UCL researchers have made the troubling discovery that macrolides, the antibiotics frequently prescribed to sufferers of cystic fibrosis, foster resistance in Pseudomonas aeruginosa.
Pseudomonas aeruginosa is a bacterium found just about everywhere in nature. To healthy people, it’s innocuous, ‘but it’s an opportunistic bacterium’, explains Prof. Françoise Van Bambeke, an FNRS researcher at the Louvain Drug Research Institute (LDRI). ‘That is, it can provoke urinary, respiratory or post-operative infections in people with weakened immune systems.’ The bacterium is also implicated more and more frequently in nosocomial infections, making its resistance to antibiotics all the more problematic.
Macrolides and cystic fibrosis
Macrolides are prescribed all the time to cystic fibrosis suffers, less for their antibiotic effect than for their anti-inflammatory effect. ‘The disease inflames their lungs almost constantly’, Prof. Van Bambeke says. ‘Inflammation alters the tissue and makes it even more vulnerable to infection. Macrolides diminish immune cells’ production of inflammatory mediators. This in turn reduces the frequency and severity of infections and preserves respiratory function longer.’ In Belgium, more than 40% of cystic fibrosis patients receive constant macrolide treatment.1
In vitro vs. ‘real’ life
For a long time it was thought that macrolides had no effect on Pseudomonas aeruginosa. Researchers had observed in the laboratory that the bacterium didn’t react to them, because the antibiotics didn’t permeate its membrane. ‘But there’s a difference between the traditional laboratory culture medium, which is calibrated to induce the bacterium’s maximum proliferation, and the real, heterogeneous environment of the human body’, Prof. Van Bambeke explains. ‘We discovered that by putting this bacterium in human serum, whether the liquid that keeps our lungs moist or the laboratory medium used to grow human cells, Pseudomonas has to adapt in order to absorb the nutrients it needs to survive. Because it finds itself in a less favourable environment, its membrane becomes more permeable and thus more susceptible to macrolides.’2 This test – inserting Pseudomonas and macrolides into human serum – helped Prof. Van Bambeke’s team make another discovery.
When Pseudomonas resists
Antibiotic susceptibility implies a risk of developing resistance. Muhammad-Hariri Mustafa, an LDRI PhD student, examined a collection of Pseudomonas aeruginosa in 333 samples of phlegm from cystic fibrosis patients. The result: in 40% of cases, the bacterium had mutated and developed a new defence mechanism against macrolides. More disturbing: the mutation was present in half of the patients treated with macrolides, compared to one-quarter of patients not treated with macrolides.3 Thus the conclusion that such antibiotic treatment clearly increases the risk of mutating Pseudomonas.
A discovery that raises questions
According to some specialists,4 this discovery raises serious questions regarding macrolide treatment for cystic fibrosis. It improves patient health in the short and long terms. But is it worth it in the long term? Would it be better to fall back on other anti-inflammatories?
This discovery also raises other questions. For example, how long does it take for Pseudomonas to develop resistance to macrolides? Can the same adaptation be observed concerning other bacterial species, pathologies, antibiotics? To what extent do bacteria potentially pathogenic to humans react differently to antibiotics when in a traditional in vitro culture than in the human body? At a time when the entire scientific community is worried about (multi)resistant bacteria, these questions certainly merit study.
Other articles about the resistance of bacteria to antibiotics:
- When bacteria fight back
- Bacteria and bleach: all-out war
- Tuberculosis: Where do we stand?
- Bacterial biofilms under the microscope
(1) According to the European Cystic Fibrosis Society Patient Register, at least 42% of Belgian patients received constant macrolide treatment in 2013.
(2) This discovery was the subject of the 2012 article: J.M. Buyck et al., ‘Increased susceptibility of Pseudomonas aeruginosa to macrolides and ketolides in eukaryotic cell culture media and biological fluids (serum, bronchoalveolar lavage) by decreased expression of OprM (efflux impairment) and increased outer membrane permeability’, Clin Infect Dis, 2012; 55:534-542.
(3) M.-H. Mustafa et al., ‘Acquired resistance to macrolides in Pseudomonas Aeruginosa from cystic fibrosis patients’, Eur Respir J, 2017;49: 1601847.
(4) See James D. Chalmers’s commentary at http://www.facm.ucl.ac.be/Full-texts-FACM/Chalmers-commentary-ERJ-2017.pdf.
A glance at Françoise Van Bambeke's bio
1991 Degree in Pharmacology, UCL
1995 PhD in Pharmaceutics, UCL
1997 Postdoctorate, Antibacterial Agents Unit, Institut Pasteur, Paris
1997 Award of the Belgian Society for Infectiology and Infectious Diseases
2000 FNRS Research Associate
2005 Higher Education Teacher Training Certificate, UCL
2006 FNRS Senior Research Fellow
Since 2008 Professor of Pharmacology, UCL
Since 2010 Expert, Belgian Antibiotic Policy Coordination Committee
Since 2012 Scientific Secretary, International Society of Anti-infective Pharmacology
2013 AstraZeneca Foundation Award for Infectiology
Since 2016 Vice-President, Louvain Drug Research Institute
Since 2017 FNRS Research Director
Prof. Van Bambeke’s research is financed mainly by the FNRS, the Walloon and Brussels Regions and ‘interuniversity attraction centres’. M.-H. Mustafa’s research has been financed entirely by InnovIris (Brussels Capital Region).