Antibiotic Combinations Could Fight Resistant Germs

Opposition to one drug may bolster the other's killing power, study finds

WEDNESDAY, April 4, 2007 (HealthDay News) -- Using two competing antibiotics against a bacterium -- even when the bug is resistant to one of them -- appears to help conquer the germ and suppress the resistance, new research shows.

The finding is a bit counterintuitive, since for years, doctors have been warning of the overuse of antibiotics, because it encourages germ resistance.

But the new study suggests that sometimes, "antibiotics can be used in suppressive combinations" to limit resistant bacteria, said senior researcher Roy Kishony, an assistant professor in the department of systems biology at Harvard Medical School.

The finding, published in the April 5 issue of the journal Nature, is preliminary and does not have immediate implications for the way doctors use antibiotics. However, the researchers said the study does offer tantalizing new avenues for research.

The advent of antibiotics remains one of the great achievements of modern medicine, credited with saving millions of lives. But the emergence of strains of bacteria that are resistant to nearly all antibiotics has health officials worried.

For example, in 2006, experts warned that methicillin-resistant Staphylococcus aureus (MRSA) had moved from hospital wards to the general community, threatening to become a global epidemic.

And "the issue is broader than MRSA," Dr. Edward Chapnick, director of infectious diseases at Maimonides Medical Center in New York City, told HealthDay at the time. "The issue is antibiotic resistance as a whole. That's not the only resistant organism. It's a big problem, but it's not the only one."

Alarmed by the threat, medical groups and doctors have warned against overusing antibiotics in both humans and animals.

But the Harvard study suggests that combining these drugs in a surprising new way could curb the problem.

In their laboratory experiments, Kishony and Harvard graduate student Remy Chait focused on two strains of the E. coli bacterium -- one that was resistant to doxycycline, a widely used antibiotic, and one that was not.

They exposed the two bacteria to both doxycycline and ciprofloxacin (Cipro), a drug from a different class of antibiotics. Experts call this combination of antibiotics "hyper-antagonistic," because under normal circumstances, doxycycline works to suppress Cipro's germ-killing effects.

Typically, when using antibiotics in combination, any resistant strain should flourish at the expense of strains that had not developed resistance, Kishony explained.

But that's not what happened when he and Chait used doxycycline and Cipro together to fight E. coli. Instead, the more dangerous resistant strain of E. coli got pummeled the hardest, the researchers reported.

"The reason is that, in such cases, although (bacterial) resistance to drug A would indeed diminish the burden imposed by drug A, it also seems to remove its suppressive effect on drug B," Kishony said.

In other words, when drug A -- doxycycline -- was faced with the resistant strain of E. coli, it gave up much of its suppressive effect on drug B, Cipro. And because Cipro was still very effective in killing the doxycycline-resistant strain, this rendered "the combined treatment more effective against the resistant mutant," Kishony said.

The two researchers pointed out that this same combination would probably not work against a Cipro-resistant strain of E. coli. That's because the antagonistic relationship of the two antibiotics is a one-way street, with doxycycline suppressing the effects of Cipro. So, "we do not expect that this particular combination would necessarily select against ciprofloxacin resistance," Kishony said.

Finding drug combinations that mutually antagonize each other -- and might work in both directions -- is an intriguing subject of future research, the researchers said.

Kishony stressed that it's far too early to suggest that doctors use these types of antagonistic antibiotic combinations in everyday practice, however. "Our work is limited to sub-lethal drug concentrations, in a controlled environment in vitro, and any possible therapeutic implications from these findings are beyond its scope," he said.

"However," he added that "we do hope that these findings may suggest avenues of research into new treatment strategies employing antimicrobial combinations with improved selection against resistance."

More information

There's more on antibiotic resistance at the U.S. Centers for Disease Control and Prevention.

SOURCES: Roy Kishony, Ph.D., assistant professor, department of systems biology, Harvard Medical School, Boston; Edward Chapnick, M.D., director, infectious diseases, Maimonides Medical Center, New York City; April 5, 2007, Nature
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