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 could affect the development of antimicrobial resistance. In laboratory experiments, they found that a small increase in temperature from 37 to 40 degrees Celsius dramatically changed the mutation frequency in E.coli bacteria, which facilitates the development of resistance. If these results can be replicated in human patients, fever control could be 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 and is recognized by the WHO as one of the main 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 mutation rate of bacteria,” explains Timo van Eldijk, co-author of the article. “What we wanted to discover was how the increase in temperature associated with fever influences the mutation rate towards antibiotic resistance.”
Three antibiotics
“Most studies on resistance mutations were performed by reducing ambient temperature and, to our knowledge, none used a moderate increase above normal body temperature,” Van Eldijk reports. Together with master’s student Eleanor Sheridan, Van Eldijk cultivated E.coli bacteria at 37 or 40 degrees Celsius, and subsequently exposed them to three different antibiotics to evaluate the effect. “Again, some previous human trials have looked at temperature and antibiotics, but in these 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, increasing temperature caused an increase in the mutation rate toward resistance. However, the third drug, ampicillin, caused a decrease in the mutation rate toward resistance to febrile temperatures. “To be sure of this result, we replicated the study with ampicillin in two different laboratories, at the University of Groningen and at the University of Montpellier, and obtained the same result,” says Van Eldijk.
Medicines to suppress fever
The researchers hypothesized that this result could be explained by the temperature dependence of ampicillin’s effectiveness, and confirmed this in an experiment. This explains why resistance to ampicillin is less likely to emerge at 40 degrees Celsius. “Our study shows that a very slight change in temperature can dramatically change the mutation rate towards antimicrobial resistance,” concludes Van Eldijk. “This is interesting, since other parameters, such as growth rate, do not seem to change.”
If the results are replicated in humans, this could open the way to addressing antimicrobial resistance by reducing temperature with fever-reducing drugs or by giving feverish patients antimicrobial drugs more effectively at higher temperatures. The team concludes in the article: “An optimized combination of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.”