Beyond ciprofloxacin and ofloxacin: the future of antibiotics

Issue: July 2001

The increasing incidence of microbial resistance to fluoroquinolones and a search for improved gram-negative coverage is prompting clinical studies of new fluoroquinolones and combination treatments. Many practitioners today are looking beyond the most commonly used fluoroquinolones, ciprofloxacin and ofloxacin, to fight emerging resistance.

Before he began his presentation at the Hawaii 2001 meeting, Jerold S. Gordon, MD, polled the audience members regarding their use of fluoroquinolones. By his estimation, 60% of the audience chose Ciloxan (ciprofloxacin, Alcon) as their fluoroquinolone of choice. About 45% of the audience answered “yes” to using ofloxacin. And in comparison, about 45% said they found both drugs more or less equivalent for ophthalmic use.

“Fluoroquinolones are the topoisomerase inhibitors, and they have had a profound effect on eye care,” Dr. Gordon said. “They’re effective systemically as well as topically, and they are generally broad spectrum. We’re mostly interested in their effect on gram-positives, where 90% of cases of conjunctivitis and 75% of cases of keratitis are gram positive. The more serious infections, the gram-negatives, such as Pseudomonas and Serratia, are very effectively dealt with by the fluoroquinolones.”

Dr. Gordon warned, though, that there was a cloud on the horizon — emerging resistance. His lab has reported a ciprofloxacin resistance in Staphylococcus aureus, and others have reported on resistance with Pseudomonas.

What is the best of the best?

The chemical structure of the fluoroquinolone molecule accounts for the differences in potency. Fluoroquinolones have eight positions on the molecule, which allows for an infinite variety of chemicals that can be attached to each of these eight positions. Dr. Gordon said that there are now more than 10,000 fluoroquinolones currently being studied.

In terms of which drug is the best, Dr. Gordon pointed out that levofloxacin is a third-generation fluoroquinolone introduced by Santen (Quixin), but that gatifloxacin is the future. “It is fourth generation, and it’s the horse that Allergan has chosen to ride into the future,” he said. “Moxifloxacin is the horse that Alcon has chosen to ride into the future, and linezolid is a totally different type of drug. It is currently available for systemic use.”

Levofloxacin is a third-generation fluoroquinolone and a levo-isomer of ofloxacin. “It is not a new drug; it is the active form of a mixture that we’re already using. It’s 0.5% levofloxacin, compared to 0.3% ofloxacin, but it is 3.3 times more concentrated,” Dr. Gordon said.

Quixin was approved by the Food and Drug Administration (FDA) in August of last year and became available to retail pharmacies on Nov. 1, 2000. The drop is indicated for the treatment of bacterial conjunctivitis. A key factor in Quixin’s success is its solubility, which allows it to be formulated at higher concentrations than current quinolone anti-infectives, practitioners say.

In the lab, Dr. Gordon looked at 93 isolates of Staphylococcus and 107 isolates of Pseudomonas that were taken from corneas that were both fluoroquinolone sensitive and resistant and compared all three of these drugs to see if the newer levofloxacin would offer an advantage. Using minimal inhibitory concentrations (MICs) and time kill studies, he found that, for susceptibilities, all three drugs were equivalent for both sets of isolates. If there was resistance, it was comparable across all three drugs.

“So the question is, will levofloxacin offer any advantage in practice over the second-generation fluoroquinolones? And the answer will depend on whether or not the concentration effect is significant,” Dr. Gordon said.

A time kill study comparing the three drugs showed there was absolutely no difference in the time kill for Staphylococcus aureus as well as for Pseudomonas.

Gatifloxacin and moxifloxacin

“However, I think the true excitement and the next giant leap into the future is with the fourth-generation gatifloxacin,” Dr. Gordon said. “It is FDA-approved, is called Tequin and is made by Bristol-Myers Squibb. It’s principally developed as a respiratory agent, and its major claim to fame is increased gram-positive sensitivity. It’s generally safe orally and intravenously. It’s not approved for pediatric use, however, because of its toxicity.”

From a resistance point of view, the agent is a DNA gyrase inhibitor, and it requires two independent mutations to acquire resistance.

Moxifloxacin is a fourth-generation fluoroquinolone. Bayer Corp. markets it as Avelox, as a systemic drug, and it essentially mirrors gatifloxacin in its indications and in its general characteristics.

Dr. Gordon compared gatifloxacin and moxifloxacin to ciprofloxacin, using it as a standard. What he found was that, with sensitive gram-positives, the new medications are far more potent against resistant organisms. “For gram-negatives, the new medications are a little less potent. But this may not be significant clinically when we put it into patients’ eyes,” Dr. Gordon said.

In terms of the half-life in patients, the new-generation agents have longer half-lives, but more importantly, for gatifloxacin and moxifloxacin, it took longer to make mutants than it did for ciprofloxacin.

Richard Eiferman, MD, was involved in an Alcon double-masked study of moxifloxacin for treating conjunctivitis. The fluoroquinolone derivative, in an eye drop form, is considered the “next generation” of fluoroquinolones, Dr. Eiferman said.

“Some of the patients responded dramatically to it,” he told Primary Care Optometry News. “The advantage is that you only had to use it twice a day instead of every 2 hours, so it seems to be much more potent, and you can dose it less frequently, which is a real plus.”

One thing that practitioners should be looking at regarding fluoroquinolones is the kill curve, or how long it takes a certain drug to kill certain bugs, said Dr. Eiferman. “All people talk about are the MICs, and that’s wrong,” he noted. “We don’t want to inhibit it, we want to kill it. So we shouldn’t be talking about MIC 90s, we should be talking about minimal bactericidal concentration 99s, or how long it takes to kill 99% of all of the bugs.

“And with some of the fluoroquinolones we’ve tested, some of those bugs are dead in less than 5 minutes,” he continued. “That’s very impressive — and very important if, for example, you’re talking about someone who’s going to have laser surgery.”

Dr. Eiferman estimated that moxifloxacin boasts about the same spectrum of activity as ciprofloxacin and ofloxacin. And as with all fluoroquinolones, expanded gram-negative coverage is always the goal. “That’s the Holy Grail, but no matter what you pick, there’s always a hole,” he said. “There’s no perfect antibiotic.”

New fluoroquinolones on the horizon

Dr. Gordon mentioned several other drugs that are on the horizon. “Linezolid is an oxalidinone from Pharmacia called Zyvox,” he said. “It is FDA approved, and it’s a fully synthetic antibiotic. It works by inhibiting RNA translation, and it inhibits the virulence factors of S. aureus. It is a gram-positive-only antibiotic, and it is static for Staphylococcus and cidal for Streptococcus. It’s indicated for vancomycin resistance and community-acquired pneumonias and skin infections. There is a toxicity profile, particularly myclosuppression, and it potentiates MAO inhibitors. But, most importantly, there is no cross-resistance with current antibiotics.”

A ciprofloxacin/dexamethasone combination drug, ciprodex, is a new fluoroquinolone by Alcon. It is currently undergoing clinical trials, said Clay Conn, marketing director for Alcon.

For the future, Dr. Gordon sees newer fluoroquinolones, such as temafloxacin, which is in the final stages of FDA approval.

He also mentioned peptide deforymlase inhibitors as a group of drugs that block a critical bacterial enzyme in protein synthesis. Also in the future, physicians can expect to see pleuromutulins, which are drugs that are currently in veterinary use for enteric and respiratory infections. They block protein synthesis of bacteria.

A group called the efflux pump inhibitors should overcome existing resistance. The cationic peptides make holes in bacteria. Also on the horizon are quorum-sensing inhibitors that block the expression of virulence factors. Finally, sortase inhibitors block adherence.

For Your Information:

Jerold S. Gordon, MD, can be reached at 203 Lothrop Street, Pittsburgh, PA 15213; (412) 647-2212; fax: (412) 647-5119; e-mail: yjgordon@vision.eei.upmc.edu. Dr. Gordon has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Richard Eiferman, MD, is the clinical professor of ophthalmology at the University of Louisville. He may be reached at 6400 Dutchmans Pkwy., Ste. 220, Louisville, KY 40205; (502) 895-4200; fax: (502) 895-0819; e-mail: reiferman@compuserve.com. Dr. Eiferman has no direct financial interest in the companies mentioned in this article, nor is he a paid consultant for any companies mentioned.