October 3, 2013

Beating Bacterial Resistance

Drug-resistant bacteria often have vulnerabilities that can be exploited by other drugs, making better treatments possible.

Long-time coffee drinkers may notice that they now need more than just a cup or two to get a noticeable java jolt. So it is with patients treated frequently or for long periods with the same antibiotic: they may find the drug becoming less effective, as the bacteria in their bodies become more resistant to it.

The solution may be to issue a surprise attack. A new study has found that switching and using a different type of antibiotic before bacteria have a chance to develop resistance could help prevent resistance from building.

The vulnerability of resistant bacteria to other drugs presents new possibilities for improving the treatment of bacterial infections.

When bacteria become resistant to one drug, they develop vulnerabilities that make them become more sensitive to a different drug. This effect is called collateral sensitivity, and it has basically been swept under the scientific rug, so to speak, and forgotten by researchers, until now.

A group of Danish researchers found that it is possible to prevent resistant bacteria from thriving by alternating antibiotics to target the vulnerabilities that come along with resistance. The approach holds the promise of extending the lifespan of existing drugs to continue fighting even the most persistent pathogens such as MRSA.

The researchers helped Escherichia coli bacteria to become resistant to 23 different commonly used antibiotics in the laboratory, and then tested how each of the resistant E. coli bacteria responded to other antibiotics. The researchers repeated the experiment with two E.coli strains taken from infected patients. Then they put this data into a computer program and came up with more than 200 drug combinations that doctors could use to achieve collateral sensitivity and wipe out resistant variants.

When E. coli strains developed resistance to one antibiotic, the researchers found they often became sensitive to several others. For example, when an E. coli bacterium became resistant to drug A, at the same time it became sensitive to drug B. By switching treatment to drug B, A-resistant E. coli were more likely to be eradicated.

If treatment with drug B is successful, drug treatment ends. However, if the treatment is unsuccessful and resistance towards drug B develops, then the treatment can revert to drug A. This alternating line-up results in the preferential killing of drug B-resistant pathogens, which by this time have become sensitive to drug A. The drugs could be prescribed in cycles as either double, triple, or quadruple treatments to maximize sensitivity.

“We were surprised by our findings, but we were even more excited to confirm the Achilles' heel of bacterial resistance to currently used drugs,” Lejla Imamovic, a postdoctoral fellow at the Technical University of Denmark told TheDoctor in an e-mail. The alternating vulnerability of resistant bacteria to other drugs presents new possibilities for improving the treatment of bacterial infections.

By switching antibiotic treatment among drugs known to elicit collateral sensitivity, drug regimens can be designed to stay one step ahead of bacteria and continuously avoid resistance.

“Our study indicates that collateral sensitivity cycling could be applicable using already approved drugs in the clinic,” said Imamovic. She and her colleagues believe that collateral sensitivity cycling could prove useful for treating chronic bacterial infections. “Our next step would be to move beyond the laboratory and test these findings in clinical studies.”

Imamovic explained that antibiotics are scarce goods, and strategies of drug deployment are needed to increase the chances of having effective antibiotics in the future. Collateral sensitivity as a side effect of resistance development might be a way to overcome the resistance that can develop during the antibiotic treatment. Said Imamovic, “If we can exploit bacterial vulnerabilities to counteract resistant pathogens, this might prolong the life span of antibiotics and improve the treatment outcomes.”

The study is published online in Science Translational Medicine.

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