More antibiotics may not always be better

Finish the course of pills: that's what all doctors say when they prescribe antibiotics, and for now, you should heed them. But new research suggests that might not always work as well as they assume, and may even compound the problem of antibiotic-resistant bacteria.

Doctors consider it good practice to hit bacterial infections with high doses of antibiotics for days or longer, to make sure all the bacteria are dead. To treat tough infections such as TB, they combine two or more antibiotics in order to prevent the evolution of resistance, so if a bug starts resisting drug A, it will still be killed by drug B.

But much of this is based on assumption rather than evidence, says Robert Beardmore at the University of Exeter in the UK. He and his colleagues tested this by treating cultures of E. coli with two antibiotics considered synergistic ? they kill more bacteria together than separately. They found that bacteria did indeed die off fast on the first day.

But any bacteria that survived were those with genes for resisting both drugs, and they boomed as drug-sensitive competitors died. Bacterial loads were higher after treatment than they had been before it, and higher drug doses just quickened the growth of resistant populations.

"It's a double-edged sword," says Andrew Read of Pennsylvania State University in University Park, who was not involved in the work. "If you kill all the bacteria with your initial dose, great." But if not ? and antibiotics fall to sub-lethal levels at some time or in some part of the body during treatment ? then problems arise.

Further experiments performed by Beardmore's team suggest that not only synergistic drugs but also longer treatment might not hammer the surviving bacteria as intended. Instead such approaches might make more of the survivors antibiotic-resistant, and may even worsen the infection. "We need to base treatment on better evidence," says Read.

"I'm not advocating low dosing," says Beardmore, as this does lead to resistance. But, he says, we need a better understanding of how antibiotics work in different situations instead of going on untested assumptions.

He is now testing whether antibiotics that antagonise each other ? one may interfere with another's binding to bacteria, for instance ? might actually work better than synergistic drugs. This counter-intuitive possibility, thrown up by a mathematical model of bacterial evolution, might work in practice because antibiotics that antagonise each other do not make antibiotic resistance so advantageous.

Journal reference: PLoS Biology, DOI: 10.1371/journal.pbio.1001540

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