Inquiry in Action
Possible Secret Revealed
A recent discovery about how Pseudomonas interacts with Staphylococcus points the way to understanding its drug resistance – and defeating chronic lung infections.
Pseudomonas aeruginosa is an opportunistic bacterium that targets people weakened by lung disease, severe burns, immunodeficiencies and other serious medical conditions. Two things set it apart from many other bacteria: its eerie green color and its resistance to antibiotics.
“In a lot of infections, we can knock it down,” says Dr. Luke Hoffman, “but we can’t knock it out.”
Hoffman is a pediatric pulmonologist at Seattle Children’s. His work on fighting chronic lung infections in children – especially those with cystic fibrosis – led to a discovery about Pseudomonas that has opened a line of inquiry into what makes this and other bacteria such stubborn foes.
“We’re learning that bacteria act differently in groups than a single species acts in isolation,” Hoffman says. “They appear to adjust to each other metabolically.”
According to Hoffman, the purpose of the bacteria’s metabolic adaptations is probably to avoid competing for the same nutrients. But the result is that bacteria often become less susceptible to antibiotics even though the antibiotics have been proven to treat the bacteria when isolated.
Legacy of research breakthroughs continues
It’s long been known that many combinations of bacteria inhabit the lungs of patients with cystic fibrosis. The thick mucus that clogs their lungs offers a fertile breeding ground, and bacteria that become established in these secretions can cause chronic and destructive infections. Most research has focused on Pseudomonas because it commonly infects people with CF, is virulent, and is very difficult to eradicate.
“If Pseudomonas was on the TV show ‘Survivor’ it would win every time,” says Dr. Bonnie Ramsey, a pediatric pulmonologist who leads CF research at Seattle Children’s. “Once it gets established, it’s almost impossible to totally clear from a patient’s lungs.”
Hoffman hopes his work will help end that winning streak. In the past, researchers studied Pseudomonas in isolation despite the fact that it’s rarely the lone bacterium in the lungs of people with CF. Hoffman decided to study how Pseudomonas and Staphylococcus aureus – the other bacterium most commonly found in the lungs of cystic fibrosis patients – behave when the two are grown together.
Hoffman discovered that Pseudomonas produces a compound that causes Staphylococcus (aka “staph”) to grow more slowly, making it more difficult to detect. The compound also makes staph highly resistant to the antibiotic tobramycin. The findings suggest two hypotheses. First, staph may actually be more common in cystic fibrosis patients than thought because it’s difficult to detect whenever Pseudomonas is around. Second, this molecular interaction between Pseudomonas and staph may be just one example of how a bacterium can become more resistant to antibiotics as a result of adjusting to other bacteria.
Hoffman’s findings are the latest breakthrough made by researchers at Children’s in the fight against cystic fibrosis and chronic lung infections. The first breakthrough (in the 1980s and ’90s) was developing TOBI, an inhalable form of the antibiotic tobramycin. This antibiotic preparation has become a standard treatment for CF and has helped increase the life expectancy of cystic fibrosis patients to nearly 40 years.
Ramsey, who worked with Dr. Arnold Smith and others to develop TOBI, has continued the quest to improve treatment for chronic lung infections in cystic fibrosis patients. Now, after training under Ramsey, Hoffman is looking for answers in the lab to the questions his mentor is raising in the clinic.
Findings spur ongoing investigations
Hoffman is pursuing three lines of inquiry related to his earlier discovery about Pseudomonas. One study seeks to determine the clinical significance of his findings about Pseudomonas and staph interactions by looking at bacteria from a small group of local cystic fibrosis patients. Hoffman and his lab team are searching for molecular evidence of interspecies interactions and exploring whether the presence of those interactions alters patient outcomes.
Hoffman also is working with Dr. Nicole Hamblett at Seattle Children’s to build upon a nationwide clinical study led by Ramsey. Pseudomonas infections don’t immediately make patients sick, so they haven’t always been treated with antibiotics right away. Recently, evidence has shown that Pseudomonas infections are easier to eradicate with antibiotics when treated very early, and that this response decreases as the infection becomes more established.
Ramsey’s study used TOBI to treat Pseudomonas infections in young cystic fibrosis patients 1- to 3-years old before they showed any signs of illness. The study led by Hoffman and Hamblett is examining whether the Pseudomonas that was successfully eradicated in these children differs in some way from the Pseudomonas that was not successfully eradicated.
“We were very successful with 85% of the patients,” says Ramsey. “Luke and Nicole’s study may shed light on why the remaining 15% did not respond as well and why Pseudomonas is easier to clear in young patients and almost impossible to clear in older patients.”
Another study in Hoffman’s laboratory will examine the behavior of various combinations of bacteria (not just Pseudomonas and staph) found in the lungs of cystic fibrosis patients.
“Ideally, we would study these bacteria inside a patient’s lungs, but we haven’t figured out an easy way to do that,” Hoffman says. “So we’re developing models for growing these bacteria in the lab that closely resemble the conditions inside a patient’s lungs.”
The study poses three main questions. Do infecting bacteria respond differently to antibiotics when part of a community of bacteria? Are there treatments that could achieve better results by targeting the overall community rather than targeting one bacterium at a time? Does the composition of a community have a bigger influence on outcomes than the presence or absence of any single bacterium such as Pseudomonas?
“The defining characteristic of chronic lung infections is their persistence, despite antibiotic treatment,” says Hoffman. “In many cases, we don’t understand why we can’t cure them. Our hope is that learning more about how bacteria respond to antibiotics and interact holds the key to providing more effective treatment.”