Test, Treat Lung Infections Early, Analysis Suggests
Antibiotic-resistant infection with Mycobacterium abscessus bacteria in people with cystic fibrosis (CF) can evolve rapidly to become more virulent, a genetic analysis suggests.
The findings support early testing and treatment of lung infections before symptoms emerge to prevent further complications.
The study, “Stepwise pathogenic evolution of Mycobacterium abscessus,” was published in the journal Science.
CF is characterized by the buildup of thick mucus in various organs, including the lungs, intestines, pancreas, and liver. This can create an ideal environment for bacteria to grow in the lungs, resulting in frequent chest infections.
M. abscessus — a species of antibiotic-resistant bacteria — can cause lung infections in people with CF and is extremely difficult to treat, with fewer than one in three cases treated successfully. M. abscessus infection rates in CF individuals are increasing worldwide, driven in part by indirect person-to-person transmission.
To understand how this bacteria evolves and is transmitted, a team led by scientists at the University of Cambridge in the U.K. examined whole-genome data for 1,173 M. abscessus samples collected from 526 patients obtained at CF clinics in the U.K., other countries in Europe, the U.S., and Australia.
“M. abscessus can be a very challenging infection to treat and can be very dangerous to people living with cystic fibrosis, but we hope insights from our research will help us reduce the risk of transmission, stop the bug evolving further, and potentially prevent the emergence of new disease-causing mutations,” Julian Parkhill, PhD, a senior co-author of the study, said in a press release.
Bacteria evolve by frequent mutations in their DNA. Depending on the environment, these mutations may lead to more or less-virulent bacteria in successive generations.
The genetic analysis revealed two key processes that played an essential role in the evolution of M. abscessus toward a lung-infecting bacteria.
The first was horizontal gene transfer, in which the bacteria pick up genes or pieces of DNA from other bacteria in the environment. In particular, the team found the horizontal transfer of DNA that controls gene activity, leading to rapid evolution, allowing it to become suddenly more virulent in humans.
The second process identified was within-host evolution. By studying several samples from different parts of the lungs within chronically infected patients, the team found multiple versions of M. abscessus evolving separately.
Mathematical models were used to trace the bacteria’s evolution back to single individuals to find key mutations in each organism. Then, comparing samples from multiple patients, important sets of genes were found that drove the change into a potentially disease-causing bacteria.
“What you end up with is parallel evolution in different parts of an individual’s lung,” said senior co-author Andres Floto, PhD, from Cambridge. “This offers bacteria the opportunity for multiple rolls of the dice until they find the most successful mutations. The net result is a very effective way of generating adaptations to the host and increasing virulence.”
One of the most important genetic changes led to M. abscessus becoming resistant to nitric oxide — a compound produced by the human immune system.
The team said it would initiate a clinical trial to boost nitric oxide in the lungs of patients by using inhaled acidified nitrite, with the potential to become a new treatment for the infection. They also explained how these findings support early intervention in people with M. abscessus infections, which is opposed to current medical practice.
“At the moment, because the drugs can cause unpleasant side effects and have to be administered over a long period of time — often as long as 18 months — doctors usually wait to see if the bacteria cause illness before treating the infection,” added Floto. “But what this does is give the bug plenty of time to evolve repeatedly, potentially making it more difficult to treat.”
Notably, while the mutations occurred fairly rapidly, the data suggested the ability of these highly adapted strains to transmit between patients was limited due to reduced survival on external surfaces (fomites) and in the air. “As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect,” the scientists wrote.
However, increases in population density or patient susceptibility might accelerate its evolution to direct transmission, the team predicted.
“Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict existing pathogens and prevent new, emergent ones,” the scientists concluded.
Lucy Allen, PhD, at the Cystic Fibrosis Trust, which co-funded the study, said: “This exciting research brings real hope of better ways to treat lung infections that are resistant to other drugs.”
“Our co-funded Innovation Hub with the University of Cambridge really shows the power of bringing together world-leading expertise to tackle a health priority identified by people with cystic fibrosis. We’re expecting to see further impressive results in the future coming from our joint partnership,” added Allen.
Luke, a CF patient who has lived with M. abscessus infection for many years, said in another press release: “After I was first infected with M. abscesses in 2003 I spent four months in hospital and since then have had several long stays. Spending huge swathes of time in hospital results in disrupted lives and time lost. And months of arduous IV [into the vein] antibiotics with very unpleasant side effects can also lead to longer-term medical issues. I remain hopeful that new ways of treating this terrible and exhausting infection are on their way, and [this] exciting news … is one step towards that.”