3 FEB. 2023, 4:45 P.M.
BY KATHERINE KORNEI
MRI scans of a man whose brain was infected with the amoeba Balamuthia mandrillaris show a dramatic difference in inflammation (white) before and after (right) treatment with an experimental drug.N. SPOTTISWOODE ET AL., EMERG. INFECT. DIS. (1) 197-201 (2023)
In the summer of 2021, a 54-year-old man was brought to a hospital in Northern California after an unexplained seizure. When an MRI revealed a mysterious mass in the left side of his brain, he was transferred to the University of California, San Francisco (UCSF), Medical Center. A brain biopsy and other tests revealed not a tumor, but an incredibly rare infection of the central nervous system caused by the amoeba Balamuthia mandrillaris. One of several “brain-eating” amoebae that occasionally spark headlines, the pathogen kills more than 90% of people who contract it.
But despite initial setbacks, the patient survived and has largely recovered after experimental treatment with a decades-old drug. As his UCSF medical team recounted in a paper last month, a desperate hunt for a cure led them to a study published several years ago in which researchers showed a drug originally developed in Europe to quell urinary tract infections was effective against Balamuthia in the laboratory. That discovery sent the medical team rushing to obtain the drug, nitroxoline, from abroad so it could be given for the first time to a Balamuthia patient.
Researchers not involved with the case call the man’s recovery a breakthrough in treating a brain infection that’s long been presumed to be a death sentence. “It’s the best that I ever remember seeing with Balamuthia,” says Dennis Kyle, a cell biologist at the University of Georgia, Athens, who studies amoebic diseases. The drug, which is not approved for regular use in the United States, has also been effective against other pathogenic amoebae in laboratory tests, according to the UCSF team.
Balamuthia mandrillaris was first identified in 1986—not in a hospital but at the San Diego Wild Animal Park, where staff were eagerly anticipating the birth of a mandrill, the largest species of monkey. But one day, Nyani, the mother-to-be, began dragging her right arm on the ground. Within 48 hours she became lethargic, and she eventually stopped moving and died. A postmortem evaluation of Nyani’s brain tissue revealed hemorrhaging and centimeter-scale lesions. The culprits were plainly visible: Amoebae were eating Nyani’s brain.
Researchers later determined the organism represented a new species of amoeba, constituting its own genus. Balamuthia lives in soil, dust, and water, and it’s believed to enter the body via the lungs or via skin cuts. (Its name is a nod to both Nyani’s species and the late William Balamuth, a zoologist at the University of California, Berkeley, who studied amoebae.)
In the past few decades, only about 100 human cases of Balamuthia have been confirmed in the United States. “The vast majority of doctors, even infectious disease doctors, have never seen a case,” says UCSF infectious disease physician-scientist Natasha Spottiswoode.
That was true for her as well until just 2 years ago. But even after the California man’s initial MRI results came back, his UCSF medical team, led by Spottiswoode, had no reason to contemplate a Balamuthia infection because brain masses can be caused by a slew of more common ailments such as cancer, bacterial abscesses, and tuberculosis. But after a biopsy of the brain mass revealed what appeared to be amoebae, the team sent a piece of the man’s infected tissue to the University of Washington, Seattle, for a polymerase chain reaction (PCR) test that could confirm that. The results came back positive for Balamuthia.
Spottiswoode and her colleagues started the patient on an aggressive suite of antiparasitic, antibacterial, and antifungal drugs delivered via 47 daily pills and an intravenous drip. But the drug cocktail was somewhat ad hoc, Spottiswoode admits. “It’s what’s recommended because it was what happened to be used in patients who survived,” she says. It also happens to sometimes be highly toxic: The man’s blood sugar levels and white blood cell count both dipped dangerously low, and he suffered from kidney failure. All the while, the man’s lesions kept growing. Desperate to save her patient, Spottiswoode began poring over research about Balamuthia.
One day, she found a 2018 study in the journal mBio in which a team led by Joseph DeRisi, a biochemist also at UCSF and president of the Chan Zuckerberg Biohub, had painstakingly screened more than 2100 drugs in the laboratory to identify compounds effective against Balamuthia. The effort, DeRisi recalls, “was inspired by our frustration” of watching an ultimately fatal progression of Balamuthia in a 74-year-old woman being cared for at UCSF.
Balamuthia mandrillaris YAMANOUCHI, K., ARIMA, H., SAKAMOTO, Y. ET AL./WIKIMEDIA COMMONS
One compound stood out in their screening: nitroxoline. But DeRisi and his collaborators haven’t, until now, had a chance to see it tested in an infected person. Balamuthia cases are so rare, DeRisi says, and “by the time you contact the treating clinical team, the patients are dead.”
When Spottiswoode reached out to DeRisi, he urged her on. But nitroxoline is not approved by the Food and Drug Administration, which meant the medical team had to file an Emergency Investigational New Drug application for permission to use it—and then find a source for the drug. Asieris Pharmaceuticals, a company developing nitroxoline to treat bladder cancer, ultimately provided several hundred pills from its R&D facility in Shanghai and has continued to send resupply shipments, all pro bono.
After just 1 week of treatment with nitroxoline, the patient’s lesions shrank. Follow-up MRIs have revealed continued improvement, and the patient is now living at home. “I think he’s very much on his way to being one of the survivors of this disease,” Spottiswoode told a group of her colleagues in October 2022. (The research group reported its results in January in Emerging Infectious Diseases.)
The UCSF team has been in touch with the Centers for Disease Control and Prevention about keeping nitroxoline on hand for future use. It should be available as an “emergency standby medication for 24-hour delivery anywhere in the United States,” DeRisi says. But to save patients, doctors also have to rapidly diagnose a Balamuthia infection. Currently, a clinician must suspect an amoebic infection in the first place and then order a specific PCR test. “If you don’t think of what’s there, then you’ll never find it,” says Michael Wilson, a neurologist at UCSF and a member of the research team.
He notes that a technique called metagenomic next-generation sequencing, pioneered by DeRisi, could speed diagnosis. The approach involves sequencing genetic material from a patient sample and comparing it with enormous libraries of genetic code from millions of known pathogens. “You let the database match tell you what organisms are in there,” Wilson says. “You’re not going in with a preconceived notion.”
Spottiswoode and her colleagues are now working with other doctors overseeing Balamuthia cases. Just recently, a second patient was started on the drug, and the initial results are already encouraging, she says. Spottiswoode is hoping her frantic search will have a lasting payoff for other Balamuthia patients. “For every patient who exists with this disease, there’s a team of doctors where I was, which is basically desperate to find something that will help.”
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