Repurposed drug fights ‘brain-eating’ amoebas | Science

In the summer of 2021, a 54-year-old man was rushed to a Northern California hospital after suffering 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 no tumor, but an incredibly rare central nervous system infection caused by the amoeba Balamuthia mandrillaris. The pathogen is one of several “brain-eating” amoebas that occasionally make headlines, killing more than 90% of people who contract it.

But despite initial setbacks, the patient survived and largely recovered after experimental treatment with a decades-old drug. As his UCSF medical team reported in a paper last month, a desperate search for a cure led them to a study published a few years ago, in which researchers showed that a drug originally developed in Europe to suppress UTIs in the laboratory was effective against Balamuthia . This discovery prompted the medical team to procure the drug Nitroxoline from abroad so that it could be administered to a Balamuthia patient for the first time.

Researchers not involved in the case call the man’s recovery a breakthrough in treating a brain infection that has long been considered a death sentence. “It’s the best I can ever remember with Balamuthia,” says Dennis Kyle, a cell biologist at the University of Georgia, Athens, who studies amoeba diseases. The drug, which isn’t approved for regular use in the United States, was also effective against other pathogenic amoebas in laboratory tests, according to the UCSF team.

Balamuthia mandrillaris was first identified in 1986 — not at a hospital, but at the San Diego Wild Animal Park, where staff anxiously awaited the birth of a mandrill, the largest species of monkey. But one day, Nyani, the mother-to-be, started dragging her right arm across the floor. Within 48 hours she became lethargic and eventually stopped moving and died. A postmortem examination of Nyani’s brain tissue revealed bleeding and centimeter-sized lesions. The culprits were clearly visible: amoebas were eating Nyani’s brain.

Researchers later determined that the organism represented a new species of amoeba that formed a genus of its own. Balamuthia lives in soil, dust, and water, and is believed to enter the body via the lungs or through cuts in the skin. (His name is a reference both to Nyani’s species and to the late William Balamuth, a zoologist at the University of California, Berkeley who studied amoebas.)

Only about 100 human cases of Balamuthia have been confirmed in the United States in the last few decades. “The vast majority of physicians, even infectious disease physicians, have never seen a case,” says Natasha Spottiswoode, UCSF infectious disease physician and scientist.

That was also true for her until 2 years ago. But even after the Californian’s initial MRI results came back, his UCSF medical team, led by Spottiswoode, had no reason to suspect Balamuthia infection, since brain masses can be caused by a number of more common conditions, including cancer, bacterial abscesses and tuberculosis . But after a biopsy of the brain matter appeared to reveal amoebas, 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 it. The results for Balamuthia were positive.

Spottiswoode and her colleagues started the patient on an aggressive array of antiparasitic, antibacterial, and antifungal medications administered via 47 daily pills and an IV drip. But the drug cocktail was rather ad hoc, Spottiswoode admits. “It’s recommended because it’s been used in surviving patients,” she says. It’s also sometimes highly toxic: the man’s blood sugar and white blood cell count both dropped dangerously low, and he suffered kidney failure. Meanwhile, the man’s lesions continued to grow. Desperate to save her patient, Spottiswoode began poring over research into 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 co-president of the Chan Zuckerberg Biohub, carefully examined more than 2,100 drugs in the lab to identify compounds effective against Balamuthia. The effort, DeRisi recalls, “was inspired by our frustration” to observe an ultimately fatal course of balamuthia in a 74-year-old woman being cared for at UCSF.

One compound stood out in their screening: nitroxoline. But DeRisi and his associates have not had a chance to see it tested on 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 turned to DeRisi, he pushed her further. But nitroxoline isn’t approved by the Food and Drug Administration, which meant the medical team had to file an emergency application for a new drug to get permission to use it — and then find a source for the drug. Asieris Pharmaceuticals, a company developing nitroxoline to treat bladder cancer, eventually shipped several hundred pills from its Shanghai R&D facility and has continued to send out resupply shipments, all pro bono.

After only 1 week of treatment with nitroxoline, the patient’s lesions shrank. Follow-up MRIs have shown continued improvement and the patient is now living at home. “I think he’s well on his way to becoming one of the survivors of this disease,” Spottiswoode told a group of her colleagues in October 2022. (The research group reported their findings in January in Emerging infectious diseases.)

The UCSF team has contacted the Centers for Disease Control and Prevention to stockpile nitroxoline for future use. It should be available as an “emergency standby drug for 24-hour delivery anywhere in the United States,” DeRisi says. But to save patients, doctors must also diagnose Balamuthia infection quickly. Currently, a doctor must first suspect an amoeba infection and then order a specific PCR test. “If you don’t think about what’s there, 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 next-generation metagenomic sequencing developed by DeRisi could speed diagnosis. In this approach, genetic material from a patient sample is sequenced and compared to vast libraries of genetic codes from millions of known pathogens. “You can let the database comparison tell you which organisms are in it,” says Wilson. “You don’t go in with a preconceived notion.”

Spottiswoode and her colleagues are now working with other doctors treating Balamuthia cases. A second patient was recently started on the drug and the early results are already encouraging, she says. Spottiswoode hopes her frantic search will pay off in the long term for other Balamuthia patients. “For every patient with this disease, there’s a team of doctors where I’ve been that’s basically desperate to find something that will help.”

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