A new weapon in the fight against antibiotic resistance: Temperature

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

In laboratory experiments, they found that a small increase in temperature from 37 to 40 degrees Celsius drastically changed the frequency of mutations in E. coli bacteria, making it easier for resistance to develop. If these results can be replicated in human patients, controlling fever could be a new way to mitigate the emergence of antibiotic resistance. The results were published in the journal JAC-antimicrobial resistance.

Antimicrobial resistance in pathogens is a global 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 emergence of resistance.

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

“Most studies on resistance mutations have been done by lowering the ambient temperature, and none, as far as we know, have used a slight increase above normal body temperature,” reports Van Eldijk. Together with master’s 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 looked at temperature and antibiotics, but the type of drug was not controlled in those studies.” In their laboratory study, the team used three different antibiotics with different modes of action: ciprofloxacin, rifampicin and ampicillin.

The results showed that for two drugs, ciprofloxacin and rifampicin, increased temperature led to an increase in the rate of mutation towards resistance. However, a third drug, ampicillin, caused a decrease in the mutation rate towards resistance in fevers.

“To be sure of this result, we actually replicated 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’s effectiveness could explain this result, and confirmed it in an experiment. This explains why ampicillin resistance is less likely at 40 degrees Celsius.

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

If the results are replicated in humans, this could pave the way for addressing antimicrobial resistance by lowering the temperature with fever-reducing drugs or giving fever patients antimicrobial drugs with greater efficacy at higher temperatures. The team concludes in the paper: “An optimized combination of antibiotics and fever suppression strategies may be a new weapon in the fight against antibiotic resistance.”