26 September 2002 14:15 EST

by Apoorva Mandavilli

[caption and credit]

Even as pharmaceutical companies brought new fluoroquinolones to the market, scientists knew it was only a matter of time before bacteria devised elegant resistance mechanisms and passed them along to their kin. What they didn't predict is how quickly this would happen.

The first comprehensive study of fluoroquinolone resistance reveals that in the last two years, resistance to the powerful broad-spectrum antibiotics has nearly tripled. "Literally as we speak, fluoroquinolones are being compromised by resistance," said Gary Doern, director of clinical microbiology and professor of pathology at the University of Iowa.

Fluoroquinolones, which target enzymes required for bacterial DNA synthesis, are popular because they have mild side-effects, can be given orally, and have a long half-life. The oldest and best-known of the class is ciprofloxacin, in use for more than 15 years. Five years ago, pharmaceutical companies began marketing fluoroquinolones aggressively for diseases that can be treated by traditional antibiotics.

Over-prescribing is the best way to promote resistance and in the last two years, anecdotal reports of resistance began to emerge from all over the world. In a systematic study of 45 US medical centers, Doern and his colleagues have found that the rates have risen from a once-stable 1.2% to 3.5%. Doern is to present the new results Friday at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy in San Diego.

Although the numbers are still small, the 3-fold increase is a "huge statistical change," Doern said.

Faced with resistance to one class of antibiotics, physicians usually turn to a new group of drugs. This time, Doern says, no new drugs are forthcoming.

Developing a new antibiotic can cost close to a billion dollars, and the US Food and Drug Administration (FDA) has tightened rules for approval. The ketolide Ketek, manufactured by Aventis and awaiting approval in February 2003, had to be tested with 25,000 patients in its phase III trial before being submitted for FDA approval, Doern noted. Ketek is "arguably the only new antibiotic - and that's no exaggeration - we're likely to see in the next 10 years."

What the field needs - and fast - is not just new drugs, but entirely new classes of drugs, those in the field agree. Among fluoroquinolones and many other classes, resistance to one drug in a class tends to affect all members of its class.

As the first line of defense, healthcare workers often use less potent drugs, which either bind the target poorly or are easily expelled by the bacteria's efflux pumps. This allows more first-stage mutants to evolve, and compromises the usefulness of more potent drugs.

For example, when cipro first came on the market, it was used against Staphylococcus aureus. But the drug proved ineffective against the bacterium, and resistance emerged rapidly. Those strains are now likely to be resistant to newer and more potent fluoroquinolones like moxifloxacin and gatifloxacin.

"The big worry is that for certain pathogens, we're close to being in the post-antibiotic era," said William Shafer, professor of microbiology and immunology at Emory University.

Once resistant bugs emerge, they can spread quickly, even to far reaches of the world, adds Shafer. In the early 1990s, when penicillin became ineffective against Neisseria gonorrhoeae, physicians in South East Asia began prescribing cipro. Within just a short time, Shafer recalled, there were instances of clinical failures, and resistant strains began to appear first in the region, then on the West coast of the US. Now, he says, 1-3% of N. gonorrhoeae in the US, and more than 90% in Thailand and Vietnam, are resistant.

Fluoroquinolone resistance has been reported in many common pathogens, including E. Coli, Enterobacteria, Haemophilus influenzae, Salmonella, and the digestive pathogen Campylobacter. Increased incidence of the last even prompted the FDA to propose a ban on enrofloxacin, used to prevent infections in chickens.

The strategies to prevent resistance are straightforward: Decrease unnecessary antibiotic use, and improve the way they are used, Doern and Glenn Tillotson of the Public Health Research Institute (PHRI) in Newark, New Jersey, write in the current Antimicrobics and Infectious Diseases Newsletter. Given the dire forecast for new antibiotics, researchers are creating new answers from old solutions.

For example, the pneumococcal conjugate vaccine recommended to protect children against severe infections like meningitis, has decreased ear infections by 10%, notes Marc Lipsitch, assistant professor of epidemiology at the Harvard School of Public Health. This has unexpectedly decreased antibiotic use.

Rather than invest in expensive and time-consuming clinical trials, Lipsitch and his colleagues are using mathematical modeling to compare anti-resistance strategies. They have found, for instance, that combining two drugs at equal frequencies is more effective than cycling different antibiotics.

Other researchers are developing inhibitors of the bacterial efflux pump, which if successful, would revive a whole slew of discarded antibiotics. But that strategy is still several years from fruition.

PHRI researcher Karl Drlica is pushing yet another idea: Rather than dosing at the minimal inhibitory concentration (MIC) to block growth of new cells, physicians should use the mutant prevention concentration (MPC). This would go after mutants, instead of just after susceptible cells.

But dosing at the MPC would likely be too toxic to be practical, says Doern; A more logical solution would be to use the strongest drugs available.

If things continue as they are, "at some point, the bugs are going to win the race," Doern said. But that may not be as bad as it sounds, he added. Because the machinery for resistance compromises the pathogen in other ways, the victory will cost the bugs dearly.

There are "tons of examples" to prove that "all things being equal, the bug would rather be susceptible," Doern explained. If the antibiotic disappears, the bacterium will go back to being susceptible, he said. "We just have to come up with creative and clever ways to remove the selective pressure."

Picture caption and credit:
Ciprofloxacin. Image courtesy of NIH Clinical Center.

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