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Scientists from the University of Groningen (Netherlands), together with colleagues from the University of Montpellier (France) and the University of Oldenburg (Germany), have tested how fever can affect the development of antimicrobial resistance.

In laboratory experiments, they found that a slight increase in temperature from 37 to 40 degrees Celsius dramatically changed the mutation rate in E. coli bacteria, making it easier for resistance to develop. If these results can be replicated in humans, fever control could be a new way to mitigate the emergence of antibiotic resistance. The results are published in the journal JAC-antimicrobial resistance.

Antimicrobial resistance of pathogens is a worldwide problem and is recognized by the WHO as one of the greatest global threats to public health and development. There are two ways to combat this: by developing new drugs or by preventing the development of resistance.

“We know that temperature affects the rate of mutation in bacteria,” explains Timo van Eldijk, co-author of the paper. “What we wanted to understand was how the increase in temperature associated with fever affects the rate of mutation to antibiotic resistance.”

“Most studies on resistance mutations have been done by lowering ambient temperature, and none, as far as we know, have used a modest rise above normal body temperature,” Van Eldijk reports. Together with graduate student Eleanor Sheridan, Van Eldijk cultivated E. coli bacteria at 37 or 40 degrees Celsius and then exposed them to three different antibiotics to assess the effect.

He adds, “Again, some previous human studies have looked at temperature and antibiotics, but in those studies the type of drug was not controlled.” In their lab study, the team used three different antibiotics with different modes of action: ciprofloxacin, rifampicin, and ampicillin .

The results showed that for two of the drugs, ciprofloxacin and rifampicin, increased temperature increased the rate of mutation to resistance. However, the third drug, ampicillin, caused a reduction in the rate of mutation to resistance at feverish temperatures.

“To be sure of this result, we actually repeated the study with ampicillin in two different laboratories, at the University of Groningen and the University of Montpellier, and we got the same result,” says Van Eldijk.

The researchers hypothesized that the temperature dependence of ampicillin efficacy might explain this result and confirmed this in an experiment. This explains why ampicillin resistance is less likely to occur at 40 degrees Celsius.

“Our study shows that a very slight change in temperature can dramatically change the rate of mutation to antimicrobial resistance,” concludes Van Eldijk. “This is interesting because other parameters such as growth rate do not seem to change.”

If the results are replicated in humans, it could pave the way for tackling antimicrobial resistance by lowering fever with fever-suppressing drugs or by giving patients with fever antimicrobial drugs with higher efficacy at higher temperatures. The team concluded in the paper: “An optimized combination of antibiotics and fever suppression strategies could be a new weapon in the battle against antibiotic resistance.”