.5% ophthalmic solution, Quixin, in 2000. It's approved for the treatment of bacterial conjunctivitis in patients over the age of one.

Quixin, which is the L-isomer of the D,L-racemate ofloxacin, has a greater binding affinity to the bacterial DNA-DNA gyrase complex. This binding affinity increases the inhibition of bacterial DNA synthesis, thereby destroying the offending bacteria.

Any bacteria not killed initially can't replicate again for approximately 2 to 6 hours after exposure to Quixin.

Round one: pharmacodynamics

Pharmacodynamic studies using agar disk diffusion and broth-diluted methodologies indicate that Quixin has statistically superior overall antiinfective activity against up to 70 different bacterial species when compared to oflaxacin and ciprofloxacin. When the organisms were further classified, Quixin was as effective as ofloxacin and ciprofloxacin against the Gram-negative isolates but superior against the Gram-positive isolates. The study also indicated that a greater number of isolates were resistant to ofloxacin and/or ciprofloxacin than to Quixin.

Round two: pharmacokinetics

The pharmacodynamic abilities of Quixin are impressive in the petri dish, but what about its ability to penetrate ocular tissue? To answer this, let's look at the pharmacokinetics of Quixin. Effective treatment of bacterial conjunctivitis is dependent upon achieving and maintaining drug levels in the tear film at or above the minimum inhibitory concentration at which 90% of the bacteria are inhibited (MIC90).

Friedlaender, M.H. et. al, measured the concentration of Quixin in human tears at 4 hours post administration and showed a mean levofloxacin concentration of 17.0 mg/mL. This is greater than concentrations in previous studies of ciprofloxacin (16.2 mg/mL) and almost double that of ofloxacin (9.2 mg/mL). Quixin maintained its MIC90 concentration of 2 mg/mL for at least 6 hours post administration.

The aqueous solubility of Quixin is excellent -- 10 times more soluble than either ofloxacin or ciprofloxacin -- patients can use a higher concentration with no worry of corneal precipitate formation. Quixin is a 0.5% concentration compared to the 0.3% concentrations of ofloxacin and norfloxacin. This increase in solubility doesn't appear to jeopardize levofloxacin systemic safety. Plasma levels of topically administered levoflox-acin appear safe even with the frequent dosing of every 2 hours for several days. The maximum plasma concentration was more than 1,000 times lower than that reported after dosing with oral and injectable levofloxacin.

Tallying the score

FDA Phase III clinical studies evaluated the safety and efficacy of Quixin. One study compared Quixin to a placebo and another compared Quixin to an active control, ofloxacin ophthalmic solution 0.3%. Both were prospective, randomized, multi-centered, double-blinded, parallel studies. The primary efficacy measures were clinical and microbial outcomes in both studies.

Each study evaluated 208 patients aged 1 year and older who were culture positive for bacterial conjunctivitis. Both groups received either one or two drops of Quixin, ofloxacin or the placebo instilled in the affected eye.

Researchers instructed the patients to use the eye drops every 2 waking hours the first 2 days, to a maximum of eight doses. Beginning on day three, the patients reduced use to every 4 hours, up to a maximum of four doses per day.

Researchers evaluated patients twice after their initial presentation and again between days three and five. They conducted the final evaluation between days six and 10.

Clinical cure indicates the absence of conjunctival discharge, bulbar conjunctival hyperemia and palpebral conjunctival hyperemia. Microbial eradication indicates the absence of colony-forming units when re-cultured.

The studies show that Quixin is statistically equivalent in clinical cure rate compared to ofloxacin at both the interim and final study evaluations. The clinical cure rate for patients receiving Quixin was 79% (81/103) and 81% (75/93) for patients receiving ofloxacin. The microbial eradication rates were higher in Quixin-treated group at 89% (92/103) than at 80% (74/92) for ofloxacin.

Quixin was statistically superior to the placebo-treated group in both clinical care and in microbial eradication rates. The clinical cure rate for Quixin was 78% (46/59), compared to 61% (34/56) for the placebo. Microbial eradication rates were 92% (54/59) for Quixin and 53% (29/55) for the placebo.

There were no significant differences between study groups in the incidence of overall adverse events or treatment-related events. Most adverse events were mild or moderate in severity.

Post fight analysis

Quixin appears to have several impressive characteristics when compared to other topical fluoroquinolones. Here's a quick recap of some of the beneficial characteristics we've covered:

• Quixin is ten times more soluble at the pH of tears than ofoxacin and approximately 400 times more than ciprofloxacin
• Quixin's concentration is 0.5% compared to the 0.3% concentration of ofloxacin and ciprofloxacin, which enables it to deliver more medication to ocular tissues. Because of its superior solubility, this higher concentration of medication doesn't cause the unwanted side affect of corneal precipitates.
• Quixin easily reached and maintained therapeutic concentrations for up to 6 hours after the administration of one drop.
• The safety profile of Quixin is similar to Ocuflox and Ciloxan in both adults and children over one year in age.
• Quixin is currently FDA approved for the treatment of bacterial conjunctivitis; however, it may soon become popular for treating corneal ulcers and for postoperative prophylaxis.

Call it a draw

Quixin should enjoy just as much success as the previous topical fluoroquinolones, which have become popular due to effectiveness, patient tolerance and their few adverse events. However, all fluoroquinolones are only successful when combined with proper diagnosis and early identification of the offending pathogens.

Dr. Henry is clinical director for BVA Advanced Surgical Eyecare in Edmond, Okla. He also serves as adjunct professor and residency supervisor for Northeastern State University College of Optometry.

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.