People with cystic fibrosis use macrolides to modulate the immune system, but a new study shows that macrolides can make the bacteria resistant. Researchers say that this is a problem because developing antimicrobial resistance changes the behaviour of the bacteria, which can change the illness trajectory in cystic fibrosis and other lung diseases.
Many people with cystic fibrosis use macrolides to modulate the immune system and thus improve some of the symptoms associated with cystic fibrosis.
Typically, macrolides are used for up to several years based on historical experience that people with cystic fibrosis respond very well to macrolide treatment and their overall well-being is improved.
However, new research shows that macrolides do more than merely modulate the immune system, and this can be problematic.
Macrolides are an antibiotic, but the assumption has been that these drugs do not have a direct antibacterial effect on Pseudomonas aeruginosa, the most problematic lung bacterium for people with cystic fibrosis and therefore would not lead to resistance development. However, this research rejects this assumption.
Although macrolides are not used to attack P. aeruginosa, the fact that resistance develops may have implications for how P. aeruginosa acts in general in the lungs and how well it adapts to a human host.
“We probably need to pay more attention to how people with cystic fibrosis use macrolides, and we need to examine how P. aeruginosa developing antibiotic resistance affects the outcome of macrolide treatment,” explains a researcher behind the study, Ruggero La Rosa, Senior Researcher, Rigshospitalet, Copenhagen and the Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby.
The research has been published in Nature Communications.
Bacteria not tested for macrolide resistance
The research group behind the new study is based at Rigshospitalet in Copenhagen and the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark and has collected samples from the lungs of people with cystic fibrosis for many years at Rigshospitalet’s Cystic Fibrosis Center.
This has enabled researchers to monitor how bacteria develop in the lungs as cystic fibrosis progresses.
The bacteria in the lungs of people with cystic fibrosis are constantly bombarded with antibiotics, and they defend themselves by developing antibiotic resistance – which over time makes effective treatment increasingly difficult, and this also affects the bacteria.
In this context, macrolides are not strictly considered as an antibiotic but more as a modulator of the immune system. The new study questioned this assumption.
“The development of antibiotic resistance in lung bacteria among people with cystic fibrosis is routinely monitored because it can help to guide treatment. However, this has traditionally not been carried out for macrolides, because there has been no reason to think that this drug has antibiotic effects against P. aeruginosa. However, failure to determine whether bacteria are developing resistance to macrolides also poses a risk of neglecting a blind spot in the treatment of people with cystic fibrosis,” says co-author Lise Goltermann, Assistant Professor, Department of Immunology and Microbiology, University of Copenhagen, Denmark.
Testing for antibiotic resistance in artificial lungs
The researchers experimented with lung tissue that mimicked the environment in the lungs of people with cystic fibrosis, applying macrolides to P. aeruginosa on actual lung tissue.
They then investigated the quantity of bacteria in the lung tissue treated with macrolides and how the treatment affected antibiotic-resistant mutant strains of P. aeruginosa versus non-resistant P. aeruginosa.
“This is the first time researchers have used real lung tissue to investigate what happens to P. aeruginosa treated with macrolides,” explains Ruggero La Rosa.
P. aeruginosa develops antibiotic resistance
The results showed very clearly that macrolides have antibiotic effects towards P. aeruginosa.
The macrolides reduced the number of P. aeruginosa in the lung tissue. Macrolides were very effective in treating wild-type P. aeruginosa but not as effective for P. aeruginosa that had mutated and developed antibiotic resistance.
The assumption that macrolides only have immunomodulatory effects for people with cystic fibrosis is therefore incorrect.
Further, the researchers found that the mutated bacteria also changed the behaviour and phenotype of P. aeruginosa in the form of slower growth, reduced virulence and altered pathogenicity.
“This is important because it shows that macrolides are ineffective as an antibiotic after the P. aeruginosa have developed resistance while potentially being better adapted to the lungs of people with cystic fibrosis. In addition, we found that P. aeruginosa can remain resistant to macrolides for years,” notes Lise Goltermann.
Antibiotic resistance needs to be investigated
Ruggero La Rosa says that the new discovery has several clinical perspectives and that using macrolides for people with cystic fibrosis requires more oversight.
Doctors and laboratory personnel may need to monitor the development of antibiotic resistance in P. aeruginosa, which has not been a focus area before but should be tested for in the future according to Ruggero La Rosa.
Further, according to the researchers, more studies should aim to identify the balance between using and not using macrolides for people with cystic fibrosis.
Macrolides may modulate the immune system but may not be optimal if antibiotic resistance develops in some of the most problematic bacteria in the lungs. In any case, this should be investigated.
“Perhaps macrolides could be used until the first signs of antibiotic resistance and then determine the implications for the illness trajectory when P. aeruginosa changes its phenotype by developing resistance. Consideration should be given if this means that the P. aeruginosa become more problematic because they grow more slowly and establish themselves as a chronic infection,” says Ruggero La Rosa.
May be relevant for people with other diseases?
Finally, the researchers think that this problem may not be limited to people with cystic fibrosis.
Other people using macrolides have lung infections with P. aeruginosa, such as people with chronic obstructive pulmonary disease.
“From a clinical perspective, we would like to eliminate these bacteria in the lungs of people with cystic fibrosis and people with chronic obstructive pulmonary disease. We must therefore be sure that treatment affecting the immune system does not create resistance mutations in the bacteria that make them survive more easily and create chronic infections in the lungs,” concludes Ruggero La Rosa.
