Sensitive to antibiotics for longer

When bacteria cause lung infections, antibiotics are important for treating them. These medicines kill the bacteria or prevent them from multiplying. One problem with antibiotics is that, after a while, the bacteria may no longer respond to them.

“This is particularly difficult for people with long-term lung infections, such as cystic fibrosis,” explains Coen van Hasselt. “They often use antibiotics for extended periods of time. As a result, there is a high risk that these medicines will become less effective. There are different types of antibiotics. If the bacteria become resistant to one type, switching to another antibiotic can sometimes help. But after a while, the bacteria may become resistant to that one as well. This leaves fewer and fewer options for treating the infection.”

In this video, pharmacologist Coen van Hasselt receives the 2022 Dirkje Postma Talent Award from Michael Rutgers, director of the Dutch Lung Foundation. 

Smart switching

This problem may be solved by combining different antibiotics. A bacterium that becomes resistant to one antibiotic may then become particularly sensitive to another. After some time, this can reverse: the bacterium no longer responds to the second antibiotic but becomes sensitive to the first one again.

Coen van Hasselt explains: “This property is known as ‘collateral sensitivity’. By switching between the medicines in a carefully planned way, you may be able to ensure that the bacterium always remains sensitive to one of the two antibiotics. This would allow the lung infection to be treated with the same medicines for longer.”

This idea has been known for some time. Until now, however, it has mainly been studied in bacteria grown in test tubes in the laboratory.

“What we do not yet fully understand is how this can be applied in people. Which combinations of antibiotics work best? How much should be given, and at what time? Developing an effective treatment schedule is quite complicated. There are many factors to consider.”

Antibiotics do not behave in exactly the same way in everyone. In some people, more or less of the antibiotic may reach the lungs than in others, or it may reach the lungs at a different time. Bacteria can also vary between patients. Even when two people have the same species of bacterium in their lungs, there may still be small differences. These are known as different strains of the bacterium, and different bacterial strains may respond differently to antibiotics.

“Ideally, we want to develop an antibiotic treatment schedule that works for as many different people and bacterial strains as possible,” says Van Hasselt. “Together with my team, I want to take the first steps towards developing such a schedule.”

A four-step study

Van Hasselt’s research consists of four steps. First, he investigates which combinations of antibiotics work best. To do this, he uses different strains of one bacterial species: more specifically, Pseudomonas aeruginosa, which is commonly found in the lungs of people with cystic fibrosis.

“We are looking for a combination of antibiotics with a strong effect: two antibiotics that together produce this ‘collateral sensitivity’. We also want the antibiotics to work against as many different bacterial strains as possible. Finally, they should be as easy and comfortable to use as possible. This includes factors such as how and when they need to be taken and whether they cause many side effects. We consult doctors and patients about this, as they have the most experience with using these antibiotics.”

Bacteria in the laboratory

The second step of the research consists of laboratory experiments.

“Once we have identified several promising antibiotic combinations, we want to test exactly how the medicines should be administered, for example at what dose and at what time. To do this, we grow bacteria in the laboratory and add antibiotics. We repeatedly use different doses and administer them at different times. This teaches us how the bacteria respond to the various treatment schedules.”

For the third step of the research, Coen van Hasselt uses a computer model.

“This model contains data on how antibiotics behave in the human body. We have already collected this information in previous studies. It includes, for example, the amount of an antibiotic present in the body at a particular time after it has been taken, and how this differs between people. We also include the data on the bacteria from the laboratory experiments in the computer model. By combining all this information, we can predict how the antibiotic treatment schedule will work in actual patients.”

Collaboration

The laboratory experiments and the computer model reinforce each other.

Coen van Hasselt explains: “We can use the results from the computer model to further improve the laboratory experiments. We then enter the new laboratory data back into the computer model. We continue this process until we find an antibiotic treatment schedule that we are satisfied with.”

Before the treatment schedule can be tested in people, one final step is required. In this step, the researchers examine whether the treatment schedule works well in laboratory animals.

“We do not carry out this part of the research ourselves,” says Coen van Hasselt. “My research group does not work with laboratory animals. We therefore collaborate with researchers in Denmark who are experts in this field. They will test the treatment schedule in mice with a long-term lung infection.”

An effective treatment schedule

The research began in March 2022 and will last at least three years.

“By then, we hope to understand how we can help disease-causing bacteria in the lungs remain sensitive to antibiotics for longer. We also hope to have a strong proposal for a treatment schedule. We want to answer the questions of which combination of antibiotics should be given, at what dose and at what time.”

Coen van Hasselt sees many possibilities for the future.

“Once we have found an effective treatment schedule, the next step would be to test it in people in clinical practice. That would also be an extensive study that could take several years. The research could also be broadened. At present, we are looking for an antibiotic treatment schedule targeting one bacterial species in people with cystic fibrosis. It would also be possible to investigate whether a similar schedule could be developed for other bacterial species and for other lung diseases in which people frequently experience long-term lung infections, such as bronchiectasis or COPD.”

Major benefits

Ultimately, the researchers want to improve the treatment of long-term lung infections.

“We hope that our treatment schedule will help bacteria in the lungs remain sensitive to antibiotics for longer. This would allow us to continue using antibiotics that are easy to administer and cause fewer side effects. Hopefully, people with lung disease will then feel better and experience fewer flare-ups. That would be a major benefit.”

Back to the news overview