A study found that much higher doses of antibiotics are needed to eliminate a bacterial infection in the respiratory tract when other microbes are present. This helps explain why respiratory infections often persist in people with lung diseases such as cystic fibrosis despite treatment.
In the study, published today in The ISME magazineresearchers say that even a low level of one type of microbe in the airways can have a profound effect on how other microbes respond to antibiotics.
The results highlight the need to consider the interaction between different species of microbes when treating infections with antibiotics – and to adjust the dosage accordingly.
“People with chronic infections often have multiple pathogens co-infected, but the problem is that we don’t take that into account when deciding how much of a particular antibiotic to treat them with. Our findings could help explain why, in these people, antibiotics just don’t work as well as they should,” said Thomas O’Brien, who did the research for his PhD in the Department of Biochemistry at the University of Cambridge and is co-lead author of the paper.
Chronic bacterial infections such as those in the human respiratory tract are very difficult to cure using antibiotics. Although these types of infection are often associated with a single pathogenic species, the site of infection is frequently co-colonized by a number of other microbes, most of which are generally not pathogenic on their own.
Treatment options generally revolve around targeting the pathogen with little consideration of cohabiting species. However, these treatments often fail to resolve the infection. Until now, scientists had few ideas about why this happened.
To obtain their results, the team developed a simplified model of the human airway, containing artificial sputum (“phlegm”) designed to chemically resemble the real phlegm expelled during an infection, filled with bacteria.
The model allowed them to grow a mixture of different microbes, including pathogens, stably for weeks at a time. This is new, because usually one pathogen will overtake the others very quickly and spoil the experience. It has allowed researchers to replicate and study in the laboratory infections by several species of microbes, called “polymicrobial infections”.
The three microbes used in the experiment were bacteria Pseudomonas aeruginosa and Staphylococcus aureus, and the mushroom Candida albicans — a combination commonly present in the airways of people with cystic fibrosis.
The researchers treated this microbial mixture with an antibiotic called colistin, which is very effective in killing Pseudomonas aeruginosa. But when the other pathogens were present alongside Pseudomonas aeruginosa, the antibiotic didn’t work.
“We were surprised to find that an antibiotic that we know should eliminate an infection from Pseudomonas indeed, it just didn’t work in our lab model when other bugs were present,” said Wendy Figueroa-Chavez from the University of Cambridge’s Department of Biochemistry, co-lead author of the paper.
The same effect occurred when the microbial mixture was treated with fusidic acid – an antibiotic that specifically targets Staphylococcus aureus, and with fluconazole, an antibiotic that specifically targets Candida albicans.
The researchers found that significantly higher doses of each antibiotic were needed to kill the bacteria when they were part of a polymicrobial infection, compared to when no other pathogen was present.
“The three species-specific antibiotics were less effective against their target when three pathogens were present together,” said Martin Welch, professor of microbial physiology and metabolism in the University of Cambridge’s department of biochemistry and lead author of the study. item.
Currently, antibiotics are usually only tested in the laboratory against the primary pathogen they are intended to target, to determine the lowest effective dose. But when the same dose is used to treat an infection in a person, it often doesn’t work, and this study helps explain why. The new model system will test the efficacy of potential new antibiotics against a mixture of microbial species.
Polymicrobial infections are common in the airways of people with cystic fibrosis. Despite treatment with high doses of antibiotics, these infections often persist over the long term. Chronic respiratory tract infections in people with asthma and chronic obstructive pulmonary disorder (COPD) are also often polymicrobial.
By examining the genetic code of Pseudomonas bacteria in their lab-grown mix, the researchers were able to identify specific mutations that give rise to this antibiotic resistance. Mutations were found to be more frequent when other pathogens were also present.
Comparison with the genetic code of 800 samples of Pseudomonas from around the world revealed that these mutations also occurred in human patients who had been infected with Pseudomonas and treated with colistin.
“The problem is that as soon as you use an antibiotic to treat a microbial infection, the microbe begins to develop resistance to that antibiotic. This has been happening since colistin began to be used in the early 1990s. This is another reminder of the vital need to find new antibiotics to treat human infections,” Welch said.
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