Broader coverage anti-infectives in the pipeline

The agents in development, gatifloxacin and moxifloxacin, are expected to reach the market next year.

Fourth-generation fluoroquinolones now in the development pipeline are expected to be effective against organisms that are resistant to other drugs. Increased potency, solubility, penetration, time-kill curves and post-antibiotic effects are some of the reasons the drugs are being eagerly awaited.

Moxifloxacin, in development by Alcon, and gatifloxacin, in development by Allergan, are both in clinical investigational trials for approval by the Food and Drug Administration and should reach the market next year.

Although not much is known yet about how the agents will compare to each other, there have been some early indications of their performance.

“From in vitro data we’ve been seeing, against ocular isolates they have very similar activities; however, gatifloxacin may be slightly better against gram-negative organisms, and moxifloxacin may be slightly better against gram-positives compared to current-generation agents. But that hasn’t been comparatively well-studied in vivo against ocular isolates,” said Terrence P. O’Brien, MD, director of ocular infectious diseases at the Wilmer Eye Institute and a researcher at the Ocular Microbiology Laboratory of the Johns Hopkins Hospital. Dr. O’Brien has investigated both gatifloxacin and moxifloxacin as an ad-hoc consultant.

The two antibiotics are built from the same basic quinolone nucleus, with an 8-methoxy group added to the ciprofloxacin molecule, changing the C-7 group. They may behave similarly because of their close molecular structure, Dr. O’Brien said.

The antibiotics bind with equal affinity to the bacterial enzymes DNA gyrase and topoisomerase IV, hopefully making it more difficult for gram-positive and gram-negative organisms to become resistant, Dr. O’Brien said.

“There are many advantages with the fourth generation” of fluoroquinolones, said James P. McCulley, MD, a principal investigator for moxifloxacin. “They are expected to be more soluble, penetrate tissue better and have superior pharmacodynamics and time-kill curves.”

Comparisons with earlier generation

While ocular infections after corneal, cataract and refractive surgeries are rare, a rise in the incidence of endophthalmitis in recent years has been reported.

One in vitro study comparing the potency and susceptibility of moxifloxacin and gatifloxacin against ocular isolates has been done. Researchers at the University of Pittsburgh found that both agents have a broader range of coverage, and that organisms resistant to the second- and third-generation fluoroquinolones are sensitive to the newer drugs.

“In the study, they basically did have equal susceptibility,” said Regis P. Kowalski, MS, one of the researchers. “Regarding gram-positive bacteria, we found that moxifloxacin was the most potent because it had the lowest minimum inhibitory concentration (MIC) required to kill the concentration of bacteria.”

Both new drugs are equally susceptible against gram-negative bacteria, he said. In vivo comparisons have yet to be done, he said.

Not only are gram-negative and gram-positive organisms said to be more sensitive to both agents, but both agents are less likely to acquire multiple-step mutations, Mr. Kowalski said in the study.

Although results showed moxifloxacin was more effective against organisms resistant to second- and third-generation fluoroquinolones, the Pittsburgh study is not a complete comparison, according to Dr. McCulley. The MIC data is part of the therapeutic effect (ie, potency), but there have been no comparisons of the two drugs’ penetration, which he said is the other part of determining the drugs’ therapeutic index.

“The hope for moxifloxacin is that it will be more effective against the gram-positives and that it will maintain its effectiveness against the gram-negatives,” he said.

Leaving the third generation

While ocular infections after corneal, cataract and refractive surgeries are rare, a rise in the incidence of endophthalmitis in recent years has been reported. Dr. O’Brien cited a prospective study from the Moran Eye Center in Utah that evaluated nearly 10,000 patients undergoing phacoemulsification with clear corneal incision and foldable IOL implantation over 4 years. Twenty-one cases of endophthalmitis were documented, he said.

This represents a doubling of the incidence of endophthalmitis compared to rates from the past 10 years, he said.

Although the reason for the rise is unclear, he said clear corneal incisions that may have a tendency to leak might have contributed to the increased infection rate.

Kenneth R. Kenyon, MD, of Corneal Consultants in Boston, noted that no bacterial infections have occurred in more than 25,000 excimer laser refractive surgical procedures performed at the Laser Eye center of Boston, where current-generation fluoroquinolones are routinely used both pre- and postoperatively. Nevertheless, he said, there is always a need for better efficacy, especially against organisms that may become resistant.

“Obviously the need for newer drugs becomes self-evident because they may have intrinsically better efficacy as the bugs get smarter in terms of resistance. Fortunately, we have not seen clinically significant resistance on a widespread scale,” he said.

According to Dr. Kenyon, there are still many benefits to the currently available fluoroquinolones: Ocuflox (ofloxacin, Allergan), Ciloxan (ciprofloxacin, Alcon) and Quixin (levofloxacin, Santen). In his practice, he said, he uses the three interchangeably.

“There are many studies that show increased kill curve or penetration, but the reality is that most all microbial species, with the exception of a few Streptococcus organisms, remain sensitive to the enormous concentration of drugs we can deliver to the ocular surface,” he said.

Recent studies have showed levofloxacin to have a slight advantage over ofloxacin, according to Eduardo C. Alfonso, MD, of the Bascom Palmer Institute.

“I am beginning to shift to levofloxacin for prophylaxis and for treatment of conjunctivitis,” Dr. Alfonso said. He said he has been using levofloxacin more because data show that it has slightly better coverage of gram-positive organisms than ofloxacin and ciprofloxacin.

Dr. Alfonso said he also uses Polytrim (polymyxin B, trimethoprim sulfate, Allergan), which is not a fluoroquinolone. He said in vitro sensitivity data show that trimethoprim does well against most ocular isolates; however, its penetration into the aqueous is not as high as with ofloxacin and levofloxacin. He prefers the fluoroquinolones to Polytrim because of their higher levels of penetration.

Dr. McCulley said physicians should not rely completely on studies showing levels of penetration.

“Penetration alone does not tell the story. I think ophthalmologists should base their choice on clinical trials and in vitro assessment,” he said.

Increased penetration does not necessarily mean an antibiotic is reaching therapeutic levels, he added. With typical acceptable postop prophylactic dosing (eg, four times daily), none of the available fluoroquinolones reach therapeutic aqueous humor levels, Dr. McCulley said. Ofloxacin in the past showed higher penetration, and now levofloxacin has surpassed it. But more important is how the antibiotic kills organisms on the ocular surface. In that aspect, ciprofloxacin has a faster time-kill curve on the surface and can be administered the day of surgery, he explained.

The same type of information will be needed to evaluate the efficacy of the fourth-generation fluoroquinolones when they become available, he said.

Inevitable evolution of bacteria

There are some concerns about leaving behind the earlier-generation fluoroquinolones. According to Dr. O’Brien, although the fourth-generation drugs are supposed to be more effective for a broader spectrum of organisms, widespread inappropriate use of generic forms of ofloxacin and ciprofloxacin could lead to the creation of more resistant bacteria against even the newer-generation compounds.

The patents for Ocuflox and Ciloxan will expire in the near future (2003 to 2004). Although patent expiration is a natural progression in the pharmaceutical industry, so is the evolution of bacteria, he said.

Increased resistance against earlier-generation fluoroquinolones may eventually affect the fourth-generation drugs, he added. Although the fourth-generation drugs target the DNA enzymes responsible for replicating organism resistance, indiscriminate use of earlier-generation generics could make multiple-step mutation occur more frequently, he said.

When resistance develops to the earlier-generation fluoroquinolones, this will make it easier to develop multiple-step mutations against gatifloxacin and moxifloxacin, Dr. O’Brien explained.

“Only time will tell if the bacteria will somehow become even more clever, but we think the unique activity of these drugs will allow them to be less prone to the development of resistance. Hopefully, it will be more challenging for the bacteria to develop multiple mutations in order to develop resistance,” he said.

For Your Information:

• Terrence P. O’Brien, MD, can be reached at the Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD 21287-9121; (410) 847-3510; fax: (410) 847-3519; e-mail: tobrien@jhmi.edu. Dr. O’Brien has no direct financial interest in the products mentioned in this article. He is a nonsalaried ad hoc consultant for Alcon and Allergan.
• James P. McCulley, MD, can be reached at the University of Texas Southwestern Medical Center, Department of Ophthalmology, 5323 Harry Hines Blvd., Dallas, TX 75390; (214) 648-3407; fax: (214) 648-9061; e-mail: james.mcculley@utsouthwestern.edu. Dr. McCulley has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned. He is on the Alcon speakers bureau and has done fluoroquinolone trials for Alcon, Allergan and Santen.
• Regis P. Kowalski, MS, can be reached at the Eye and Ear Institute Building, Ophthalmic Microbiology, Room 642, 203 Lothrop St., Pittsburgh, PA 15213; (412) 647-7211; fax: (412) 647-5331; e-mail: kowalskirp@msx.upmc.edu. Dr. Kowalski has no direct financial interest in the products mentioned in this article. He is a paid consultant for Alcon.
• Kenneth R. Kenyon, MD, can be reached at Cornea Consultants and the Laser Eye Center of Boston, 100 Charles River Plaza, Third Floor, Boston, MA 02114; (617) 523-2010; fax: (617) 523-4888; e-mail: kkenyon@compuserve.com. Dr. Kenyon has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Eduardo C. Alfonso, MD, professor and the Edward WD Norton Chair in Ophthalmology, can be reached at the Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136; (305) 326-6366; fax: (305) 326-6195; e-mail: ealfonso@med.miami.edu. Dr. Alfonso has no direct financial interest in any of the products mentioned. He has done research sponsored by Alcon, Allergan and Santen.

• Alcon Pharmaceuticals can be reached at 6201 South Freeway, Fort Worth, TX 76134; (817) 293-0450; fax: (817) 568-6142. Allergan can be reached at 2525 Dupont Drive, Irvine, CA 92612; (800) 433-8871; fax: (714) 246-5913; Web site: www.allergan.com.