Joshua Wolf, MD (at left), and Jason Rosch, PhD
Scientific Sleuths Solve Medical Mystery
Why wouldn’t Milah’s infection respond to antibiotics? Two scientists set out to solve the mystery. The answer offers hope to other children with compromised immune systems.
By Chris Pennington; Photos by Peter Barta
Milah Kimber was only 2 weeks old when her mother, Marketia, noticed red spots on her baby’s skin. Doctors immediately sent Milah to St. Jude Children’s Research Hospital, where she began chemotherapy treatments for acute myeloid leukemia, a cancer of the white blood cells.
Complications arose when Milah developed a bloodstream infection. No matter which antibiotics were used, the infection wouldn’t go away.
Antibiotics helped the little girl survive during treatment, says Joshua Wolf, MD, of St. Jude Infectious Diseases, but there was still the issue of the infection’s resistance. For nearly a month, Milah battled both her cancer and the infection.
“We moved into the hospital,” Marketia says. “Milah kept going in and out of the ICU.”
“She just stayed ill,” Wolf says. “Eventually, her immune system recovered, and she cleared the bacteria.”
Milah’s cancer went into remission, and regular checkups since have been reassuring. Now she is a happy, healthy 2-year-old—but until recently clinicians could not explain why the infection had persisted. It simply had not responded to antibiotics.
In search of answers
Wolf and his colleagues were determined to solve the mystery.
“After Milah recovered and I met with her mom to get permission, we began researching the issue,” Wolf says. “We saw it as an opportunity to learn from her case and derive information we can use to help future kids.”
The bacteria, known as vancomycin-resistant Enterococcus faecium (VRE), normally lives inside the gut. But in Milah’s case, the bacteria entered her bloodstream.
“What happened when the bacteria moved into this new place?” Wolf asked. “How did it adapt?”
To find out, he enlisted the help of Jason Rosch, PhD, of St. Jude Infectious Diseases. Using samples taken from Milah each day of her infection, Rosch looked at the genetic sequences to see how the bacteria changed.
He had no idea what to expect.
“One mutation kept showing up intermittently throughout the course of treatment,” Rosch says. “It came up early and was there at the end, which surprised us a little bit.”
The mutant bacteria responsible for her prolonged infection had never been described before.
A haystack of needles
The mutation occurred in one of the bacteria’s genes. This gene, known as relA, affected the bacteria’s alarm system when the bacteria were growing in what is called biofilm.
“Like slime on rocks in a river,” Rosch says. “That’s a biofilm. It’s just a complex community of bugs.”
Most bacteria live in your body by forming such communities. Like many children undergoing cancer treatment, Milah had a central venous catheter implanted in her body. Medicines, blood products and fluids could be delivered through this tube.
“The infections Milah had were probably related to the catheter,” Rosch says. “Bacteria don’t just sit there and float; they attach to surfaces and stick there.”
Rosch and his colleagues spent nearly a year investigating the bacteria. The scientists found that when floating freely, bacteria could be treated with antibiotics. But in biofilm, mutant bacteria couldn’t be killed.
“Part of the challenge is finding the mutation,” Rosch says. “The consequences of that could be a needle in a haystack of needles.”
Lessons from Milah
Milah’s parents, Marketia and Andrew, are grateful their daughter is now healthy and doing well. They recall the first few months of Milah’s life as a blur—from seeing red spots on her skin to visiting a local hospital to entering St. Jude. Both mother and father remained hopeful during those weeks of doubt.
“It was an experience,” Andrew says. “I thank God. It was a bad thing to have cancer, but we also understand it can be cured. It takes a lot of patience by the doctors.”
Milah’s case was a first.
“The mutant bacteria responsible for her prolonged infection had never been described before,” Wolf says. “Part of that is nobody has had the resources and the opportunity to look. And it may be that once you start looking for these things, they’re much more common than anyone ever thought.”
With the hope that other children might benefit from their findings, Wolf and Rosch shared results of their research in the scientific journal mBio. As part of their work, the researchers also identified that an experimental compound being investigated at St. Jude may help cure such infections in the future.
Looking to the future
“With Milah, we had a young child with an aggressive cancer, who received aggressive chemotherapy and had a very, very prolonged infection,” Rosch says. “It’s like three strikes. It speaks to the quality of doctors here that they were able to cure her.”
Wolf met the family again during their recent visit to St. Jude. The last time he’d seen Milah, she was just a few weeks old.
“This was an opportunity to learn,” Wolf says. “We’ve now started talking about looking for such prolonged infections in other patients.”
In other words, how often do antibiotic-tolerant bacteria develop in patients like Milah? And what does this mean when it happens to a patient whose immunity is diminished because of chemotherapy?
“If you look at the literature, there is really not all that much information available,” Rosch says. “That’s an important question not only for the patients, but also from a public health perspective.”
“We’re going to use this as a jumping-off point to start thinking more about how VRE evades antibiotics,” Wolf says. “As we go forward, understanding that phenomenon in a patient is going to be important.”
Abridged from Promise, Spring 2017