The treatment of bacterial infections with antibiotics is a crucial weapon in the armory of modern medicine. However, bacteria can evolve resistance to antibiotics, creating an arms race that renders the drugs useless. The standard approach to mitigate this has been to use treatments as potent and as early as possible, in order to kill the cells that are susceptible before they have the chance to multiply.
However new research, published 23 April in the open access journal PLOS Biology, casts doubt on the wisdom of such approaches, and specifically on the purported benefit of using two or more antibiotics in combination–a technique generally considered to be the most effective way of administering the drugs.
Researchers from the University of Exeter in the UK and Kiel University in Germany treated E. coli bacteria with antibiotics (alone and in combination) in laboratory experiments. They found that using more potent treatments could speed up the evolution of resistance to the antibiotics, and produce resistant bacterial cells. Indeed, they found that the most effective combinations of antibiotics on day one were barely working by day two, demonstrating just how fast the resistance can evolve.
This was happening because using antibiotics in combination eliminated the non-resistant cells, creating a lack of competition that allowed the resistant bacteria to multiply quickly. These cells went on to create copies of their resistance genes that further reduced the effectiveness of the drugs. During conventional treatment, these counter-intuitive effects can emerge as levels of antibiotic in the body fall to so-called “sub-inhibitory” levels.
“We were concerned by how quickly the bacteria evolved resistance,” said Professor Robert Beardmore of the University of Exeter, lead author of the new study. “We nearly stopped the experiments because we didn’t think some of the treatments should be losing potency that fast; sometimes within a day. But we now know that the bacteria that remain after the initial treatment quickly duplicate specific areas of their genome that contain large numbers of resistance genes. These gene copies appear more quickly when the antibiotics are combined, resulting in the rapid evolution of very resistant bacteria.”
Co-author Professor Hinrich Schulenberg, from Kiel University in Germany, added: “The interesting thing is that the bacteria didn’t just make copies of the genes they needed. Just in case, they copied other genes as well, increasing resistance to antibiotics that they weren’t even treated with.”
The team also used mathematical modelling and whole-genome analyses of both resistant and non-resistant E. coli to define and explore the underlying mechanisms of their experimental results. The findings potentially have important implications for the way in which antibiotics are used in medicine; lengthy courses of antibiotics are commonly prescribed, often in combination, but current treatment conventions do not necessarily account for the speed at which resistance evolves in bacteria, and may not represent the optimal course of action.
“When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition”,
Pena-Miller R, Laehnemann D, Jansen G, Fuentes-Hernandez A, Rosenstiel P, et al. (2013)
PLoS Biol 11(4): e1001540. doi:10.1371/journal.pbio.1001540
Funding: Structural funding by the DFG Excellence Clusters Inflammation at Interfaces and Future Ocean. REB and RPM were funded by EPSRC grants EP/I00503X/1 and EP/I018263/1 (http://www.epsrc.ac.uk/Pages/default.aspx). AFH was funded by an Exeter University CLES award (no grant number). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.