Generations apart: Making sense of the new fluoroquinolones

The next generation of ophthalmic fluoroquinolones is here. But for now there may be more questions about them than answers.

The next generation of ophthalmic fluoroquinolones is finally a reality. With two new so-called “fourth-generation” anti-infectives recently approved for commercial use, ophthalmologists are faced with an expanded array of options for eradicating stubborn microbes.

These new options present a challenge for clinicians seeking solid data on which to base their choice, amid a flurry of information that so far includes no head-to-head comparative studies involving human clinical data.

Yet armed with an arsenal of in vitro data, animal studies and marketing savvy, the rival manufacturers of the two newest ophthalmic fluoroquinolones each promise that their drugs will surpass previous generations in their spectrum of coverage and their ability to avoid the development of bacterial resistance.

For now, the fourth generation belongs to Vigamox (moxifloxacin 0.5%, Alcon) and Zymar (gatifloxacin 0.3%, Allergan), both of which received Food and Drug Administration approval within weeks of each other in the spring.

In the ophthalmic world, Vigamox and Zymar join an anti-infective armamentarium that includes the established fluoroquinolones Quixin (levofloxacin 0.5%, Santen), Ocuflox (ofloxacin, Allergan) and Ciloxan (ciprofloxacin, Alcon).

Clinical trials are also under way for Santen’s new formulation of levofloxacin (1.5%), which if approved would be the highest concentration ophthalmic fluoroquinolone available, according to the company. The current clinical trials of levofloxacin are for treatment of corneal ulcers, the company said.

Same family, similar structures

Regardless of their generation, fluoroquinolones — the first class of man-made antibiotics — all share a common molecular core. Their precursor was nalidixic acid, which was developed in 1962, several years after the molecule 7-chloroquinolone was determined to have antibiotic properties.

Moxifloxacin and gatifloxacin, built from the same basic quinolone nucleus, both have what is known as an 8-methoxy group, which studies have shown enables them to prevent gram-positive and gram-negative organisms from becoming resistant better than previous generations.

Anticipation of the new generation anti-infectives was evident at this year’s Association for Research in Vision and Ophthalmology meeting, which featured nearly two dozen posters and numerous podium presentations comparing gatifloxacin and moxifloxacin to each other and to their predecessors.

Several in vitro and rabbit eye studies concluded that both gatifloxacin and moxifloxacin behave similarly in terms of their range of coverage. They have both demonstrated extended in vitro coverage of gram-positive organisms. Recent studies have also shown that these two agents offer broad-spectrum coverage against specific pathogens — including atypical mycobacteria — that have proven resistant to third-generation fluoroquinolones in vitro.

One study presented at ARVO concluded that both moxifloxacin and gatifloxacin demonstrated increased potency over their predecessors for the atypical mycobacteria Mycobacterium fortuitum. Moxifloxacin, gatifloxacin and levofloxacin all demonstrated equal coverage for Mycobacterium gastri and Mycobacterium chelonae. Mycobacterium abscessus was resistant to all tested antibiotics. That study was conducted by researchers from the New York Eye and Ear Infirmary.

Another study found that gatifloxacin and moxifloxacin displayed similar activities in vitro against most gram-positive ocular pathogens, as well as against Serratia marcescens. In this study, conducted by researchers at the University of Oklahoma and the Dean A. McGee Eye Institute in Oklahoma City, gatifloxacin was found to have lower minimum inhibitory concentrations (MICs) than moxifloxacin against certain ocular isolates, such as Pseudomonas aeruginosa, Streptococcus viridans, Nocardia asteroides, Mycobacterium chelonae and others. Some of the authors of this paper disclosed a commercial relationship with Allergan.

Other studies have shown that moxifloxacin is more potent against gram-positive pathogens, such as a 2001 in vitro study conducted by researchers from the University of Pittsburgh that was published in the American Journal of Ophthalmology.

Several studies assert that gatifloxacin and moxifloxacin are no more potent against gram-negative bacteria than earlier-generation fluoroquinolones, while others have concluded that the latest generation is actually slightly less potent than ciprofloxacin and ofloxacin — although not to a statistically significant degree.

All in all, a comprehensive review of the latest data on the fourth generation reveals that the jury is still out on which fluoroquinolone will offer all a physician could want: broad spectrum coverage, penetration, low MICs and — perhaps most important — decreased resistance.

Making sense of it all

In light of the abundance of data on all available fluoroquinolones — much of it set forth by the companies seeking to sell them — how does one arrive at a conclusion regarding which drug might be right for a given patient?

Douglas Katsev, MD, a cornea and external disease specialist in Santa Barbara, Calif., believes that, ultimately, only time will tell which drugs perform better in clinical settings.

Furthermore, he said, some of the in vitro studies presented at ARVO did not use the commercial preparations of the antibiotics.

“Studies are needed to compare the three commercial preparations of Zymar, Vigamox and Quixin. They are under way, and we will await the data,” he said.

The issue is complicated even further by fact that the classifications of generations appear to shift depending on who is asked, and whether they are in ophthalmology or general medicine.

“The whole generation issue has been clouded by the fact that there is no standard authority that determines the generation of a medication,” John D. Sheppard Jr., MD, MMS, who specializes in cornea and surface disease in Virginia, told Ocular Surgery News.

“There seems to be not only controversy, but also changing of opinions, regarding which generation is which when it comes to fluoroquinolones. Even the systemic literature cannot agree upon fluoroquinolone classification,” Dr. Sheppard said. He noted that he prefers to use the term “next generation,” rather than fourth generation to “be on the safe side.”

There is no doubt that both Allergan and Alcon have dubbed their products “fourth-generation” fluoroquinolones in their marketing literature, and studies seem to corroborate that these agents represent a step above and beyond what was formerly available.

However, as Dr. Sheppard pointed out, some articles in the literature identify the agent trovafloxacin — not currently in development for ophthalmic use — as the only true fourth-generation antibiotic.

For example, an article published in American Family Physician (Am Fam Physician) classifies gatifloxacin, moxifloxacin and levofloxacin as third-generation fluoroquinolones in the systemic world, and ciprofloxacin and ofloxacin as second-generation.

The Am Fam Physician article, entitled “Quinolones: A Comprehensive Review,” defines third-generation fluoroquinolones as those which retain expanded gram-negative and atypical intracellular activity but have improved gram-positive coverage. Fourth-generation agents, it says, improve gram-positive coverage, maintain gram-negative coverage and gain anaerobic coverage.

“Although gatifloxacin and moxifloxacin have in vitro anaerobic activity, only trovafloxacin is labeled for the treatment of anaerobic infections,” according to the article.

However, a review article that appeared in 1999, also in Am Fam Physician, titled “Choosing Correct Quinolone Therapy: Which Generation?” contradicts that assertion, classifying gatifloxacin, moxifloxacin and trovafloxacin all as fourth-generation quinolones, and putting levofloxacin in the third generation and ciprofloxacin and ofloxacin in the second generation.

That earlier article also uses spectrum of coverage as the primary determinant of generation. This differs from the criteria set forth in marketing materials from Alcon and Allergan, both of which cite structural differences in their products as what separates them from previous generations.

Still another source classifies gatifloxacin as a third-generation quinolone and moxifloxacin and trovafloxacin as fourth-generation. This classification was set forth in The Quinolones, edited by Vincent T. Andriole of Yale.

Deepinder K. Dhaliwal, MD, a cornea specialist at the University of Pittsburgh, said that, despite the seeming discrepancies among classification systems, she believes there is no doubt that gatifloxacin and moxifloxacin belong in a fourth generation. She said they are significantly more potent and less likely to be subject to resistance than other fluoroquinolones.

“For me it’s a clear-cut situation. If I were having ocular surgery, I would want a fourth-generation fluoroquinolone as surgical prophylaxis,” Dr. Dhaliwal said.

“In the eye, we have definitely seen an enhanced spectrum of activity with these agents — they’re covering anaerobes, chlamydia and atypical mycobacteria better than we could with the second- and third-generation fluoroquinolones,” she said.

Dr. Sheppard said he does not believe it is disingenuous for the companies to market their products as the next generation when the classification system is so unclear.

“You can call it marketing, classification or clarification. Or you can call it the adaptation of available systemic data to the ophthalmic milieu,” Dr. Sheppard said. “I think that the use of the term ‘fourth-generation’ has actually increased clarity in the minds of ophthalmologists by fostering intense interest in ocular microbiology.”

A question of resistance

Perhaps the main reason why ophthalmologists — and the industry at large — are excited about these new fluoroquinolones has to do with resistance.

Experts cite growing bacterial resistance as a serious — albeit expected — problem facing all medical specialties.

“Every major class of bacterial pathogens has found a way to become resistant to every major class of antibiotics that has ever been introduced,” Theodore Eickhoff, MD, director of the Infection Control Program of University of Colorado Hospital, told Ocular Surgery News.

Dr. Eickhoff said the roots of the problem of bacterial resistance are threefold, stemming from patient demand for antibiotics, pharmaceutical promotion and excessive or inappropriate prescription by physicians.

Low dosing levels are a primary example of inappropriate prescribing, he said.

“If you don’t give enough of an antibiotic, you may reach levels that fail to inhibit or kill the organism, thereby encouraging development of further resistance,” Dr. Eickhoff explained.

Dr. Sheppard said he does not believe ophthalmologists are guilty of contributing to the problem of excessive use. But he does believe ophthalmologists have an important role to play when it comes to appropriate use by patients.

“We have no business allowing patients to use drops once a day, or for more than 4 weeks four times a day. These extreme practices make no sense and increase the risk of resistance,” he said. “Low dose frequency and prolonged use are unacceptable in the ophthalmic world.”

The key to the next generation’s ability to impede bacterial resistance is dual targeting, Dr. Dhaliwal said. She noted that both gatifloxacin and moxifloxacin target two bacterial enzymes — the DNA gyrase and topoisomerase IV. (This is also true of levofloxacin, according to Quixin’s labeling.) This dual targeting means that microbes must undergo two spontaneous mutations instead of just one in order to become resistant.

“This is wonderful, but the problem is that if an organism is already resistant to ciprofloxacin or levofloxacin or ofloxacin, that counts as one hit, and then you only need one more hit to become resistant to the fourth generation,” Dr. Dhaliwal said.

The take-home message for practitioners, according to Dr. Dhaliwal, is that they need to switch to the fourth generation.

“If we stay with the less-potent antibiotics, we’re going to end up having more resistant organisms that could spontaneously mutate and become resistant to the fourth generation as well. I just hope that ophthalmologists don’t try to save (the fourth generation fluoroquinolones), because if we try to save them we may actually shorten the amount of time they are effective,” she said.

Looking at preservatives

One element that distinguishes gatifloxacin from its brethren is its preservative, benzalkonium chloride 0.005% (BAK). Zymar is manufactured without BAK. According to Alcon, the antimicrobial action necessary to meet all FDA requirements is supplied by the active ingredient in moxifloxacin. Levofloxacin 1.5% also contains no added preservative.

Opinions vary over whether a preservative should make a difference in the selection of a fluoroquinolone.

According to Dr. Sheppard, some evidence has shown that a preservative can increase the penetration of an antibiotic, but he noted that “whether that’s clinically relevant is totally speculative at this point.”

He said the lack of a preservative could be an effective marketing tool, in that this might make the product more appealing to refractive surgeons worried about toxicity.

Furthermore, in patients with ocular surface disease or a compromised corneal surface, “we might be very concerned about even the most minimal toxicity,” Dr. Sheppard said.

Still, other surgeons noted that, in most cases, if the preservative is used for a brief time it is not a major issue.

“I think that when an antibiotic is used for only a short time, the preservative-free issue plays a very small role. When we look at chronically used medications such as artificial tears, the preservative-free issue is important,” Dr. Katsev said.

Does concentration matter?

Experts interviewed for this article tended to agree that a higher concentration is better, especially because ophthalmic fluoroquinolones are considered safe agents with little or no risk of toxicity.

Moxifloxacin, at 0.5%, has a higher concentration than gatifloxacin, at 0.3%. If it secures FDA approval, levofloxacin 1.5% will be the most highly concentrated of all. An agent’s concentration depends in large part on its solubility, several surgeons said.

According to Santen, levofloxacin’s higher solubility, at neutral pH, allows the drug to be produced at a higher concentration than other fluoroquinolones. Early human studies, reported in a poster at ARVO by T.R. Walters and colleague, have shown it maintains high concentration in the eye.

Dr. Sheppard said the difference between gatifloxacin and moxifloxacin in terms of concentration should not have much effect, if any, in the clinical setting, but he stressed that it is still hard to predict how the drugs will perform in the human eye.

“Unfortunately, I cannot quote to you enough good face-to-face comparison studies in humans, in real clinical situations, that would allow me to tell you if the intraocular concentrations are sufficiently different,” he said.

Dr. Sheppard said the high concentration of levofloxacin could lend it an edge.

“Levofloxacin is soon to be released at 1.5% — you cannot do this with any other agent. It is by far the most soluble, which gives it the advantage in the interior of the eye,” he said.

Dr. Dhaliwal said she does not believe there will be much clinically significant difference between gatifloxacin and moxifloxacin in terms of their respective MICs.

The major distinction she foresees has to do with penetration, she said.

Dr. Dhaliwal cited a study, also from ARVO this year, which evaluated the potential of moxifloxacin to prevent endophthalmitis following bacterial anterior chamber challenge in rabbit eyes.

The moxifloxacin-treated animals demonstrated no signs of endophthalmitis, compared to virtually all the rabbit eyes that received saline, according to the study’s authors, who are colleagues of Dr. Dhaliwal at the University of Pittsburgh.

“This is some very powerful evidence — much more powerful than in vitro data,” she said.

But Dr. Katsev cautioned that, while animal studies might be more predictive than in vitro data regarding how an antibiotic might perform in the human eye, it is not possible to draw conclusions regarding penetration based solely on animal studies.

“Rabbits don’t have a Bowman’s layer, so you can’t correlate the aqueous penetration very well with what you would expect to see in humans,” Dr. Katsev said.

Looking ahead

Some head-to-head human studies are expected to be presented later this year at the American Academy of Ophthalmology, with more to follow next year at ARVO.

“You’ll see the big three (Alcon, Allergan and Santen) really duking it out in terms of sensitivity data, penetration data and toxicity data. Prepare to be annihilated by data,” Dr. Sheppard said.

This will hardly be the last of it, either. Experts agree that, just as this new generation was made necessary by resistance that developed to earlier generations, so too will a fifth generation be coming down the pipeline soon.

“There will be a continual need for new antibiotics because bacteria are very adaptable. We’re already seeing some resistance to fourth-generation fluoroquinolones in some ocular isolates, mainly because they have been used in the systemic world for years,” Dr. Dhaliwal said. “Typically antibiotics have a 7- to 10-year lifespan. We hope with proper use this will be the case with the fourth-generation fluoroquinolones as well.”

From there to here: A timeline of ocular fluoroquinolones

Fluoroquinolones have evolved steadily since the development of their predecessor, nalidixic acid. The first member of the family of quinolones, nalidixic acid was discovered in 1962 during the purification of chloroquine. It was the single addition of a fluorine molecule at the sixth position of the basic quinolone nucleus that led to the development of fluoroquinolones. Nalidixic acid is still commercially available — primarily for the treatment of urinary tract infections — but has been surpassed by several generations of increasingly sophisticated fluoroquinolones for both ophthalmic and systemic use. The definition of generations continues to be hazy. The original quinolone antibiotics included cinoxacin and oxolinic acid, neither of which did well clinically because of toxicity. These products were not soluble, and therefore were not suitable for ophthalmic formulations. From the mid-1980s until now, a handful of successful fluoroquinolone agents have been introduced for ophthalmic use. Ciprofloxacin, under the brand name Ciloxan (Alcon) was introduced for ophthalmic use in 1990, followed by Chibroxin (norfloxacin, Merck Sharp & Dohme), in 1991. In 1993, Allergan introduced Ocuflox (ofloxacin) for ophthalmic use. Santen followed in 2000 with the introduction of Quixin (levofloxacin 0.5%). Patents for both Ciloxan and Ocuflox will expire in 2004 because of pediatric extensions, according to the manufacturers. The two most recent additions, Zymar (gatifloxacin, Allergan) and Vigamox (moxifloxacin, Alcon) were approved this year. At around the same time, Santen filed with the FDA a new application for levofloxacin 1.5%, which is now undergoing clinical trials.

For Your Information:

• Douglas Katsev, MD, can be reached at Sansum Santa Barbara Medical Foundation Clinic, 29 W. Anapamu St., Santa Barbara, CA 93101; (805) 681-8950; fax: (805) 568-1933. Ocular Surgery News was unable to determine whether Dr. Katsev has a direct financial interest in the products mentioned in this article or whether he is a paid consultant for any companies mentioned.
• John D. Sheppard Jr., MD, MMS, can be reached at Virginia Eye Consultants, 403 Medical Tower, Norfolk, VA 23507; (757) 622-2200; fax: (757) 622-9136. Dr. Sheppard has no direct financial interest in the products mentioned in this article. He is a paid consultant for Allergan, Santen and Alcon.
• Deepinder K. Dhaliwal, MD, is chief of refractive surgery and associate professor of ophthalmology, University of Pittsburgh. She can be reached at University of Pittsburgh, 203 Lothrop St., Pittsburgh, PA 15211; (412) 647-2214; fax: (412) 647-5119. Dr, Dhaliwal has no direct financial interest in the products mentioned in this article, nor is she a paid consultant for any company mentioned in this article.
• Theodore Eickhoff, MD, is director of the Infection Control Program at the University of Colorado Hospital and professor of infectious diseases at University of Colorado Health Sciences Center. He can be reached at 4200 E. Ninth Ave., Denver, CO 80262; (303) 315-3052. Dr. Eickhoff has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any company mentioned in this article.

• Alcon Pharmaceuticals, maker of Vigamox and Ciloxan, can be reached at 6201 South Freeway, Fort Worth, TX 76134; (817) 293-0450; fax: (817) 568-6142; Web site: www.alconlabs.com. Allergan, maker of Zymar and Ocuflox, can be reached at 2525 Dupont Drive, Irvine, CA 92612; (800) 433-8871; fax: (714) 246-5913; Web site: www.allergan.com.
• Santen Pharamceuticals, maker of Quixin, can be reached at 555 Gateway Drive, Napa, CA 94588; (707) 254-1750; fax: (707) 254-1769; Web site: www.santeninc.com.

References:

• Kowalski RP, Romanowski EG, et al. The prevention of bacterial endophthalmitis by topical moxifloxcin in a rabbit prophylaxis model. Paper presented at: Association for Research in Vision and Ophthalmology; May 4-8, 2003; Fort Lauderdale, Fla.
• Mather R, Karenchak LM, et al. Fourth generation fluoroqinolones: New weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.
• Ramirez R, Jensen H, et al. Antibacterial activity of fourth-generation fluoroquinolones against ocular pathogens. Paper presented at: Association for Research in Vision and Ophthalmology; May 4-8, 2003; Fort Lauderdale, Fla.
• King DE, Malone R, Lilley SH. New classification and update on the quinolone antibiotics. Am Fam Physician. 2000;61:2741-2748.
• Oliphant CM, Green GM. Quinolones: A comprehensive review. Am Fam Physician. 2002;65:455-464.
• Sadovsky R. Choosing quinolone therapy: Which generation? Am Fam Physician. 1999;60.
• Andriole VT. The Quinolones. 3rd ed. San Diego: Academic Press; 2000.
• Shah MK, Ritterband DC, et al. Will the topical fourth generation fluoroquinolones become the antibiotics of choice for treating atypical mycobacteria related eye disease? Paper presented at: Association for Research in Vision and Ophthalmology; May 4-8, 2003; Fort Lauderdale, Fla.
• Walters TR, Hart W. Tear concentration of 1.5% levofloxacin ophthalmic solution following topical administartion in healthy adult volunteers. Poster presented at: Association for Research in Vision and Ophthalmology; May 4-8, 2003; Fort Lauderdale, Fla.