A new weapon in the fight against antibiotics

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 could 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 frequency of mutations in E.coli bacteria, which facilitates the development of resistance. If these results can be replicated in human patients, controlling fever could provide a new way to mitigate the emergence of antibiotic resistance. The results were published in the journal JAC-Antimicrobial resistance.

Antimicrobial resistance of pathogens is a global problem recognized by the WHO as one of the main global threats to public health and development. There are two ways to combat this phenomenon: by developing new drugs or by preventing the development of resistance. “We know that temperature affects the mutation rate of bacteria,” explains Timo van Eldijk, co-first author of the paper. “What we wanted to find out was how increased temperature associated with fever influences the rate of mutation toward antibiotic resistance.”

Three antibiotics

“Most studies of resistance mutations have been performed by lowering ambient temperature and none, to our knowledge, have used a moderate increase above normal body temperature,” reports Van Eldijk. With master's student Eleanor Sheridan, Van Eldijk cultivated E.coli bacteria at 37 or 40 degrees Celsius, then exposed them to three different antibiotics to evaluate the effect. “Again, some previous human trials have looked at temperature and antibiotics, but in those studies the type of drug was not controlled.” 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 of the drugs, ciprofloxacin and rifampicin, an increase in temperature led to an increase in the rate of mutation towards resistance. However, the third drug, ampicillin, caused a decrease in the rate of mutation toward resistance to feverish temperatures. “To be sure of this result, we replicated the study with ampicillin in two different laboratories, at the University of Groningen and the University of Montpellier, and obtained the same result,” explains Van Eldijk.

Fever medications

The researchers hypothesized that a temperature dependence of ampicillin's effectiveness could explain this result and confirmed it with 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 towards 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 combating antimicrobial resistance by lowering the temperature with fever-reducing drugs, or giving fever patients more effective antimicrobial drugs at higher temperatures. The team concludes in the article: “An optimized combination of antibiotics and fever suppression strategies could provide a new weapon in the battle against antibiotic resistance. »

Reference: Timo JB Van Eldijk, Eleanor A. Sheridan, Guillaume Martin, Franz J. Weissing, Oscar P. Kuipers, G. Sander Van Doorn: Temperature dependence of the mutation rate towards antibiotic resistance/ JAC-Antimicrobial Resistance, June 6, 2024.